Conditions: ADHD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 223
Healthy volunteers: no

Brief summary:
The goal of this clinical trial is to evaluate the efficacy and safety of NRCT-101SR compared to placebo in adult patients with ADHD aged 18 years and older.

Detailed description:
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-arm design, laboratory classroom (LC) trial to assess the efficacy and safety of NRCT-101SR compared to inactive placebo for the treatment of ADHD in adults aged 18 years and older.

After Screening, Orientation, and Baseline evaluations are complete, eligible subjects will be randomized into one of two groups (1:1) to receive NRCT-101SR or matching placebo orally twice daily, in the morning and evening, beginning the day after the Baseline visit for 6 weeks. Subjects will receive a fixed dose of 1,500 or 2,000 mg/day, based on lean body mass, split evenly between the morning and evening dosing.

Total subject participation in the study is up to approximately 13 weeks, including a screening period (up to 6 weeks), a 6-week treatment period, and an approximate 1-week follow-up period. Within 8 days prior to Baseline LC visit, subjects will complete an LC Orientation Visit. LC visits will be repeated at Week 3 and Week 6.

The primary outcome measures of the study include Permanent Product Measure of Performance (PERMP) Math Tests (number of correctly answered problems; PERMP-C) and ADHD Investigator Symptom Rating Scale (AISRS). At Baseline, Week 3 visit, and Week 6 visit, serial PERMP Math Tests at pre-dose and at 2, 4, 6, 8, 10, and 12 hours post-dose, and AISRS will be administered. LC visits will be repeated at Week 3 and Week 6. Secondary and exploratory assessments will also be conducted at the Baseline, Week 3, and Week 6 LC visits. A clinic visit will be conducted at Week 1. Pharmacokinetic (PK) sampling will be collected at the Week 3 LC visit. Safety assessments (concomitant medications, adverse events, and suicide risk) will be conducted at all clinic and remote visits/phone calls (Week 5, and follow-up); safety labs will be conducted at screening, Week 3, and Week 6.

Arms:
arm 1: Two-tiered fixed dose of 1,500 or 2,000 mg/day. Two NRCT-101SR tablets (375 mg or 500 mg based on lean body mass) by mouth twice daily arm 2: Two-tiered fixed dose of 1,500 or 2,000 mg/day. Two NRCT-101SR placebo tablets (375 mg or 500 mg based on lean body mass) by mouth twice daily

Interventions: intervention 1: NRCT-101-SR intervention 2: Placebo
Intervention descriptions: intervention 1: NRCT-101SR is a sustained release formulation. Subjects ≥ 50 kg LBM receive a total of four 500 mg tablets/day and subjects \< 50kg LBM receive a total of four 375 mg tablets per day. intervention 2: Matching placebo

Protocol document:
Prot_000.pdf: 
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Protocol Title: Clinical trial to evaluate the safety and efficacy of 
NRCT-101SR in Adult Attention Deficit Hyperactivity Disorder 
 
 
Protocol #: NC-018 
 
Sponsor: 
Neurocentria, Inc 
1855 Olympic Blvd 
Suite 225 
Walnut Creek, CA, USA 94596 
925-954-4868 
www.neurocentria.com 
gbar-klein@neurocentria.com 
 
 
 
 
Version Number: 5.0 
 
 27 February 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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STATEMENT OF COMPLIANCE 
 
Each institution engaged in this research will hold a current Federal Wide 
Assurance (FWA) issued by the Office of Human Research Protection (OHRP) 
for 
federally 
funded 
research. 
The 
Institutional 
Review 
Board 
(IRB)/Independent or Institutional Ethics Committee (IEC) must be registered 
with OHRP as applicable to the research. 
 
The study will be carried out in accordance with the following as applicable: 
 All National and Local Regulations and Guidance applicable at each site 
 The International Council for Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) E6 (R2) Good Clinical 
Practice, and the Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research, Report of the National 
Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research 
 United States (US) Code of Federal Regulations (CFR) 45 CFR Part 46: 
Protection of Human Subjects 
 US Food and Drug Administration (FDA) Regulations: 21 CFR Part 50 
(Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by 
Clinical Investigators), 21 CFR Part 56 (IRBs), 21 CFR Part 11, and 21 
CFR Part 312 (Investigational New Drug Application), and/or 21 CFR 812 
(Investigational Device Exemptions) 
 
 
The signature below provides the necessary assurance that this study will be 
conducted according to all stipulations of the protocol including statements 
regarding confidentiality, and according to local legal and regulatory 
requirements, US federal regulations, and ICH E6(R2) GCP guidelines. 
 
 
Site Investigator Signature: 
 
 
 
Signed:                                                                  Date:   
 
Name and Title 
 
 
 
 
 
 


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Table of Contents 
List of Abbreviations and Definitions of Terms ..................................................................... 8 
1.0 PROTOCOL SYNOPSIS ............................................................................................... 12 
1.1 Rationale for Proposed Clinical Study ....................................................................... 12 
1.2 Study Design............................................................................................................... 13 
1.3 Study Schema ............................................................................................................. 14 
1.4 Study Objectives and Endpoints ................................................................................. 14 
1.4.1 Primary Objective ................................................................................................ 14 
1.4.2 Key Secondary Objectives................................................................................... 14 
1.4.3 Other Secondary Objectives ................................................................................ 14 
1.4.4 Exploratory Objectives ........................................................................................ 15 
1.4.5 Pharmacoeconomic objective .............................................................................. 15 
1.4.6 Safety Objective .................................................................................................. 15 
1.4.7 Study Endpoints ................................................................................................... 15 
1.5 Study Population......................................................................................................... 17 
1.5.1 Inclusion Criteria ................................................................................................. 17 
1.5.2 Exclusion Criteria ................................................................................................ 18 
1.6 Prior and Concomitant Medications ........................................................................... 20 
1.7 Study Phase................................................................................................................. 22 
1.8 Study Sites .................................................................................................................. 22 
1.9 Study Intervention ...................................................................................................... 22 
1.10 Study Duration .......................................................................................................... 23 
1.11 Schedule of Events ................................................................................................... 24 
Table S1 – Schedule of Events ..................................................................................... 24 
2.0 INTRODUCTION .......................................................................................................... 27 
2.1 Background ................................................................................................................. 27 
2.2 Study Rationale........................................................................................................... 28 
2.3 Study Population......................................................................................................... 29 
2.4 Dose Rationale ............................................................................................................ 29 
2.5 Study Endpoint Rationale ........................................................................................... 30 
2.5.1 Dual Primary Outcome Measures ........................................................................ 30 
2.6 Risks and Benefits for Subjects .................................................................................. 31 
3.0 STUDY OBJECTIVES AND ENDPOINTS ................................................................. 31 
3.1 Study Objectives ......................................................................................................... 31 
3.1.1 Primary Objective ................................................................................................ 31 
3.1.2 Key Secondary Objectives................................................................................... 31 
3.1.3 Other Secondary Objectives ................................................................................ 32 
3.1.4 Exploratory Objectives ........................................................................................ 32 
3.1.5 Pharmacoeconomic objective .............................................................................. 32 
3.1.6 Safety Objectives ................................................................................................. 32 
3.2 Study Endpoints .......................................................................................................... 33 
3.2.1 Primary Efficacy Endpoints................................................................................. 33 
3.2.2 Key Secondary Efficacy Endpoints ..................................................................... 33 
3.2.3 Other Secondary Endpoints ................................................................................. 33 




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5.0 ADVERSE EVENT REPORTING ................................................................................ 63 
5.1 Definitions and Criteria .............................................................................................. 63 
5.1.1 Adverse Events .................................................................................................... 63 
5.1.2 Serious Adverse Events ....................................................................................... 64 
5.1.3 Unexpected Adverse Reactions ........................................................................... 64 
5.1.4 Abnormal Laboratory Values .............................................................................. 65 
5.2 Assessing Intensity and Relationship ......................................................................... 65 
5.2.1 Intensity ............................................................................................................... 65 
5.2.2 Relationship ......................................................................................................... 66 
5.3 Reporting Procedures and Requirements ................................................................... 67 
5.3.1 Adverse Events .................................................................................................... 67 
5.3.2 Serious Adverse Events ....................................................................................... 67 
5.3.3 Pregnancy ............................................................................................................ 68 
6.0 DATA MANAGEMENT AND STATISTICAL ANALYSIS ...................................... 69 
6.1 Data Management Considerations .............................................................................. 69 
6.1.1 Data Clarification ................................................................................................ 69 
6.2 Statistical Considerations ........................................................................................... 69 
6.2.1 Statistical Methods .............................................................................................. 70 
6.2.2 Power/Sample Size Analysis ............................................................................... 70 
6.2.3 Analysis Populations ........................................................................................... 71 
6.2.4 Protocol Deviations ............................................................................................. 71 
6.2.5 Subject Disposition .............................................................................................. 71 
6.2.6 Demographic and Baseline Characteristics ......................................................... 71 
6.2.7 Measurement of Study Drug Compliance ........................................................... 71 
6.3 Efficacy Analyses ....................................................................................................... 72 
6.3.1 Dual Primary Estimand #1 PERMP-C ................................................................ 72 
6.3.2 Dual Primary Estimand #2 AISRS ...................................................................... 72 
6.3.3 Primary Efficacy Endpoint – PERMP-C and AISRS .......................................... 73 
6.3.5 Missing Data Imputation ..................................................................................... 74 
6.3.6 Secondary Efficacy Analysis ............................................................................... 75 
6.3.7 Other Endpoints ................................................................................................... 75 
6.3.8 Sensitivity and Supportive Analyses ................................................................... 76 
6.3.9 Multiplicity .......................................................................................................... 76 
6.4 Safety Analyses .......................................................................................................... 76 
6.4.1 Extent of Exposure .............................................................................................. 77 
6.4.2 Adverse Events .................................................................................................... 77 
6.4.3 Electrocardiographic Data ................................................................................... 77 
6.4.4 Vital Signs ........................................................................................................... 77 
6.4.5 C-SSRS ................................................................................................................ 78 
6.4.6 Laboratory Data ................................................................................................... 78 
6.5 PK Analysis ................................................................................................................ 78 
6.6 Interim Analyses ......................................................................................................... 78 
7.0 STUDY MANAGEMENT ............................................................................................. 78 
7.1 Ethics and Consent ..................................................................................................... 78 
7.1.2 Regulations and Guidelines ................................................................................. 78 


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7.1.3 Institutional Review Board/Independent Ethics Committees .............................. 78 
7.1.4 Informed Consent ................................................................................................ 79 
7.2 IRB and Investigator Responsibilities: ....................................................................... 79 
7.3 Confidentiality ............................................................................................................ 80 
7.4 Discontinuation of the Study by the Sponsor ............................................................. 80 
7.5 Study Documentation ................................................................................................. 80 
7.6 Study Monitoring and Auditing .................................................................................. 80 
7.7 Retention of Records .................................................................................................. 81 
7.8 Use of Study Findings ................................................................................................ 81 
8.0 REFERENCES ............................................................................................................... 82 
 
 
List of Figures 
Figure 1 - Study Schema ............................................................................................................................. 35 
 
List of Tables 
Table S1 – Schedule of Events ................................................................................................................... 24 
Table 1 - Details of Study Drug .................................................................................................................. 44 
Table 2 - Dosage Schedule by 
 ............................................. 45 
Table 3 - Schedule of Events ...................................................................................................................... 49 
Table 4 - Criteria for Intensity Grading of Adverse Events (CTCAE Severity Grading) ........................... 65 
Table 5 - Criteria used for Determining Causality of Adverse Events to Study Drug Administration ....... 66 
 
 


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List of Abbreviations and Definitions of Terms 
 
Abbreviation 
Definition 
AAQoL 
Adult ADHD Quality of Life scale 
ADHD 
Attention Deficit Hyperactivity Disorder 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AISRS 
ADHD Investigator Symptom Rating Scale 
ALT 
Alanine Aminotransferase (Serum Glutamic Pyruvic 
Transaminase) 
ANCOVA 
Analysis of Covariance 
API 
Active pharmaceutical ingredient 
ASRS 
ADHD Self Report Scale 
AST 
Aspartate Aminotransferase (Serum Glutamic 
Oxaloacetic Transaminase) 
AUC 
Area Under Curve 
bpm 
Beats Per Minute 
BRIEF-A 
Behavior Rating Inventory Executive Function for Adults 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
bw 
Total Body Weight 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CBC 
Complete Blood Count  
CDR-SB 
Clinical Dementia Rating- Sum of Boxes 
CGI-S 
Clinical Global Impression - Severity 
CNS 
Central Nervous System 
CO2 
Carbon Dioxide 
CPK 
Creatine Phosphokinase 
Cr 
Creatinine 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVD 
Cardiovascular Disease 
DDI 
Drug-drug interaction 


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DMN 
Default Mode Network 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EF 
Executive Function 
ET 
Early Termination 
eGFR 
Estimated glomerular filtration rate 
eGFRcorr 
Corrected estimated glomerular filtration rate  
EOS 
End of Study 
F 
Fahrenheit 
FAD 
Full Analysis Dataset 
FCSRT 
Free and Cued Selective Reminding Test 
FDA 
Food and Drug Administration 
g 
Gram 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
h 
Hour 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
Hemoglobin A1c 
Hct 
Hematocrit 
HDL 
High-Density Lipoprotein 
HDPE 
High Density Polyethylene 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ID 
Identification 
IEC 
Independent Ethics Committee 
IL-6 
Interleukin-6 
IND 
Investigational New Drug 


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IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat (Dataset) 
IU 
International Units 
iv 
Intravenous 
IRT 
Interactive Response Technology 
kg 
Kilogram 
LAR 
Legally Authorized Representative 
 
 
LC 
Laboratory Classroom 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 
LM II 
Logical Memory II 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mg 
Milligram 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
 
 
MINI 
Mini International Neuropsychiatric Interview 
mIU 
Milli International Unit 
MITT 
Modified Intent-To-Treat 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeters of mercury 
MMRM 
Mixed Model for Repeated Measures 
MOP 
Manual of Operations 
MPV 
Mean Platelet Value 
MRI 
Magnetic Resonance Imaging 
msec 
Millisecond 
NCS 
Not Clinically Significant 
NNT 
Number Needed to Treat 
NSAE 
Non-Serious Adverse Event 
NSAID 
Non-Steroidal Anti-Inflammatory Drugs 


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PACC 
Preclinical Alzheimer’s Cognitive Composite 
PCRS 
Placebo Control Reminder Script 
PERMP 
Permanent Product Measure of Performance 
PFC 
Prefrontal Cortex 
PHI 
Protected Health Information  
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per-Protocol  
 
 
 
PTSD 
Post-Traumatic Stress Disorder 
QTc 
Corrected QT interval 
r 
Pearson’s Correlations Coefficient 
RBC 
Red Blood Cells 
RDW 
Red Blood Cell Distribution Width 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TIA 
Transient Ischemic Attack 
sTNFRII 
Soluble Tumor Necrosis Factor Receptor 2 
UAR 
Unexpected Adverse Reaction 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
UPSA 
UCSD Performance-Based Skills Assessment 
US 
United States 
WASI-II 
Wechsler Abbreviated Scale of Intelligence 
WBC 
White Blood Cells 
 
 
 
 




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1.2 Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-arm design, 
laboratory classroom (LC) trial to assess the efficacy and safety of NRCT-101SR 
 
 compared to inactive placebo over a 6-
week period in approximately 216 subjects ≥ 18 years of age with ADHD. Study population will 
include adult male and female subjects of all race/ethnicity with ADHD, recruited from sites across 
the US. All subjects will either be naïve to stimulant or non-stimulant ADHD medications, or prior 
to enrollment, have been off stimulants for at least 2 weeks and non-stimulants for at least 3 weeks.  
Total subject participation in the study is up to approximately 13 weeks, including a screening 
period (up to 6 weeks), a 6-week treatment period, and an approximate 1-week follow-up period. 
Each study subject will be randomized into one of two groups (1:1) to receive either active drug 
or placebo during the entirety of the 6-week treatment period. Within 8 days of Baseline LC visit, 
subjects will complete an LC Orientation Visit. At the Baseline LC visit, subjects will be 
randomized, assigned to a group, and dispensed study drug (first dose to be taken the next 
morning). The primary endpoints of the study include Permanent Product Measure of Performance 
(PERMP) Math Tests and the ADHD Investigator Symptom Rating Scale (AISRS). To familiarize 
the subjects with the PERMP, prior to the Baseline LC visit, they will complete 8 practice PERMP 
assessments (3 at screening and 5 at the LC Orientation visit). LC visits will be repeated at Week 
3 and Week 6. Secondary and exploratory assessments will also be conducted at the Baseline, 
Week 3, and Week 6 LC visits. A clinic visit will be conducted at Week 1 to administer AISRS 
with expanded version, HADS, and BRIEF-A. Safety assessments (concomitant medications, 
adverse events, and suicide risk) will be conducted at all clinic and remote visits/phone calls (Week 
5, and follow-up); safety labs will be conducted at screening, Week 3, and Week 6. For population 
PK analysis, PK sampling will be conducted at the Week 3 LC visit. Blood samples for PK will 
be collected prior to dosing, at 4 hours and 7 hours after dosing (with a 30-minute window). See 
Study Schema and Schedule of Events below. 
The primary analysis will be on effects of 6-week treatment of NRCT-101SR versus placebo on 
performance and ADHD core symptoms in subjects with adult ADHD. The dual primary endpoints 
are PERMP (performance) and AISRS (core symptoms). The study will be declared successful by 
reaching statistical significance on either primary endpoint with adjustment for multiplicity.  
Randomization will be stratified by:  
 Site 
 LC Cohort 
 Sex (approximately equal number of male and female in the study) 
 
 
 


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1.3 Study Schema 
 
  
      
1.4 Study Objectives and Endpoints 
1.4.1 Primary Objective  
1. To determine if treatment with NRCT-101SR improves objective performance and/or 
reduces core symptoms in adult subjects with ADHD compared to placebo as assessed 
by the change from baseline in the PERMP and AISRS at Week 6. The trial will be 
declared successful by reaching statistical significance on either primary endpoint. 
1.4.2 Key Secondary Objectives 
1. To determine if treatment with NRCT-101SR reduces executive function symptoms in 
adult subjects with ADHD compared to placebo as assessed by the change from 
baseline in the BRIEF-A at Week 6 
2. To determine if treatment with NRCT-101SR reduces neuropsychiatric symptoms 
(anxiety and depression) in adult subjects with ADHD compared to placebo as assessed 
by the change from baseline in the HADS at Week 6 
1.4.3 Other Secondary Objectives 
1. To determine if NRCT-101SR treatment has rapid-acting effects on reducing core 
symptoms in adult subjects with ADHD compared to placebo as assessed by the change 
from baseline in the AISRS at Week 1 
2. To determine if NRCT-101SR treatment has same-day effects on improving objective 
performance in adult subjects with ADHD compared to placebo as assessed by change 
from pre-dose timepoint in PERMP at Week 6 


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3. To determine if treatment with NRCT-101SR improves quality of life in adult subjects 
with ADHD compared to placebo as assessed by the change from baseline in the 
AAQoL at Week 6 
4. To determine if treatment with NRCT-101SR reduces disease severity in adult subjects 
with ADHD compared to placebo as assessed by the change from baseline in the CGI-
S at Week 6 
5. To evaluate responder rate with NRCT-101SR compared to placebo as assessed by 
AISRS response and change from baseline in CGI-S at Week 6 
6. To assess the population pharmacokinetics of NRCT-101SR in ADHD subjects 
7. To determine if treatment with NRCT-101SR improves objective performance and/or 
reduces core symptoms in adult subjects with ADHD compared to placebo as assessed 
by the change from baseline in the AISRS Expanded Version at Week 6 
1.4.4 Exploratory Objectives 
1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1.4.5 
 objective 
1. 
 
