Clinical trial NCT03834766
Conditions: ADHD
Sponsor: Tris Pharma, Inc.
Start date: 2019-02-06; Completion date: 2019-10-19
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of AMPH ER TAB compared to placebo in adult patients with ADHD aged 18 to 60 years.

Detailed description:
This is a randomized, double-blind (DB), placebo-controlled, parallel, study to assess the efficacy and safety of AMPH ER TAB compared to placebo for the treatment of ADHD in adults aged 18 to 60 years.

After Screening and Baseline evaluations are complete, eligible subjects will be randomized in the study to take DB AMPH ER TAB or matching placebo orally once daily in the morning beginning the day after the Baseline visit for 5 weeks. Dose will be titrated on a weekly basis to reach 20 mg per day. Subjects who cannot tolerate the study drug will be discontinued from the study.

A Math Test placement test will be done at Screening or at Baseline. At Visit 5, efficacy assessments will include the administration of serial Math Tests at pre-dose and at 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours post-dose (Primary Endpoint) Adult Investigator Symptom Rating Scale (AISRS) and Clinical Global Impression Scale Severity (CGI-S) will be conducted at Baseline and Visits 1 to 5. Digit Symbol Substitution Test (DSST) will be administered at Baseline and Visit 5 (Secondary Endpoints).

Safety assessments will include treatment-emergent adverse events, physical examination, vital signs, body weight, Columbia Suicide Severity Rating Scale (C-SSRS), and direct questioning to assess for sleep, appetite, mood and psychotic events.

Arms: arm 1: Amphetamine Extended Release Tablets 5, 10, 15 and 20 mg arm 2: Matching Placebo Tablets 5, 10, 15 and 20 mg
Interventions: intervention 1: AMPH ER Tab 5, 10, 15 and 20 mg intervention 2: AMPH ER Tab Matching Placebo 5, 10, 15 and 20 mg
Intervention descriptions: intervention 1: Amphetamine intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
Tris Pharma, Inc. 
Protocol v. 3.1 
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Page 1 of 67 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Title: Amphetamine Extended-Release Tablets in the Treatment of Adults with ADHD. 
 
 
Protocol Number:  
TRI108-ADD-400 
Investigational Drug: 
Amphetamine ER Tablets, 5, 10, 15, and 20 mg 
(Manufactured by Tris Pharma, Inc., U.S.A) 
Version: 
v. 3.1 (March 2019) 
IND Applicant/Sponsor: 
Tris Pharma, Inc. 
2033 US 130 
Monmouth Junction, NJ 08852 
Authorized Signatory: 
Barry K. Herman, MD, MMM 
Chief Medical Officer  
Tris Pharma, Inc. 
Primary Study Contact: 
Antonio Pardo, MD 
Associate Director, Clinical Affairs and Pharmacovigilance  
Tris Pharma, Inc. 
Protocol Amendments:  
N/A 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and all 
applicable regulatory requirements.  
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for review by you, your staff, 
and the applicable Institutional Review Board.  Your acceptance of this document constitutes agreement that you will not 
disclose the information contained herein to others without written authorization from the Sponsor. 


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INVESTIGATOR’S SIGNATURE 
 
 
I have read this protocol and agree to conduct the study as outlined. I agree to maintain the confidentiality 
of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date (mm/dd/yyyy) 


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SPONSOR’S SIGNATURE 
 
Approved by: 
 
 
 
 
 
 
Barry K. Herman MD, MMM 
Chief Medical Officer  
Tris Pharma, Inc. 
 
 Date (mm/dd/yyyy) 
 
 
 
 
 
 


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PROCEDURES IN CASE OF EMERGENCY 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Study Leader  
Antonio Pardo, MD 
Tris Pharma, Inc. 
2033 US 130, Suite D 
Monmouth Junction, NJ 08552 
apardo@trispharma.com 
(732) 823-4755 (office) 
(917) 514-9058 
Chief Medical Officer 
Barry K. Herman, MD, 
MMM 
Tris Pharma, Inc. 
2033 Route 130, Suite D 
Monmouth Junction, NJ 08552 
bherman@trispharma.com 
(732) 823-4720 (office) 
(512) 422-6429 
Premier Research 
Medical Monitor 
Thomas Laage, MD, MPH 
Senior Medical Director 
Premier Research 
Research Triangle Park 
One Park Drive, Suite 150 
Durham, NC 27709 
Thomas.Laage@premier-research.com 
Work: +1 978 254 5632 
Mobile: +1 978 831 4156 
FAX: +1 267 285 2562 
Please include Safety@trispharma.com on all your correspondence 
 


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SYNOPSIS 
Title of Study 
Amphetamine Extended-Release Tablets in the Treatment of Adults with ADHD 
Study Number 
TRI108-ADD-400 
Study Center(s) 
Multicenter (up to 3 sites) 
Clinical Phase 
Phase 3 
Indication 
ADHD (Attention-deficit/hyperactivity disorder) 
Sample Size 
Approximately 108 subjects – Maximum allowable cohort size of 18 subjects at up to 3 sites  
Treatment 
Duration 
~11 weeks 
Main Entry 
Criteria 
Adult male and female subjects aged 18 to 60 years who meet Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for ADHD, otherwise healthy. 
Test Product  
Amphetamine Extended-Release Tablets (AMPH ER TAB), 5, 10, 15 or 20 mg 
(manufactured by Tris Pharma, Inc., USA) 
Reference  
Matching placebo including flavor, 5, 10, 15 or 20 mg (manufactured by Tris Pharma, Inc., 
USA) 
Objectives 
Efficacy Objective: To evaluate the efficacy of AMPH ER TAB compared to placebo in adult 
patients with ADHD aged 18–60 years. 
Safety Objective: To assess the safety and tolerability of AMPH ER TAB in adult patients 
with ADHD aged 18–60 years. 
Methodology 
 
This is a randomized, double-blind (DB), placebo-controlled, parallel, study to assess the 
efficacy and safety of AMPH ER TAB compared to placebo for the treatment of ADHD in 
adults aged 18 to 60 years. 
After Screening and Baseline evaluations are complete, eligible subjects will be randomized 
in the study to take DB AMPH ER TAB or matching placebo orally once daily in the 
morning beginning the day after the Baseline visit. 
There will be a 5-week DB dose titration phase. The starting dose of AMPH ER TAB or 
matching placebo will be 5 mg in the morning before 10 am, with or without food, swallowed 
whole or chewed. Subjects will then be titrated up by 5 mg increments each week. After Visit 
3 subjects will receive a final dose of 20 mg for 14 (± 3) days prior to Visit 5. Subjects who 
cannot tolerate the study drug will be discontinued from the study.  
A Permanent Product Measure of Performance (PERMP) placement test will be done at 
Screening or at Baseline. PERMP practice sessions will be done before and after efficacy and 
safety assessments during Baseline and Visits 1 to 3. An abbreviated administration of serial 
PERMPs will take place at Visit 4 where PERMP will be administered at pre-dose, 0.5, 1, 2 
and 4 hours post-dose.  
At Visit 5, efficacy assessments will include the administration of serial PERMPs at pre-dose 
and at 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours post-dose. 
Adult Investigator Symptom Rating Scale (AISRS) and Clinical Global Impression 
Scale-Severity (CGI-S) will be conducted at Baseline and Visits 1 to 5. Digit Symbol 
Substitution Test (DSST) will be administered at Baseline and Visit 5.  


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Safety assessments will include treatment-emergent adverse events, physical examination, 
vital signs, body weight, Columbia Suicide Severity Rating Scale (C-SSRS), and direct 
questioning to assess for sleep, appetite, mood and psychotic events. 
Inclusion/ 
Exclusion 
Criteria 
Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in 
the study: 
1. Male or female aged 18 to 60 years, inclusive at the time of Screening. 
2. Diagnosed with ADHD using the DSM-5 criteria based on the Adults ADHD Clinical 
Diagnostic Scale (ACDS). 
3. IQ within normal range based upon clinical opinion of the Investigator. 
4. Baseline AISRS total score greater than or equal to 26. 
5. Baseline score of 4 or higher in CGI-S. 
6. Females who participate in this study will be of childbearing or non-childbearing 
potential: 
• 
Childbearing potential: Physically capable of becoming pregnant 
• 
Non-childbearing potential: 
o Permanently sterile (i.e., both ovaries removed, uterus removed, or bilateral 
tubal ligation for at least 6 weeks or documented successful hysteroscopic 
sterilization); and/or  
o Post-menopausal (no menstrual period for at least 12 consecutive months 
without any other medical cause). 
7. Females of childbearing potential must be non-lactating and must have a negative serum 
pregnancy test at Screening. 
8. Willing to use acceptable, effective methods of contraception. 
9. Be able to attend the clinic regularly and reliably. 
10. Be able to understand, read, write, and speak English fluently to complete the 
study-related materials. 
11. Be informed of the nature of the study and give written consent prior to any study 
procedure. 
Exclusion Criteria 
1. Current or lifetime history of bipolar disorder or any psychotic disorder as established by 
Mini International Neuropsychiatric Interview (M.I.N.I.) 7.0.2.  
2. Current history of major depression generalized anxiety disorder, obsessive-compulsive 
disorder, panic disorder, or post-traumatic stress disorder as established by the M.I.N.I. 
7.0.2. 
3. Known history of chronic medical illnesses including untreated thyroid disease, 
peripheral vasculopathy, known structural cardiac disorders, serious cardiac conditions, 
serious arrhythmias, cardiomyopathy, and known family history of sudden death. 
4. History of uncontrolled hypertension or a resting systolic blood pressure >140 mmHg or 
diastolic blood pressure >90 mmHg. Subjects with well-controlled hypertension on a 
stable dose for at least 3 months of anti-hypertensives will be allowed to participate. 


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5. Have clinically significant findings in vital signs measurements at Screening including:  
• 
Systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg 
• 
Heart rate >100 bpm 
6. Known history or presence of significant renal or hepatic disease, as indicated by clinical 
laboratory assessment (clinically significant liver function tests, blood urea nitrogen, or 
creatinine levels) 
7. Clinically significant abnormal electrocardiogram or cardiac findings on physical 
examination (including the presence of a pathologic murmur). 
8. Use of the following medications within 14 days of Baseline Visit: 
• 
Atomoxetine 
• 
Monoamine oxidase inhibitors (e.g., selegiline, isocarboxazid, phenelzine, 
tranylcypromine) 
• 
Tricyclic antidepressants (e.g., desipramine, protriptyline). 
9. Use of the following medications within 3 days of Baseline Visit: 
• 
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid 
hydrochloride [HCl], ascorbic acid) 
• 
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, 
methenamine salts). 
10. Use of fluoxetine within 30 days of Baseline Visit. 
11. Use of stimulant medications within 1 week of Baseline Visit. 
12. Planned use of prohibited drugs or agents from the Screening visit through the end of the 
study. 
13. Participation in a clinical study in which an investigational drug was administered within 
30 days prior to Screening. 
14. Abnormal clinically significant laboratory test values at Screening that, in the opinion of 
the Medical Monitor or Sponsor, would preclude study participation. 
15. Known history of allergy/hypersensitivity to amphetamine or any of the components of 
AMPH ER TAB. 
16. Known history of lack of clinical response to amphetamine based upon Investigator 
judgment. 
17. Positive test result for HIV, Hepatitis B surface antigen, or Hepatitis C antibody. 
18. Any uncontrolled medical condition that, in the opinion of Medical Monitor or Sponsor, 
would preclude study participation. 
19. History or presence of alcohol dependence or substance abuse disorder according to 
DSM-5 or within the last 12 months. 
20. Subject’s inability or unwillingness to follow directions from the study research staff. 
21. Answer of “yes” to questions 4 or 5 of the C-SSRS within the last 2 years. 


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Assessments 
• 
CGI-S 
• 
AISRS DSM-V Update 
• 
DSST 
• 
ACDS DSM-V Update 
• 
M.I.N.I. 7.0.2 
• 
PERMP 
• 
C-SSRS 
• 
Questionnaire for Sleep, Appetite, Mood and Psychotic Adverse Events 
• 
Adverse Events 
• 
Electrocardiogram 
• 
Safety Labs 
• 
Physical Exam 
• 
Vital Signs  
• 
Body weight 
• 
Medical History 
• 
Concomitant Medications 
Statistical 
Analysis 
Efficacy: 
The primary efficacy estimand is defined by the following 3 components: 
a. 
Target population: adult patients with ADHD aged 18 to 60 years who can tolerate 
AMPH ER TAB at 20 mg once daily. 
b. Primary efficacy endpoint: PERMP-T score over all post-dose time points assessed 
during the administration of serial PERMPs at Visit 5 
c. 
Measure of intervention effect: treatment difference in means averaged over all post-
dose time points for endpoint described above between AMPH ER TAB and 
placebo in target population regardless of use of any concomitant medications. 
The primary efficacy endpoint will be assessed using a linear Mixed Model Repeated 
Measures (MMRM) analysis. This is a restricted maximum likelihood (REML)-based 
analysis implemented using SAS® PROC MIXED. The model will include treatment, time 
and treatment by time as fixed effects and subject as a random effect. Pre-dose PERMP-T 
score will be included as a covariate. The difference between AMPH ER TAB and placebo 
will be assessed at the alpha = 0.05 level of significance. The covariance structure used in the 
final MMRM model will be the one that has the lowest Akaike Information Criterion (AIC) 
among the following selections: SP(POW), unstructured, compound symmetry (CS), 
heterogeneous CS or heterogeneous Toeplitz. Kenwood-Roger correction will be used to 
estimate denominator degrees of freedom. The treatment effect is estimated by the overall 
adjusted least square mean difference between two treatment groups. 95% CI for the adjusted 


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least square mean will be constructed and p-value for the treatment comparison will also be 
provided.  
Key secondary efficacy outcomes as determined by the comparison of each PERMP-T score 
at each time point (0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours post-dose) with pre-dose PERMP-
T scores at Visit 5 are: 
• 
Onset of clinical effect 
• 
Duration of clinical effect 
The key secondary outcomes of onset and duration of efficacy (clinical effect) of AMPH ER 
Tab vs. placebo will be tested using the same MMRM analysis as performed on the primary 
efficacy variable. 
Additional secondary efficacy outcomes will be: 
• 
Change from Baseline in AISRS scores at each post-baseline visit 
• 
Change from Baseline in CGI-S at each post-baseline visit 
• 
Change from Baseline in DSST at Visit 5 
A detailed statistical analysis plan will be written and finalized prior to unblinding of the 
data. 
Safety: 
The Safety Population will include all subjects who receive ≥1 dose of AMPH ER TAB or 
matching placebo and had at least one assessment after dosing. 
Safety assessments will include treatment-emergent adverse events, physical examination, 
vital signs, body weight, Columbia Suicide Severity Rating Scale (C-SSRS), and direct 
questioning to assess for sleep, appetite, mood and psychotic adverse events. 
Statistical analysis of safety: Safety parameters will be reported using descriptive statistics.  