 
 
 
 
1.4.6 Safety Objective  
1. To evaluate the safety and tolerability of NRCT-101SR compared to placebo as 
assessed by the incidence of adverse events, vital sign measurements, clinical 
laboratory evaluations, electrocardiogram (ECG) parameters, proportion of subjects 
who discontinue from the study due to any adverse event (tolerability), and the 
Columbia Suicide Severity Rating Scale (C-SSRS) 
1.4.7 Study Endpoints 
All primary and secondary endpoints will be evaluated as the difference between NRCT-
101SR and placebo following the 6-week treatment period unless as noted. 
 


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1.4.7.1 Primary Efficacy Endpoints  
1. Objective Performance: Permanent Product Measure of Performance – Correct 
(PERMP-C) 
2. Core Symptoms: ADHD Investigator Symptom Rating Scale (AISRS) 
 
1.4.7.2 Key Secondary Efficacy Endpoints 
1. Cognition 
 Subjective Executive Function: Behavior Rating Inventory of Executive Function 
– Adult Version (BRIEF-A)  
2. Neuropsychiatric Symptoms 
 Hospital Anxiety and Depression Scale (HADS) 
 
1.4.7.3 Other Secondary Endpoints 
1. Core Symptoms 
 AISRS Expanded Version at Week 6 
2. Clinician Rated Scales 
 Clinical Global Impression - Severity (CGI-S) 
3. Responder Rate 
 The proportion of responders (≥ 25% reduction of AISRS and ≥ 2-point 
reduction of CGI-S from baseline to Week 6)  
4. Subjective Subject Rated Symptoms Scales 
 Adult ADHD Quality of Life scale (AAQoL) 
5. Population PK 
 
Plasma levels of NRCT-101 
for PK modeling in ADHD subjects 
 
1.4.7.4 Exploratory Efficacy Endpoints 
1. 
 
 
 
 
 
  
 
 




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7. Hearing and Vision ability sufficient to complete cognitive testing, in investigator’s 
opinion 
8. Willing and able to give informed consent 
9. Total Body weight (bw) ≥ 50 kg and ≤ 120 kg 
 
 
10. Naïve to stimulant or non-stimulant medications used for the treatment of ADHD or 
have discontinued stimulants at least 2 weeks and non-stimulants at least 3 weeks prior 
to randomization 
1.5.2 Exclusion Criteria 
Exclusions to rule out subjects with impairment likely due to something other than 
 
ADHD: 
11. Subject is functioning below an age-appropriate level intellectually, as judged by the 
investigator. 
12. Lifetime history of severe psychiatric symptoms of major depression requiring 
hospitalization, bipolar disorder, schizophrenia of schizoaffective disorder, 
hallucinations, or delusions. Severe comorbid disorders such as PTSD, severe 
obsessive-compulsive disorder, or other symptomatic presentation that, in the opinion 
of the examining physician, will contraindicate NRCT-101SR treatment or confound 
efficacy or safety assessments. Subjects with mild to moderate forms of social phobia 
or dysthymia, for instance, may be included. 
13. History of seizures (other than infantile febrile seizures), any tic disorder (except 
transient tic disorder and subject has no episodes for at least 1 year), or a current 
diagnosis of Tourette’s Disorder.  
14. Recent history (within the past 1 year) of suspected substance abuse or dependence 
disorder (excluding stable nicotine use) in accordance with DSM-5 criteria. (Note: 
subject’s average nicotine use should not be exceeded during each LC visit)  
15. Current abnormal thyroid function as defined as abnormal screening thyroid 
stimulating hormone. Treatment for at least 3 months with a stable dose of thyroid 
medication is permitted. 
Exclusions to rule out subjects with potential issues absorbing or metabolizing 
 
NRCT-101SR: 
16. Poor kidney function; corrected estimated glomerular filtration rate (eGFRcorr) 
< 40 mL/min/m2 


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17. History of significant gastrointestinal disorders, such as chronic diarrhea, irritable 
bowel syndrome, ulcerative colitis, Crohn’s disease, etc.  
Exclusions to rule out subjects with conditions that could affect their safety: 
18. Female subjects who are pregnant and/or lactating 
19. A "yes" answer to "suicidal ideation" item 4 (active suicidal ideation with some intent 
to act, without specific plan) or item 5 (active suicidal ideation with specific plan and 
intent) on the C-SSRS assessment at screening (in the past 12 months). 
20. Has history of severe drug allergy or hypersensitivity to the study medication or its 
excipients.  
21. Hypermagnesemia; magnesium > 2.5 mg/dL 
22. Reproduction: 
a. Females of childbearing potential (FOCP) must be either sexually inactive 
(abstinent) or, if sexually active, must agree to use one of the following 
acceptable birth control methods beginning 30 days prior to the first dose of 
study drug and throughout the study: 
i. 
Simultaneous use of male condom and intra-uterine contraceptive device 
placed at least 4 weeks prior to first study drug administration 
ii. 
Surgically sterile male partner 
iii. 
Simultaneous use of male condom and diaphragm with spermicide 
iv. 
Established hormonal contraceptive 
b. Males must: 
i. 
Use 2 methods of contraception in combination if his female partner is of 
childbearing potential; this combination of contraceptive methods must be 
used from the Baseline Visit to ≥ 1 month after the last dose of study drug, 
or 
ii. 
Have been surgically sterilized prior to the Screening Visit. 
Exclusions to rule out subjects with conditions that could inhibit or confound the 
 
effects of NRCT-101SR or the ability of the subject to complete the study: 
23. Is currently participating in another clinical trial or has participated in a clinical trial 
within 30 days prior to the Screening Visit. 


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24. Currently living in an institutional facility such as a nursing home 
25. Severe physical disability not associated with cognitive function that limits ability to 
complete testing (e.g., severe tremor, debilitating arthritis, etc.) 
26. Known history of symptomatic cardiac disease, advanced atherosclerosis, structural 
cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary 
heart disease, transient ischemic attack or stroke or other serious cardiac problems. 
27. Known family history of sudden cardiac death or ventricular arrhythmia. 
28. Serious or unstable clinically important systemic illness or disease that, in the judgment 
of the investigator, is likely to affect cognitive assessment, deteriorate, or affect the 
subject's safety or ability to complete the study, including hepatic (e.g., Child-
Pugh grade C), renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, 
immunologic, infectious, or hematologic disorders 
29. Has previously participated in a NRCT-101SR / 
 investigational study 
30. Investigators and their immediate family members are not permitted to participate in 
the study. 
31. Consumes more than a weekly average of: 2 drinks / day or more than 3 drinks in any 
day for males; 1 drink / day or more than 2 drinks in any day for females 
32. Changes in medications or doses of medication as follows: 
a. All allowed concomitant medications, supplements, or other substances must 
be at stable doses for at least 30 days prior to screening and must be kept as 
stable as medically possible during the trial. For allowed concomitant 
medications, any dosing change within 30 days of Screening may be allowed 
if, in the opinion of the investigator, it will not affect or influence study results. 
1.6 Prior and Concomitant Medications 
Prior treatments, defined as any treatment taken within 3 months or any ADHD drug taken within 
6 months before screening, are to be recorded in the electronic case report form (eCRF) as prior 
medications. Concomitant treatments, defined as treatments taken after the first dose of study drug, 
are to be recorded in the eCRF as concomitant medications. 
If a change in medication dosage occurs during the study it may lead to discontinuation from study 
participation unless it relates to a medication that, in the view of the study investigator and in 
consultation with the medical monitor, does not affect the subject’s participation in the trial or the 
study results. Any medication or therapy that is taken by or administered to the subject during the 
study should be recorded in the eCRF. The entry must include the dose, regimen, route, indication, 
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After randomization, medication(s) to treat minor treatment-emergent illness(es) is generally 
permitted and subjects may be allowed to continue in the study after being evaluated by the 
clinician and discussed with the Sponsor. However, for certain classes of drugs (listed below; not 
inclusive of every drug and brand or generic name), subjects must follow dosing guidelines listed 
below (i.e., restricted medications/substances) and before Baseline visit and throughout the study, 
must not take ADHD stimulants for at least 2 weeks, ADHD non-stimulants for at least 3 weeks, 
and other prohibited substances for at least 4 weeks (or as listed below). Any subject taking these 
substances during the study will be evaluated by the Clinician (to be discussed with Sponsor) for 
ability to continue in the study. 
Substance use will be collected in the eCRF at screening to document the subjects previous and 
current use of cannabis, nicotine/tobacco, caffeine, opioids, sedatives, and hypnotics. During LC 
days, caffeine is limited to one cup of coffee/caffeinated drink in the morning and one caffeinated 
drink at meals. 
The following are classes of medication used for treatment of ADHD and comorbid disorders that 
are prohibited during the study: 
 Classical drugs (CNS stimulants), including: 
o Amphetamines, Adderall, Dexamphetamine, Lisdexamphetamine, 
Methamphetamine, Methylphenidate, Dexmethylphenidate 
 Non-classical drugs (non-stimulant), including: 
o Atomoxetine, Modafinil, Viloxazine ER 
 α2 adrenoceptor agonists (non-stimulant), including: 
o Clonidine, Guanfacine 
 Any Antidepressants / Anxiolytics / antipsychotics, such as (but not limited to): 
o Selective Serotonin Reuptake Inhibitor (SSRI), Amitriptyline, Bupropion, 
Buspirone, Clomipramine, Desipramine, Duloxetine, Imipramine, Milnacipran, 
Moclobemide, Nortriptyline, Reboxetine, Selegiline, Venlafaxine 
 Miscellaneous other drugs 
o NMDA receptor blockers, such as Amantadine and Memantine-containing drugs 
(e.g., Namenda®) 
o Mood stabilizers (for example, Carbamazepine, Valproate, lithium, and 
Lamotrigine) 
Other prohibited/restricted medication/substances 
 
Marijuana / cannabinoids 
 
Alcohol  
o Men: greater than weekly average of 2 drinks / day or more than 3 drinks in any 
day  






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1.11 Schedule of Events 
 
Table S1 – Schedule of Events 
Schedule of Events   
Screening  
LC 
Orientation 
 
Baseline  
(LC) 
 
Week 1 
(clinic) 
Week 3 
(LC) 
Weeks 5 
(remote) 
Week 6  
or ET 
(LC) 
Week 7 
Follow-up 
(remote) 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
 Day 
Day -42 to -2 
Day -8 to -1 
Day 1 
 
Day 8  
(+/- 1 day) 
Day 22  
 
Day 36 (+/-
3 days) 
Day 43  
Day 50  
(+/- 2 day) 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics & 
Medical History 
X 
 
 
 
 
 
 
 
Substance Abuse 
History 
X 
 
 
 
 
 
 
 
Prior/Concomitant 
Meds 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
X 
 
X 
 
X 
 
MINI with DSM-5 
probes 
X 
 
 
 
 
 
 
 
Vital Signs 
including weight 
X 
X 
X 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
Safety Labs/ 
Urinalysis 
X 
 
Xf 
 
X 
 
X 
 
Urine pregnancy  
X 
 
X 
 
 
 
 
 
Urine Drug Screen 
X 
 
X 
 
X 
 
X 
 




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Schedule of Events   
Screening  
LC 
Orientation 
 
Baseline  
(LC) 
 
Week 1 
(clinic) 
Week 3 
(LC) 
Weeks 5 
(remote) 
Week 6  
or ET 
(LC) 
Week 7 
Follow-up 
(remote) 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
 Day 
Day -42 to -2 
Day -8 to -1 
Day 1 
 
Day 8  
(+/- 1 day) 
Day 22  
 
Day 36 (+/-
3 days) 
Day 43  
Day 50  
(+/- 2 day) 
Study Drug 
Dispensation 
 
 
X 
 
X 
 
Xe 
 
Study Drug 
Accountability 
 
 
 
 
X 
 
X 
 
ET = early termination;  LC = Laboratory Classroom; AISRS = ADHD Investigator Symptom Rating Scale; ECG = electrocardiogram; 
CGI-S = Clinician Global 
Impression – Severity; 
 AAQoL = adult ADHD Quality of Life;  BRIEF-A = Behavior Rating 
Inventory of Executive Function – Adult; HADS = Hospital Anxiety and Depression Scale; C-SSRS = Columbia Suicide Severity Rating Scale; 
PERMP = Permanent Product Measure of Performance; PK = Pharmacokinetic (samples collected pre-dose and post-dose); 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  


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2.0 INTRODUCTION 
2.1 Background 
Attention-Deficit/Hyperactivity 
Disorder 
(ADHD) 
is 
considered 
a 
common neurodevelopmental disorder. Individuals with ADHD are characterized by difficulties 
in attention, impulsive behaviors, and overactivity. These manifestations are widely considered as 
the ‘core symptoms’ of ADHD. Other common challenges include deficits in cognitive 
performance, executive dysfunction, and dysfunctional emotional regulation (Shanahan, 
Pennington et al. 2006, Katzman, Bilkey et al. 2017, Claesdotter, Cervin et al. 2018, Silverstein, 
Faraone et al. 2020). 
In most cases, ADHD is first diagnosed in childhood and symptoms often carry into adulthood. 
The estimated prevalence of adult ADHD in the US is 4.4% (~11M), with more males than females 
(5.4% and 3.2%, respectively) (Kessler, Adler et al. 2006). Worldwide adult ADHD prevalence is 
assessed to be 3.4% (Fayyad, De Graaf et al. 2007). While the cause and risk factors for ADHD 
remain unknown, it is evident that genetics play an important role (Thapar and Stergiakouli 2008). 
Other factors found to be associated with ADHD include brain injury, exposure to hazardous 
materials during pregnancy or at a young age, alcohol and tobacco use during pregnancy, 
premature delivery, and low birth weight. 
Current treatments for adult ADHD are similar to treatments for childhood ADHD. The available 
pharmacological treatments are categorized as stimulants and non-stimulants, with the former 
considered as the first-line. Stimulants are designed to increase dopamine and norepinephrine 
neurotransmission, and include non-specific monoamine reuptake inhibitors (e.g., Adderall and 
amphetamine) and norepinephrine-dopaminergic reuptake inhibitors (e.g., Ritalin and Focalin). 
Non-stimulants are designed to act on norepinephrine neurotransmission and include 
norepinephrine reuptake inhibitor (Atomoxetine) and α-2 adrenergic receptor agonists (e.g., 
Clonidine and Guanfacine).  
Generally, stimulants (both short- and long-acting) are known for improving core ADHD 
symptoms in 65%–75% of patients in all age groups (Pliszka 2009). However, their efficacy varies 
between patients, requiring trying multiple medications and doses (Kolar, Keller et al. 2008). 
Non-stimulants normally do not generate immediate effects and require a longer treatment period 
before improving symptoms. Generally, they are significantly less effective than stimulants in 
reducing core ADHD symptoms (Wigal, McGough et al. 2005, Wietecha, Clemow et al. 2016). 
Non-stimulants, however, specifically atomoxetine, may improve quality of life (Adler, Spencer 
et al. 2009). 
Treatment discontinuation rate is circa 30% (Steer 2005), and only 11% of adults with ADHD are 
treated. The main reasons patients lack treatments are tolerability issues and social stigma; side 
effects of stimulants are a major concern for patients and include insomnia (32%), 
anorexia/decreased appetite (32%), headache (30%), and nervousness (26%) (Biederman, Spencer 
et al. 2005, Wolraich, Hagan et al. 2019) (Greenhill, Pliszka et al. 2001). Mild increase in blood 
pressure and pulse were also documented in individuals treated with stimulants, generally found 


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not to be clinically significant. However, for adults with borderline hypertension or other 
cardiovascular disease, such adverse effects could impose health risk. 
Non-stimulant side-effects include sleepiness, headaches, fatigue, stomachaches, nausea, erectile 
dysfunction, and in some medications may increase seizure probability (Kolar, Keller et al. 2008, 
Adler, Spencer et al. 2009). 
Considering the shortcomings of the current medications, including their substantial side effects, 
there is a need for new drugs that will improve ADHD core symptoms, executive function and 
overall cognitive performance, and emotional regulation with a good tolerability profile. 
2.2 Study Rationale 
NRCT-101SR is being developed for patients with neurological disorders, including 
neuropsychiatric disorders and cognitive decline. Studies conducted over the last two decades 
demonstrated that prefrontal cortex (PFC) dysfunction, underlined by glutamatergic synapse 
dysfunction, play a critical role in the pathophysiology of neuropsychiatric disorders, including 
Attention Deficit Hyperactivity Disorder (ADHD) (Opel, Goltermann et al. 2020) (Seidman, 
Biederman et al. 2011) (Duman, Aghajanian et al. 2016) (Zarate, Singh et al. 2006) (Duman 2014). 
In this regard, the active pharmaceutical ingredient (API) of NRCT-101-SR – 
 
 clinical code: NRCT-101) has been shown to increase synaptic density 
and the number of functional presynaptic release sites, while reducing release probability in the 
PFC. Systemically, NRCT-101 treatment leads to the enhancement of learning ability, working 
memory, and short- and long-term memory in young rats, reverses cognitive impairment in aged 
rats (Slutsky, Abumaria et al. 2010), and improves emotional regulation (Abumaria, Yin et al. 
2011, Abumaria, Luo et al. 2013). 
In a preliminary efficacy study conducted at the Massachusetts General Hospital (MGH) in adult 
ADHD subjects, NRCT-101 was shown to significantly reduce core symptoms of ADHD (AISRS 
and ASRS). This 12-week, single-site, open-label trial included relatively few subjects (17 enrolled 
and 15 in efficacy population). Importantly, NRCT-101 administration significantly improved 
overall function (Global Assessment of Function) and cognition, using both objective (WASI-II 
and CANTAB) and self-reported measurements (global executive function: BRIEF-A). Effects of 
NRCT-101 
 were observed by the first time point at 3 weeks and maintained through 
the end of study at 12 weeks. 
Many ADHD symptoms are problems with executive function and emotional regulation. From 
five preliminary single-site clinical trials in other patient populations with neuropsychiatric 
symptoms and/or varying degrees of cognitive impairment, NRCT-101SR was shown to improve 
emotional regulation in less than 1 week. Importantly, NRCT-101SR also improved executive 
function. 
Overall, the preliminary studies show that NRCT-101SR has a strong tolerability and safety 
profile, with a safety database of more than 200 subjects enrolled in studies with NRCT-101 (L-
TAMS) to date. 
Study NC-018 will evaluate the efficacy of NRCT-101SR in approximately 216 adult ADHD 




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2.5 Study Endpoint Rationale 
2.5.1 Dual Primary Outcome Measures 
The primary objectives of the study are to evaluate the clinical efficacy of NRCT-101SR versus 
placebo on objective performance and/or ADHD core symptoms. The study will be declared 
successful by reaching statistical significance on either primary endpoint with adjustment for 
multiplicity.  
2.5.1.1 PERMP-C 
Objective performance will be evaluated with the permanent product measure of performance 
(PERMP), a validated performance-based objective measure of attention and function. It is the 
standard primary outcome measure for most adult LC studies and is accepted by the FDA for 
assessing efficacy of an investigational new drug for ADHD (FDA 2019, Wigal 2019). PERMP 
Math Test covers at least five symptoms of ADHD related to attention and executive function, 
including initiation of activity, careless mistakes, failure to finish, easily distracted, unsustained 
attention, and avoidance of mentally effortful tasks. These cover symptoms likely to be improved 
by 
 Because PERMP is an objective measure with a quantifiable result, it should have 
reduced variability and increased sensitivity relative to other subjective measures. PERMP-correct 
(PERMP-C), which is the number of correctly answered math problems will serve as the primary 
analysis for efficacy. PERMP-attempted (PERMP-A) will also be collected and will be used to 
calculate PERMP-Total (PERMP-T), which is the sum of PERMP-C and PERMP-A. PERMP-A 
and PERMP-T will be analyzed as exploratory measures.  
PERMP will be collected in an LC setting, an FDA-approved method (Wigal 2019, Childress, 
Cutler et al. 2022, Cutler, Childress et al. 2022). It provides a controlled environment in which 
ADHD symptoms are likely to occur, to allow for measurement of onset and reduction of 
symptoms throughout the day.  
PERMP will be administered at Baseline, Week 3, and Week 6 LC visits. At each visit, there will 
be a pre-dose assessment followed by 6 assessments at hours 2, 4, 6, 8, 10, and 12-hours post-dose. 
To ensure subjects are sufficiently familiar with the administration of PERMP and to limit learning 
effects, practice PERMP tests will be administered at Screening visit (3x), and at an LC Orientation 
visit (5x). 
PERMP-C will also be evaluated at Week 6 at each time point relative to the pre-dose timepoint 
to evaluate effects throughout the day. 
2.5.1.2 AISRS 
In addition to assessment of function, this study will also evaluate the effects of NRCT-101SR on 
reducing core symptoms of ADHD. The AISRS is an FDA-accepted clinician rated scale that 
assesses the core ADHD symptoms listed in DSM-5 (FDA 2019). It covers both inattentive 
symptoms and hyperactive/impulsive symptoms. An age-appropriate version will be used. It will 
be administered with the expanded version at Screening, Baseline, Week 1, Week 3, and Week 6. 
Assessment of AISRS at Week 6 will be a co-primary outcome measure. Sensitivity analysis of 
Week 1 timepoint will be conducted to evaluate rapid-acting effects of NRCT-101SR. In addition, 




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(anxiety and depression) in adult subjects with ADHD compared to placebo as assessed 
by the change from baseline in the HADS at Week 6. 
 
3.1.3 Other Secondary Objectives 
1. To determine if NRCT-101SR treatment has rapid-acting effects on reducing core 
symptoms in adult subjects with ADHD compared to placebo as assessed by the change 
from baseline in the AISRS at Week 1. 
2. To determine if NRCT-101SR treatment has same-day effects on improving objective 
performance in adult subjects with ADHD compared to placebo as assessed by change 
from pre-dose timepoint in PERMP at Week 6.  
3. To determine if treatment with NRCT-101SR improves quality of life in adult subjects 
with ADHD compared to placebo as assessed by the change from baseline in the AAQOL 
at Week 6. 
4. To determine if treatment with NRCT-101SR reduces disease severity in adult subjects 
with ADHD compared to placebo as assessed by the change from baseline in the CGI-S 
at Week 6. 
5. To evaluate responder rate with NRCT-101SR compared to placebo as assessed by 
AISRS response and change from baseline in CGI-S at Week 6. 
6. To assess the population pharmacokinetics of NRCT-101SR in ADHD subjects. 
7. To determine if treatment with NRCT-101SR improves objective performance and/or 
reduces core symptoms in adult subjects with ADHD compared to placebo as assessed 
by the change from baseline in the AISRS Expanded Version at Week 6. 
 
3.1.4 Exploratory Objectives 
1. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
3.1.6 Safety Objectives  
1. To evaluate the safety and tolerability of NRCT-101SR compared to placebo as assessed 


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by the incidence of adverse events, vital sign measurements, clinical laboratory 
evaluations, electrocardiogram (ECG) parameters, proportion of subjects who discontinue 
from the study due to any adverse event (tolerability), and the Columbia Suicide Severity 
Rating Scale (C-SSRS). 
3.2 Study Endpoints 
All primary and secondary endpoints will be evaluated as the difference between NRCT-101SR 
and placebo following the 6-week treatment period unless as noted. 
3.2.1 Primary Efficacy Endpoints 
1. Objective Performance: Permanent Product Measure of Performance – Correct (PERMP-
C) 
2. Core Symptoms: ADHD Investigator Symptom Rating Scale (AISRS) 
 
3.2.2 Key Secondary Efficacy Endpoints 
1. Cognition 
 Subjective Executive Function: Behavior Rating Inventory of Executive Function – 
Adult Version (BRIEF-A)  
2. Neuropsychiatric Symptoms 
 Hospital Anxiety and Depression Scale (HADS) 
 
3.2.3 Other Secondary Endpoints 
1. Core Symptoms 
 AISRS Expanded Version at Week 6 
2. Clinician Rated Scales 
 Clinical Global Impression – Severity (CGI-S) 
3. Responder Rate 
 The proportion of responders (≥ 25% reduction of AISRS and ≥ 2-point reduction of 
CGI-S from baseline to Week 6)  
4. Subjective Subject Rated Symptoms Scales 
 Adult ADHD Quality of Life scale (AAQoL) 
5. Population PK 
 
Plasma levels of NRCT-101 
for PK modeling in ADHD subjects 
 


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3.2.4 Exploratory Efficacy Endpoints 
1. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2.6 Safety Endpoints 
1. The proportion of subjects with adverse events or serious adverse events (SAEs) over the 
6-week study intervention period. 
2. The proportion of subjects who discontinue from the study due to any adverse event 
(tolerability) over the 6-week study intervention period. 
3. The change relative to placebo from baseline to each post-baseline measure in labs, vitals, 
ECG, and C-SSRS responses. 
 
4.0 STUDY DESIGN 
4.1 Overall Design 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-arm design, 
laboratory classroom (LC) trial to assess the efficacy and safety of NRCT-101SR 
 
 compared to inactive placebo over a 6-
week period in approximately 216 subjects ≥ 18 years of age with ADHD. Study population will 
include adult male and female subjects of all race/ethnicity with ADHD, recruited from sites across 
the US. All subjects will either be naïve to stimulant or non-stimulant ADHD medications, or prior 
to enrollment, have been off stimulants for at least 2 weeks and non-stimulants for at least 3 weeks.  
Total subject participation in the study is up to approximately 13 weeks, including a screening 
period (up to 6 weeks), a 6-week treatment period, and an approximate 1-week follow-up period. 
Each study subject will be randomized into one of two groups (1:1) to receive either active drug 
or placebo during the entirety of the 6-week treatment period. Within 8 days of the Baseline visit, 
subjects will complete an LC Orientation Visit. At the Baseline LC visit, subjects will be enrolled, 


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assigned to a group, and receive study drug (first dose to be taken the next morning). The primary 
endpoints of the study include Permanent Product Measure of Performance (PERMP) Math Tests 
and the AISRS. To familiarize the subjects with the PERMP, prior to the Baseline LC visit, they 
will complete 8 practice PERMP assessments (3 at screening and 5 at the LC Orientation visit). 
LC visits will be repeated at Week 3 and Week 6. Secondary and exploratory assessments will also 
be conducted at the Baseline, Week 3, and Week 6 LC visits. A clinic visit will be conducted at 
Week 1 to administer AISRS with expanded version, HADS, and BRIEF-A. Safety assessments 
(concomitant medications, adverse events, and suicide risk) will be conducted at all clinic and 
remote visits/phone calls (Week 5, and follow-up); safety labs will be conducted at screening, 
Week 3, and Week 6. For population PK analysis, PK sampling will be conducted at the Week 3 
LC visit. Blood samples for PK will be collected prior to dosing and at 4 hours and 7 hours after 
dosing (with a 30-minute window). See Study Schema and Schedule of Events below. 
The primary analysis will be on effects of 6-week treatment of NRCT-101SR versus placebo on 
performance (PERMP-C) and ADHD core symptoms (AISRS) in subjects with adult ADHD.  
Randomization will be stratified by:  
 Site 
 LC Cohort 
 Sex (approximately equal number of male and female in the study) 
 
Figure 1 - Study Schema 
 
4.2 Study Duration  
Subject participation in the study will be approximately 13 weeks (up to 6 weeks of screening, 6 
weeks of study drug administration and clinic visits, and 1 week of follow-up).  


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4.3 Selection of Study Population 
The study will enroll approximately 216 subjects ≥ 18 years of age with ADHD. Study population 
will include male and female subjects of all race/ethnicity with ADHD, recruited from sites across 
US. 
4.3.1 Inclusion Criteria 
1. Male or female, ≥ 18 years of age at screening 
2. Has a primary diagnosis of ADHD according to the DSM-5 classification, confirmed with 
MINI using DSM-5 probes 
3. AISRS ≥ 26 at screening and baseline, and does not change by more than 25% from 
screening to baseline, except subjects who stop taking ADHD medication after screening 
may have increase of more than 25% 
4. Has a minimum score of 4 on the CGI-S at Baseline 
5. Must be fluent in English, and capable of reading, writing, and communicating effectively 
with others and willing to participate in laboratory classroom  
6. Completion of at least 10 years of formal education 
7. Hearing and Vision ability sufficient to complete cognitive testing, in investigator’s 
opinion 
8. Willing and able to give informed consent 
9. Total Body weight (bw) ≥ 50 kg and ≤ 120 kg a
 
 
10. Naïve to stimulant or non-stimulant medications used for the treatment of ADHD or have 
discontinued stimulants at least 2 weeks and non-stimulants at least 3 weeks prior to 
randomization 
4.3.2 Exclusion Criteria 
Subjects meeting any of the following exclusion criteria may not be enrolled in the study: 
Exclusions to rule out subjects with impairment likely due to something other than ADHD: 
11. Subject is functioning at an age-appropriate level intellectually, as judged by the 
investigator 
12. Lifetime history of severe psychiatric symptoms of major depression requiring 
hospitalization, bipolar disorder, schizophrenia of schizoaffective disorder, hallucination, 
or delusions. Severe comorbid disorders such as PTSD, severe obsessive-compulsive 
disorder, or other symptomatic presentation that, in the opinion of the examining physician, 
will contraindicate NRCT-101SR treatment or confound efficacy or safety assessments. 
Subjects with mild to moderate forms of social phobia or dysthymia, for instance, may be 
included. 


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13. History of seizures (other than infantile febrile seizures), any tic disorder (except transient 
tic disorder and subject has no episodes for at least 1 year), or a current diagnosis of 
Tourette’s Disorder  
14. Recent history (within the past 1 year) of suspected substance abuse or dependence disorder 
(excluding stable nicotine use) in accordance with DSM-5 criteria. (Note: subject’s average 
nicotine use should not be exceeded during each LC visit)  
15. Current abnormal thyroid function as defined as abnormal screening thyroid stimulating 
hormone. Treatment for at least 3 months with a stable dose of thyroid medication is 
permitted. 
Exclusions to rule out subjects with potential issues absorbing or metabolizing NRCT-
101SR: 
16. Poor kidney function; corrected estimated glomerular filtration rate (eGFRcorr) 
< 40 mL/min/m2 
17. History of significant gastrointestinal disorders, such as chronic diarrhea, irritable bowel 
syndrome, ulcerative colitis, Crohn’s disease, etc.  
Exclusions to rule out subjects with conditions that could affect their safety: 
18. Female subjects who are pregnant and/or lactating 
19. A “yes” answer to “suicidal ideation” item 4 (active suicidal ideation with some intent to 
act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) 
on the C-SSRS assessment at screening (in the past 12 months).  
20. Has history of severe drug allergy or hypersensitivity to the study medication or its 
excipients.  
21. Hypermagnesemia; magnesium > 2.5 mg/dL  
22. Reproduction: 
a. Females of childbearing potential (FOCP) must be either sexually inactive 
(abstinent) or, if sexually active, must agree to use one of the following acceptable 
birth control methods beginning 30 days prior to the first dose of study drug and 
throughout the study: 
i. 
Simultaneous use of male condom and intra-uterine contraceptive device 
placed at least 4 weeks prior to first study drug administration 
ii. 
Surgically sterile male partner 
iii. 
Simultaneous use of male condom and diaphragm with spermicide 
iv. 
Established hormonal contraceptive 


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b. Males must: 
i. 
Use 2 methods of contraception in combination if his female partner is of 
childbearing potential; this combination of contraceptive methods must be 
used from the Baseline Visit to ≥ 1 month after the last dose of study drug, 
or 
ii. 
Have been surgically sterilized prior to the Screening Visit. 
Exclusions to rule out subjects with conditions that could inhibit or confound the effects of 
NRCT-101SR or the ability of the subject to complete the study: 
23. Is currently participating in another clinical trial or has participated in a clinical trial within 
30 days prior to the Screening Visit. 
24. Currently living in an institutional facility such as a nursing home 
25. Severe physical disability not associated with cognitive function that limits ability to 
complete testing (e.g., severe tremor, debilitating arthritis, etc.) 
26. Known history of symptomatic cardiac disease, advanced atherosclerosis, structural 
cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary heart 
disease, transient ischemic attack or stroke or other serious cardiac problems. 
27. Known family history of sudden cardiac death or ventricular arrhythmia. 
28. Serious or unstable clinically important systemic illness or disease that, in the judgment of 
the investigator, is likely to affect cognitive assessment, deteriorate, or affect the subject’s 
safety or ability to complete the study, including hepatic (e.g., Child-Pugh grade C), renal, 
gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, infectious, or 
hematologic disorders 
29. Has previously participated in a NRCT-101SR / 
investigational study 
30. Investigators and their immediate family members are not permitted to participate in the 
study. 
31. Consumes more than a weekly average of: 2 drinks / day or more than 3 drinks in any day 
for males; 1 drink / day or more than 2 drinks in any day for females 
32. Changes in medications or doses of medication as follows: 
a. All allowed concomitant medications, supplements, or other substances must be at 
stable doses for at least 30 days prior to screening and must be kept as stable as 
medically possible during the trial. For allowed concomitant medications, any 
dosing change within 30 days of Screening may be allowed if, in the opinion of the 
investigator, it will not affect or influence study results. 
4.4 Prior and Concomitant Medications 
Prior treatments, defined as any treatment taken within 3 months or any ADHD drug taken within 
6 months before screening, are to be recorded in the electronic case report form (eCRF) as prior 


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medications. Concomitant treatments, defined as treatments taken after the first dose of study drug, 
are to be recorded in the eCRF as concomitant medications. 
If a change in medication dosage occurs during the study it may lead to discontinuation from study 
participation unless it relates to a medication that, in the view of the study investigator and in 
consultation with the medical monitor, does not affect the subject’s participation in the trial or the 
study results. Any medication or therapy that is taken by or administered to the subject during the 
study should be recorded in the eCRF. The entry must include the dose, regimen, route, indication, 
and dates of use. 
After randomization, medication(s) to treat minor treatment-emergent illness(es) is generally 
permitted and subjects may be allowed to continue in the study after being evaluated by the 
clinician and discussed with the Sponsor. However, for certain classes of drugs (listed below; not 
inclusive of every drug and brand or generic name), subjects must follow dosing guidelines listed 
below (i.e., restricted medications/substances) and before Baseline visit and through the study, 
must not take ADHD stimulants for at least 2 weeks, ADHD non-stimulants for at least 3 weeks, 
and other prohibited substances for at least 4 weeks (or as listed below). Any subject taking these 
substances during the study will be evaluated by the Clinician (to be discussed with Sponsor) for 
ability to continue in the study. 
Substance use will be collected in the eCRF at screening to document the subjects previous and 
current use of cannabis, nicotine/tobacco, caffeine, opioids, sedatives, and hypnotics. During LC 
days, caffeine is limited to one cup of coffee/caffeinated drink in the morning and one caffeinated 
drink at meals. 
The following are classes of medication used for treatment of ADHD and comorbid disorders that 
are prohibited during the study: 
 Classical drugs (CNS stimulants), including: 
o Amphetamines, 
Adderall, 
Dextroamphetamine, 
Lisdexamphetamine, 
Methamphetamine, Methylphenidate, Dexmethylphenidate 
 Non-classical drugs (non-stimulant), including: 
o Atomoxetine, Modafinil, Viloxazine ER 
 α2 adrenoceptor agonists (non-stimulant), including: 
o Clonidine, Guanfacine 
 Any Antidepressants/ Anxiolytics / antipsychotics, such as (but not limited to): 
o Selective Serotonin Reuptake Inhibitor (SSRI), Amitriptyline, Bupropion, 
Buspirone, Clomipramine, Desipramine, Duloxetine, Imipramine, Milnacipran, 
Moclobemide, Nortriptyline, Reboxetine, Selegiline, Venlafaxine 
 Miscellaneous other drugs 
o NMDA receptor blockers, such as Amantadine and Memantine-containing drugs 
(e.g., Namenda®) 




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randomization into the study, the investigator will make every effort (refer to Site Operations 
Manual for guidance) to have the subject complete the final Visit 7 clinic visit/early termination 
(ET) assessments (as soon as possible after the discontinuation of study drug) as well as the Visit 
8 follow-up phone call 7 days later. PERMP math tests will not be performed for the Early 
Termination Visit.  Subjects who discontinue from the study treatment period will not be replaced. 
An eCRF page should be completed for every subject who receives study drug, whether or not the 
subject completes the study indicating the reason for any early termination. It is important to 
distinguish the stopping rules between early termination of a subject from study drug and early 
termination of the study.  
4.5.1 Stopping Rules for Subject Early Termination 
Subject may be withdrawn from the study if any of the following occur: 
a) Adverse Event (Adverse Reaction): Clinical or laboratory events occurred that, in the 
medical judgment of the investigator for the best interest of the subject, are grounds for 
withdrawal. This includes serious and non-serious adverse events (SAE and NSAE) 
regardless of relation to the study drug. 
b) Death: The subject died. 
c) Withdrawal of Consent: The subject desired to withdraw from further participation in the 
study in the absence of an investigator-determined medical need to withdraw. If the subject 
gave a reason for withdrawing, it should be recorded in the eCRF. 
d) Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements, which compromises the safety of 
subject or data quality. 
e) Lost to Follow-Up: The subject stopped coming for visits and study personnel were unable 
to contact the subject. 
f) Other: Termination of study by sponsor. 
g) ALT or AST > 3 times baseline with direct bilirubin > 2 times upper limit of normal (ULN) 
or international normalized ratio (INR) increased from baseline and is > 1.5 times ULN, 
unless the investigator in consultation with the Medical Monitor determines it is unlikely 
related to the study drug. 
h) Creatinine > 1.8 times ULN and > 2 times baseline, unless the investigator in consultation 
with the Medical Monitor determines it is unlikely related to the study drug.  
i) Magnesium > 3.0 mg/dL; > 1.23 mmol/L. 
j) Study drug should also be discontinued in the setting of any SAE or a clinically significant 
grade 4 adverse event or confirmed grade 4 laboratory abnormality for an individual subject 
which is considered by the investigator in consultation with the Medical Monitor to be 
related to the study drug. 
k) Intolerance to study drug. 