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TABLE OF CONTENTS  
INVESTIGATOR’S SIGNATURE .................................................................................................2 
SPONSOR’S SIGNATURE ............................................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
SYNOPSIS .......................................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................15 
LIST OF ABBREVIATIONS ........................................................................................................16 
1 
INTRODUCTION ........................................................................................................18 
1.1 
Background ...................................................................................................................18 
1.2 
Pharmacotherapy ...........................................................................................................18 
1.3 
Amphetamine Extended-Release Tablets .....................................................................18 
2 
OBJECTIVES ...............................................................................................................20 
2.1 
Efficacy Objective .........................................................................................................20 
2.2 
Safety Objective ............................................................................................................20 
3 
STUDY DESIGN ..........................................................................................................21 
3.1 
Design ...........................................................................................................................21 
3.2 
Study Endpoints ............................................................................................................22 
3.2.1 
Primary Efficacy Endpoint ............................................................................................22 
3.2.2 
Secondary Endpoints .....................................................................................................22 
3.2.3 
Safety Endpoint .............................................................................................................23 
3.3 
Inclusion Criteria ...........................................................................................................23 
3.4 
Exclusion Criteria..........................................................................................................24 
3.5 
Effective Methods of Contraception .............................................................................25 
3.6 
Subject Withdrawal Criteria ..........................................................................................25 
3.7 
Study Stopping Rules ....................................................................................................26 
4 
STUDY SCHEDULE AND PROCEDURES ...............................................................27 
4.1 
Study Schedule ..............................................................................................................27 
4.2 
Efficacy and Safety Assessments ..................................................................................27 
4.2.1 
Permanent Product Measurement of Performance (PERMP) .......................................27 


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4.2.2 
Adults ADHD Clinical Diagnostic Scale (ACDS) DSM-V Update .............................27 
4.2.3 
Mini International Neuropsychiatric Interview (M.I.N.I.) 7.0.2 ...................................27 
4.2.4 
Adult Investigator Symptom Rating Scale (AISRS) DSM V Update ..........................27 
4.2.5 
Clinical Global Impression Scales ................................................................................27 
4.2.6 
Digit Symbol Substitution Test (DSST) .......................................................................28 
4.2.7 
Columbia Suicide Severity Rating Scale (C-SSRS) .....................................................28 
4.2.8 
Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events ...................28 
4.2.9 
Study Visits and Procedures .........................................................................................28 
4.2.10 
Study Periods ................................................................................................................28 
4.2.10.1 Screening .......................................................................................................................29 
4.2.10.2 Baseline (Day -1) ..........................................................................................................30 
4.2.10.3 Visits 1 (Day 7) to 3 (Day 21), Double-Blinded Titration ............................................32 
4.2.10.4 Visit 4 (Day 28) Abbreviated administration of serial PERMPs ..................................32 
4.2.10.5 Visit 5 (Day 35) Administration of serial PERMPs ......................................................33 
4.2.10.6 Early Termination Visit.................................................................................................34 
5 
INVESTIGATIONAL DRUG INFORMATION AND MANAGEMENT ..................36 
5.1 
Investigational Drug Dose Regimen .............................................................................36 
5.2 
Investigational Drug Packaging, Labeling and Dispensing ..........................................36 
5.3 
Investigational Drug Storage ........................................................................................36 
5.4 
Drug Administration .....................................................................................................36 
5.5 
Investigational Drug Accountability .............................................................................36 
5.6 
Investigational Drug Handling and Disposal ................................................................37 
6 
SUBJECT COMPLIANCE ...........................................................................................38 
6.1 
Concomitant Medication and/or Therapy .....................................................................38 
6.2 
Prohibited Concomitant Medications ............................................................................38 
6.2.1 
Prohibited Concomitant Medications ............................................................................38 
6.3 
Treatment Compliance ..................................................................................................39 
6.3.1 
Acceptable Compliance ................................................................................................39 
7 
RANDOMIZATION AND BLINDING PROCEDURES ............................................40 
8 
ADVERSE AND SERIOUS ADVERSE EVENTS .....................................................41 
8.1 
Definition of an Adverse Event.....................................................................................41 


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8.2 
Definition of a Serious Adverse Event (SAE) ..............................................................42 
8.2.1 
Serious Adverse Events That Occur Before Administration of Study Medication ......42 
8.2.2 
Serious Adverse Events That Occur After Study Completion ......................................42 
8.3 
Collecting, Recording and Evaluating Adverse Events and Serious Adverse Events ..43 
8.3.1 
Assessment of Adverse Events and Serious Adverse Events .......................................43 
8.3.2 
Assessment of Intensity ................................................................................................43 
8.3.3 
Assessment of Causality ...............................................................................................44 
8.3.4 
Assessment of Outcome ................................................................................................44 
8.4 
Documentation ..............................................................................................................45 
8.5 
Follow-up of Adverse Events and Serious Adverse Events..........................................45 
8.6 
Prompt Reporting of Serious Adverse Events ..............................................................46 
8.7 
Regulatory Reporting Requirements for Serious Adverse Events ................................47 
8.7.1 
Procedures for Reporting Pregnancy Exposure and Birth Events ................................47 
8.7.2 
Overdose .......................................................................................................................48 
9 
STATISTICAL CONSIDERATIONS ..........................................................................49 
9.1 
Power and Sample Size Determination .........................................................................49 
9.2 
Analysis Populations .....................................................................................................49 
9.3 
Efficacy and Safety Analyses........................................................................................50 
9.3.1 
Disposition and Withdrawals ........................................................................................50 
9.3.2 
Protocol Deviations .......................................................................................................50 
9.3.3 
Background and Demographic Characteristics .............................................................50 
9.3.4 
Concomitant Medications and Concomitant Therapies ................................................50 
9.3.5 
Efficacy Analyses..........................................................................................................50 
9.3.5.1 
Primary Efficacy Analysis ............................................................................................50 
9.3.5.2 
Secondary Efficacy Analyses ........................................................................................51 
9.3.6 
Safety Analyses .............................................................................................................52 
9.3.6.1 
Adverse Events..............................................................................................................52 
9.3.6.2 
Columbia Suicide Severity Rating Scale (C-SSRS) .....................................................52 
9.3.6.3 
Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events ...................52 
9.3.6.4 
Clinical Laboratory Evaluations ...................................................................................52 
9.3.6.5 
Vital Signs and Body Weight ........................................................................................52 


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9.3.6.6 
Electrocardiograms (ECG) ............................................................................................53 
9.3.7 
Other Statistical Considerations ....................................................................................53 
9.3.7.1 
Significance Levels .......................................................................................................53 
9.3.7.2 
Missing Data .................................................................................................................53 
9.3.8 
Visit Windows ...............................................................................................................53 
10 
DIRECT ACCESS TO PROCEDURAL DOCUMENTS ............................................54 
10.1 
Study Monitoring ..........................................................................................................54 
10.2 
Source Documents ........................................................................................................54 
10.3 
Data Collection and Management .................................................................................54 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................55 
12 
ETHICS .........................................................................................................................56 
12.1 
Ethics Review................................................................................................................56 
12.2 
Ethics Committees ........................................................................................................56 
12.3 
General Considerations .................................................................................................56 
12.4 
Informed Consent Form (ICF) ......................................................................................57 
12.5 
Subject Confidentiality..................................................................................................57 
12.6 
Publications of the Clinical Study .................................................................................57 
12.7 
Protocol Amendments and Deviations ..........................................................................57 
13 
DATA HANDLING AND RECORD KEEPING ........................................................59 
13.1 
Inspection of Records ....................................................................................................59 
13.2 
Retention of Records .....................................................................................................59 
14 
REFERENCES ..............................................................................................................60 
APPENDIX A. SCHEDULE OF EVENTS ................................................................................62 
APPENDIX B. QUESTIONNAIRE FOR SLEEP, APPETITE, MOOD, AND PSYCHOTIC 
ADVERSE EVENTS .....................................................................................................................64 
APPENDIX C. REVISION HISTORY ........................................................................................66 
 


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LIST OF TABLES 
TABLE 1: ACCEPTABLE EFFECTIVE METHODS OF CONTRACEPTION .........................25 
TABLE 2: LABORATORY TESTS AT SCREENING ................................................................29 
TABLE 3: DRUGS OF ABUSE SCREENING TEST AT BASELINE .......................................31 
TABLE 4 LABORATORY TESTS AT VISIT 5 ..........................................................................33 
TABLE 5 DRUGS OF ABUSE SCREENING TEST AT VISIT 5 ..............................................34 
TABLE 6 SPONSOR'S CONTACT INFORMATION FOR UNBLINDING PROCEDURES ...40 
TABLE 7 CONTACT INFORMATION FOR SAE REPORTING ..............................................46 
 


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LIST OF FIGURES 
FIGURE 1: STUDY DESIGN .......................................................................................................21 
FIGURE 2: DOSE TITRATION ...................................................................................................32 


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LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
 
 
ACDS 
Adults ADHD Clinical Diagnostic Scale 
ADHD 
Attention-deficit hyperactivity disorder 
AE 
Adverse event 
AISRS 
Adult Investigator Symptom Rating Scale 
AR 
Adverse reaction 
ATC 
Anatomical Therapeutic Chemical 
CFR 
Code of Federal Regulations 
CGI-S  
Clinical Global Impression Scale–Severity 
cGMP 
Current Good Manufacturing Practice 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DB 
Double-blind 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
DSST 
Digit Symbol Substitution Test 
ECG 
Electrocardiogram/electrocardiography 
EDC 
Electronic Data Capture 
ER 
Extended Release 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
ICH 
International Conference for Harmonisation 
ID 
Identification 
IND 
Investigational New Drug 
IR 
Immediate release 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 


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Abbreviation or specialist term 
Explanation 
MAOI 
Monoamine oxidase inhibitors  
M.I.N.I. 7.0.2 
Mini International Neuropsychiatric Interview 7.0.2 
MMRM 
Mixed Effect Model Repeat Measurement 
MedDRA 
Medical Dictionary for Regulatory Activities 
PERMP 
Permanent Product Measure of Performance 
PP 
Per-Protocol Population 
RAND 
Randomized Population 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SNRI 
Serotonin and Norepinephrine Reuptake Inhibitor 
SSRI 
Selective Serotonin Reuptake Inhibitor 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent adverse event 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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1 INTRODUCTION 
1.1 Background 
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by 
pervasive impairment in symptoms of inattention, hyperactivity, and impulsivity1. Symptoms of ADHD 
typically manifest in early childhood, often leading to diagnosis and treatment. Recent prevalence data 
indicate approximately 9.4% of children 2 to 17 years of age are diagnosed with ADHD2. Even with 
current psychopharmacologic treatment, ADHD can persist into adulthood, with a reported 40 to 66% of 
individuals diagnosed with ADHD as a child continuing to show symptoms of ADHD as an adult3,4. The 
prevalence of adult ADHD in the United States in 2006 was 4.4%5. Adult ADHD is associated with 
impairments in activities of daily living, including educational attainment, social interacting, and 
disrupted or poor work performance6-9. Difficulties adhering to medication regimens have been noted in 
patients with ADHD10. ADHD poses safety risks with higher rates of accidents associated with driving 
and operating heavy machinery8,9,11,12. Diagnosis of ADHD is based on a complete evaluation of the 
patient, and assessments based on criteria published in the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) 1.  
1.2 Pharmacotherapy 
Clinical practice guidelines recommend a combination of behavior therapy and psychostimulant 
medication for treatment of ADHD in children, adolescents, and adults13,14. Psychostimulants are 
commonly prescribed for ADHD in adults15, and amphetamine is considered to be a first-line treatment 
for this population15. As adult patients seek symptomatic improvement during the work day and into the 
early evening hours, with fewer required doses, ER formulations are often considered as a first-line 
treatment option. Patients with ADHD may frequently require supplemental (immediate-release [IR]) 
stimulant medication for maximum treatment efficacy, resulting in lowered compliance (due to the need 
for frequent administration of multiple medications at varying dosages). Patients taking multiple doses of 
varying psychostimulant medications also may face social stigmas associated with frequent medication 
use16. The demands of work environment and personal and family life, coupled with the need for a simple 
medication strategy, suggest that adults with ADHD will benefit from a once-daily psychostimulant 
medication with an extended duration of effect.  
1.3 Amphetamine Extended-Release Tablets  
Amphetamine is a well-established therapeutic agent for the treatment of ADHD. Since the original Food 
and Drug Administration (FDA) approval of amphetamine for ADHD, various forms have been approved 
for use (both IR dosage forms, oral solution, and tablets, and ER dosage forms, capsules, and tablets with 
various release technologies).  
Amphetamine Extended-Release Tablets (AMPH ER TAB) is an ER tablet formulation of a combination 
of 3 well-established and well-characterized racemic mixtures of d, l amphetamine sulfate, d, l-
amphetamine aspartate monohydrate, and dextroamphetamine sulfate. The d, l amphetamine sulfate and 
the dextroamphetamine sulfate are bound to polistirex, a sodium polystyrene sulfonate. This amphetamine 
polymer complex is further coated with a flexible, semi-permeable coating material that provides for the 
gradual release of amphetamine. The final drug product is prepared by adding a specific ratio of coated 


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amphetamine-ion exchange polymer complex, uncoated amphetamine-ion exchange polymer complex, 
and unbound amphetamine salts (amphetamine aspartate monohydrate and dextroamphetamine sulfate)17.  
No product-specific non-clinical pharmacology or toxicology studies have been conducted for 
AMPH ER TAB.   
AMPH ER TAB formulation will be available in 4 strengths: 5, 10, 15, and 20 mg. AMPH ER TAB 
(20 mg) showed comparable bioavailability in 29 healthy adults with respect to both d- and 
l-amphetamine, when administered as a chewable tablet or swallowed whole, compared to an equivalent 
20 mg dose of the reference product, DYANAVEL® XR (amphetamine) ER Oral Suspension, 2.5 mg/mL, 
(Tris Pharma, Inc., USA), under fasted conditions17. The results also supported the absence of food effect 
on AMPH ER TAB when administered as a chewable tablet. The bioavailability of d- and l-amphetamine 
was comparable after administration of AMPH ER TAB when administered as a chewable tablet 
compared to being swallowed whole under fasted conditions17.  
Lastly, the concentration versus time profiles following single-dose administration of AMPH ER TAB 
suggests that the test product meets the goals of once-daily dosing, without any indicative potential of 
dose dumping upon repeated administration17.  
Safety findings in the study were consistent with that reported previously for other amphetamine 
products17.  
The purpose of this study is to evaluate the efficacy, safety, and tolerability of AMPH ER TAB compared 
to placebo in adults with ADHD aged 18 to 60 years.  
 