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4.5.2 Study Stopping Rules 
The following are the study stopping rules which may lead to a pause in enrollment or cancellation 
of the study. The Medical Monitor will review the event that triggered the pause in enrollment 
with the Sponsor to determine study status. 
a) Death in any subject in which the cause of death is assessed to be probably or definitely 
related to the study drug by the investigator and as confirmed by the medical monitor; 
b) The occurrence in any subject of a life-threatening SAE assessed to be probably or 
definitely related to the study drug by the investigator and as confirmed by the medical 
monitor; 
c) Two (2) occurrences of Grade 3 or higher (according to CTCAE scale) adverse events that 
are assessed to be definitely related to the study drug by the investigator and as confirmed 
by the medical monitor; 
d) Two (2) occurrences of a clinically significant Grade 3 or higher (according to CTCAE 
scale) laboratory abnormality assessed to be definitely related to the study drug by the 
investigator and as confirmed by the medical monitor; 
e) Any single SAE or ≥ grade 4 AE or laboratory abnormality unless the investigator 
determines it is unlikely related to the study drug and as confirmed by the medical monitor; 
f) Any pattern of significant symptoms, physical findings, or laboratory abnormalities that, 
although individually minor, collectively represent a safety concern for the subject in the 
opinion of the investigator that are assessed to be at least possibly related to study drug and 
as confirmed by the medical monitor. 
4.6 Study Drug 
4.6.1 Details of Study Drug Administration 
Information about the study drug is provided in the investigator brochure. Study drug will be 
provided by the Sponsor and transferred to study sites by the Sponsor. Study drug includes the 
active product – NRCT-101SR (375 mg and 500 mg), and corresponding placebos. NRCT-101SR 
is a sustained release formulation, dissolving in approximately 
hours, consisting of 375 or 500 
mg of 
 Subjects will take the study drug, via oral administration, in both morning and 
evening. Study drug MUST be taken immediately AFTER (within 30 minutes) eating a full meal. 
Study drug will be dispensed in bottles. Daily dosage will be administered as outlined in Table 1.  
 
 
 
 
 
 Both morning and evening administrations 
must be taken orally within 30 minutes after eating a full meal.  
 




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NRCT-101SR, 375 and 500 mg and placebo tablets are packaged 
 
 Each bottle 
contains 32 NRCT-101SR, 375 or 500 mg or placebo tablets.  
Table 1 - Details of Study Drug 
 
Subjects will take their first dose of NRCT-101SR or corresponding placebo the following day 
after the Baseline LC Visit and will continue morning and evening administration until the Week 
6 visit. On the days of LC visits at week 3 and week 6, subjects will not take their daytime dose 
until arriving at the clinic and are instructed to do so by the study staff. Every effort should be 
made to take dosages at the same times each day.  
 
 




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An IRT system will be used to  randomize subjects to either the active or placebo study drug as 
well as maintain blinding of the study drug assignment. In the event of an SAE, Neurocentria, in 
consultation with the investigator and medical monitor, will decide whether to unblind a given 
subject’s study drug assignment, except in circumstances where the investigator believes it is in 
the subject’s best medical interest to do so immediately. 
The randomization codes will be stored electronically in a secure manner, which are only 
accessible to the designated unblinded study team member(s).  
4.6.6 Study Drug Inventory and Accountability 
Sponsor will ship the study drug as an overnight shipment to the site per the Certificate of Analysis 
document. Sites are required to verify receipt of the shipment within the IRT system by recording 
the bottles received and any damage or temperature excursions noted. The sites are required to 
notify the Sponsor if a temperature excusion occurs or the shipment contains damaged study drug 
so it can be quarantined as needed per Sponsor requirements. The study drug will be stored at the 
site per protocol. Sites needs to maintain a daily temperature monitoring log where the study drug 
is stored. The Sponsor and/or Contract Research Organization (CRO) needs to be notified 
immediately in case of any temperature excursion. 
The investigator must keep an accurate accounting of the number of study drug bottles that are 
delivered to the site, dispensed to subjects, returned to the investigator by the subject, and returned 
to the sponsor or other disposition during and at the completion of the study, as recorded in the 
IRT system. The study drug is to be used in accordance with the protocol by subjects who are 
under the direct supervision of the investigator. Investigators should maintain records that 
document adequately that the subjects were provided the doses specified by the protocol and 
reconcile all study drug received at the site before final disposition. At the end of the study, or as 
directed, all unused study drug will be returned to the sponsor. 
4.6.7 Study Drug Compliance 
Study drug is dispensed at the Baseline LC Visit and the Week 3 Visit during the study. Study 
drug bottles must be returned at Week 3 and Week 6 visits, as compliance will be assessed by 
tablet counts. Noncompliance is defined as taking less than 80% or more than 120% of study drug  
between each clinic visit. Subjects who are noncompliant with administration of study drug should 
be counseled about the study drug administration requirements at the scheduled visits, and 
documentation of counseling should be kept along with the source documents. Discontinuation for 
noncompliance is at the investigator’s discretion and is to be noted on the eCRF. 
 4.7 Overview of Study Visits 
Total subject participation in the study is up to approximately 13 weeks, including a screening 
period (up to 6 weeks), a 6-week treatment period, and an approximate 1-week follow-up period:  
o Screening period of up to 6 weeks: The Screening visit will include obtaining ICF signature 
and review of eligibility criteria per screening visit assessments. During the screening period, 
there will be an LC Orientation Visit to familiarize the subjects with the LC day. The LC 


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Orientation Visit should be within 8 days of the Baseline LC visit. The Baseline LC visit should 
be no more than 42 days from the original screening visit.  
o Treatment period of 6 weeks: During the treatment period, study subjects will receive either 
NRCT-101SR or placebo. After the Baseline visit, there is one clinic visit (Week 1) and two 
LC visits (Week 3 and Week 6.). A remote visit will occur at Week 5. During the remote visit, 
concomitant medications, adverse events, and suicide risk information will be collected.  
o Follow-up period: One week following last administration of study drug at the Week 6 clinic 
visit, concomitant medications, adverse events, and suicide risk will be assessed via a phone 
call with subjects. 
Unless otherwise indicated, all assessments will be performed by the investigator or designated 
study personnel. At the investigator’s discretion, subjects may attend unscheduled visits for 
evaluation of reported adverse events and laboratory retesting, as necessary. Subjects that meet 
the criteria for withdrawal from the study should make every effort (refer to the Site Operations 
Manual for guidance) to complete the Early Termination and Follow-Up visit assessments.  
4.7.1 Rationale for Study Visits 
This study is a parallel design planned for 6 weeks of administration of NRCT-101SR, a sustained 
release tablet formulation with the API 
 or 6 weeks of placebo. Previous studies in adult 
ADHD subjects and subjects with neuropsychiatric symptoms and/or cognitive impairment show 
effects of 
 within 1-6 weeks. Specifically, in adult ADHD subjects, reduction in ADHD 
symptoms and improvement in quality of life and cognition are observed by 3 weeks and 
maintained through 12 weeks of 
 administration. Evaluations at 3 and 6 weeks should be 
sufficient to observe effects of NRCT-101SR on ADHD symptoms and cognition. 
In support of safety for 6 week administration of NRCT-101SR, Sponsor has conducted 7 efficacy 
clinical trials with study drug containing 
 ranging from one week to 24 weeks. Five of 
these clinical trials were 8-24 weeks in length, including a 12 week study in subjects with Adult 
ADHD (NC-004). In these trials, safety assessments (physical exam, ECG, and safety labs) were 
conducted as part of in-clinic visits at baseline, every 6-12 weeks during the study, and at the end 
of study visit. These studies provide relevant safety information for the population and support 
safety of at least 6 week exposure of NRCT-101SR. 
In previous studies, effects on emotional regulation and overall mood have been observed by 
approximately 
 of NRCT-101SR administration and effects on ADHD symptoms were 
observed at the first timepoint of 
. 
 
Administration of  AISRS at Week 1 will allow for evaluation of rapid-acting 
effects of NRCT-101SR compared to placbeo. This is an important assessment considering most 
other non-stimulant ADHD drugs may require up to 4-6 weeks for clinically meaningful effects 
(Wietecha, Clemow et al. 2016). 
In line with previous studies, all safety assessments in this study will be performed at 6 weeks with 
additional evaluations done in clinic and on the phone at interim timepoints. A follow-up phone 
call one week after cessation of study drug will evaluate AEs, concomitant medications, and 


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suicidal risk. Considering the short half-life of NRCT-101SR (
 hour), one week should be 
sufficient time to evaluate any effects of study drug cessation. 
4.7.2 Schedule of Events 
The procedures to be performed throughout the study are outlined in the Schedule of Events (Table 
3).  


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Table 3 - Schedule of Events 
Schedule of Events   
Screening  
LC 
Orientation 
 
Baseline 
(LC) 
 
Week 1 
(clinic) 
Week 3 
(LC) 
Weeks 5 
(remote) 
Week 6 
or ET 
(LC) 
Week 7 
Follow-up 
(remote) 
Visit 
Visit 1 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
 Day 
Day -42 to -2 
Day -8 to -1 
Day 1 
 
Day 8 
(+/- 1 day) 
Day 22 
Day 36 
(+/-3 days) 
Day 43 
Day 50  
(+/-2 day) 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Demographics & 
Medical History 
X 
 
 
 
 
 
 
 
Substance Abuse 
History 
X 
 
 
 
 
 
 
 
Prior/Concomitant 
Meds 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
X 
 
X 
 
X 
 
MINI with DSM-5 
probes 
X 
 
 
 
 
 
 
 
Vital Signs 
including weight 
X 
X 
X 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
Safety 
Labs/Urinalysis 
X 
 
Xf 
 
X 
 
X 
 
Urine pregnancy  
X 
 
X 
 
 
 
 
 
Urine Drug Screen 
X 
 
X 
 
X 
 
X 
 


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Schedule of Events   
Screening  
LC 
Orientation 
 
Baseline 
(LC) 
 
Week 1 
(clinic) 
Week 3 
(LC) 
Weeks 5 
(remote) 
Week 6 
or ET 
(LC) 
Week 7 
Follow-up 
(remote) 
Visit 
Visit 1 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
 Day 
Day -42 to -2 
Day -8 to -1 
Day 1 
 
Day 8 
(+/- 1 day) 
Day 22 
Day 36 
(+/-3 days) 
Day 43 
Day 50  
(+/-2 day) 
 
 
 
 
X 
 
 
 
X 
 
ECG 
 
 
X 
 
 
 
X 
 
PK Samplinga 
 
 
 
 
X 
 
 
 
AISRS with 
expanded version 
X 
 
Xg 
Xg  
Xg 
 
Xg  
 
 
 
 
X 
 
X 
 
X 
 
CGI-S 
X 
 
X 
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
AAQoL 
 
 
X 
 
X 
 
X 
 
BRIEF-A 
 
 
X 
X 
X 
 
X 
 
HADS 
 
 
X 
X 
X 
 
X 
 
C-SSRS 
(Baseline/Screening 
version) 
X 
 
 
 
 
 
 
 
C-SSRS (since last 
visit version) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
 
PERMP placement 
X 
 
 
 
 
 
 
 
PERMP practicec 
X 
X 
 
 
 
 
 
 
PERMP 
 
 
Xbg  
 
Xbg  
 
Xbdg  
 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 


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Schedule of Events   
Screening  
LC 
Orientation 
 
Baseline 
(LC) 
 
Week 1 
(clinic) 
Week 3 
(LC) 
Weeks 5 
(remote) 
Week 6 
or ET 
(LC) 
Week 7 
Follow-up 
(remote) 
Visit 
Visit 1 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
 Day 
Day -42 to -2 
Day -8 to -1 
Day 1 
 
Day 8 
(+/- 1 day) 
Day 22 
Day 36 
(+/-3 days) 
Day 43 
Day 50  
(+/-2 day) 
Study Drug 
Dispensation 
 
 
X 
 
X 
 
Xe 
 
Study Drug 
Accountability 
 
 
 
 
X 
 
X 
 
ET = early termination;  LC = Laboratory Classroom; AISRS =  ADHD Investigator Symptom Rating Scale; ECG = 
electrocardiogram; 
;  
CGI-S = Clinician Global Impression - Severity; 
; AAQoL = adult ADHD Quality of 
Life;  BRIEF-A = Behavior Rating Inventory of Executive Function – Adult; HADS = Hospital Anxiety and Depression Scale; C-
SSRS = Columbia Suicide Severity Rating Scale; PERMP = Permanent Product Measure of Performance; PK = Pharmacokinetic 
(samples collected pre-dose and post-dose); 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 


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4.7.3 Study Procedures 
4.7.3.1 Screening Visit: Visit 1 (day -42 to day -2) 
The assessments during the screening phase will determine the subjects’ eligibility for the study 
and their ability to comply with protocol requirements by completing all screening assessments. 
The following procedures will be performed and recorded during the screening period:  
 Obtain informed consent from study subject  
 Review inclusion and exclusion criteria for eligibility. Any subject that does not meet 
inclusion/exclusion criteria may be rescreened with Sponsor approval 
 Confirm ADHD diagnosis (MINI with DSM-5 probes) 
 Administer AISRS with expanded version 
 Administer CGI-S 
 Urine pregnancy and drug screen 
 Evaluate Demographic information (age, sex, race, ethnicity) and medical history 
including significant medical illnesses and conditions, including history of diabetes, 
hypertension, and smoking, etc. 
 Collect substance abuse history 
 Collect Prior and Concomitant medications information (also reference the prohibited 
medications/substances list)  
 Physical exam 
 Vital signs and body weight  
 Measure height (cm) 
 Administer the C-SSRS, Baseline/Screening version 
 Administer PERMP placement and practice tests (x3) 
 Collect samples for Safety Labs, including urinalysis 
Formula for calculating Corrected eGFR (eGFRcorr) 
To allow for comparison between individuals, eGFR is typically normalized to body surface area 
(BSA) because high filtration rates are needed for people with larger bodies to maintain the same 
amount of clearance as people with smaller bodies. Typically, 1.73 m2, the BSA of the average 
size male, is used when calculating eGFR, resulting in final eGFR units of mL/min/1.73m2. 
However, when normalizing to a set BSA, values may be erroneously high for people with a BSA 
greater than average and erroneously low for people with a BSA lower than average. To avoid 
this problem, eGFR should be corrected using the following calculation: 


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𝑒𝐺𝐹𝑅𝑐𝑜𝑟𝑟=
𝑒𝐺𝐹𝑅∗1.73
𝐵𝑆𝐴
,  
where  
𝐵𝑆𝐴= 0.007184 ∗𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔)
0.425 ∗𝐻𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)
0.725 
 
eGFRcorr < 40 mL/min/m2 is exclusionary. 
 
4.7.3.2 LC Orientation Visit: Visit 2 (Day -8 to day -1) 
 Review prior and concomitant medications 
 Administer C-SSRS, since last visit version  
 Administer PERMP practice tests (x5) 
 Vital signs and body weight 
4.7.3.3 Baseline LC Visit: Visit 3 (day 1) 
Baseline visit must begin in the early morning to allow adequate time to complete all procedures. 
Since meals are required prior to administration of study drug, meals will be provided at this visit 
as per the LC schedule (refer to LC manual) to replicate what will be done on Week 3 and Week 
6 LC visits. 
 Review of eligibility criteria for subject randomization 
 Review concomitant medications 
 Physical examination   
 Vital signs and body weight 
 Urine Pregnancy and drug screen 
 
 
 Electrocardiogram 
 Administer PERMP per LC schedule (refer to LC manual) and provide PCRS* prior to 
administration of first PERMP math test of the day 
 Administer AISRS with expanded version (provide PCRS* prior to administration)  
 
 
 Administer CGI-S 
 
 
 Administer AAQoL 


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 Administer BRIEF-A 
 Administer HADS 
 Administer C-SSRS, since last visit version 
 
 
 Collect samples for Safety Labs, including urinalysis (Does not need to be collected if 
screening visit results are within 30 days of the Baseline visit. However, samples may 
still be collected to confirm subject eligibility as needed)  
Provide the subject with study drug for home use with first dose taken the following morning 
(provide written and verbal instructions on how to take the product).  
* PCRS will be administered only once per visit prior to PERMP or AISRS assessments whichever 
occurs first. 
4.7.3.4 Week 1 Clinic Visit: Visit 4 (+/- 1 day) 
A clinic visit will be conducted at Week 1 (± 1 day). During this visit, the following procedures 
will be conducted: 
 Review concomitant medications 
 Review adverse events  
 Administer AISRS with expanded version (provide PCRS prior to administration) 
 Administer CGI-S 
 Administer BRIEF-A 
 Administer HADS 
 
Administer C-SSRS, since last visit version  
4.7.3.5 Week 3 LC Visit: Visit 5   
Prior to arriving at clinic, subjects should NOT have taken study drug. Subject will take study drug 
at LC visit when instructed, within 30 minutes after eating a meal.  
 Review concomitant medications 
 Review of adverse events 
 Physical examination   
 Vital signs and body weight 
 Collect samples for Safety Labs, including urinalysis 
 Urine drug screen  
 Administer PERMP per LC schedule (refer to LC manual) and provide PCRS* prior to 
administration of first PERMP math test of the day 


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 Collect PK samples (pre-dose and at hours 4 and 7 post-dose with a 30-minute window 
for completion of sampling) 
 Administer study drug in clinic (morning and evening doses) 
 Administer AISRS with expanded version (provide PCRS* prior to administration)  
 
 
 Administer CGI-S 
 
 
 Administer AAQoL 
 Administer BRIEF-A 
 Administer HADS 
 Administer C-SSRS, since last visit version 
 
 
 Provide subject with study drug for home use (provide written and verbal instructions on 
how to take the product).  
 Perform study drug accountability   
* PCRS will be administered only once per visit prior to PERMP or AISRS assessments 
whichever occurs first. 
4.7.3.6 Week 5 Remote Visit: Visit 6 (+/- 3 days) 
A remote visit will be conductedat Week 5 (± 3 days). During this visit, the following procedures 
will be conducted: 
 Review concomitant medications 
 Review adverse events 
 Administer C-SSRS, since last visit version 
4.7.3.7 Week 6 LC Visit/ET: Visit 7  
Prior to arriving at clinic, subjects should NOT have taken study drug. Subject will take study drug 
at LC visit when instructed, within 30 minutes after eating a meal as per the LC manual. For those 
subjects that have discontinued study drug, the following procedures excluding PERMP will be 
conducted as soon as possible after discontinuation of the study drug. 
 Review concomitant medications 
 Review of adverse events 
 Physical examination   
 Vital signs and body weight 


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 Collect samples for Safety Labs, including urinalysis 
 Urine drug screen 
 
 
 Electrocardiogram 
 Administer PERMP per LC schedule (refer to LC manual) and provide PCRS* prior to 
administration of first PERMP math test of the day 
 Administer study drug in clinic (morning and evening doses) 
 Administer AISRS with expanded version (provide PCRS* prior to administration)  
 
 
 Administer CGI-S 
 
 
 Administer AAQoL 
 Administer BRIEF-A 
 Administer HADS 
 Administer C-SSRS, since last visit version 
 
 
 Perform study drug accountability   
* PCRS will be administered only once per visit prior to PERMP or AISRS assessments 
whichever occurs first. 
4.7.3.8 Week 7 Remote Follow-up Visit: Visit 8 (+/- 2 days) 
 Review concomitant medications 
 Review adverse events 
 Administer C-SSRS, since last visit version 
4.7.4 LC Visit Days 
During the LC visit day, subjects will be grouped in cohorts where they will complete scheduled 
PERMP math tests and other assessments throughout the day. Subjects’ activities, behavior, and 
function will be monitored. Cohorts may contain 10-12 subjects; any cohort size smaller or larger 
requires sponsor approval. 
AEs and con meds will be reviewed, and vitals will be collected at these visits. A pre-dose PERMP 
math test will be administered as well as a total of 6 post-dose PERMP math tests throughout the 
day, approximately every two hours. In between PERMP math tests, subjects will complete other 


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assessments per the schedule of events. Study drug will be provided according to the dosing 
schedule. Refer to the LC manual for more detailed information on the LC schedule. 
An LC Orientation Visit is scheduled to familiarize the subjects with the LC visit days (Baseline, 
Week 3, and Week 6). The orientation day is similar to the other LC visit days except the time 
between PERMP administrations is shorter (a minimum of 20 minutes apart from start to start). 
Refer to the LC manual for more details. 
4.8 Efficacy Assessments 
4.8.1 Dual Primary Efficacy Assessments 
4.8.1.1 Permanent Product Measure of Performance (PERMP) 
The Permanent Product Measure of Performance (PERMP) is a skill adjusted math test. It is a 
series of 10-minute age-appropriate math tests consisting of five pages of 80 math problems each. 
The level of difficulty is established during a pretest administered at the screening visit. There is 
one of four difficulties that the subject is assigned to for the duration of the study (difficulty level 
assignment can be changed prior to the first baseline timepoint if difficulty is determined to be 
considerably too easy or too difficult).  
PERMP-C is the number of math problems answered correctly in a 10-minute session and typically 
ranges from 0-400 with higher scores indicating better performance. The PERMP total score 
(PERMP-T) is the sum of the number of math problems attempted (PERMP-A) plus the number 
of math problems answered correctly (PERMP-C). The PERMP-T scores typically range from 0-
800 with higher scores indicating better performance.  
To limit learning effects, subjects will complete practice PERMP tests at screening and the LC 
Orientation Visit. Placement and practice PERMP tests are administered as follows (refer to the 
LC manual for more details): 
 Screening 
o Placement test 
o 3 practice tests (with a minimum of 20 minutes apart from start to start) 
 LC Orientation Day 
o 5 practice tests administered during the classroom period according to LC schedule 
(with a minimum of 20 minutes apart from start to start) 
PERMP tests for analysis will be administered at Baseline, Week 3 and Week 6 LC visits.  
For each LC visit, PERMP tests will be administered pre-dose and at 2, 4, 6, 8, 10, and 12-hours 
post dose. For analysis, the average of PERMP-C scores at the post-dose timepoints at the Baseline 
LC visit (however, no dosing) will serve as the baseline value. For evaluation of effects, the 
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4.8.1.2 ADHD Investigator Symptom Rating Scale (AISRS) 
The ADHD Investigator Symptom Rating Scale (AISRS) consists of 18 items scored on a 4-point 
scale ranging from 0 (no symptoms) to 3 (severe symptoms) with a total score ranging from 0 to 
54. Each item has multiple prompts; the highest score that is generated from each prompt should 
be used as the score for that item.  Responses from the 18 items will be used to assess the primary 
efficacy endpoint for AISRS. The expanded version has an additional 13 accessory questions 
which will be used to assess a secondary endpoint.  Evaluations will be based on symptoms over 
the week prior to the administration.  
The AISRS with expanded version will be administered at Screening, Baseline, Week 1, Week 3, 
and Week 6 to evaluate effects of NRCT-101SR on core ADHD symptoms. Administration of  
AISRS at Week 1 will allow for evaluation of rapid-acting effects of NRCT-101SR compared to 
placbeo.  
4.8.1.3 Placebo-Control Reminder Script (PCRS) 
The Placebo-Control Reminder Script (PCRS)© Hassman and Cohen, 2019, Version 5.0 educates 
clinical study subjects of key causes of the placebo and nocebo effects, namely the tempering of 
study expectations, reminding study subjects what a placebo is and how that relates to their 
reporting of symptoms and potential side effects, and explaining how interactions with research 
site staff differ from their experience with previous providers. To do this, the PCRS informs 
subjects that they are to be honest about their symptoms, site staff have no expectations of 
symptom improvement or worsening and will not be disappointed if they feel better, worse or the 
same, and asks subjects to explain in their own words its content to ensure comprehension. Per the 
instructions on the PCRS, site staff will read the script verbatim immediately before administering 
the AISRS with expanded version at the Week 1, 3 and 6 visits as well as the first PERMP test at 
the Week 3 and 6 visits. The PCRS is read to each subject typically taking about 3 minutes to read. 
The PCRS has been empirically found to significantly manage (reduce) the placebo and nocebo 
effects (Cohen, Hassman et al. 2021). 
4.8.2 Key Secondary Efficacy Assessments 
4.8.2.1 Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A) 
The BRIEF-A is a standardized self-report measure of executive functions/self-regulation in an 
everyday environment. It includes 75 items with nine overlapping clinical scales including inhibit, 
self-monitor, plan/organize, shift, initiate, task monitor, emotional control, working memory, and 
organization of materials. All items are rated in terms of frequency on a 3-point scale (0 = never, 
1 = sometimes, 2 = often). Raw scores for each scale are summed for an overall summary score – 
the Global Executive Composite (GEC) - and T scores (mean = 50, standard deviation = 10) are 
determined. BRIEF-A will be administered at baseline, Week 1, Week 3, and Week 6. 
4.8.2.2 Hospital Anxiety and Depression Scale (HADS) 
The HADS consists of 14 items, divided into two 7 item subscales: anxiety (HADS-A) and 
depression (HADS-D). HADS-A questions reflect a state of generalized anxiety and HADS-D 
focuses on the concept of anhedonia. Subjects will rate each of the questions on a 4-point scale 




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4.9.3 Exploratory 
 
 
 
 
 
 
 
 
 
 
4.10 Safety Assessments 
4.10.1 Physical Exam 
A general physical examination is to be performed by a qualified health care practitioner as 
designated by and trained on the protocol by the PI. “Qualified health care practitioner” refers to 
any licensed health care professional who is permitted by institutional policy to perform physical 
examinations and who is identified within the Delegation of Authority Log. Physical examinations 
will include examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, heart, lungs, abdomen, lymph nodes, extremities, and central nervous system. Any 
clinically significant changes after the first dose of the study drug and up to the last study procedure 
must be recorded on the AE eCRF. Height without shoes will be recorded in cm at screening.  
A physical exam will be performed at screening, baseline, and Week 3 and 6 clinic visits. 
4.10.2 Vital Signs and Body Weight 
Vital signs and body weight may be collected by a qualified health care practitioner as designated 
by and trained on the protocol by the PI. Vital signs will include body temperature (°F), respiratory 
rate (per minute), sitting radial pulse rates (beats per min – bpm), and sitting systolic and diastolic 
blood pressures (mmHg). Vital signs are to be collected after subject has been sitting for at least 5 
minutes. Body weight without shoes will be recorded in kilograms whenever vital signs are 
recorded.  
Vital signs and body weight will be evaluated at screening, LC Orientation Visit, baseline, Week 
3, and Week 6.  
4.10.3 Electrocardiogram  
Standard 12-lead ECGs will be taken to identify a multitude of cardiac disease processes and 
examine any changes throughout study participation. ECG is to be collected by a qualified health 
care practitioner as designated by and trained on the protocol by the PI. The following parameters 
need to be collected - heart rate, cardiac rhythm, PR interval, QRS interval, QT interval, and QTc 


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interval.The ECG needs to be reviewed by the study physician and/or appropriately-trained 
specialist to rule out any clinically significant abnormal findings. Any clinically significant 
abnormal findings on the ECG after the first dose of study drug must be recorded on the AE eCRF.  
ECG will be evaluated at baseline and Week 6 clinic visit. 
4.10.4 Columbia Suicide Severity Rating Scale (C-SSRS)  
The US FDA recommends the use of a suicidality assessment instrument that maps to the 
Columbia Classification Algorithm for Suicide Assessment (C-CASA). The C-CASA was 
developed to assist the FDA in coding suicidality data accumulated during the conduct of clinical 
trials of antidepressant drugs. One such assessment instrument is the C-SSRS. The C-SSRS 
involves a series of probing questions to inquire about possible suicidal thinking and behavior. 
The scale can be completed as an interview or as a self-report. 
At the Screening Visit, the C-SSRS Baseline/Screening version will be administered. This version 
is used to assess suicidality over the participant’s lifetime and the last 12 months. 
At all other visits, the Since Last Visit version of the C-SSRS will be administered. This version 
of the scale assesses suicidality since the subject’s last visit. 
If there is a positive response to question 4 or 5 on the severity of ideation subscale or any positive 
response on the suicidal behavior subscale of suicide attempt or suicidal ideation by the subject 
during the administration of the C-SSRS, the appropriately qualified clinician will be notified 
during the study visit to determine the appropriate actions required to ensure the subject’s safety. 
The site must ensure that the subject is seen by a licensed physician (or other qualified individual 
as required by local institutional policy) before leaving the study site. For visits post the Baseline 
visit, the investigator in consultation with the Sponsor will determine whether the subject should 
remain on study drug. 
It is recommended that a medically licensed physician, nurse, nurse practitioner, or physician 
assistant assess the C-SSRS. All evaluators must be certified to perform the C-SSRS. Certification 
is required prior to performing the C-SSRS.  
The C-SSRS will be administered at all Visits (including remote visits). 
4.10.5 Adverse Events 
All AEs occurring or worsening after the subject takes the first dose of study drug and up to the 
last study  visit will be recorded in the AE eCRFs. The definition of adverse events and reporting 
requirements of adverse events are explained in the Adverse Event Reporting section￼. The 
evaluation for safety includes determination of percentage of subjects who reported adverse events 
between the active treatment group and placebo group in the study. 
Tolerability will be calculated as the proportion of subjects who discontinue from the study due to 
any adverse event. An Odds Ratio will be calculated as the ratio of the tolerability in the NRCT-
101SR group to the tolerability in the placebo group.  
AEs will be reviewed at all visits (including remote visits) beginning at the Baseline LC Visit.  


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4.10.6 Laboratory Parameters 
4.10.6.1 Safety Labs - Blood 
General safety laboratory testing will be performed at a Clinical Laboratory Improvement 
Amendments (CLIA)-certified central laboratory, Eurofins, using standard clinical pathology 
methods. 
The following blood tests are completed as part of safety labs. 
o Complete Blood Count (CBC) with differential: RBC, WBC, Hgb, hematocrit (Hct), 
MCV, MCH, MCHC, RDW, Platelets, MPV and absolute cell counts. 
o Chemistry and metabolic panel: Alanine aminotransferase (ALT), albumin, alkaline 
phosphatase (ALP), aspartate aminotransferase (AST), blood urea nitrogen (BUN), 
calcium, chloride, creatinine, glucose, magnesium, potassium, sodium, total bilirubin, 
total protein, and creatine phosphokinase (CPK). 
The samples will be collected and analyzed using routine methods per the central laboratory’s 
guidelines. In the event of an unexplained clinically significant abnormal laboratory test value, the 
test should be repeated immediately at an unscheduled visit and followed up until it has returned 
to the normal range and/or an adequate explanation of the abnormality is found. 
Safety labs will be performed at Screening, Baseline, Week 3, and Week 6 Visits. Baseline safety 
labs do not need to be collected if screening visit results are within 30 days of the Baseline visit. 
However, samples may still be collected to confirm subject eligibility as needed. 
4.10.6.2 Urinalysis 
Urine pregnancy tests and urinalyses will be performed at the study sites. 
 Urinalysis is performed in clinic as part of the safety labs at screening, baseline, week 3 
and week 6 including: 
o pH of freshly voided specimen, specific gravity, protein, glucose, ketones, blood, 
nitrite, bilirubin, urobilinogen using a dipstick 
o microscopic examination will only be performed at the central laboratory if results 
from two consecutive tests noted above are abnormal; sites will send the abnormal 
sample to the central laboratory for further examination 
 Other urine tests 
o Pregnancy: to be performed at screening and baseline in clinic using a pregnancy 
dipstick 
o drug screen: to be performed in clinic using a dipstick at Screening, Baseline, 
Week 3 and 6 visits; includes a 10-panel drug screen for cocaine, amphetamines, 
methamphetamines, tetrahydrocannabinol, methadone, opioids, phencyclidine, 
barbiturates, benzodiazepines, and tricyclic anti-depressants 


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4.11 Additional study assessments 
4.11.1 Specialty Laboratory Assessments 
 
4.11.2 MINI with DSM-5 Probes 
The ADHD module (Module Q) of the MINI will be administered at Screening to confirm the 
subject has a diagnosis of Adult ADHD. The questionnaire will be administered electronically. 
4.11.3 PK Sampling 
For pharmacokinetic analyses, evaluation of NRCT-101SR blood concentrations will be 
performed using a validated assay at a contract laboratory designated by the sponsor. Samples 
from a minimum of 120 subjects will be analyzed by the lab. Samples will be collected at the Week 
3 visit at the pre-dose, 4- and 7-hour post-dose timepoints (with a 30-minute window for 
completion of sampling). 
 
5.0 ADVERSE EVENT REPORTING 
Throughout the course of the study, all AEs will be monitored and recorded on an AE eCRF, 
including the AE’s description, start and end date, seriousness, severity, action taken, outcome and 
relationship to the studydrug. AEs and SAEs will be collected from the time of first dose through 
the last follow-up visit at Week 7. All events prior to this will be documented as medical history. 
If AEs occur, the first concern will be the safety of the study subjects. All AEs should be followed 
by the investigator until resolved or stable.  
5.1 Definitions and Criteria 
5.1.1 Adverse Events 
Per International Conference on Harmonization (ICH) E2A: An AE is “any untoward medical 
occurrence in a patient or clinical investigation patient administered apharmaceutical product and 
which does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.” 
Medical interventions such as surgeries, diagnostic procedures, and therapeutic procedures are not 
AEs but the action taken to treat the medical condition. Only the medical condition should be 
recorded as an AE in the AE eCRF. Any medications given as a result of treating the AE should 
be recorded on the Concomitant Medications eCRF. 


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5.1.2 Serious Adverse Events 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event that may not meet the above criteria but may be considered 
serious when, based upon appropriate medical judgment, that may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe. 
Suicidal ideation and behavior will be monitoried via C-SSRS throughout the study. While not 
necessarily considered a serious adverse event, throughout the trial, an affirmative response on the 
C-SSRS may require a referral to a trained mental health professional, an emergency psychiatrist 
evaluation, or other relevant resource.  
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. An SAE 
is not necessarily severe; e.g., an overnight hospitalization for a diagnostic procedure must be 
reported as an SAE even though the occurrence is not medically serious. By the same token, a 
severe AE is not necessarily serious: nausea of several hours’ duration may be rated as severe but 
may not be considered serious. 
5.1.3 Unexpected Adverse Reactions 
An unexpected adverse reaction (UAR) is a reaction for which the nature or severity is not 
consistent with the applicable information in the Investigator’s Brochure. Until product 
information is amended, expedited reporting is required for additional occurrences of the reaction. 
Reports that add significant information on specificity or severity of a known, already documented 
SAE constitute unexpected events. For example, an event more specific or more severe than 
described in the Investigator's Brochure would be considered "unexpected.” Specific examples 
would be (a) acute renal failure as a labeled UAR with a subsequent new report of interstitial 
nephritis and (b) hepatitis with a first report of fulminant hepatitis. 
Guidance on reporting AEs and SAEs is described in the Reporting Procedures and Requirements 
section. 


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5.1.4 Abnormal Laboratory Values 
Any abnormality in a laboratory value that is new in onset or that has worsened in severity or 
frequency from the baseline condition and meets 1 of the following criteria will be recorded on the 
AE pages of the eCRF: 
 
Requires therapeutic intervention or diagnostic tests 
 
Leads to discontinuation of study drug 
 
Has accompanying or inducing symptoms or signs 
 
Is judged by the investigator as clinically significant 
5.2 Assessing Intensity and Relationship 
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to the study drug: 
 Intensity refers to the severity of an event and references impact on a subject’s 
functioning. 
 Relationship refers to the likelihood that the event being assessed was caused by the study 
drug. 
5.2.1 Intensity 
Each AE will be classified according to the following criteria (Table 4): 
Table 4 - Criteria for Intensity Grading of Adverse Events (CTCAE Severity Grading) 
Grade 1 Mild: 
asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated. 
Grade 2 Moderate: 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of dailing living (ADL). Instrumental ADL
refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
Grade 3 Severe: 
Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting
self-care ADL. Self-care ADL refers to bathing, dressing, and undressing,
feeding self, using the toilet, taking medications, and not bedridden.  
Grade 4 Life-
threatening 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
 


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When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
those changes should be recorded separately (with distinct onset dates). 
5.2.2 Relationship 
The investigator will evaluate the causal relationship of each AE to a study drug and/or to a study 
procedure (e.g., venipuncture or ECG evaluation) and record that relationship on the appropriate 
CRFs. Causality will be assessed considering whether the AE is reasonably related to the study 
drug or procedure or whether the AE is not reasonably related to the study drug or procedure 
considering the definitions in Table 5.  
Table 5 - Criteria used for Determining Causality of Adverse Events to Study Drug 
Administration 
Relationship 
Description 
Definite 
A clinical event in which a relationship to the use of the study drug seems definite because 
of such factors as consistency with known effects of the drug; a clear temporal association 
with the use of the drug; lack of alternative explanations for the event; improvement upon 
withdrawal of the drug (de-challenge); and recurrence upon resumption of the drug 
(rechallenge).  
Probable 
A clinical event in which a relationship to the study drug seems probable because of such 
factors as consistency with known effects of the drug; a reasonable temporal association 
with the use of the drug; lack of alternative explanations for the event; and improvement 
upon withdrawal of the drug (de-challenge). 
Possible 
A clinical event with a reasonable temporal association with administration of the study 
drug, and that is not likely to be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking. 
Unlikely 
A clinical event with a temporal relationship to study drug administration that makes a 
causal relationship improbable and for which other factors suggesting an alternative etiology 
exist. Such factors might include a known relationship of the clinical event to a concomitant 
drug, past medical history of a similar event, the subject’s disease state, intercurrent illness, 
or environmental factors. 
Unrelated 
A clinical event in which a relationship to the study drug seems improbable because of 
factors such as inconsistency with known effects of the study drug; lack of a temporal 
association with study drug administration; lack of association of the event with study drug 
withdrawal or rechallenge; and/or presence of alternative explanations for the event. 
Alternative explanations might include a known relationship of the clinical event to a 
concomitant drug, past medical history of a similar event, the subject’s disease state, 
intercurrent illness, or environmental factors. 
 