 


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2 OBJECTIVES 
2.1 Efficacy Objective 
To evaluate the efficacy of AMPH ER TAB compared to placebo in adult patients with ADHD aged 18 to 
60 years. 
2.2 Safety Objective 
To assess the safety and tolerability of AMPH ER TAB in adult patients with ADHD aged 18 to 60 years. 
 
 


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3 STUDY DESIGN 
3.1 Design 
Figure 1: Study Design 
 
 
This is a randomized, double-blind (DB), placebo-controlled, parallel, study to assess the efficacy and 
safety of AMPH ER TAB compared to placebo for the treatment of ADHD in adults aged 18 to 60 years. 
After Screening and Baseline evaluations are complete, eligible subjects will be randomized to take 
double-blinded (DB) AMPH ER TAB or matching placebo orally once daily in the morning beginning the 
day after the Baseline visit. 
There will be a 5-week DB dose titration phase. The starting dose of AMPH ER TAB or matching 
placebo will be 5 mg in the morning before 10 am, with or without food, swallowed whole or chewed. 
Subjects will then be titrated up by 5 mg increments each week. After Visit 3 subjects will receive a final 
dose of 20 mg for 14 (± 3) days prior to Visit 5. Subjects who cannot tolerate the study drug will be 
discontinued from the study.  
A Permanent Product Measure of Performance (PERMP) placement test will be done at Screening or 
Baseline. PERMP practice sessions will be done before and after efficacy and safety assessments during 


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Baseline and Visits 1 to 3. An abbreviated administration of serial PERMPs will take place at Visit 4 where 
PERMP will be administered at pre-dose, 0.5, 1, 2 and 4 hours post-dose.  
At Visit 5, efficacy assessments will include the administration of serial PERMPs at pre-dose and at 0.5, 1, 2, 
4, 8, 10, 12, 13, and 14 hours post-dose.  
AISRS and CGI-S will be conducted at Baseline and Visits 1 to 5. DSST will be administered at Baseline 
and Visit 5. 
Safety assessments will include treatment-emergent adverse events, physical examination, vital signs, 
body weight, Columbia Suicide Severity Rating Scale (C-SSRS), and direct questioning to assess for 
sleep, appetite, mood and psychotic adverse events. 
A schematic of the overall study design is presented in Figure 1.  
The full schedule of events is found in Appendix A. 
This study will be conducted in the United States.  
3.2 Study Endpoints 
3.2.1 Primary Efficacy Endpoint 
The PERMP is a validated, time-sensitive, skill-adjusted test consisting of simple math problems to be 
completed at multiple time points (administration of serial PERMPs). The PERMP Total or PERMP-T 
score is the sum of the number of math problems attempted plus the number of math problems answered 
correctly and it provides an objective measure of performance that is time-sensitive, ADHD medication-
sensitive, and well documented as a measure to evaluate ADHD medication effectiveness throughout the 
day. The PERMP score range from 0-800 with higher scores indicating better performance. 
The primary efficacy estimand is defined by the following 3 components: 
a. Target population: adult patients with ADHD aged 18 to 60 years who can tolerate AMPH ER 
TAB at 20 mg once daily. 
b. Primary efficacy endpoint: PERMP-T score over all post-dose time points assessed during the 
administration of serial PERMPs at Visit 5 
c. Measure of intervention effect: treatment difference in means averaged over all post-dose time 
points for endpoint described above between AMPH ER TAB and placebo in target population 
regardless of use of any concomitant medications. 
The primary efficacy endpoint will be assessed using a linear MMRM model using SAS® PROC MIXED. 
The model will include treatment, time and treatment by time as fixed effects and subject as a random 
effect. Pre-dose PERMP-T score will be included as a covariate. The difference between AMPH ER TAB 
and placebo will be assessed at the alpha = 0.05 level of significance. 
3.2.2 Secondary Endpoints 
Key secondary efficacy outcomes as determined by the comparison of each PERMP-T score at 
each time point (0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours post-dose) with pre-dose PERMP-T 
scores at Visit 5 are: 


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• Onset of clinical effect 
• Duration of clinical effect  
The key secondary outcomes of onset and duration of efficacy (clinical effect) of AMPH ER Tab 
vs. placebo will be tested using the same MMRM analysis as performed on the primary efficacy 
variable. 
Additional secondary efficacy outcomes will include: 
• 
Change from Baseline in CGI-S at each post-baseline visit 
• 
Change from Baseline in AISRS scores at each post-baseline visit 
• 
Change from Baseline in DSST at Visit 5 
 
3.2.3 Safety Endpoint 
Safety will be monitored by adverse events (AEs) assessed at each visit.  
Medical history will capture all medical conditions at the Screening visit. Physical examination, 12-lead 
electrocardiogram (ECG), and clinical laboratory tests will be conducted as described on Appendix A, or 
at the discretion of the Principal Investigator. 
In addition, the following assessments will be conducted at Baseline and all subsequent scheduled visits: 
C-SSRS, vital signs (BP and HR), body weight and direct questioning to assess for sleep, appetite, mood 
and psychotic adverse events. 
3.3 Inclusion Criteria 
Subjects must meet all of the following criteria to be considered eligible to participate in the study: 
1. Male or female aged 18 to 60 years, inclusive at the time of Screening. 
2. Diagnosed with ADHD using the DSM-5 criteria based on the Adults ADHD Clinical Diagnostic 
Scale (ACDS). 
3. IQ within normal range based upon clinical opinion of the Investigator. 
4. Baseline AISRS total score greater than or equal to 26. 
5. Baseline score of 4 or higher in CGI-S. 
6. Females who participate in this study will be of childbearing or non-childbearing potential: 
• 
Childbearing potential: Physically capable of becoming pregnant 
• 
Non-childbearing potential: 
o Permanently sterile (i.e., both ovaries removed, uterus removed, or bilateral tubal 
ligation for at least 6 weeks or documented successful hysteroscopic sterilization); 
and/or  


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o Post-menopausal (no menstrual period for at least 12 consecutive months without any 
other medical cause). 
7. Females of childbearing potential must be non-lactating and must have a negative serum 
pregnancy test at Screening. 
8. Willing to use acceptable, effective methods of contraception. 
9. Be able to attend the clinic regularly and reliably. 
10. Be able to understand, read, write, and speak English fluently to complete the study-related 
materials. 
11. Be informed of the nature of the study and give written consent prior to any study procedure. 
3.4 Exclusion Criteria 
The presence of any of the following exclusion criteria precludes a subject from study enrollment:  
1. Current or lifetime history of bipolar disorder or any psychotic disorder as established by Mini 
International Neuropsychiatric Interview (M.I.N.I.) 7.0.2.  
2. Current history of major depression generalized anxiety disorder, obsessive-compulsive disorder, 
panic disorder, or post-traumatic stress disorder as established by the M.I.N.I. 7.0.2. 
3. Known history of chronic medical illnesses including untreated thyroid disease, peripheral 
vasculopathy, known structural cardiac disorders, serious cardiac conditions, serious arrhythmias, 
cardiomyopathy, and known family history of sudden death. 
4. History of uncontrolled hypertension or a resting systolic blood pressure >140 mmHg or diastolic 
blood pressure >90 mmHg. Subjects with well-controlled hypertension on a stable dose for at 
least 3 months of anti-hypertensives will be allowed to participate. 
5. Have clinically significant findings in vital signs measurements at Screening including:  
• 
Systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg 
• 
Heart rate >100 bpm 
6. Known history or presence of significant renal or hepatic disease, as indicated by clinical 
laboratory assessment (clinically significant liver function tests, blood urea nitrogen, or creatinine 
levels) 
 
7. Clinically significant abnormal electrocardiogram or cardiac findings on physical examination 
(including the presence of a pathologic murmur). 
8. Use of the following medications within 14 days of Baseline Visit: 
• 
Atomoxetine 
• 
Monoamine oxidase inhibitors (e.g., selegiline, isocarboxazid, phenelzine, 
tranylcypromine) 
• 
Tricyclic antidepressants (e.g., desipramine, protriptyline). 
9. Use of the following medications within 3 days of Baseline Visit: 


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• 
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid 
hydrochloride [HCl], ascorbic acid) 
• 
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, 
methenamine salts). 
10. Use of fluoxetine within 30 days of Baseline Visit. 
11. Use of stimulant medications within 1 week of Baseline Visit. 
12. Planned use of prohibited drugs or agents from the Screening visit through the end of the study. 
13. Participation in a clinical study in which an investigational drug was administered within 30 days 
prior to Screening. 
14. Abnormal clinically significant laboratory test values at Screening that, in the opinion of the 
Medical Monitor or Sponsor, would preclude study participation. 
15. Known history of allergy/hypersensitivity to amphetamine or any of the components of AMPH 
ER TAB. 
16. Known history of lack of clinical response to amphetamine based upon Investigator judgment. 
17. Positive test result for HIV, Hepatitis B surface antigen, or Hepatitis C antibody. 
18. Any uncontrolled medical condition that, in the opinion of Medical Monitor or Sponsor, would 
preclude study participation. 
19. History or presence of alcohol dependence or substance abuse disorder according to DSM-5 or 
within the last 12 months. 
20. Subject’s inability or unwillingness to follow directions from the study research staff. 
21. Answer of “yes” to questions 4 or 5 of the C-SSRS within the last 2 years. 
3.5 Effective Methods of Contraception 
Subjects participating in this study must use an acceptable single- or double-method of contraception as 
defined below: 
• 
Females: from 21 days prior to Baseline until 28 days after Visit 5 
• 
Males: from Baseline until 28 days after Visit 5 
Table 1: Acceptable Effective Methods of Contraception 
Single-Method 
Double-Method (must use at least two) 
Surgically sterile 
Diaphragm 
Condom 
Post-menopausal 
Cervical cap 
Spermicide 
Remain abstinent 
Vaginal sponge 
Vasectomy 
Non-hormonal IUD 
Hormonal contraception 
Hormonal contraception includes: 
Oral contraceptives, intravaginal devices, hormonal IUD, injections, transdermals, and implants 
3.6 Subject Withdrawal Criteria 
Within the provisions of informed consent and good clinical judgment with respect to the subject’s safety, 
every attempt should be made to have subjects complete the study. The following are possible reasons to 
terminate the participation of any subject from the study: 


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• 
Signs and symptoms of intolerance to the study medication. 
• 
A treatment-related, serious adverse event (SAE) is observed. 
• 
The subject is grossly non-compliant, as determined by the Investigator. 
• 
Continued participation, in the opinion of the Investigator, is no longer in the best interest of the 
subject.  
• 
The subject wishes to withdraw for any reason. 
• 
Unblinding of the Investigator, site personnel performing assessments, or subject to a subject’s 
treatment assignment. 
Subjects will be encouraged to adhere to the protocol and complete all required assessments for the study. 
A subject may also be discontinued from the study for any of the following medical and/or administrative 
reasons: 
• 
Pregnancy 
• 
At the discretion of the Investigator at any time 
• 
At the subject’s request 
• 
Occurrence of a Treatment Emergent Adverse Event (TEAE) or considerable worsening of an AE 
that represents an unacceptable risk to the subject and when continued participation in the 
investigational study is not warranted, in the judgment of the Investigator or the Sponsor. The 
Investigator must follow the subject until the AE resolves or satisfactorily stabilizes. 
Any enrolled subjects desiring to discontinue prior to study completion should be encouraged to continue 
in the study and adhere to the protocol and subsequent regularly scheduled safety and effectiveness 
evaluations. Subjects who are discontinued outside of any scheduled visit will be encouraged to complete 
the final study visit at the time of withdrawal. Subjects who are discontinued during a scheduled visit will 
be encouraged to complete all assessments for both that study visit and the final study visit at the time of 
withdrawal. A subject who withdraws following study drug administration will not be replaced in their 
cohort.   
3.7 Study Stopping Rules  
This study may be discontinued at any time if, in the opinion of the Principal Investigator or the Sponsor, 
continuation of the study represents a significant medical risk to participating subjects.   
 