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When assessing the relationship to the study drug, the following criteria will be considered: 
 
Positive rechallenge 
 
Positive dechallenge (resolution upon stopping suspect the study drug, in absence of other 
intervention or treatment) 
 
Known class effect 
 
Biological plausibility 
 
Lack of alternative explanation—concomitant drug or disease 
5.3 Reporting Procedures and Requirements 
5.3.1 Adverse Events 
Adverse events occurring from when the subject signs the ICF until the last study visit will be 
recorded in the eCRFs. Any AEs occurring before the start of study drug administration (ie, before 
the first dose of the study drug) will be recorded in the medical history. Any sign, symptom, or 
disease present before starting the administration of the study drug are only considered AEs if they 
worsen after starting the administration. 
If the investigator detects an AE in a study subject after the last scheduled follow-up visit and 
considers the event at least possibly related to prior study drug administration, the investigator is 
to report it to the sponsor. 
The investigator should report all AEs on the AE eCRF and within source documentation, 
regardless of seriousness, severity, and causality. Whenever possible, an AE will be reported using 
a diagnostic term, (e.g., “common cold” or “upper respiratory infection” rather than by the 
symptoms “runny nose, cough, mild fever”) and should be assessed for the attributes described in 
the Assessing Intensity and Relationship Section. 
5.3.2 Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria (refer to the Serious 
Adverse Events Section). If the AE is considered serious, the investigator should report this event 
to Neurocentria or their designee as outlined below and to the institutional review board (IRB) 
according to its standard operating procedures. 
If the investigator detects an SAE in a study subject after the last scheduled follow-up visit and 
considers the SAE at least possibly related to prior study drug use, the investigator is to report it 
to the sponsor. 
All information about SAEs will be collected and reported digitally via an electronic form. The 
investigator should complete the initial report within 24 hours of becoming aware of the SAE. At 
minimum, the initial report should include the following information: 
1. Event 
2. Protocol Number 
3. Subject number, initials, and date of birth 


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4.
Study drug
5.
Reporter name and contact information
In the case of a “minimum report” (one that solely comprises the information bulleted above), a 
more detailed follow-up report should be sent as soon as more information becomes available but 
no later than 7 calendar days after the date of the initial report. Each SAE should be followed up 
until resolution or stabilization and for reported deaths, the investigator should supply the sponsor 
and the IRB with any additional requested information (e.g., autopsy reports and terminal medical 
reports). The sponsor or its designee will be responsible for determining and in turn, reporting 
SAEs to regulatory authorities according to the applicable regulatory requirements. 
The sponsor must report in an IND safety report any Suspected Unexpected Serious Adverse 
Reactions (SUSARs) defined as a suspected adverse reaction to study drug (i.e., including active 
comparators) that is both serious and unexpected (21 CFR 312.32(c)(1)(i)). Before submitting an 
IND safety report, the sponsor needs to ensure that the event meets all three of the criterion below:   

Suspected adverse reaction

Serious

Unexpected
 If the adverse event does not meet all three criterion, it should not be submitted as an IND safety 
report. SUSARs will be reported to regulatory authorities within 7 calendar days for life 
threatening and fatal events, or 15 calendar days for all others. These timeframes begin with the 
first notification of the event from the reporting investigator to the sponsor (or designee), which 
represents the start of the regulatory clock (Day 0).  
The sponsor (or designee) will also provide all investigators with a safety letter describing the 
SUSAR. The information will be provided by e‑ mail within 15 calendar days from Day 0.  
5.3.3 Pregnancy 
Each female subject should be instructed to inform the investigator immediately if she becomes 
pregnant at any time between the start of study screening until 30 days after the last administration 
of study drug. All initial reports of pregnancy must be reported to the sponsor by the investigational 
staff within 24 hours of their knowledge of the event using the appropriate pregnancy notification 
form. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, stillbirth, and congenital anomaly) are 
considered serious adverse events and must be reported using the Serious Adverse Event Form. 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study. 
Follow-up information regarding the outcome of the pregnancy will be required to be reported on 
the pregnancy notification form. 


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6.0 DATA MANAGEMENT AND STATISTICAL ANALYSIS 
6.1 Data Management Considerations 
Electronic CRFs (eCRFs) will be employed for this study. Data will be entered into electronic 
CRFs within 3 business days by the investigator and/or the investigator’s dedicated site staff. 
Queries are to be responded to in a similar fashion. Data entered onto eCRFs are stored on a secure 
server and accessed via a secure website. The EDC system will be designed and validated by 
Neurocentria prior to activation for data entry by sites. The investigator must review data entered 
and electronically sign the eCRFs to verify their accuracy.  
This study will utilize EDC, a software toolset and workflow methodology for electronic collection 
and management of clinical and research data, to collect and store data. EDC software provides a 
secure, web-based application that provides an intuitive data manipulation interface, custom 
reporting capabilities, audit trail functionality, real-time data monitoring/querying of subject data, 
and variations of data exporting/importing.  
Access to the EDC system for data entry or review will require documentation of training. Data 
are collected within the EDC system to which the sponsor and site monitors have “read only” 
access. eCRF data will be reviewed routinely by sponsor and/or sponsor designated monitors.  
6.1.1 Data Clarification 
Sponsor and/or sponsor delegates may have questions or note discrepancies on entered data, as 
referred to as queries. Queries will be issued for any inconsistencies, omissions, and discrepancies 
and will be resolved by the appropriate parties. The sponsor and its delegates are the only parties 
that can generate a Manual Query. Entered data that falls outside parameters set by sponsor 
according to protocol may also create a System Generated Query. All corrections and clarifications 
will be entered into the EDC system and will be identified by the person entering the information, 
the time changes were made, and reason for change. If changes are made to a previously 
electronically signed eCRF, the investigator must confirm the changes and re-sign the page.  
The statistical analysis of these data will be performed by the sponsor or its representative. All 
AEs will be coded using the latest version of the Medical Dictionary for Regulated Activities 
(MedDRA). Prior and concomitant medications will be coded using the latest version of the World 
Health Organization Drug Dictionary. Data management details will be outlined in a separate data 
management plan. 
6.2 Statistical Considerations 
The statistical analysis will be undertaken by the sponsor or its representative. 
A detailed Statistical Analysis Plan (SAP) will be finalized and signed before database lock, before 
the randomization code for all subjects is broken, and before analysis of the study is carried out. 
Any deviations from the analyses described below will be included in the SAP, which will be 
included in the clinical study report. 


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6.2.1 Statistical Methods 
Descriptive summaries of variables by treatment group will be provided where appropriate. For 
continuous variables, the number of non-missing values (n) and the median, mean, standard 
deviation, minimum, and maximum will be tabulated by treatment group. For categorical 
variables, the counts and proportions of each value will be tabulated by treatment group. All 
statistical comparisons will be tested at two-sided alpha=0.05; however,  only those included in 
the multiplicity algorithm will be considered for significance. 
6.2.2 Power/Sample Size Analysis 
Previous studies of ADHD drugs using PERMP as the primary endpoint showed improvement of 
~10% with effect sizes approximately 0.4-0.7 (Wigal, Brams et al. 2010, Wigal, Brams et al. 2011, 
Wigal, Childress et al. 2018). In one study, Wigal et. al. reported a mean difference between 
treatment and placebo of 23.4  with a standard deviation of approximately 40.5 (effect size = 0.58) 
(Wigal, Brams et al. 2010). The effect size of currently approved ADHD drugs on reduction of 
core symtpom measurements is approxmatly 0.5-1.0 (Cortese, Adamo et al. 2018).  
To determine expected effect size for this study, Sponsor considered the effects of treatment on 
performance and core symptom reduction separately. In several previous studies with study drug, 
a cognitive performance evaluation was adminsitered with an improvement of approximatley 10% 
with active treatment. Typically, a 10% net improvement over placebo in PERMP is observed with 
ADHD drugs, with an effect size of approximatley 0.7 (Wigal, Brams et al. 2010, Wigal, Brams 
et al. 2011, Wigal, Childress et al. 2018). For reduction of core symptoms, NC-004 study showed 
reduction of AISRS with study drug was approximately 25%. With an estimated starting AISRS 
score of approximately 35 points, a 25% improvement is approximatley -8 to -9 points. Since the 
standard deviation of change for AISRS is approximately 13.5 (Spencer, Adler et al. 2010), the 
effect size is approximately 0.65. Based on this, Sponsor conservatively estimates an effect size of 
0.5 for PERMP and AISRS in this study.   
Sample size estimates for power = 85% were calculated using the following assumptions:  
 1:1 randomization ratio between placebo and NRCT-101SR 
 Two-sample t test 
 Two sided alpha = 2.5% 
 Effect size = 0.5 
Based on these, the total sample size for 85% power = 172. Due to the dual pimary outcomes and 
alpha control adjustment, an alpha of 0.025 is utilized and power is based on the above assumptions 
for PERMP; it is possible that the overall power, taking into account the additional primary of 
AISRS, is greater than 85%.To account for attrition increased variaiblity due to dropout, a total of 
approximately 216 subjects (108 in each treatment group) are planned for 85% power.  


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6.2.3 Analysis Populations 
The analysis populations will include the following: 
 The Safety Population will include all subjects who receive at least one dose of study drug. 
Subjects will be analyzed as treated. 
 The Intent-To-Treat (ITT) population will include all subjects who are randomized. 
Subjects will be analyzed as randomized. The ITT population is the primary population for 
the efficacy analyses. 
 The Modified Intent-To-Treat (MITT) population will include all subjects who are 
randomized, receive at least one dose of study drug, and have at least one non-missing 
post-baseline efficacy measurement (PERMP-C or AISRS). Subjects will be analyzed as 
randomized.  
 The Per Protocol (PP) population will include all subjects in the mITT population who did 
not incur a protocol violation that impacts the efficacy evaluation. Subjects will be 
analyzed as randomized. 
6.2.4 Protocol Deviations 
Summaries of key protocol deviations are to be maintained on the study protocol deviation log. 
Protocol deviations should be collected and grouped into different categories, such as: 
−those who entered the study even though they did not satisfy the entry criteria; 
−those who met withdrawal criteria during the study but were not withdrawn; 
−those who received the wrong study drug, incorrect dose, or who had poor study drug 
compliance; 
−those who received an excluded concomitant treatment.  
Major protocol violations will be determined by the principal investigator and sponsor prior to the 
unblinding of data and will lead to exclusion from the PP population. 
6.2.5 Subject Disposition 
The  number of  screening failures, study completers, and early terminations will be summarized. 
The number of subjects in each analysis popualtion will also be summarized. 
6.2.6 Demographic and Baseline Characteristics 
The baseline data will be summarized using the Safety, MITT, ITT, and PP populations.  
6.2.7 Measurement of Study Drug Compliance 
Compliance is defined as taking at least 80% but not more than 120% of study drug between each 
clinic visit. Subjects will return all bottles and unused tablets at each clinic visit. The number of 
tablets taken divided by the number of tablets the subject should have taken in between visits 
multiplied by 100% will be used to calculate study drug compliance.  


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6.3 Efficacy Analyses 
6.3.1 Dual Primary Estimand #1 PERMP-C 
 Population 
The target population is adults with ADHD as defined by the inclusion/exclusion criteria. 
 Variable 
This primary efficacy endpoint is defined as the change from Baseline to Week 6 in mean PERMP-
C score over course of the visit (post-dose). 
 Intercurrent Events 
A hybrid approach of treatment policy and hypothetical strategy will be used to address 
intercurrent events of study discontinuation. No special data handling will be used for other 
intercurrent events, such as subjects who initiate concomitant medications. Likewise, subjects that 
discontinue treatment but return for the Week 6 visit will have those data analyzed as 
reported.  Subjects that discontinue the study due to adverse events and lack of efficacy and 
consequently have missing data at Week 6 are assumed to be representative of subjects that would 
not continue to use the drug outside of a clinical trial and their missing values following 
discontinuation will be imputed using multiple imputation based off the distribution of placebo 
values at the matching time point, conditioned on the observed data (including baseline) and sex. 
All other missing values (both intermittent and following study discontinuation will be imputed 
using multiple imputation assuming that they are missing at random, conditioned on the observed 
data (including baseline) and sex. Sensitivity analyses will explore the results under different 
analysis assumptions. 
 Population-Level Summary 
The population-level summary will be the difference in least-square means between treatment 
arms (analyzed as randomized) at Week 6 from the primary analysis model. See below for details. 
6.3.2 Dual Primary Estimand #2 AISRS 
 Population 
The target population is adults with ADHD as defined by the inclusion/exclusion criteria. 
 Variable 
This primary efficacy endpoint is defined as the change from Baseline to Week 6 in AISRS score. 
 Intercurrent Events 
A hybrid approach of treatment policy and hypothetical strategy will be used to address 
intercurrent events study discontinuation. No special data handling will be used for other 
intercurrent events, such as subjects who initiate concomitant medications. Likewise, subjects that 
discontinue treatment but return for the Week 6 visit will have those data analyzed as 
reported. Subjects that discontinue the study due to adverse events and lack of efficacy and 
consequently have missing data at Week 6 are assumed to be representative of subjects that would 


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not continue to use the drug outside of a clinical trial and their missing values following 
discontinuation will be imputed using multiple imputation based off the distribution of placebo 
values at the matching time point, conditioned on the observed data (including baseline) and sex. 
All other missing values (both intermittent and following study discontinuation) will be imputed 
using multiple imputation assuming that they are missing at random, conditioned on the observed 
data (including baseline) and sex. Sensitivity analyses will explore the results under different 
analysis assumptions. 
 Population-Level Summary 
The population-level summary will be the difference in least-square means between treatment 
arms (analyzed as randomized) at Week 6 from the primary analysis model. See below for details. 
 
6.3.3 Primary Efficacy Endpoint – PERMP-C and AISRS 
6.3.3.1 Primary Efficacy Endpoint #1 
The first primary efficacy endpoint is the change in PERMP-C from baseline to Week 6 in those 
receiving NRCT-101SR compared to those receiving placebo. The primary analysis population 
will be the ITT population. 
PERMP is a timed (10-minute sessions) performance-based assessment for evaluating function in 
ADHD subjects. PERMP-C is the number of math problems answered correctly and typically 
ranges from 0-400 with higher scores indicating better performance. The PERMP total score 
(PERMP-T) is the sum of the number of math problems attempted (PERMP-A) and the number of 
math problems answered correctly (PERMP-C). The PERMP-T scores typically range from 0-800 
with higher scores indicating better performance. At each visit where collected (Baseline, Week 
3, and Week 6), PERMP-C from six post-dose time points (2, 4, 6, 8, 10, and 12 hours) will be 
averaged to get the PERMP-C score for analysis.  
The change from baseline in PERMP-C scores at the Week 3 and Week 6 visits will be compared 
between the treatment and placebo groups.  
The null hypothesis is that there is no significant effect of study drug type (NRCT-101SR versus 
placebo) on change in PERMP-C. The alternative hypothesis is that there is a significant effect of 
study drug type (NRCT-101SR versus placebo) on change in PERMP-C controlling for 
appropriate covariates and cofactors. Alpha ≤ 0.05 will be used as criteria for rejecting the null 
hypothesis and accepting the alternative hypothesis (see section 6.3.9 Multiplicity).  
The primary efficacy endpoint will be analyzed using a restricted maximum likelihood (REML)-
based mixed model for repeated measures (MMRM) with fixed effects for treatment group 
(NRCT-101SR and placebo), time (week 3, and week 6), the treatment-by-visit interaction, site 
(possibly using pooled sites), and sex. Baseline PERMP-C value will be included as a covariate. 
The outcome variables will be the PERMP-C change from baseline to each timepoint; the primary 
comparison will be the contrast between treatment groups at Week 6. An unstructured within-
subject covariance matrix will be utilized along with Kenward-Rogers denominator degrees of 
freedom. Should this fail to converge under the standard Newton-Raphson algorithm, the Fisher 


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scoring method will be attempted, followed by alternative methodology given in Lu, Mehrotra (Lu 
and Mehrotra 2010). In the unlikely event that none of these converge, the following structures 
will be attempted in order with the first to converge being selected: first-order ante dependence, 
heterogeneous first-order autoregressive, heterogeneous compound symmetry, and compound 
symmetry; sandwich estimator will be utilized for each. 
LS means and differences across the twenty MI reps (see missing data imputation below) will be 
combined using SAS procedure MIANALYZE (Rubin, 1976). Significance testing will be based 
on least-squares means and two-sided 95% confidence intervals will be presented. 
6.3.3.2 Primary Efficacy Endpoint #2 
The second primary efficacy endpoint is the change in AISRS from baseline to Week 6 in those 
receiving NRCT-101SR compared to those receiving placebo. The primary analysis population 
will be the ITT population. 
The null hypothesis is that there is no significant effect of study drug type (NRCT-101SR versus 
placebo) on change in AISRS. The alternative hypothesis is that there is a significant effect of 
study drug type (NRCT-101SR versus placebo) on change in AISRS controlling for appropriate 
covariates and cofactors. Alpha ≤ 0.05 will be used as criteria for rejecting the null hypothesis and 
accepting the alternative hypothesis (see section 6.3.9 Multiplicity). 
The change from baseline in AISRS will be analyzed using an MMRM similar to the primary 
efficacy endpoint #1. However the analysis of AISRS will also include values collected at week 1 
and will not require averaging within visit since it is collected only once at each visit.  
6.3.5 Missing Data Imputation 
Missing values for subjects in the ITT population will be imputed via multiple imputation (MI). 
When the study medication is discontinued due to lack of efficacy (LOE) or due to an adverse 
event (AE), missing values will be imputed drawing from the placebo distribution at the matching 
time points, conditioned on the obsevered data under the assumption that they are missing not at 
random (MNAR), with a covariate for sex. If the study medication was discontinued for any other 
reason (including impacts from the COVID-19 pandemic), values will be imputed within treatment 
group using MI under the assumption that they are missing at random (MAR) with covariates sex 
and observed values recorded at each time point. For the purposes of the imputation algorithm, AE 
discontinuations due solely to COVID and COVID sequelae will be included in the MAR 
imputation grouping. Subjects that withdraw due to COVID and have an independent, unrelated, 
adverse event that also results in study discontinuation will be included in the MNAR imputation 
grouping (with all other AE withdrawals other than the aforementioned COVID exclusion). The 
MAR approach will also be applied for sporadic missing values (prior to discontinuation). The MI 
process will use twenty repeats in the analysis datasets generated. 
The steps will be as follows: 
1. 
Intermittent missing values for both completers and dropouts prior to discontinuation will 
be imputed using the Markov Chain Monte Carlo (MCMC) method implemented with the SAS 
MI procedure. 


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2. 
For subjects that do not discontinue for LOE or AEs, a MAR imputation will be applied: 
the monotone missing values will be imputed with the SAS MI procedure using the monotone 
regression method. Baseline and the post-baseline scores at each visit will be included as covariates 
as well as sex; imputation will be done within treatment group. This will also apply for subjects 
that complete, but have their final value missing. 
3. 
For subjects that discontinue for LOE or AEs, values will be imputed using the placebo 
group as reference. Missing values will be imputed with the SAS MI procedure using the monotone 
regression method. Baseline and the post-baseline scores at each visit will be included as covariates 
as well as sex. 
Subjects that discontinue study drug or early terminate from the study but provide data will have 
all observed data used. 
6.3.6 Secondary Efficacy Analysis 
Secondary efficacy endpoints include: 
Key Secondary Efficacy Endpoints  
 
BRIEF-A 
 HADS 
Other Secondary Efficacy Endpoints  
 CGI-S 
 Responder Rate 
 AAQoL 
 AISRS Expanded Version  
The  change from baseline in the above secondary efficacy endpoints will be analyzed using an 
MMRM similar to the primary efficacy endpoint. For all endpoints, the time point of primary 
interest is week 6.  
Responder rate will be summarized descriptively and analyzed with a logistic regression model, 
providing odds ratio and 95% confidence interval. The number needed to treat (NNT) will be 
estimated by taking the reciprocal of the risk difference, i.e., 
 𝑁𝑁𝑇𝑟𝑒𝑠𝑝𝑜𝑛𝑑𝑒𝑟𝑠=
100
%𝑟𝑒𝑠𝑝𝑜𝑛𝑑𝑒𝑟𝑠𝑁𝑅𝐶𝑇−101𝑆𝑅 𝑔𝑟𝑜𝑢𝑝 − %𝑟𝑒𝑠𝑝𝑜𝑛𝑑𝑒𝑟𝑠𝑃𝑙𝑎𝑐𝑒𝑏𝑜 𝑔𝑟𝑜𝑢𝑝 
6.3.7 Other Endpoints 
 
 
 
 
 
 
  


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6.3.8 Sensitivity and Supportive Analyses 
Efficacy analyses (primary, key secondary, other secondary, and other endpoints) will also be 
performed using the mITT and PP populations as sensitivity analyses. The multiple imputation 
techniques will investigate inclusion of dropouts for lost to follow up and unspecified reasons 
among those utilizing the placebo distribution. A tipping point analysis will also be performed. 
Supportive analyses include analyses at Week 1 and Week 3 utilizing the MMRMs described 
above, including additional covariates in the models (e.g., age, sex, ADHD subtype score, prior 
ADHD medication and time of withdrawal prior to enrollment, neuropsychiatric symptoms as 
measured by HADS and 
 etc.), and subgroup analyses for the efficacy endpoints. 
Because PERMP is collected multiple times per visit, additional analyses will be performed 
comparing within visit timepoints (e.g., pre-dose vs. post-dose).  
 