 


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4 STUDY SCHEDULE AND PROCEDURES 
4.1 Study Schedule 
The study schedule table can be found in Appendix A. 
4.2 Efficacy and Safety Assessments 
4.2.1 Permanent Product Measurement of Performance (PERMP) 
The PERMP is a validated, time-sensitive, skill-adjusted test consisting of simple math problems to be 
completed at multiple time points (administration of serial PERMPs) and is a robust, objective measure of 
the ability to initiate a task, self-monitor/stay on task, and complete written seatwork18. The PERMP does 
not test for mathematical ability or the ability to learn math because the difficulty of problems is adjusted 
to the existing math skill level of each participant to ensure that each individual achieves high accuracy 
rates. 
A PERMP placement test will be done at Screening or at Baseline to determine the appropriate level of 
math test difficulty. PERMP practice sessions will be done before and after efficacy and safety 
assessments during Baseline and Visits 1 to 3. An abbreviated administration of serial PERMPs will take 
place at Visit 4 where PERMP will be administered at pre-dose, 0.5, 1, 2 and 4 hours post-dose. 
At Visit 5 administration of serial PERMPs will be done at pre-dose and at 0.5, 1, 2, 4, 8, 10, 12, 13, and 
14 hours post-dose. 
Training on the PERMP will be required to all personnel assigned to perform this study assessment. A 
designated, qualified individual from the study research team will perform the assessment.   
4.2.2 Adults ADHD Clinical Diagnostic Scale (ACDS) DSM-V Update 
The ACDS will be used to determine study eligibility. An ACDS assessment will be done at Screening 
and/or Baseline. The Investigator or other designated, qualified individual from the study research team 
will perform the assessment.  
4.2.3 Mini International Neuropsychiatric Interview (M.I.N.I.) 7.0.2 
The M.I.N.I. 7.0.2, a validated, structured diagnostic interview, will be administered at Baseline or 
Screening to confirm exclusions 1 and 2. The M.I.N.I. 7.0.2 may be administered by a psychiatrist or 
PhD-level psychologist. Other staff must be approved by Sponsor to administer the M.I.N.I. 7.0.2. 
4.2.4 Adult Investigator Symptom Rating Scale (AISRS) DSM V Update 
The AISRS will be used to determine study eligibility and as additional efficacy scale during Visits 1 to 
519. 
4.2.5 Clinical Global Impression Scales 
The Clinical Global Impression Scales are used to measure features associated with ADHD. A global 
assessment of disease severity (CGI-S) will be done at the Screening, Baseline, and at Visits 1 to 5. The 
Investigator or other designated, qualified individual from the study research team will perform the 
assessment.  


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4.2.6 Digit Symbol Substitution Test (DSST) 
The DSST is a paper-and-pencil cognitive test presented on a single sheet of paper that requires a subject 
to match symbols to numbers according to a key located on the top of the page. The DSST is sensitive to 
the presence of cognitive dysfunction as well as to change in cognitive function20. This assessment will be 
done at Baseline, and at Visit 5.  
4.2.7 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 
behavior21.   
The baseline version of the C-SSRS will be administered to all subjects at Screening. The “Since Last 
Visit” version will be used at all subsequent study visits (and Early Termination, if applicable). The 
Investigator or other designated, qualified individual from the study research team will perform the 
assessment.  
4.2.8 Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events 
Refer to Appendix B Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events. This 
assessment will be administered at Baseline and Visits 1 to 5. 
4.2.9 Study Visits and Procedures 
All study visit assessments will be collected on electronic case report forms (eCRF).  
Safety will be monitored by observation of and direct inquiry regarding AEs at Screening, Baseline, and 
each post-dose visit. Subjects may experience AEs that necessitate an unscheduled visit. Situations may 
also arise wherein the Investigator asks a subject to report for an unscheduled visit (UNS) following the 
report of an AE or SAE. Additional examinations may be conducted at these visits as necessary to ensure 
the safety and well-being of subjects during the study. All eCRFs should be completed for each 
unscheduled visit. Refer to Section 8.3 for information on AE collection, recording, and reporting.  
Medical history will capture all medical conditions at the Screening visit. Physical examination, 12-lead 
electrocardiogram (ECG), and clinical laboratory tests will be conducted as described on Appendix A, or 
at the discretion of the Principal Investigator. 
In addition, the C-SSRS will be administered at Screening, Baseline, and all subsequent scheduled visits 
to assess emergent suicidal thoughts or behaviors. Vital signs (BP and HR), body weight and direct 
questioning to assess for sleep, appetite, mood and psychotic events will be conducted at Baseline and 
Visits 1 to 5. The Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events will be 
administered at Baseline and all subsequent scheduled visits. 
During Visit 5, subjects who are smokers will be allowed to have up to 3 cigarette breaks.  
4.2.10 Study Periods 
Study duration is up to 11 weeks consisting of the following: 
• 
Screening (up to 6 weeks prior to Baseline) 
• 
Baseline 


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• 
Visits 1 to 3 (DB Titration) 
• 
Visit 4 (Abbreviated administration of serial PERMPs)  
• 
Visit 5 (Administration of serial PERMPs) 
4.2.10.1 Screening  
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 (ICF). Potential subjects who give their informed consent will undergo a screening period 
(up to 6 weeks) to determine eligibility prior to Baseline. 
During the Screening visit, the following activities will be performed: 
• 
Subject’s informed consent 
• 
Review of inclusion/exclusion criteria 
• 
Review of medical history 
• 
Review of medication history including prior and concomitant medications 
• 
Demographics (i.e., sex, age, race, and ethnicity) 
• 
Physical examination 
• 
Body weight and height 
• 
M.I.N.I. 7.0.2 
• 
AISRS 
• 
ACDS 
• 
CGI-S 
• 
“Baseline” C-SSRS 
• 
PERMP placement test (may be performed at Baseline) 
• 
Vital Signs: Blood pressure (BP) and pulse (average of triplicate measurements), respiratory rate 
(RR), and temperature (T). 
• 
Resting 12-lead ECG 
• 
AE assessment 
• 
Laboratory tests (see Table 2) 
Table 2: Laboratory Tests at Screening 
Biochemistry 
Non-fasting random serum glucose 
Total bilirubin 
Blood urea nitrogen (BUN) 
Creatinine with estimated glomerular filtration rate (eGFR) 
Alkaline phosphatase 
Calcium 


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Lactate dehydrogenase (LD) 
Aspartate aminotransferase [AST (SGOT)] 
Alanine aminotransferase [ALT (SGPT)] 
Serum electrolytes (sodium, potassium, and chloride) 
Gamma glutamyl transpeptidase (GGT) 
Hematology 
Complete blood count (CBC) with differential: 
• 
White blood cell count (WBC) with differential 
• 
Hemoglobin 
• 
Hematocrit 
• 
Red blood cell count (RBC) to include indices 
Platelet count 
Serology 
HIV 
Hepatitis C antibody 
Hepatitis B surface antigen 
Immunohematology: 
Serum hCG (females only) 
Urinalysis 
Specific gravity 
Urine color 
Appearance 
Bilirubin 
pH 
Leukocytes 
Nitrites 
Protein 
Glucose 
Ketones 
Blood 
Microscopic examination 
Note: Microscopic examination will only be performed when any 
of the following urinalysis tests are reported abnormal (i.e., 
outside of normal ranges): leukocyte, nitrite, protein, and/or 
blood. The microscopic examination will be conducted on the 
same urine sample as the abnormal urinalysis test. 
Drugs of Abuse: 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Methadone 
Opiates 
Phencyclidine 
Tricyclic antidepressants 
 
4.2.10.2 Baseline (Day -1) 
Once the subject is determined to be initially eligible at Screening, Baseline evaluations will be 
performed. If the subject continues to meet eligibility criteria at Baseline, the subject may be enrolled into 
the study and randomized to start the DB titration phase. 


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AMPH ER TAB (or matching placebo) will be dispensed to enrolled subjects. The starting dose of 
AMPH ER TAB (or matching placebo) will be 5 mg in the morning before 10 am, with or without food, 
swallowed whole or chewed. 
The following assessments will occur at the Baseline Visit: 
• 
Review of inclusion/exclusion criteria 
• 
M.I.N.I. 7.0.2 (if not performed at Screening) 
• 
PERMP placement test (if not performed during Screening) 
• 
PERMP practice before and after safety and efficacy assessments 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
“Since Last Visit” C-SSRS 
• 
AISRS  
• 
ACDS (if subject did not meet eligibility criteria at Screening) 
• 
CGI-S  
• 
DSST 
• 
Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events 
• 
Vital Signs: BP and pulse (average of triplicate measurements) 
• 
Body weight 
• 
AE assessment 
• 
Concomitant medications assessment 
• 
DB AMPH ER TAB 5 mg or matching placebo dispensing, accountability, and subject training 
regarding investigational product 
• 
Drugs of Abuse Screening Test (see Table 3) 
Table 3: Drugs of Abuse Screening Test at Baseline 
Drugs of Abuse: 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Methadone 
Opiates 
Phencyclidine 
Tricyclic antidepressants 
 


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4.2.10.3 Visits 1 (Day 7) to 3 (Day 21), Double-Blinded Titration 
During Visits 1 to 3, enrolled subjects will continue to receive AMPH ER TAB or matching placebo as 
described in Figure 2 Dose Titration. Subjects will be titrated up by 5 mg increments each week. After 
Visit 3 subjects will receive a final dose of 20 mg for 14 (± 3) days prior to Visit 5. Subjects who cannot 
tolerate the study drug will be discontinued from the study. 
Figure 2: Dose Titration  
 
The following assessments will be performed at each visit during Visit 1 to 3: 
• 
Blood pressure and pulse (average of triplicate measurements) 
• 
Body weight 
• 
PERMP practice before and after efficacy and safety assessments 
• 
AISRS 
• 
CGI-S 
• 
“Since Last Visit” C-SSRS 
• 
Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events 
• 
AE assessment 
• 
Concomitant medications assessment 
• 
DB AMPH ER TAB (10 mg after Visit 1, 15 mg after Visit 2 and 20 mg after Visit 3) or 
matching placebo dispensing, accountability, and subject training regarding Investigational Drug. 
4.2.10.4 Visit 4 (Day 28) Abbreviated administration of serial PERMPs 
The following assessments will be performed at Visit 4: 
• 
Blood pressure and pulse (average of triplicate measurements) at pre-dose and ~3 hours post-dose  
• 
Body weight 
• 
Abbreviated administration of serial PERMPS at pre-dose, 0.5, 1, 2 and 4 hours post-dose. Pre-
dose PERMP will be administered approximately 30 minutes prior to dosing, followed by on-site 
administration of AMPH ER TAB 20 mg or matching placebo by the clinic staff. 


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• 
AISRS 
• 
CGI-S 
• 
“Since Last Visit” C-SSRS 
• 
Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events 
• 
AE assessment 
• 
Concomitant medications assessment 
• 
DB AMPH ER TAB 20 mg or matching placebo dispensing, accountability, and subject training 
regarding investigational drug. 
4.2.10.5 Visit 5 (Day 35) Administration of serial PERMPs 
The following activities will be performed during Visit 5: 
• 
Administration of serial PERMPs at pre-dose and at 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours post-
dose 
• 
Physical examination 
• 
Blood pressure and pulse (average of triplicate measurements) at pre-dose and ~3 hours post-dose 
• 
Body weight 
• 
On-site drug administration of AMPH ER TAB 20 mg or matching placebo 
• 
AE assessment 
• 
Concomitant medications assessment 
• 
Study drug accountability and drug reconciliation 
 
The following activities will be performed at or within 2 days of Visit 5: 
• 
AISRS 
• 
CGI-S 
• 
DSST 
• 
“Since Last Visit” C-SSRS 
• 
Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events 
• 
Resting 12-lead ECG   
• 
Laboratory tests (see Table 4) 
Table 4 Laboratory Tests at Visit 5 
Biochemistry 
Non-fasting random serum glucose 
Total bilirubin 
Blood urea nitrogen (BUN) 
Creatinine with estimated glomerular filtration rate (eGFR) 


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Alkaline phosphatase 
Calcium 
Lactate dehydrogenase (LD) 
Aspartate aminotransferase [AST (SGOT)] 
Alanine aminotransferase [ALT (SGPT)] 
Serum electrolytes (sodium, potassium, and chloride) 
Gamma glutamyl transpeptidase (GGT) 
Hematology 
Complete blood count (CBC) with differential: 
• 
White blood cell count (WBC) with differential 
• 
Hemoglobin 
• 
Hematocrit 
• 
Red blood cell count (RBC) to include indices 
Platelet count 
Immunohematology: 
Urine hCG (females only) 
Urinalysis 
Specific gravity 
Urine color 
Appearance 
Bilirubin 
pH 
Leukocytes 
Nitrites 
Protein 
Glucose 
Ketones 
Blood 
Microscopic examination 
Note: microscopic examination will only be performed when any of the following 
urinalysis tests are reported abnormal (i.e., outside of normal ranges): 
leukocyte, nitrite, protein, and/or blood. The microscopic examination will be 
conducted on the same urine sample as the abnormal urinalysis test. 
• 
Drug of Abuse Screening Test (see Table 5) 
Table 5 Drugs of Abuse Screening Test at Visit 5 
Drugs of Abuse: 
Barbiturates 
Benzodiazepines 
Cannabinoids 
Cocaine 
Methadone 
Opiates 
Phencyclidine 
Tricyclic antidepressants 
For all activities performed, the results are to be recorded in the eCRF.   
4.2.10.6 Early Termination Visit 
The following activities may be done for subjects that withdraw prior to completion of Study Visit 5 (i.e., 
terminate early): 
• 
Physical examination 
• 
Body weight 


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• 
BP and pulse (average of triplicate measurements) 
• 
AE assessment 
• 
Concomitant medications assessment 
• 
“Since Last Visit” C-SSRS 
• 
Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events 
• 
AISRS 
• 
CGI-S 
• 
DSST 
• 
Study drug accountability and reconciliation 
• 
A urine pregnancy test (for females of child-bearing potential only) may be performed in the 
event of a suspected pregnancy per Investigator’s clinical judgment 
• 
Any other assessments as determined by the Investigator 
For all activities performed, the results are to be recorded in the eCRF.   
 
 


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5 INVESTIGATIONAL DRUG INFORMATION AND MANAGEMENT 
5.1 Investigational Drug Dose Regimen 
DB AMPH ER TAB or matching placebo will be dispensed to enrolled subjects. Subjects will be 
instructed to take AMPH ER TAB in the morning before 10 am, with or without food, swallowed whole 
or chewed. The starting dose of AMPH ER TAB (or placebo) after Baseline will be 5 mg. Subjects will 
then be titrated up by 5 mg each week. After Visit 3 subjects will receive a final dose of 20 mg for 14 (± 
3) days prior to Visit 5. Subjects who cannot tolerate the study drug will be discontinued from the study. 
5.2 Investigational Drug Packaging, Labeling and Dispensing 
AMPH ER TAB or matching placebo will be provided in blinded packaging at Baseline and Visits 1 to 4. 
AMPH ER TAB and placebo will have identical physical characteristics and matching flavor. 
All investigational products used in this study will be prepared, packaged, and labeled in accordance with 
the standard operating procedures (SOPs) of Tris Pharma or those of its designee, Current Good 
Manufacturing Practices (cGMP) guidelines, International Conference for Harmonisation (ICH) 
guidelines for Good Clinical Practice (GCP), and applicable regulations. 
5.3 Investigational Drug Storage 
The study drug should be stored between 15°C to 30°C (59°F to 86°F) at the study center in a secure, 
locked cabinet with limited access. When dispensed, the subjects will be instructed to store the drug at 
ambient temperature in a cool, dry place and out of reach of children.  
5.4 Drug Administration 
The study drug will be administered orally once daily before 10 am with or without food. Subjects will be 
instructed to take each study drug dose by swallowing or chewing. Drug administration for Visits 4 and 5 
will occur on-site. 
5.5 Investigational Drug Accountability 
The Investigator or designee will verify and acknowledge receipt of the study drug. All study drug 
samples must be stored in a secure area under the proper storage requirements with limited access (i.e., 
restricted to the Investigator or designees). Medication designated for this clinical study must not be taken 
by any subjects other than those enrolled in this specific investigation and may not be utilized for any 
laboratory or animal research. All study drug dispensed to subjects must be accurately recorded on the 
Drug Accountability Record maintained at the study site. Subjects should be instructed to return all study 
drug dispensed to them (including remaining tablets and empty containers) at each study visit.   
Drug accountability will be performed at each study visit starting with Baseline. Subjects will be provided 
with a new bottle containing 10 tablets at each visit (Baseline and Visits 1 to 4). Containers including the 
remaining study drug samples should be returned to the site at each subsequent visit. Remaining drug 
product samples and empty containers will be retained at the site for Study Monitor and/or Sponsor 
verification. All drug product samples should be stored at the study site until further instruction from the 
Sponsor.   


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


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6 SUBJECT COMPLIANCE 
6.1 Concomitant Medication and/or Therapy 
Concomitant medications information will be collected beginning at Screening and will continue during 
all study visits or Early Termination (EOT) visit, if applicable.   
6.2 Prohibited Concomitant Medications 
Psychotropic medications are not allowed during the study except for stimulants (other than study drug), 
which must be discontinued within 7 days of Baseline. No anticonvulsant, antidepressant, or 
antipsychotic medications are permitted during the study. Melatonin is permitted. Prohibited concomitant 
medications may be resumed 1 day after Study Visit 4 (or EOT). 
6.2.1 Prohibited Concomitant Medications 
Any stimulant (e.g., methylphenidate, dexmethylphenidate, amphetamine, and dextroamphetamine) 
should be discontinued 7 days prior to Baseline. The following medications are prohibited during the 
study: 
Selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine) 
Serotonin and norepinephrine reuptake inhibitors (SNRIs) (e.g., desvenlafaxine, duloxetine, 
venlafaxine – with the exception of fluoxetine which is restricted for 30 days prior to Baseline)                 
MAOIs  
Mood stabilizers (e.g., lithium, valproate, quetiapine) 
Antipsychotics (e.g., risperidone, olanzapine) 
Anticonvulsants (e.g., phenobarbital, phenytoin, primidone) 
Sedative hypnotics, except melatonin 
Anticoagulants 
Halogenated anesthetics 
Tricyclic antidepressants 
Atomoxetine 
Guanfacine 
Clonidine 
CYP2D6 inhibitors (e.g., paroxetine and fluoxetine, quinidine, ritonavir) 
Fentanyl, tramadol, tryptophan, buspirone, St. John’s Wort 
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) 
Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts 
Decongestants (e.g. oxymetazoline, phenylephrine, pseudoephedrine) 
Sedating antihistamines (e.g. alimemazine, chlorphenamine, clemastine, cyproheptadine, hydroxyzine, 
promethazine) 
 
Acetaminophen is permitted for control of fever or pain if needed. Short courses of prescription and 
non-prescription medications needed for treatment of acute illnesses such as the common cold, viral 
illnesses, and ear infections are permitted as long as these do not contain medications listed above. 
Ongoing antihypertensive treatment will be assessed by the Investigator and the Sponsor. 


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Alcohol consumption will be restricted form Baseline to 24 hours after Visit 5. 
All concomitant medications must be recorded on the Concomitant Medication CRF. 
The Investigator should contact the Medical Monitor for a written Note to File or Memo to File for 
evidence that the Sponsor is aware of a chronic or acute medication and a judgment on whether the 
subject may continue in the study. 
6.3 Treatment Compliance 
Subject training at Baseline and subsequent ongoing retraining regarding proper dosing of study drug will 
occur to ensure subject compliance. Subjects must be instructed to return to every visit any unused study 
drug and/or the empty bottle. Starting with Visit 1, study staff will assess compliance by inspecting 
returned study drug bottles at every study visit to confirm that the subject is taking study drug according 
to the protocol. Drug accountability per subject will be recorded on drug accountability logs. If the subject 
forgets to bring the bottle to the visit, the visual inspection will occur when the bottle is returned.   
6.3.1 Acceptable Compliance  
Acceptable compliance is defined as 80% or higher which is inclusive.  
If compliance between subsequent scheduled visits is outside this acceptable range and/or cannot be 
determined (when, for example, the subject did not return unused study drug), the Investigator or designee 
will determine subject’s continued participation, after consultation with the Clinical Monitor and the 
Sponsor. 
 
 


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7 RANDOMIZATION AND BLINDING PROCEDURES 
Enrollment will occur after all Screening procedures have been performed and eligibility for the study is 
confirmed at Baseline. After Baseline, subjects will enter a 4-week randomized, DB, placebo-controlled 
phase. Subjects will be randomized at Baseline to take DB AMPH ER TAB (or matching placebo) orally 
once daily. 
All study drug product samples will be supplied in identical containers and will be similar in physical 
characteristics (color, smell, flavor, and appearance), thereby enabling DB conditions. 
Unblinding should occur only when knowing the treatment assignment has a bearing on the medical 
treatment or evaluation of a subject. Whenever possible, the need to unblind should be discussed with the 
Sponsor prior to unblinding. For emergency unblinding, study personnel will use the IWRS unblinding 
module. 
Table 6 Sponsor's Contact Information for Unblinding Procedures 
Contact 
Phone number 
Fax number 
Tris Pharma, Inc 
Cary Sax 
Director, Regulatory Affairs 
 
csax@trispharma.com 
 
Direct # 732-823-4690 
NA 
A subsequent written report, including all pertinent details, must be submitted to the Sponsor within 
24 hours of the unblinding. Whenever possible, the blind of the subject should be maintained. 
If Investigator or site personnel or subject unblinded, the subject must be withdrawn from the study, and 
procedures accompanying withdrawal are to be performed. 
 
 


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8 ADVERSE AND SERIOUS ADVERSE EVENTS 
This section defines AEs and outlines the procedures for appropriately collecting, grading, recording, and 
reporting them. Information in this section complies with 21 Code of Federal Regulations (CFR) 312, 
ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, and ICH Guideline E6(R2):  Good Clinical Practice. 
The Investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE, as provided in this protocol. During the study, when there is a safety 
evaluation, the Investigator or site staff will be responsible for detecting AEs and SAEs, as detailed in this 
section of the protocol. 
8.1 Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation subject 
administered a pharmaceutical product, whether or not the event has a causal relationship with this 
treatment.  
An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study medication, whether or not considered 
causally associated with the use of the study medication. Any abnormal laboratory value deemed 
clinically significant by the Investigator, regardless of causal relationship, must be reported as an AE. 
Examples of an AE include the following: 
• 
significant or unexpected worsening or exacerbation of the condition or indication under 
study, taking into consideration the daily fluctuation of symptoms of ADHD. 
• 
exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency or intensity of the condition (e.g., abnormal physical examination 
finding) 
• 
signs, symptoms, or clinical sequelae of a suspected interaction 
• 
signs, symptoms, or clinical sequelae of a suspected overdose of the study medication or 
a concurrent medication (overdose per se should not be reported as an AE or SAE, unless 
non-serious or serious sequelae occur) 
The following examples are not considered AEs: 
• 
medical or surgical procedure (e.g., endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE 
• 
anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) (including 
laboratory values) present or detected at the start of the study that do not worsen 
• 
the disease or disorder being studied, or expected progression, signs, or symptoms of the 
disease or disorder being studied, unless they become more severe or occur with a greater 
frequency than expected for the subject’s condition 


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8.2 Definition of a Serious Adverse Event (SAE)  
An SAE is defined as any event that meets the following criteria: 
• 
It results in death  
• 
It is life-threatening (i.e., presents an immediate risk of death from the event as it 
occurred) (This criterion does not mean that the AE hypothetically might have caused 
death if it were more severe) 
• 
It results in persistent or substantial disability or incapacitation (This criterion is not 
intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, diarrhea, or sprained ankle) 
• 
It results in hospitalization 
• 
It results in prolongation of an existing hospitalization 
• 
It is a congenital anomaly or birth defect 
• 
It requires medical or surgical intervention to prevent any of the above outcomes 
• 
Other medically important condition  
(Note: Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency.) 
Medical and scientific judgment should be exercised in determining whether an AE is serious when 
considering important medical events that may not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the subject or may require intervention to prevent any of the other 
outcomes listed.  
Hospitalization for elective treatment of a pre-existing condition that did not worsen from Baseline does 
not meet the definition of an SAE. 
Admission to a hospital or prolongation of a hospitalization for social or convenience reasons (e.g., 
cosmetic surgery) not associated with the occurrence of an AE does not meet the definition of an SAE. 
8.2.1 Serious Adverse Events That Occur Before Administration of Study Medication 
Before administration of study medication, only SAEs assessed by the Investigator as related to study 
participation (e.g., related to study procedures or a change in existing therapy) will be transcribed onto the 
SAE reporting form and reported to the Sponsor via Premier Research Pharmacovigilance 
8.2.2 Serious Adverse Events That Occur After Study Completion 
If the Investigator becomes aware of an SAE or death that occurs in a subject within 30 days after Visit 
4and that Investigator considers the event to be related to the study medication, the Investigator is 
obligated to report the SAE to the Sponsor. 


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8.3 Collecting, Recording and Evaluating Adverse Events and Serious 
Adverse Events 
The AE reporting period for this study begins at Screening and ends at Visit 4. All AEs that occur in trial 
subjects during this reporting period must be reported, without consideration to drug relatedness. In 
addition, any known AE that occurs subsequent to the AE reporting period that the investigator assesses 
as related to the study medication should also be reported as an adverse event. 
The Investigator will attempt to establish a diagnosis of the event on the basis of signs, symptoms, or 
other clinical information. In such cases, the diagnosis, not the individual signs or symptoms, should be 
documented as the AE or SAE. AEs will be collected from the point the ICF is signed through EOT or 
Early Termination Visit. 
Both total and treatment-emergent AEs will be reported. Treatment-emergent AEs are defined as those 
that occur after dosing of study medication until EOT or Early Termination Visit. 
8.3.1 Assessment of Adverse Events and Serious Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE described previously. At each visit, the subject will be allowed time to 
spontaneously report any issues since the last visit or evaluation. The investigator will then monitor 
and/or ask about or evaluate AEs using nonleading questions, such as  
 
* “How are you feeling?”  
 
* “Have you experienced any issues since your last visit?”  
 
* “Have you taken any new medications since your last visit?”  
 
Any clinically relevant observations made during the visit will also be considered AEs. 
 
8.3.2 Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study, 
using his or her clinical judgment. The intensity of each AE and SAE recorded on the CRF should be 
assigned to one of the following categories: 
• 
Mild: An event that is easily tolerated by the subject, causes minimal discomfort, and 
does not interfere with everyday activities 
• 
Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities 
• 
Severe: An event that prevents normal everyday activities 
An AE that is assessed as severe should not be confused with an SAE. Severity is a term used to describe 
the intensity of a specific event, and both AEs and SAEs can be assessed as severe. The event itself, 
however, may be of relatively minor medical significance (such as a severe headache). This is not the 
same as serious, which is based on the subject’s or event’s outcome or on action criteria usually 
associated with events that pose a threat to a subject’s life or functioning (see Section 8.2). 


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8.3.3 Assessment of Causality 
The Investigator is obligated to use his or her clinical judgment to assess the relationship between the 
study medication and the occurrence of each AE or SAE. The Investigator will assess the relationship to 
the study medication by using the following criteria:  
• 
Definitely Related: An AE has a strong temporal relationship to the study drug. The AE 
is most likely explained by study drug. Dechallenge and rechallenge (if possible) are 
positive. The AE is consistent with a known response to the study drug. Another etiology 
is unlikely or significantly less likely 
• 
Probably Related: An AE has a strong temporal relationship to the study drug. The AE 
is more likely explained by study drug than by another cause. Dechallenge (if performed) 
is positive 
• 
Possibly Related: An AE has a reasonable temporal relationship to study drug. The AE 
could have been due to another equally likely cause; dechallenge is positive 
• 
Not Related: The subject did not receive the study drug OR the AE has no temporal 
relationship to study drug OR the AE has a much more likely alternate etiology OR the 
AE is due to an underlying or concurrent illness or effect of another drug 
Even in situations in which minimal information is available for the initial SAE report, it is important that 
the Investigator always makes an assessment of causality for every event before transmitting the SAE 
reporting form and AE CRF page(s) to the Sponsor. The causality assessment is one of the criteria used 
when determining regulatory reporting requirements. The Investigator may change his or her opinion of 
causality in light of follow-up information and amend the SAE reporting form and AE CRF page(s) 
accordingly. 
8.3.4 Assessment of Outcome 
All SAEs must be followed until they are resolved, the condition stabilizes, the events are otherwise 
explained, or the subject is lost to follow-up. The Investigator will assess the outcome of the event by 
using the following terms: 
• 
Resolved: The event resolved or the subject recovered without sequelae. An event (either 
serious or non-serious) occurred and had an endpoint, and the subject experienced no 
restrictions. Examples include stent placement for coronary artery disease (a device 
implanted is not a sequelae), an appendectomy (a scar is not a sequelae), a post-operative 
wound infection, or an upper respiratory tract infection 
• 
Resolved with sequelae: The event has at least 1 secondary outcome that may result in 
permanent disability, functional limitation, or both. Such sequelae are usually limited to 
SAEs. Examples include hip replacement resulting in foot drop (foot drop is not the 
intended outcome but is a risk of surgery), stroke resulting in paralysis, or emboli 
formation after a bacterial infection resulting in a renal infarct and loss of renal function 
• 
Resolving  
• 
Not resolved: At the end of the study, an event either has not changed in intensity or may 
not have recovered to baseline values, and the outcome is unknown.  