 
6.3.9 Multiplicity 
The dual primary endpoints and key secondary efficacy endpoints will be tested with control for 
multiplicity. All tests will be two-sided. An alpha recycling approach will be utilized to maintain 
alpha = 0.05 and pass alpha to secondary endpoints. 
1. The 0.05 alpha will be split equally and 0.025 allocated to each of the dual primary 
endpoints (change from Baseline to Week 6 in PERMP-C and in AISRS). The smaller p-
value of the dual primary efficacy endpoints will be tested at the 0.025 level. 
2. If the endpoint with the smaller p-value is not significant at 0.025, all testing will halt and 
all p-values will be declared non-significant. 
3. If  significant at 0.025, it will be declared successful and its 0.025 alpha passed to the 
second of the dual primary endpoints. 
4. If the second of the dual primary endpoints is not significant at alpha=0.05, it will be 
declared non-significant, all testing will halt and all subsequent p-values will be declared 
non-significant; success will only be declared on the stronger endpoint (step 3). 
5. If the second of the dual primary endpoints is significant at alpha=0.05, it will be declared 
significant and the remaining alpha=0.05 passed to the key secondary endpoints. 
6. If the first key secondary endpoint (BRIEF-A) is significant at alpha=0.05, its 0.05 alpha 
will be passed to the second key secondary endpoint (HADS). 
7. No additional adjustments for multiplicity will be applied to any of the other endpoints; p-
values will be reported, but will be purely nominal. 
6.4 Safety Analyses 
Safety variables include adverse events, laboratory test results, ECG results, vital sign measures 
as well as change in C-SSRS responses completed throughout the study. Tolerability will be 


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calculated as the propotion of subjects in each group who discontinue from the study due to any 
adverse event. For tolerability, an Odds Ratio will be calculated comparing the tolerability in the 
NRCT-101SR group to the tolerability in the placebo group. 95% confidence intervals will be 
reported for the Odds Ratio.  
6.4.1 Extent of Exposure 
Extent of exposure will be described by whether the subject took any study drug along with the 
number of days of exposure (last date of dosing minus first day of dosing plus 1). If the date of 
last dosing is completely missing, then the date of last dosing will be taken for analysis purposes 
as the date the relevant study drug was last dispensed. If only the month of the last dose is recorded, 
the first day of the month will be assumed as the last dosing date. 
6.4.2 Adverse Events 
All AEs will be coded using the most up-to-date version of the Medical Dictionary for Regulatory 
Affairs (MedDRA). 
The incidence of treatment-emergent AEs (TEAEs) (number and percent of subjects reporting the 
AE at least once during the study), serious adverse events (SAEs), TEAEs related to study drug, 
SAEs related to study drug, and TEAEs leading to study discontinuation will be summarized by 
study drug. 
A TEAE is defined as any AE that has an onset on or after the dose of study drug, or any pre-
existing condition that has worsened on or after the first dose of study drug. 
The incidence of TEAEs and study drug administration-related TEAEs will also be summarized 
by maximum severity and most-related relationship to study drug by MedDRA primary system 
organ class and preferred term. The summary will include the total number and percentage of 
subjects reporting an event. In counting the number of events reported, a continuous event, i.e., 
reported more than once and which did not cease, will be counted only once; non-continuous AEs 
reported several times by the same subjects will be counted as multiple events. 
6.4.3 Electrocardiographic Data 
A list of subjects with abnormal 12-lead ECG parameters will be presented. Baseline and change-
from-baseline in ECG parameters (heart rate, cardiac rhythm, RR interval, QRS interval, 
uncorrected QT interval, and QTc interval) will be summarized at the Week 6 post-baseline time 
point. QT will be corrected using Fridericia’s correction (QTcF): QTC = QT/RR1/3. Accepted 
definitions for outliers (e.g., frequency counts of interval changes from baselines ≥ 30 and ≥ 60 
msec; QTc > 500 msec and QTc > 480 msec with change from baseline QTc > 60 msec) will be 
utilized as well as analyses of central tendency of active study drug vs placebo and active dose vs 
placebo. 
6.4.4 Vital Signs 
Summary statistics for the absolute vital sign value and the changes from baseline will be presented 
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Any incidence of clinically meaningful changes in heart rate (beats per minute), blood pressure 
(mmHg) and/or respiration (breaths per minute) will be summarized. A clinically meaningful 
change will be determined and at the discretion of the investigator. Vital signs are to be collected 
after subject has been sitting for at least 5 minutes.  
6.4.5 C-SSRS 
The questions of the C-SSRS will be presented in a listing of all responses for any subject with 
emergent increase in ideation or any suicidal behavior. 
6.4.6 Laboratory Data 
Mean changes from baseline at each post-baseline time point for each numeric laboratory variable 
will be presented. In addition, each reading will be classified as below, within, or above normal 
range, based on ranges supplied by the laboratory used. Shift tables for the baseline and follow-up 
measurements will be presented. 
6.5 PK Analysis 
Population PK modeling, for those receiving NRCT-101SR, will be conducted on plasma levels 
of threonic acid at pre-dose and 4 and 7 hours post-dose (with a 30-minute window) using 
appropriate structural modeling and covariates. 
6.6 Interim Analyses 
No interim analyses are planned. 
7.0 STUDY MANAGEMENT 
7.1 Ethics and Consent 
7.1.2 Regulations and Guidelines 
The study will be performed in accordance with this protocol, ICH guidelines for Good Clinical 
Practice (GCP), the regulations on electronic records and electronic signature (21 CFR 11), and 
the most recent guidelines of the Declaration of Helsinki. These guidelines are on file at 
Neurocentria, Inc. 
7.1.3 Institutional Review Board/Independent Ethics Committees 
Conduct of the study must be approved by an appropriately constituted institutional review board 
(IRB). Approval is required for the study protocol, protocol amendments, informed consent forms 
(ICFs), subject information sheets, and advertising materials. No study drug will be shipped to a 
site until written IRB authorization has been received by the sponsor or its representative. 
Sponsor/site representative will comply with the IRB requirements on submissions of adverse 
event reports, continuing review reports and major protocol deviation reports. Sites using a local 
IRB are required to submit all the IRB approved documents to Sponsor or their designee for 
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7.1.4 Informed Consent 
Before the start of the trial, the investigator will submit an informed consent form (ICF) and any 
other material to be provided to subjects to their IRB for review and approval. This review and 
approval will be documented and stored on site. The principal investigator or a designated 
representative will provide the sponsor or its representative with a blank copy of the IRB-approved 
ICF before the start of the study.  
For each eligible study subject , a signed ICF will be obtained before any protocol-related activities 
are initiated. As part of the subject consenting procedure, the investigator or a designated site 
representative must explain orally and in writing the nature, duration, and purpose of the study, 
and the action of the study drug in such a manner that the subject and legally authorized 
representative (LAR; if applicable) are aware of the potential risks, inconveniences, or adverse 
effects that may occur. Subjects and LARs (if applicable) will be asked to read and review the 
consent form.  
All questions should be answered to subject’s (or LAR’s if applicable) satisfaction by the study 
Investigator or the delegated site staff, before signing the ICF. Subjects should be informed that 
they may withdraw from the study at any time.  
Subject (or LAR if applicable) must sign the ICF prior to starting any study procedures being done 
specifically for this trial. Copies of the signed ICF will be provided to the subject (or LAR if 
applicable). 
7.2 IRB and Investigator Responsibilities: 
The protocol and the ICF template must be reviewed and approved by a properly constituted IRB 
before study start. Properly constituted IRB is defined in ICH Guideline for Good 
Clinical Proactive E6 (R1), section 3. A signed and dated statement that the protocol and 
informed consent have been reviewed and approved by the IRB must be given to Neurocentria 
before study initiation. Prior to study start and any time the protocol is amended during study 
conduct, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and give access to all relevant data and records to 
Neurocentria and designated representatives.  
The investigator is also responsible for ensuring that all persons assisting with the trial are 
adequately qualified, and informed about the protocol, any amendments to the protocol, the study 
drug, and their study-related duties and functions. The investigator should maintain a list of sub-
investigators and other appropriately qualified persons to whom he or she has delegated 
significant study-related duties.  
The investigator should not implement any deviation from, or changes to, the protocol without 
agreement by the sponsor and prior review and documented approval from the IRB of 
an  amendment, except where necessary to eliminate an immediate hazard(s) to study 
subjects, or when the change(s) involves only logistical or administrative aspects of the study 
(e.g., change in monitor(s), change of telephone number(s)). In addition, the investigator, or 
person designated by the investigator, should document and explain any deviation from the 
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as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the 
proposed protocol amendment(s) should be submitted: (a) to the IRB for review and approval, (b) 
to the sponsor for agreement and, if required, (c) to the regulatory authority(ies). 
The IRB and, if applicable, the authorities must be informed of all subsequent protocol 
amendments and administrative changes, in accordance with local legal requirements. 
Amendments must be evaluated to determine whether formal approval must be sought and whether 
the informed consent document should also be revised.  
 The investigator must keep a record of all communication with the IRB and, if applicable, between 
a coordinating investigator and the IRB. This also applies to any communication between the 
investigator (or coordinating investigator, if applicable) and the authorities. 
Investigators will apply due diligence to avoid protocol deviations. All significant protocol 
deviations will be recorded and reported in the Clinical Study Report. 
7.3 Confidentiality 
Subject names or initials will not be supplied to the sponsor. Only the subject number will be 
recorded in the eCRF, and if the subject name appears on any other document (e.g., laboratory 
report), it must be obliterated on the copy of the document before being supplied to the sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be informed that representatives of the sponsor, institutional review boards 
(IRBs), or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws. The investigator will 
maintain on-site a personal subject identification list (subject numbers with the corresponding 
subject names) to enable records to be identified. 
7.4 Discontinuation of the Study by the Sponsor 
The sponsor reserves the right to discontinue the study at a site or at multiple sites for safety or 
administrative reasons at any time. In particular, a site that does not recruit at a reasonable rate, 
has excessive protocol and/or outcome measure administration deviations may be discontinued. 
Should the study be terminated and/or a site closed for whatever reason, all documentation and 
study drug pertaining to the study must be returned to the sponsor or its representative. 
7.5 Study Documentation 
By signing a copy of Form FDA 1572, the principal investigator assures the sponsor that he/she 
will comply with the protocol and the provisions stated in Form FDA 1572. No changes in this 
protocol can be made without the sponsor’s written approval. 
7.6 Study Monitoring and Auditing 
This study will be monitored for quality assurance at all stages of its development by the clinical 
research personnel employed by the sponsor or its representative. Monitoring will include on-site 


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visits, telephone communication and remote monitoring to assure that the investigation is 
conducted according to the protocol, standard operating procedures, Guidelines of Good Clinical 
Practice, and applicable regulatory requirements. Quality control procedures will be applied to 
each stage of data handling to ensure that all data are reliable and have been processed correctly. 
On-site review of eCRFs will include a review of forms for completeness and clarity, and 
consistency with source documents available for each subject. Note that a variety of original 
documents, data, and records will be considered as source documents in this study. The eCRF itself 
is not to be used as a source document under any circumstances.  
Sponsor, medical advisors, and clinical research associates (CRAs) or assistants may request to 
witness subject assessments (in person or via video/audio recordings) conducted by study 
clinicians or study coordinators at one or more on-site study visits occurring as part of this protocol. 
These recordings will be used to evaluate the quality of the data obtained and ensure consistency 
among clinicians administering these assessments. The recordings may be retained for up to 5 
years. The investigator and appropriate site personnel will be periodically requested to attend 
meetings/workshops organized by the sponsor to assure acceptable protocol execution.  
The study may be audited by the sponsor, its designee or by regulatory authorities. If such an audit 
occurs, the investigator must agree to allow access to required subject records. By signing this 
protocol, the investigator grants permission to personnel from the sponsor, its designee, and 
appropriate regulatory authorities, for on-site monitoring of all appropriate study documentation, 
as well as on-site review of the procedures employed in eCRF generation, where clinically 
appropriate. 
7.7 Retention of Records 
The investigator must arrange for retention of study records for 2 years after the investigational 
product’s new drug application (NDA) is approved or the IND is withdrawn/abandoned, as 
required by FDA regulations. The investigator should take measures to prevent accidental or 
premature destruction of these documents. 
7.8 Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for the 
purposes of national and international registration. If necessary, the authorities will be notified of 
the investigator’s name, address, qualifications, and extent of involvement. Reports covering 
clinical and biometric aspects of the study will be prepared by the sponsor or its representative. 
 


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8.0 REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP_001.pdf: 
Neurocentria, Inc 
Statistical Analysis Plan: NC-018
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STATISTICAL ANALYSIS PLAN 
 
STUDY TITLE: 
Clinical Trial to Evaluate the Safety and Efficacy of NRCT-101SR in Adult Attention Deficit 
Hyperactivity Disorder 
PROTOCOL NUMBER:  
 
 
 
NC-018 
NCT#: 
NCT05683249 
CLIENT: 
Neurocentria, Inc 
IND 
NUMBER(S): 
159057 
PREPARED BY: 
 
 
 
 
 
 
 
 
 
This document is confidential and proprietary to Neurocentria, Inc. This study is being conducted in compliance 
with good clinical practice, including the archiving of essential documents. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of Neurocentria, Inc, except that this 
document may be disclosed to appropriate Institutional Review Boards under the condition that they keep the 
information confidential. 
 
 
 




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VERSION HISTORY 
 
SAP Version 
Version Date 
Change(s) 
Rationale 
1.0 
2023-10-23 
Initial Draft 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
PURPOSE OF THE ANALYSES ..............................................................................10 
2. 
PROTOCOL SUMMARY ..........................................................................................11 
2.1. 
Study Schema .............................................................................................................12 
3. 
ANALYSIS SAMPLES..............................................................................................13 
3.1. 
All Subjects Population ..............................................................................................13 
3.2. 
Safety Population ........................................................................................................13 
3.3. 
Intent-to-Treat Population ..........................................................................................13 
3.4. 
Modified Intent-to-Treat Population ...........................................................................13 
3.5. 
Per Protocol Population ..............................................................................................13 
4. 
ESTIMANDS FOR DUAL PRIMARY ENDPOINTS ..............................................14 
4.1. 
Dual Primary Estimand #1 PERMP-C .......................................................................14 
4.2. 
Dual Primary Estimand #2 AISRS .............................................................................14 
5. 
STUDY SUBJECTS ...................................................................................................16 
5.1. 
Disposition of Subjects ...............................................................................................16 
5.2. 
Demographic and Other Baseline Characteristics ......................................................16 
5.3. 
Prior and Concomitant Medications/Therapies ..........................................................16 
5.4. 
Medical History ..........................................................................................................17 
5.5. 
Substance Use .............................................................................................................17 
6. 
STUDY OPERATIONS .............................................................................................18 
6.1. 
Protocol Deviations ....................................................................................................18 
6.2. 
Randomization ............................................................................................................18 
6.3. 
Measures of Treatment Compliance and Exposure ....................................................18 
7. 
GENERAL ANAYLSIS AND REPORTING CONSIDERATIONS ........................20 
7.1.1. 
Multicenter Studies .....................................................................................................20 
7.1.2. 
Assessment Time Windows ........................................................................................20 
7.1.3. 
Timing of Analyses .....................................................................................................20 
7.1.4. 
Multiple Comparisons/Multiplicity ............................................................................20 
7.1.5. 
Power and Sample Size ..............................................................................................21 
8. 
ENDPOINT EVALUATION .....................................................................................22 
8.1. 
Dual Primary Endpoint #1 ..........................................................................................22 


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8.1.1. 
Computation of the Dual Primary Endpoint #1 ..........................................................22 
8.1.2. 
Primary Analysis of the Dual Primary Endpoint #1 ...................................................22 
8.1.3. 
Sensitivity Analyses of the Dual Primary #1 Analysis ...............................................23 
8.1.4. 
Secondary Analyses of the Dual Primary Endpoint #1 ..............................................23 
8.2. 
Dual Primary Endpoint #2 ..........................................................................................24 
8.2.1. 
Computation of the Dual Primary Endpoint #2 ..........................................................24 
8.2.2. 
Primary Analysis of the Dual Primary Endpoint #2 ...................................................24 
8.2.3. 
Sensitivity Analyses of the Dual Primary #2 Analysis ...............................................25 
8.2.4. 
Secondary Analyses of the Dual Primary Endpoint #2 ..............................................25 
8.3. 
Missing Data Imputation ............................................................................................26 
8.4. 
Secondary Endpoints ..................................................................................................27 
8.4.1. 
Key Secondary Endpoints ...........................................................................................27 
8.4.2. 
Additional Secondary Endpoints and Other Endpoints ..............................................27 
9. 
SAFETY EVALUATION ..........................................................................................29 
9.1. 
Overview of Safety Analysis Methods .......................................................................29 
9.2. 
Adverse Events ...........................................................................................................29 
9.3. 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ..................30 
9.4. 
Clinical Laboratory Evaluation ...................................................................................30 
9.5. 
Vital Signs, ECGs, Physical Findings, and Other Observations Related to 
Safety ..........................................................................................................................30 
9.5.1. 
Vital Signs ..................................................................................................................30 
9.5.2. 
ECGs ...........................................................................................................................31 
9.5.3. 
Physical Examinations ................................................................................................31 
9.5.4. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................31 
9.5.5. 
Pregnancy Reporting ..................................................................................................31 
10. 
OTHER ANALYSES .................................................................................................32 
10.1. 
Exploratory Analyses ..................................................................................................32 
10.2. 
PK Analysis ................................................................................................................32 
11. 
INTERIM ANALYSES ..............................................................................................33 
12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................34 
13. 
REFERENCES ...........................................................................................................35 


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14. 
APPENDIX.................................................................................................................36 
14.1. 
Schedule of Events .....................................................................................................36 
14.2. 
Random Seeds ............................................................................................................37 
15. 
ATTACHMENTS .......................................................................................................39 


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LIST OF ABBREVIATIONS 
List of Abbreviations 
Abbreviation 
Definition 
AAQoL 
Adult ADHD Quality of Life scale 
ADHD 
Attention Deficit Hyperactivity Disorder 
AE 
Adverse Event 
AISRS 
ADHD Investigator Symptom Rating Scale 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BRIEF-A 
Behavior Rating Inventory Executive Function for Adults 
CGI-S 
Clinical Global Impression - Severity 
CI 
Confidence interval 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
ET 
Early Termination 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
IRT 
Interactive Response Technology 


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Abbreviation 
Definition 
LC 
Laboratory Classroom 
LOE 
Lack of Efficacy 
LS 
Least Squares 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mg 
Milligram 
MI 
Multiple Imputation 
MEWS 
Mind Excessive Wandering Scale 
MITT 
Modified Intent-To-Treat 
mmHg 
Millimeters of mercury 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not at Random 
msec 
Millisecond 
PCRS 
Placebo Control Reminder Script 
PERMP 
Permanent Product Measure of Performance 
PERMP-A 
Permanent Product Measure of Performance  Attempted  
PERMP-C 
Permanent Product Measure of Performance  Correct 
PERMP-T 
Permanent Product Measure of Performance  Total  
PK 
Pharmacokinetics 
PP 
Per Protocol  
PROMIS-SD-
SF 
Patient Reported Outcomes Measurement Information System - Sleep 
Disturbance - Short Form 
PT 
Preferred Term 
QTc 
Corrected QT interval 
RBC 
Red Blood Cells 
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


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Abbreviation 
Definition 
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 


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1. 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Protocol 
NC-018 (Clinical Trial to Evaluate the Safety and Efficacy of NRCT-101SR in Adult Attention 
Deficit Hyperactivity Disorder).  
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the US Food and Drug Administration (FDA), European Medicines Agency 
(EMA), and International Council for Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials.  All work planned and reported for this SAP will follow internationally accepted 
guidelines for statistical practice, as published by the American Statistical Association and the 
Royal Statistical Society. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts.  Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any post-
hoc, or unplanned exploratory analysis performed will be clearly identified as such in the final 
CSR. 
In preparing this SAP, the following documents were reviewed in addition to the literature 
references cited in this SAP: 
- 
Clinical Research Protocol NC-018, Version 5.0 dated 27 FEB 2023  
- 
ICH Guidance on Statistical Principles for Clinical Trials (E9) 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study.  Operational aspects relating to 
collection and timing of planned clinical assessments are not repeated in this SAP unless they are 
relevant to the planned analysis. 