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• 
Unknown: The subject has withdrawn from the study prematurely or is lost to follow-up, 
and the status of the event is unknown 
• 
Death 
8.4 Documentation 
All AEs that occur within the period of observation for the study must be documented in the CRF with the 
following information, where appropriate. (The period of observation for the study is described in Section 
11.2.)  
 
• 
AE name or term  
 
• 
When the AE first occurred (start date and time)  
 
• 
When the AE stopped (stop date and time or an indication of “ongoing”)  
 
• 
Severity of the AE  
 
• 
Seriousness (hospitalization, death, etc.)  
 
• 
Actions taken; may consist of: 
 
o Dose increased: 
An indication that a medication schedule was modified by addition; 
either by changing the frequency, strength, or amount.  
o Dose not changed: An indication that a medication schedule was maintained.  
o Dose reduced: An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength, or amount.  
o Drug interrupted: An indication that a medication schedule was modified by 
temporarily terminating a prescribed regimen of medication.  
o Drug withdrawn: An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication.  
o Not applicable: Determination of a value is not relevant in the current context. 
o Unknown: Not known, not observed, not recorded, or refused. 
 
• 
Outcome  
 
• 
Investigator opinion regarding the AE relationship to the IP(s) 
8.5 Follow-up of Adverse Events and Serious Adverse Events 
Non-serious AEs will not be followed after the last scheduled study visit. 
SAEs will be followed until the event resolves, the condition stabilizes, the event is otherwise explained, 
or the subject is lost to follow-up. The Investigator will make a reasonable attempt to obtain follow-up 
information and provide it to the Sponsor via Premier Research Pharmacovigilance. This includes results 
of any additional laboratory tests or investigations or consultations with other healthcare professionals 
that serve to clarify the nature of the event, the cause of the event, or both. 


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New or updated information will be recorded on the originally completed SAE reporting form and CRF 
pages, with all changes signed and dated by the Investigator. The updated SAE reporting form and CRF 
pages should be resubmitted to the Sponsor via Premier Research Pharmacovigilance within the time 
frames outlined in Section 8.6. Investigators with subjects with unresolved SAEs at the time that the 
electronic database is to be closed will be informed and instructed how to make subsequent updates on the 
SAE to the Sponsor. The database will be locked and the data analyzed if unresolved SAEs remain. SAE 
updates will be reported to the Sponsor, to Regulatory Authorities, and IRBs within the timelines required 
by applicable regulations. All updates will also be filed in the Trial Master File retained by the Sponsor. 
8.6 Prompt Reporting of Serious Adverse Events 
Once the Investigator determines that an event meets the protocol definition of an SAE, he or she must 
notify the CRO within 24 hours, including weekends and holidays. 
ANY SAE OR ANY OUTCOME OF DEATH DUE TO ANY CAUSE WHICH OCCURS DURING 
THE COURSE OF THIS STUDY, REGARDLESS OF RELATIONSHIP TO STUDY 
MEDICATION, MUST BE REPORTED TO THE SPONSOR IMMEDIATELY (WITHIN 
24 HOURS).  
Complete the SAE Reporting Form and forward by e-mail or fax to Premier Research Pharmacovigilance: 
Table 7 Contact Information for SAE Reporting 
What 
Email 
Phone/ Fax 
24 Hour US 
Contact 
GlobalPV-US@premier-research.com 
Fax:  
+1 215 972 8765 
 
E-mail transmission is the preferred method to transmit SAE information. In rare circumstances, and in 
the absence of e-mail capacity, notification by fax is acceptable 
If the Investigator does not have all information regarding an SAE, he or she must not wait to receive 
additional information before notifying the CRO of the event. The form must be updated when additional 
information is received. Follow-up information received on all SAEs must be forwarded to the CRO by 
using the same procedure and timelines as for an initial report. 
Within 24 hours after a SAE detection, observation, or report of occurrence (regardless of the relationship 
to test article), the investigator/qualified designee will complete a paper SAE Report Form with required 
information regarding the SAE and submit the completed form to Premier Research Pharmacovigilance. 
The data will also be entered into the appropriate module of the electronic data capture (EDC) as soon as 
possible after the paper form is sent to Premier Research Pharmacovigilance. 
These SAE reports must contain the following information: 
1. Study name/number 
2. Study drug 


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3. Investigator details (name, phone, fax, e-mail) 
4. Subject number 
5. Subject demographics 
6. Clinical event 
7. Description 
a. Date of onset 
b. Treatment (drug, dose, dosage form) 
c. AE relationship to study drug 
d. Action taken regarding study drug in direct relationship to the AE 
e. Criteria for “Serious” applicable to the AE 
8. Cause of death (whether or not the death was related to study drug) 
9. Autopsy findings (if available) 
10. Date of firs dose of Investigational Product 
11. Date of last dose of Investigational Product, if applicable 
Any SAE that occurs during the study should be recorded by each clinical site and reported to the Sponsor 
Premier Research Pharmacovigilance. 
SAEs considered definitely, probably, or possibly related to study drug shall also be classified by the 
Sponsor as being “expected” or “unexpected.” An unexpected event is one that is not listed in the 
Investigator’s Brochure. 
The person responsible for the study shall ensure the study has been carried out in accordance with local 
pharmacovigilance regulations. All serious events reporting by Sponsor will adhere to 21 CFR 312.32 for 
IND drugs (7-day or 15-day alerts). Unexpected fatal or life-threatening SAEs considered related to the 
study drug should be reported to the FDA by the Sponsor with an Investigational New Drug (IND) Safety 
Report within 7 days. The Institutional Review Board (IRB) will be notified of the alert reports per FDA 
regulations. 
8.7 Regulatory Reporting Requirements for Serious Adverse Events 
The Investigator must promptly report all SAEs to the CRO or designee in accordance with the 
procedures detailed in Section 8.6, “Prompt Reporting of Serious Adverse Events”.   
The Investigator, or responsible person according to local requirements, must comply with requirements 
related to the reporting of SAEs to the IRB. The Sponsor is responsible for reporting to Regulatory 
Authorities. 
8.7.1 Procedures for Reporting Pregnancy Exposure and Birth Events 
Should a female subject, or a male subject’s partner become pregnant or be suspected of being pregnant 
while participating in this study, the event must be reported to the Sponsor upon receipt of information by 
the study staff. While the pregnancy itself is not considered to be an AE or a SAE, any pregnancy 


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complications will be recorded as AEs or SAEs (if applicable). Pregnancy must be reported within 24 
hours from first knowledge to the Sponsor via Premier Research Pharmacovigilance in writing via the 
Pregnancy Data Collection Form. This form shall be forwarded by e-mail or fax to the contacts details in 
Section 8.6. 
Any pregnancy will be followed through to delivery for the observation of any SAEs including congenital 
abnormalities. Fatalities and spontaneous abortions must be reported as SAEs. 
8.7.2 Overdose 
The maximal dose of Investigational Product (20 mg) should not be exceeded during the study. Overdose 
that occurs during the study will be treated and documented as an AE/UAE/SAE if it fulfills the criteria. 
If the overdose does not result in an AE, it should be documented in the CRF.  If the overdose does result 
in an SAE, it should be documented in the CRF and reported via a completed the SAE Reporting Form 
which is forwarded by e-mail or fax to Premier Research Pharmacovigilance The information contained 
therein should include study site identification, reporter identification, subject identification, 
Investigational Product, dose, action taken (e.g., administration of antidote <if available> or supportive 
measures or therapy), and any comments. 
 
 


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9 STATISTICAL CONSIDERATIONS 
This is a phase 3 randomized, double-blind (DB), placebo-controlled, parallel, study to assess the efficacy 
and safety of AMPH ER TAB compared to placebo for the treatment of ADHD in adults aged 18 to 60 
years. The objective of the statistical analysis will be to evaluate the efficacy and safety of AMPH ER 
TAB compared to placebo in adult patients with ADHD aged 18 to 60 years. 
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 0.05 significance 
level.  
A detailed statistical analysis plan (SAP) will be written and finalized prior to unblinding of the data. 
9.1 Power and Sample Size Determination 
Assuming an effect size of 0.80 of the primary efficacy endpoint (PERMP-T score averaged over all post-
dose time points assessed at Visit 5) between AMPH ER Tabs and placebo and approximately 92 
completers, this study will have at least 93% power at the level of 0.05 (2-sided). To allow for an 
estimated 15% potential dropout rate, this study plans to enroll approximately 108 subjects to ensure that 
at least 92 complete. The study will be conducted in approximately 6 cohorts of 18 subjects because 
subjects will need to be enrolled in cohorts to facilitate the administration of serial PERMPs at Visits 5. 
An additional cohort of up to 18 subjects may be added to ensure at least 92 subjects complete the study if 
there are circumstances in which any of the cohorts are unable to enroll 18 subjects, or if the dropout rate 
is higher than expected (>15%) thereby having less than 92 completers to ensure sufficient statistical 
power.  
The assumed effect size of 0.80 (expected treatment difference of 18 in average PERMP-T score divided 
by between-subject square root mean square error of 21.75) is based on differences measured between 
active and placebo in previous laboratory school studies conducted with similar drug formulations.   
9.2 Analysis Populations 
The analysis populations are defined as follows:   
• 
Safety Population (SAF): The safety population is defined as all enrolled subjects who received 
at least one dose of study drug, with treatment assignment based on the actual treatment received. 
• 
Randomized Population (RAND): The randomized population is defined as all randomized 
subjects, with treatment assignment based on the randomized treatment (regardless of actual 
treatment received).  
• 
Intent-To-Treat Population (ITT): The ITT population is defined as all randomized subjects 
who received at least one dose of study drug treatment, with treatment assignment based on the 
randomized treatment (regardless of actual treatment received).  
• 
Modified Intent-To-Treat Population (mITT): The mITT population is defined as all subjects 
who are in the ITT population and have at least one PERMP-T score at Visit 5. 
The primary efficacy analysis and key secondary efficacy analysis will be performed on the mITT 
population. Analysis of additional secondary endpoints will be performed for ITT population.  


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The safety analyses will be performed on the safety populations. 
Deviations from the original statistical plan as planned in this protocol will be reported and justified in the 
SAP and clinical study report (CSR) as appropriate.   
9.3 Efficacy and Safety Analyses 
9.3.1 Disposition and Withdrawals 
The number of subjects randomized, completing, and withdrawing, along with the reasons for withdrawal, 
will be tabulated. Additionally, the number of subjects in each analysis population will be reported. 
9.3.2 Protocol Deviations 
A by-subject listing of all protocol deviations will be reported. 
9.3.3 Background and Demographic Characteristics 
Baseline demographic variables will be summarized and presented by a subject listing. Demographic 
information will be presented for all analyses populations as defined in Section 9.2. 
9.3.4 Concomitant Medications and Concomitant Therapies 
Concomitant medications and therapies will be summarized by the number and percentage of subjects 
taking each medication, classified using World Health Organization Drug Dictionary (WHO-DD) 
Anatomical Therapeutic Chemical (ATC) class level 4 and preferred term. Concomitant medications will 
also be listed by subject.   
 
9.3.5 Efficacy Analyses 
9.3.5.1 Primary Efficacy Analysis 
The primary efficacy endpoint and estimand are defined in Section 3.2.1.  
PERMP-T scores at all post-dose time points (0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours post-dose) at visit 5 
will be assessed using a linear MMRM analysis. This is a restricted maximum likelihood (REML)-based 
analysis implemented using SAS PROC MIXED. The model will include treatment, time and treatment 
by time as fixed effects and subject as a random effect. Pre-dose PERMP-T score will be included as a 
covariate. The difference between AMPH ER TAB and placebo will be assessed at the alpha = 0.05 level 
of significance. The covariance structure used in the final MMRM model will be the one that has the 
lowest Akaike Information Criterion (AIC) among the following selections: SP(POW), unstructured, 
compound symmetry (CS), heterogeneous CS or heterogeneous Toeplitz. Kenwood-Roger correction will 
be used to estimate denominator degrees of freedom. The treatment effect is estimated by the overall 
adjusted least square mean difference between two treatment groups. 95% CI for the adjusted least square 
mean will be constructed and p-value for the treatment comparison will also be provided.  
The primary efficacy analysis will be conducted on the mITT population.  
For the primary efficacy analysis, the MMRM model will be fit to the observed data with missing 
at random assumption. The rate of missing PERMP-T for at least one post-dose time point on will be 
calculated and summary (number and percentage) of subjects discontinued prior to Visit 5 by the 


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dose level (5, 10, 15, 20 mg) prior to discontinuation will be summarized. Sensitivity analysis will 
be performed using Multiple Imputation approach with missing not at random assumption. In this 
analysis, the mean difference between the (unobserved) missing values and observed values (refer to as 
shift) will be assumed to vary independently for the different treatment groups. More details of this 
procedure will be provided in SAP. 
9.3.5.2 Secondary Efficacy Analyses 
Key secondary efficacy outcomes as determined by the comparison of each PERMP-T score at each time 
point (0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours post-dose) with pre-dose PERMP-T scores at Visit 5 are: 
• 
Onset of clinical effect 
• 
Duration of clinical effect 
The key secondary variables of onset and duration of efficacy (clinical effect) of APMH ER TAB versus 
placebo using the comparison of each PERMP-T ((attempted + correct) score at each time point will be 
tested by the same method as the primary efficacy endpoint analyses implementing a linear MMRM 
model.   
Onset of clinical effect is defined as the first time point post-dose when treatment effect is significant 
while the duration of clinical effect is defined as the time between last time point to the first time point 
post-dose with significant treatment effect. 
The key secondary efficacy analysis will be conducted on the mITT population. 
The key secondary efficacy endpoints (in the order of statistical analysis/gating) include: 
• 
PERMP-T scores at 4, 2, 8, 10, 12, 1, 0.5, 13, and 14 hours post-dose  
Descriptive statistics for the PERMP-T scores will be calculated at each time point and will be presented 
for each treatment as well for the differences between the treatments (AMPH ER TAB-placebo). In 
addition, these variables will be analyzed by the same method as the primary efficacy endpoint analyses 
implementing a linear MMRM model as described in Section 9.3.5.1 for the primary efficacy variable.   
Additional secondary efficacy endpoints will include 
• 
Change from Baseline in CGI-S at each post-baseline visit 
• 
Change from Baseline in AISRS scores at each post-baseline visit 
• 
Change from Baseline in DSST at Visit 5 
Analysis of additional secondary endpoints will be performed for ITT population. 
Descriptive statistics for the CGI-S, AISRS will be presented for each visit (Baseline and Visits 1 to 5). In 
addition, the change from Baseline in CGI-S, AISRS and DSST will be summarized.  
For the AISRS, the proportion of responders (defined as a subject who has a change from Baseline 50% 
or greater in the AISRS) will also be presented.   


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9.3.6 Safety Analyses 
Safety assessments will include TEAEs, physical examination, vital signs, body weight, Columbia 
Suicide Severity Rating Scale (C-SSRS), laboratory results, Electrocardiograms (ECG), vital signs and 
body weight, and direct questioning to assess for sleep, appetite, mood and psychotic events. 
All safety data will be analyzed descriptively by treatment group.  
The frequency of subjects reporting AEs will be summarized within each system organ class and 
preferred term.   
9.3.6.1 Adverse Events  
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0. 
Treatment-emergent AEs, any AEs recorded during the study at least one dose of study medication, will 
be summarized and categorized by severity and relationship to the investigational drug. If a subject has 
more than one occurrence of the same AE, he/she will be counted only once within that preferred term in 
the summary tables. The most severe occurrence of an AE, as well as the most extreme relationship of the 
AE to the study procedures or investigational drug, will be indicated in cases of multiple occurrences of 
the same AE. Serious adverse events and AEs of special interest, which will be defined in the SAP, will 
also be summarized separately. All AEs will be presented in a listing. Additionally, listings of SAEs and 
AEs leading to discontinuation will be generated. All SAEs will be evaluated to determine whether they 
are Unexpected Adverse Reactions. 
9.3.6.2 Columbia Suicide Severity Rating Scale (C-SSRS) 
The frequency of suicidality using the C-SSRS will be summarized by treatment group for the number of 
subjects reporting at least 1 occurrence of suicidal ideation or behavior, the number of subjects reporting 
any type of suicidal behavior, and the number of subjects reporting any type of suicidal ideation. 
9.3.6.3 Questionnaire for Sleep, Appetite, Mood, and Psychotic Adverse Events 
Occurrences related to sleep, appetite, mood, and psychotic events will be summarized descriptively by 
treatment and time point. 
9.3.6.4 Clinical Laboratory Evaluations 
Laboratory test results will be summarized descriptively by treatment and time point as both observed 
values and change from baseline values. 
The number of subjects with clinical laboratory values below, within, or above the normal range by time 
point and in relation to baseline will be tabulated for each clinical laboratory analyte by treatment group 
(shift table). 
Laboratory values that are outside the normal range will be flagged in the data listings. 
9.3.6.5 Vital Signs and Body Weight 
Descriptive summaries of actual values and changes from Baseline will be calculated for vital signs and 
weight.   
 


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9.3.6.6 Electrocardiograms (ECG) 
The number and percentage of subjects with normal and abnormal ECG results will be summarized for 
the Safety Population by study phase and treatment group.  
9.3.7 Other Statistical Considerations 
9.3.7.1 Significance Levels 
The type I error significance level for each set of study analyses as applicable will be set at alpha = 0.05. 
To preserve the family-wise error rate of 0.05, a gatekeeping testing procedure will be implemented for 
primary/secondary efficacy endpoints in the following order: 
• 
PERMP-T scores over all post-dose time points assessed at Visit 5 
• 
PERMP-T scores at 4, 2, 8, 10, 12, 1, 0.5, 13 and 14 hours post-dose 
The above will test in sequence whether a significant treatment effect is present using the models 
previously specified. If a significant effect is noticed, the following test will then be examined until all 
endpoints are exhausted or failure to reject the null hypothesis is met at alpha = 0.05. 
9.3.7.2 Missing Data 
No imputation of missing PERMP scores will be done for the primary efficacy analysis. To evaluate the 
sensitivity of the primary analysis results to the use or non-use of imputation, analyses using multiple 
imputation methods will be conducted as mentioned in Section 9.3.5.1. Additional details will be 
described in the SAP.   
 
9.3.8 Visit Windows 
All data collected will be displayed and analyzed according to the actual visit data in the eCRF. Study 
visits may occur within a ± 3-day window of the weekly scheduled visit and ensuring that the maximum 
length of exposure to the Investigational Product prior to Visit 5 shall be 35 (± 3) days. The maximum 
dose of AMPH ER TAB 20 mg (or matching placebo) will be administered for 14 (± 3) days prior to visit 
5.  
Assessments taken outside of windows described in the protocol will be displayed according to the eCRF 
assessment recorded by the Investigator. 
 
 


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10 DIRECT ACCESS TO PROCEDURAL DOCUMENTS 
10.1 Study Monitoring 
According to Good Clinical Practices (GCP) guidelines, the Sponsor of the study is responsible for 
ensuring the proper conduct of the study with regard to protocol adherence and validity of data recorded 
on the eCRFs. The contract research organization (CRO) is responsible for assigning the study monitor(s) 
to this study, with prior approval from the Sponsor. The study monitors’ duties are to aid the Investigator 
and the Sponsor in the maintenance of complete, accurate, legible, well-organized, and easily retrievable 
data. The study monitor will advise the Investigator of the regulatory necessity for trial-related 
monitoring, audits, IRB review, and inspection by providing direct access to the source data/documents. 
In addition, the study monitor will explain to and interpret for the Investigator all regulations applicable to 
the clinical evaluation of an investigational drug as documented in ICH guidelines. 
It is the study monitors’ responsibility to inspect the eCRFs throughout the study to protect the rights of 
the subjects; to verify adherence to the protocol; to verify completeness, accuracy, and consistency of the 
data; and to confirm adherence of study conduct to any local regulations. Details may be outlined in the 
study monitoring plan.  
10.2 Source Documents 
Tris Pharma requires that the Investigator prepare and maintain adequate and accurate records for each 
subject treated with the investigational drug. Source documents such as any hospital, clinic, or office 
charts and the signed ICFs are to be included in the Investigator’s files with the subject’s study records. 
Data will be captured electronically. Study site personnel will record eCRF data from source documents. 
If any data are first recorded onto documents such as laboratory reports, these documents will be 
considered source.  
10.3 Data Collection and Management 
This study will use electronic data collection techniques to collect data directly from the investigational 
site using eCRFs. The data will be stored centrally in a fully validated clinical database compliant with 
FDA regulations on electronic data integrity. The Investigator is responsible for ensuring that all sections 
of each eCRF are completed promptly and correctly and that entries can be verified against any source 
data.   
Study monitors will perform 100% source document verification to ensure there are no inconsistencies 
between the eCRFs and source documents. Discrepancies will be resolved in accordance with the 
principles of GCP. Detailed study monitoring procedures are provided in the Clinical Monitoring Plan. 
At intervals throughout the study and upon completion, data will be exported from the database into SAS 
datasets.   
Data management will be coordinated by the data managers of the designated CRO in accordance with 
their SOPs for data management and a formal study data management plan. The data managers will 
provide a quality control statement following database lock.  
Adverse events will be coded with MedDRA. Concomitant medications will be coded using World Health 
Organization – Drug Reference List.  


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


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12 ETHICS 
12.1 Ethics Review 
This research will be carried out in accordance with GCP as set out by the ICH Guidance for Industry, 
E6(R2) GCP: Good Clinical Practice; the basic principles defined in the U.S. Code of Federal Regulations 
(21 CFR Part 312); the World Medical Association Declaration of Helsinki (Fortaleza, Brazil, October 
2013); and in accordance with all national, state, and local laws and regulations. 
12.2 Ethics Committees 
The Investigator (or Sponsor, where applicable) is responsible for ensuring that this protocol, the site’s 
ICFs, and any other information that will be presented to potential subjects (e.g., advertisements or 
information that supports or supplements the ICF) are reviewed and approved by the appropriate IRB. 
The Investigator agrees to allow the IRB direct access to all relevant documents. The IRB must be 
constituted in accordance with all applicable regulatory requirements. The Sponsor will provide the 
Investigator with relevant documents or data needed for IRB review and approval of the study. Before 
investigational products can be shipped to the site, the Sponsor must receive copies of the IRB approval, 
the approved ICF, and any other information that the IRB has approved for presentation to potential 
subjects. 
If the protocol, the ICFs, or any other information that the IRB has approved for presentation to potential 
subjects is amended during the study, the Investigator is responsible for ensuring that the IRB reviews and 
approves, where applicable, these amended documents. The Investigator must follow all applicable 
regulatory requirements pertaining to the use of an amended ICF, including obtaining IRB approval of the 
amended form, before new subjects consent to take part in the study using the new version of the form. 
The Investigator must promptly forward to the Sponsor copies of the IRB approval of the amended ICF or 
other information and the approved amended ICF or other information. IRB approval of the consent forms 
must be obtained in addition to the approval given for the clinical study. 
12.3 General Considerations 
The Investigator must conduct the study in accordance with this protocol and ICH GCP guidelines which 
have their origins in the Declaration of Helsinki. The Investigator and Tris Pharma will sign the protocol 
and study contract to confirm agreement. The Investigator will not implement any amendment (deviation 
or changes of the protocol) without agreement by Tris Pharma and the IRB approval/information, except 
where necessary to eliminate immediate hazards to study subjects or when changes involve only logistical 
or administrative aspects of the study.  
When any new and important information that may be relevant to the subject’s consent is obtained, the 
Investigator and Tris Pharma will consult with each other on how to deal with the information. When Tris 
Pharma and a responsible Investigator judge it necessary, the Investigator must immediately provide the 
subjects with such information, revise the written information and other explanatory documents based on 
the new information, and obtain approval from the IRB(s). In this instance, the Investigator should also 
immediately inform subjects currently participating in the clinical study of such information, confirm 
their intention to continue participation, re-explain the study to them using the revised written information 
and other explanatory documents, and obtain written consent to continue participation based on their 
voluntary decision. 


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12.4 Informed Consent Form (ICF) 
The Sponsor will provide Investigators with a sample ICF for this study. Investigators are encouraged to 
use the sample form; however, they may adapt the information to suit the needs of their institution, if 
necessary (although it must reflect the required elements of informed consent specified in 21 CFR Part 
50.25). The final ICF must be accepted by the Sponsor and approved by the IRB. Investigators must 
provide the Sponsor with an unsigned copy of the final ICF before and after it is approved by the IRB. If 
any new information becomes available that might affect subjects’ willingness to participate in the study, 
or if any amendments to the protocol require changes to the ICF, the Sponsor will provide Investigators 
with a revised ICF. The IRB must provide written approval of any revisions to the ICF in advance of its 
use. 
Investigators must provide subjects with all the information necessary to make an informed decision 
about their participation in the study, including the nature and intended purpose of the study, possible 
benefits, and possible risks. 
Before written informed consent is obtained, the subject should be given ample time and opportunity to 
inquire about the details of the study. All questions must be answered to the satisfaction of the subject. 
Before a subject undergoes procedures specific to the protocol, the ICF must be signed and dated by the 
subject and any other signatories as required by the IRB. 
After all required signatures have been obtained, a copy of the signed ICF should be provided to the 
subject, and the original must be kept on file at the site and made available for review by the Sponsor. 
Documentation of the informed consent discussion must be noted in the subject’s case history. 
12.5 Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered confidential, and 
disclosure to third parties is prohibited. Information will be accessible to authorized parties or personnel 
only. Medical information may be given to the subject’s physician or to other appropriate medical 
personnel responsible for the subject’s well-being. Each subject will be asked to complete a form 
allowing the Investigator to notify the subject’s primary health care provider of his/her participation in 
this study.  
12.6 Publications of the Clinical Study 
The clinical study plan and the results of the study will be published on www.ClinicalTrials.gov in 
accordance with 21 CFR § 50.25(c). The results of and data from this study belong to Tris Pharma. 
Investigators may not publish on the results from the study (including data specifically from their site) 
without prior written consent from Tris Pharma.   
12.7 Protocol Amendments and Deviations 
No change or amendment to this protocol may be made by the Investigator or Tris Pharma after the 
protocol has been agreed to and signed by all parties unless such change(s) or amendment(s) has (have) 
been agreed upon by the Investigator and Tris Pharma. Any change agreed upon will be recorded in 
writing, and the written amendment will be signed by the Investigator and Tris Pharma. IRB approval is 
required prior to the implementation of an amendment, unless overriding safety reasons warrant 
immediate action, in which case the IRB(s) will be promptly notified. 


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No deviation from the protocol or investigational plan will be made except to protect the life or physical 
well-being of a subject in an emergency. Except in such emergencies, prior approval of the Sponsor and 
the regulatory authorities (e.g., FDA or the IRB[s] if applicable) is required before deviations from the 
planned protocol. All protocol deviations that occur during the study will be documented and reported to 
Tris Pharma and to the IRB(s), if applicable, according to regulations. Further details about the 
documentation, evaluation, and follow-up of protocol deviations are detailed in this study’s clinical 
monitoring plan. 
 
 


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


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14 REFERENCES 
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5). 
APA Publications, 22 May 2013. 
2. Danielson ML, Bitsko RH, Ghandour RM, et al. Prevalence of parent-reported ADHD diagnosis and 
associated treatment among U.S. children and adolescents. J Clin Child Adolesc Psychiatry. 
2018;47(2):199-212. 
3. Barkley RA, Fischer M, Smallish L, et al. The persistence of attention-deficit/hyperactivity disorder 
into young adulthood as a function of reporting source and definition of disorder. J Abnorm Psychol. 
2002;111:279-289. 
4. Lara C, Fayyad J, DeGraaf R, et al.  Childhood predictors of adult attention-deficit/ hyperactivity 
disorder: results from the World Health Organization World Mental Health Survey Initiative. Biol 
Psychiatry. 2009;65:46-54. 
5. 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. 
6. DeGraaf R, Kessler RC, Fayyad J, et al. The prevalence and effects of adult attention-deficit/ 
hyperactivity disorder on the performance of workers: results from the WHO World Mental Health 
Survey Initiative. Occup Environ Med. 2008;65:835-842. 
7. Barkley RA, Cunningham CE, Gordon M, et al. ADHD symptoms vs. impairment: revisited. ADHD 
Rep. 2006;14:1-9. 
8. Biederman J, Faraone SV, Spencer TJ, et al. Functional impairments in adults with self-reports of 
diagnosed ADHD: a controlled study 1001 adults in the community. J Clin Psychiatry. 2006;67:524-
540. 
9. Kessler R, Adler L, Ames M, et al. The prevalence and effects of adult attention-deficit/ hyperactivity 
disorder on work performance in a nationally representative sample of workers. J Occup Environ 
Med. 2005;47:565-572. 
10. Brown TE. Executive functions and attention-deficit/hyperactivity disorder: implications of two 
conflicting views. Int J Disabil Dev Ed. 2006;53:35-46. 
11. Cox DJ, Merkel MR, Kovatchev B, Seward R. Effect of stimulant medication on driving performance 
of young adults with attention-deficit/hyperactivity disorder: a preliminary double-blind placebo 
controlled trial. J Nerv Ment Dis. 2000;188(4):230-234. 
12. Barkley RA, Cox DJ. A review of driving risks and impairments associated with attention-
deficit/hyperactivity disorder and the effects of stimulant medication on driving performance. J Safety 
Res. 2007;38(1):113-128. 
13. Wolraich M, Brown L, Brown RT, et al. Subcommittee on Attention-Deficit/Hyperactivity Disorder; 
Steering Committee on Quality Improvement and Management. ADHD: clinical practice guideline 
for the diagnosis, evaluation, and treatment of attention-deficit/ hyperactivity disorder in children and 
adolescents. Pediatrics. 2011;128(5):1007-1022. 
14. Pliszka, S, AACAP Working Group on Quality Issues. AACAP Work Group on Quality Issues 
Practice parameter for the assessment and treatment of children and adolescents with attention-
deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921. 


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15. McGough JJ. Treatment controversies in adult ADHD. Am J Psychiatry. 2016;173:960-966. 
16. McCarthy S. Pharmacological interventions for ADHD: how do adolescent and adult patient beliefs 
and attitudes impact treatment adherence? Patient Prefer Adherence. 204;8:1317-1327. 
17. Tris Pharma, Inc. Data on file. 
18. Lawrence L. Greenhill, Betty B. Ossman. Ritalin: Theory and Practice, Second Edition, 2000:405-
430 
19. Silverstein MJ, Faraone SV, Alperin S, et al. Validation of the expanded versions of the Adult ADHD 
Self-Report Scale v1.1 Symptom Checklist and the Adult ADHD Investigator Symptom Rating Scale. 
J Atten Disord. Published online February 8, 2018 (doi: 10.1177/ 1087054718756198. 
20. Jaeger, Judith, PhD, MPA. Digit Symbol Substitution Test: The Case for Sensitivity Over Specificity 
in Neuropsychological Testing. Journal of Clinical Psychopharmacology: October 2018 - Volume 38 
- Issue 5 - p 513–519 
21. 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;1266-1277. 


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APPENDIX A. SCHEDULE OF EVENTS 
Procedure 
Screening 
Period 
(up to 6 
Weeks) 
Baselinea 
 
Visit 
1 
Visit  
2 
Visit  
3 
Visit 
4 
Visit 
5 n 
EOT 
UNS 
Day -1o 
Day 
7o 
Day 14 
o 
Day 21 
o 
Day 
28 o 
Day 
35 o 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
X 
Xb 
Xb 
Height and Weightc 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Laboratory 
Testsd 
X 
 
 
 
 
 
Xm 
Xb 
Xb 
Drug Screening Test 
X 
X 
 
 
 
 
Xm 
 
 
AISRS 
X 
X 
X 
X 
X 
X 
Xm 
Xb 
Xb 
ACDS 
X 
Xe 
 
 
 
 
 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
Xm 
Xb 
Xb 
DSST 
 
X 
 
 
 
 
Xm 
Xb 
Xb 
M.I.N.I. 7.0.2 
X 
Xe 
 
 
 
 
 
 
 
Pregnancy Testh 
X 
X 
 
 
 
 
Xm 
Xb 
Xb 
Vital Signs 
Xf 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
12-Lead ECGi 
X 
 
 
 
 
 
Xm 
 
Xb 
C-SSRSj 
X 
X 
X 
X 
X 
X 
Xm 
X 
X 
Questionnaire for 
Sleep, Appetite, 
Mood, and Psychotic 
Adverse Events 
 
X 
X 
X 
X 
X 
Xm 
Xb 
Xb 
Randomization to 
Study Drug IWRS 
 
X 
 
 
 
 
 
 
 
Drug Dispensing 
 
X 
X 
X 
X 
X 
 
 
 
DB Study Drug 
Titrationk 
 
X 
X 
X 
X 
 
 
 
 
In-House Drug 
Administration 
 
 
 
 
 
X 
X 
 
 
PERMP Placement 
Test 
X 
Xe 
 
 
 
 
 
 
 
PERMP Practicek 
 
X 
X 
X 
X 
 
 
 
 
Abbreviated 
administration of 
serial PERMPs 
 
 
 
 
 
X 
 
 
 
Administration of 
serial PERMPs 
 
 
 
 
 
 
 
X 
 
 
Drug Accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Tris Pharma, Inc. 
Protocol v. 3.1 
TRI108-ADD-400 
 
Confidential 
Page 63 of 67 
 
 
 
 
Procedure 
Screening 
Period 
(up to 6 
Weeks) 
Baselinea 
 
Visit 
1 
Visit  
2 
Visit  
3 
Visit 
4 
Visit 
5 n 
EOT 
UNS 
Day -1o 
Day 
7o 
Day 14 
o 
Day 21 
o 
Day 
28 o 
Day 
35 o 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACDS = Adults ADHD Clinical Diagnostic Scale; AISRS = Adult Investigator Symptom Rating Scale; CGI-I = 
Clinical Global Impression Scale–Improvement; CGI-S = Clinical Global Impression Scale–Severity; DB = Double-
Blind; ECG = electrocardiogram; EOS = end of study; ET = Early Termination Visit; IWRS = Interactive Web 
Response System; M I.N.I. 7.0.2 = Mini International Neuropsychiatric Interview 7.0.2; ; PERMP = Permanent 
Product Measure of Performance; UNS = Unscheduled Visit.  
a A phone call will be done to all eligible subjects within -14 to -7 days to stop stimulants within 7 days of Baseline. 
b To be conducted if requested by the Investigator. 
c Only weight required at Baseline and Visits 1 to 5. 
d Laboratory tests will be done at a central lab. 
e If not done at Screening. 
f BP and Pulse (average of triplicate measurements), Temperature and RR. 
g BP and Pulse (average of triplicate measurements). During Visits 4 and 5 will be taken at pre-dose and 3 hours 
post-dose. 
h Serum Pregnancy Test at Screening; Urine Pregnancy Test at Baseline and at Visit 5. 
i ECGs must be interpreted by a central reader. 
j “Baseline” version at Screening; “Since Last visit” version for subsequent visits. 
k PERMP practice before and after safety and efficacy assessments at Baseline and Visits 1, 2 and 3. 
m Can be conducted at or within 2 days of Visit 5. 
n During Visit 5, subjects who are smokers will be allowed to have up to 3 cigarette breaks. 
o Visit Windows = ±3 days. 
 
 
 


Tris Pharma, Inc. 
Protocol v. 3.1 
TRI108-ADD-400 
 
Confidential 
Page 64 of 67 
 
 
 
 
APPENDIX B. QUESTIONNAIRE FOR SLEEP, APPETITE, MOOD, AND 
PSYCHOTIC ADVERSE EVENTS 
Please ask each of the 4 questions in bold font below at Baseline and Visits 1 to 5. 
• 
If the answer is “no”, circle N and go on to the next question in bold font.  
• 
If the answer is “yes”, circle Y and ask the open-ended questions in normal font, marking the descriptions 
as applicable either Y or N or using the free text box to record verbatim responses. 
 
1. Have you had any changes in your sleeping since your last visit? 
If Yes, please tell me what you have noticed: 
Y 
N 
a. 
Trouble falling asleep  
Y 
N 
b. Trouble staying asleep 
 
Y 
N 
c. 
Decrease in sleep quality  
Y 
N 
d. Improvement in sleep quality  
Y 
N 
e. 
Other: _________________________________________________________________ 
__________________________________________________________________________ 
2. Has your appetite changed since your last visit? 
If Yes, please tell me what you have noticed: 
Y 
N 
a. 
Increased appetite 
Y 
N 
b. Decreased appetite 
 
Y 
N 
c. 
Other:_________________________________________________________________
______________________________________________________________________ 
3. Has your mood been significantly different since your last visit  
If Yes, please tell me what you have noticed: 
Y 
N 
a. 
Feeling down, depressed, or hopeless 
 
Y 
N 
b. Loss of interest or pleasure in doing things  
Y 
N 
c. 
More positive, cheerful, happy mood 
 
Y 
N 
d. Racing thoughts or too much energy 
 
 
Y 
N 
e. 
Other: ________________________________________________________________ 
______________________________________________________________________ 
4. Have you had any strange or unusual thoughts or experiences since your last 
visit? 
If Yes, please tell me what you have noticed: 
Y 
N 
a. 
Odd or unusual things going on that I can’t explain 
 
Y 
N 
b. Something interrupting or controlling my thoughts 
 
Y 
N 
c. 
Others can read my mind 
Y 
N 
d. Fear of people planning or about to hurt me  
Y 
N 


Tris Pharma, Inc. 
Protocol v. 3.1 
TRI108-ADD-400 
 
Confidential 
Page 65 of 67 
 
 
 
 
e. 
Special natural or supernatural gifts  
Y 
N 
f. 
Hearing people talking when there is no one there 
 
Y 
N 
g. Hearing my own thoughts being said out loud 
Y 
N 
h. Concerns that I might be “going crazy” 
Y 
N 
i. 
Other: _________________________________________________________________ 
__________________________________________________________________________ 
Adaptations from: Council on Nutrition Appetite Questionnaire (CNAQ), HAM-D Rating Scale PROMIS SF v1.0 ED-
Depression 8a, PROMIS SF v1.0 – Positive Affect 15a, PROMIS SF v1.0 – Sleep Disturbance 4a, Yale University PRIME 
Screening Test 


Tris Pharma, Inc. 
Protocol v. 3.1 
TRI108-ADD-400 
 
Confidential 
Page 66 of 67 
 
 
 
 
APPENDIX C. REVISION HISTORY 
 
Version 1.0 to Version 2.0 
A major update on the study design was applied to this protocol to reflect 
feedback from the FDA:  
“The study should be randomized and double-blind with parallel groups (i.e., 
not cross-over). Patients should be randomized to treatment or placebo from 
baseline (i.e., no open-label, “dose optimization” period should be included). 
Treatment arms should include fixed doses; a short, double-blind dose-
titration period is acceptable. You should measure pulse, blood pressure, and 
weight at every clinic visit. You should use direct questioning to assess for 
sleep, appetite, mood, and psychotic adverse events rather than relying on 
spontaneous reports.  
The PERMP is an acceptable outcome measure; however, you should describe 
the simulated work environment/testing day in the submitted protocol. 
Additionally, you should use the CGI-Severity at multiple time points to assess 
improvement rather than the CGI-I (which is prone to recall bias). From a 
statistical perspective, we recommend that you pre-specify the estimand and 
provide the rationale for your choice. You should justify that the proposed 
primary efficacy analysis is suitable for the chosen estimand, and pre-specify 
sensitivity analyses for your missing data assumptions.” 
DSST was included as a secondary efficacy assessment.  
Version 2.0 to Version 3.0 
Update to the statistical sections was applied to this protocol to reflect 
feedback from the FDA:  
Efficacy endpoints have been updated.  
ANCOVA was replaced by MMRM for primary and key secondary endpoints 
analyses. 
Sensitivity analysis has been updated to use MI method based on missing not 
at random assumptions to assess impact of potential imbalances in dropouts 
before visit 5. Summary of PERMP-T practice scores to be provided by 
completers/dropouts category to check potential trends. 
Sample size justification has been updated.  
Primary analysis population has been updated to be a modified ITT (mITT) 
population which will include the subjects who have at least one PERMP-T 
score at Visit 5. The primary efficacy analysis and key secondary analysis will 
be conducted on the mITT population.  
Definition of mITT population has been added. 


Tris Pharma, Inc. 
Protocol v. 3.1 
TRI108-ADD-400 
 
Confidential 
Page 67 of 67 
 
 
 
 
Included details on in which circumstances an additional cohort of 18 subjects 
will be added.  
Alcohol restriction has been added (from Baseline to 24 hours after Visit 5).  
Version 3.0 to Version 3.1 
Exclusion criteria #6 updated to :   
“Known history or presence of significant renal or hepatic disease, as 
indicated by clinical laboratory assessment (clinically significant liver function 
tests, blood urea nitrogen, or creatinine levels)”