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2. 
PROTOCOL SUMMARY 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-arm design, 
laboratory classroom (LC) trial to assess the efficacy and safety of NRCT-101SR 
 
compared to inactive placebo 
over a 6-
18 years of age with Attention Deficit 
Hyperactivity Disorder (ADHD). The study population will include adult male and female 
subjects of all race/ethnicity with ADHD, recruited from sites across the US. All subjects will 
either be naïve to stimulant or non-stimulant ADHD medications, or prior to enrollment, have 
been off stimulants for at least 2 weeks and non-stimulants for at least 3 weeks.  
Total subject participation in the study is up to approximately 13 weeks, including a screening 
period (up to 6 weeks), a 6-week treatment period, and an approximate 1-week follow-up period. 
Each study subject will be randomized into one of two groups (1:1) to receive either active drug 
or placebo during the entirety of the 6-week treatment period. Within 8 days of Baseline LC 
visit, subjects will complete an LC Orientation Visit. At the Baseline LC visit, subjects will be 
randomized, assigned to a group, and dispensed study drug (first dose to be taken the next 
morning). The primary endpoints of the study include Permanent Product Measure of 
Performance (PERMP) Math Tests and the ADHD Investigator Symptom Rating Scale (AISRS). 
To familiarize the subjects with the PERMP, prior to the Baseline LC visit, they will complete 
8 practice PERMP assessments (3 at screening and 5 at the LC Orientation visit). LC visits will 
be repeated at Week 3 and Week 6. Secondary and exploratory assessments will also be 
conducted at the Baseline, Week 3, and Week 6 LC visits. A clinic visit will be conducted at 
Week 1 to administer AISRS with expanded version, Hospital Anxiety and Depression Scale 
(HADS), and Behavior Rating Inventory Executive Function for Adults (BRIEF-A). Safety 
assessments (concomitant medications, adverse events [AEs], and suicide risk) will be conducted 
at all clinic and remote visits/phone calls (Week 5, and follow-up); safety labs will be conducted 
at screening, Week 3, and Week 6. For population pharmacokinetic (PK) analysis, PK sampling 
will be conducted at the Week 3 LC visit. Blood samples for PK will be collected prior to dosing, 
at 4 hours and 7 hours after dosing (with a 30-minute window). See Study Schema and Schedule 
of Events below. 
The primary analysis will be on effects of 6-week treatment of NRCT-101SR versus placebo on 
performance and ADHD core symptoms in subjects with adult ADHD. The dual primary 
endpoints are PERMP (performance) and AISRS (core symptoms). The study will be declared 
successful by reaching statistical significance on either primary endpoint with adjustment for 
multiplicity.  
Randomization will be stratified by:  
 Site 
 LC cohort 
 Sex (approximately equal number of male and female in the study) 
 


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2.1. 
Study Schema 
 


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3. 
ANALYSIS SAMPLES 
Five populations will be utilized for the analyses of data.  
3.1. 
All Subjects Population 
This includes all subjects available in the electronic data capture system and will be used to 
display the disposition of subjects; subjects will be presented by their randomized treatments (if 
applicable). 
3.2. 
Safety Population 
The Safety Population will include all subjects who receive at least one dose of study drug. 
Subjects will be analyzed as treated; this population will be used for reporting of safety 
outcomes. 
3.3. 
Intent-to-Treat Population 
The Intent-To-Treat (ITT) population will include all subjects who are randomized. Subjects will 
be analyzed as randomized. The ITT population is the primary population for the efficacy 
analyses. 
3.4. 
Modified Intent-to-Treat Population 
The Modified Intent-To-Treat (mITT) population will include all subjects who are randomized, 
receive at least one dose of study drug, and have at least one non-missing post-baseline efficacy 
measurement (PERMP-C or AISRS). Subjects will be analyzed as randomized. 
3.5. 
Per Protocol Population 
The Per Protocol (PP) population will include all subjects in the mITT population who did not 
incur a protocol violation that impacts the efficacy evaluation. Subjects will be analyzed as 
randomized. 


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4. 
ESTIMANDS FOR DUAL PRIMARY ENDPOINTS 
4.1. 
Dual Primary Estimand #1 PERMP-C  
Population 
The target population is adults with ADHD as defined by the inclusion/exclusion criteria. 
Variable 
This primary efficacy endpoint is defined as the change from Baseline to Week 6 in mean 
PERMP-C score over the course of the visit (post-dose). 
Intercurrent Events 
A hybrid approach of treatment policy and hypothetical strategy will be used to address 
intercurrent events of study discontinuation. No special data handling will be used for other 
intercurrent events, such as subjects who initiate concomitant medications. Likewise, subjects 
that discontinue treatment but return for the Week 6 visit will have those data analyzed as 
reported. Subjects that discontinue the study due to AEs and lack of efficacy (LOE) and 
consequently have missing data at Week 6 are assumed to be representative of subjects that 
would not continue to use the drug outside of a clinical trial and their missing values following 
discontinuation will be imputed using multiple imputation (MI), based off the distribution of 
placebo values at the matching time point, conditioned on the observed data (including baseline) 
. All other missing values (both intermittent and following study discontinuation) will be 
imputed using MI assuming that they are missing at random, conditioned on the observed data 
(including baseline)
. Sensitivity analyses will explore the results under different analysis 
assumptions. 
Population-Level Summary 
The population-level summary will be the difference in least-square means between treatment 
arms (analyzed as randomized) at Week 6 from the primary analysis model. See Section 8.1.2 for 
details.  
4.2. 
Dual Primary Estimand #2 AISRS  
Population 
The target population is adults with ADHD as defined by the inclusion/exclusion criteria. 
Variable 
This primary efficacy endpoint is defined as the change from Baseline to Week 6 in AISRS 
score. 
Intercurrent Events 
A hybrid approach of treatment policy and hypothetical strategy will be used to address 
intercurrent events of study discontinuation. No special data handling will be used for other 
intercurrent events, such as subjects who initiate concomitant medications. Likewise, subjects 
that discontinue treatment but return for the Week 6 visit will have those data analyzed as 


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reported. Subjects that discontinue the study due to AEs and LOE and consequently have 
missing data at Week 6 are assumed to be representative of subjects that would not continue to 
use the drug outside of a clinical trial and their missing values following discontinuation will be 
imputed using MI based off the distribution of placebo values at the matching time point, 
conditioned on the observed data (including baseline) 
. All other missing values (both 
intermittent and following study discontinuation) will be imputed using MI assuming that they 
are missing at random, conditioned on the observed data (including baseline) 
. Sensitivity 
analyses will explore the results under different analysis assumptions. 
Population-Level Summary 
The population-level summary will be the difference in least-square means between treatment 
arms (analyzed as randomized) at Week 6 from the primary analysis model. See Section 8.2.2 for 
details. 
  


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5. 
STUDY SUBJECTS 
5.1. 
Disposition of Subjects 
The number and percentage of subjects in each analysis population will be summarized. The 
number of subjects screened, subjects enrolled, and the number and percentage of subjects 
completing treatment, discontinuing from treatment and reasons for treatment discontinuation 
will also be reported. Likewise, this will be repeated for study status: subjects completing the 
study, discontinuing from the study and reasons for study discontinuation will be reported. All 
percentages will be calculated using the number of subjects enrolled as the denominator. 
All disposition data will also be provided in a data listing. 
5.2. 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, race/ethnicity, height, weight, 
body mass index (BMI), will be summarized by treatment group and overall for the ITT, mITT, 
PP, and Safety populations. Categorical items will be reported with counts and percentages; 
continuous items will be reported using summary statistics (mean, standard deviation [SD], 
median, minimum, maximum). 
Additionally, the characteristics listed above will be presented in a data listing. 
5.3. 
Prior and Concomitant Medications/Therapies 
All medications taken within 3 months before screening, or any ADHD drug taken within 6 months 
before screening through study discontinuation, will be recorded in the electronic case report form 
(eCRF). 
Prior treatments are defined as any treatment taken before study drug administration. Concomitant 
treatments are defined as treatments taken after the first dose of study drug. In the case of missing 
or partial dates, medications will be considered concomitant unless the available data excludes that 
possibility. 
All medications will be coded using the World Health Organization Drug Dictionary (WHO-DD 
2022-MAR, Global B3). Prior and concomitant medications will be summarized for the safety 
population by treatment group and by the number and percentage of subjects taking each 
medication, classified by using WHO-DD Anatomical Therapeutic Chemical (ATC) Level 3 and 
preferred term (PT). 
All data related to prior and concomitant medications will also be presented in a data listing, with 
a flag included to indicate whether a medication was prior and/or concomitant. 
Concomitant procedures will be presented in a listing. 


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5.4. 
Medical History 
Medical History will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
v25.0) and summarized for the safety population by system organ class (SOC) and PT using 
frequency counts and percentages by treatment group.   
5.5. 
Substance Use 
Data collected on substance use history will be provided in a data listing for all subjects in the 
Safety Population. 


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6. 
STUDY OPERATIONS 
6.1. 
Protocol Deviations 
Protocol deviations will be maintained on the study protocol deviation log. Protocol deviations 
will be collected and grouped into different categories, such as: 
 Those who entered the study even though they did not satisfy the entry criteria. 
 Those who met withdrawal criteria during the study but were not withdrawn. 
 Those who received the wrong study drug, incorrect dose, or who had poor study drug 
compliance. 
 Those who received an excluded concomitant treatment. 
Protocol violations that impact efficacy evaluations will be determined by the principal 
investigator and sponsor prior to the unblinding of data and will lead to exclusion from the PP 
population. 
Protocol deviations will be summarized by type, status as major or minor, and by treatment 
group for the Safety Population. 
Individual protocol deviations will be listed by subject. 
6.2. 
Randomization 
This is a double-blind study. Unless otherwise specified, all study personnel are to remain 
blinded to study drug prior to database lock and final analysis following study unblinding. 
Computer-generated randomization codes for each study arm will be assigned through 
Interactive Response Technology (IRT), with restrictions on the total number of subjects 
assigned to each group, thereby limiting imbalance in numbers between groups. Randomization 
will be stratified by site and LC cohort, to ensure approximately equal number of those on 
NRCT-101SR and placebo, and sex, to ensure approximately equal numbers of male and female 
subjects in NRCT-101SR and placebo groups. At randomization, the subject will automatically 
be assigned by IRT unique subject bottle numbers from the available stock on-site. The 
investigational product (IP) dispensation, accountability and destruction status will be maintained 
in the IRT system. The subject randomization status will also be maintained in the IRT system. 
6.3. 
Measures of Treatment Compliance and Exposure 
The treatment duration will be calculated and summarized for the safety population using 
summary statistics based on case report form (CRF) data for first and last dose dates (number of 
days = last dose date  first dose date + 1). If the date of last dosing is completely missing, then 
the date of last dosing will be taken for analysis purposes as the date the relevant study drug was 
last dispensed. If only the month of the last dose is recorded, the first day of the month will be 
assumed as the last dosing date. 


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Compliance is defined as taking at least 80% but not more than 120% of study drug between 
each clinic visit. Subjects will return all bottles and unused tablets at each clinic visit. The 
number of tablets taken divided by the number of tablets the subject should have taken in 
between visits multiplied by 100% will be used to calculate study drug compliance. 
Compliance as a percentage will be summarized for the Safety Population with descriptive 
statistics by treatment arm. The number and percentages of subjects within certain categories of 
compliance (e.g., 
20%, > 120%) will also be presented. 
A listing of drug accountability and study drug exposure data based on CRF data will be 
provided. 


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7. 
GENERAL ANAYLSIS AND REPORTING CONSIDERATIONS 
7.1.1. 
Multicenter Studies 
This is a multicenter study. Unless otherwise specified, data from all study sites will be pooled 
for all analyses. 
For the purposes of modeling, a pooled variable may be utilized where sites with fewer than 
5 subjects will be pooled into a single large site. If there are convergence issues, this will be 
repeated with a threshold of 10. If there are only 1-2 small sites that still result in insufficient 
counts when pooled, then they will be pooled with the next smallest site. 
7.1.2. 
Assessment Time Windows 
Subjects who withdraw/drop out from the study will have the early termination (ET) data 
collected at their ET visit included in the analysis at the closest visit where a given assessment 
should be collected per the schedule of assessments (Week 1, 3, 5, 6), using midpoints between 
visits to window the early termination. If this results in two records for a given visit, then the 
scheduled visit will be used, followed by the record closest to the targeted date.  
7.1.3. 
Timing of Analyses 
All final, planned analyses will be performed after the last subject has completed all study 
assessments, all relevant study data have been processed and integrated into the analysis 
database, and the database has been locked.  
Any post-hoc, exploratory analyses completed to support planned study analysis, which were not 
identified in this SAP, will be documented, and reported in appendices to the CSR. Any results 
from these unplanned analyses (post-hoc) will also be clearly identified in the text of the CSR. 
7.1.4. 
Multiple Comparisons/Multiplicity 
The dual primary endpoints and key secondary efficacy endpoints will be tested with control for 
multiplicity. All tests will be two-sided. An alpha recycling approach will be utilized to maintain 
alpha = 0.05 and pass alpha to secondary endpoints. 
1. The 0.05 alpha will be split equally and 0.025 allocated to each of the dual primary 
endpoints (change from Baseline to Week 6 in PERMP-C and in AISRS). The smaller 
p-value of the dual primary efficacy endpoints will be tested at the 0.025 level. 
2. If the endpoint with the smaller p-value is not significant at 0.025, all testing will halt and 
all p-values will be declared non-significant. 
3. If significant at 0.025, it will be declared successful and its 0.025 alpha passed to the 
second of the dual primary endpoints. 
4. If the second of the dual primary endpoints is not significant at alpha = 0.05, it will be 
declared non-significant, all testing will halt and all subsequent p-values will be declared 
non-significant; success will only be declared on the stronger endpoint (step 3). 


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5. If the second of the dual primary endpoints is significant at alpha = 0.05, it will be 
declared significant and the remaining alpha = 0.05 passed to the key secondary 
endpoints. 
6. If the first key secondary endpoint (BRIEF-A) is significant at alpha = 0.05, its 0.05 
alpha will be passed to the second key secondary endpoint (HADS). 
7. No additional adjustments for multiplicity will be applied to any of the other endpoints; 
p-values will be reported, but will be purely nominal. 
7.1.5. 
Power and Sample Size 
Sample size estimates for power = 85% were calculated using the following assumptions: 
 1:1 randomization ratio between placebo and NRCT-101SR 
 Two-sample t test 
 Two sided alpha = 2.5% 
 Effect size = 0.5 
Based on these, the total sample size for 85% power = 172. Due to the dual pimary outcomes and 
alpha control adjustment, an alpha of 0.025 is utilized and power is based on the above 
assumptions for PERMP; it is possible that the overall power, taking into account the additional 
primary of AISRS, is greater than 85%. To account for increased variaiblity due to dropout, a 
total of approximately 216 subjects (108 in each treatment group) are planned for 85% power. 


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8. 
ENDPOINT EVALUATION 
8.1. 
Dual Primary Endpoint #1 
The first primary efficacy endpoint is the change in PERMP-C from Baseline to Week 6 in those 
receiving NRCT-101SR compared to those receiving placebo. The primary analysis population 
will be the ITT population. 
8.1.1. 
Computation of the Dual Primary Endpoint #1 
PERMP is a timed (10-minute sessions) performance-based assessment for evaluating function 
in ADHD subjects. PERMP-C is the number of math problems answered correctly and typically 
ranges from 0 to 400, with higher scores indicating better performance. The PERMP total score 
(PERMP-T) is the sum of the number of math problems attempted (PERMP-A) and the number 
of math problems answered correctly (PERMP-C). The PERMP-T scores typically range from 
0 to 800, with higher scores indicating better performance.  
At each visit where collected (Baseline, Week 3, and Week 6), PERMP-C from six post-dose 
time points (2, 4, 6, 8, 10, and 12 hours) will be averaged across the time points to get the 
PERMP-C score for analysis. The change from Baseline in PERMP-C scores at the Week 3 and 
Week 6 visits will be calculated as this average across time points at a given visit minus the 
average across time points at baseline.  
Missing data will be imputed as described in Section 8.3 below. 
8.1.2. 
Primary Analysis of the Dual Primary Endpoint #1 
Summary statistics (mean, SD, median, minimum, maximum) for the primary efficacy endpoint 
will be reported for the change from Baseline to Week 6 for each of the treatment groups. The 
primary efficacy endpoint will be analyzed using a restricted maximum likelihood (REML)-
based mixed model for repeated measures (MMRM) with fixed effects for treatment group 
(NRCT-101SR and placebo), time (Week 3 and Week 6), the treatment-by-visit interaction; sex 
and baseline PERMP-C value will be included as a fixed covariates and site (possibly pooled) as 
a random effect. The outcome variables will be the PERMP-C change from baseline to each 
timepoint; the primary comparison will be the contrast between treatment groups at Week 6. An 
unstructured within-subject covariance matrix will be utilized along with Kenward-Rogers 
denominator degrees of freedom. Should this fail to converge under the standard Newton-
Raphson algorithm, the Fisher scoring method will be attempted, followed by alternative 
methodology given in Lu, Mehrotra (Lu and Mehrotra 2010). In the unlikely event that none of 
these converge, the following structures will be attempted in order with the first to converge 
being selected: first-order ante dependence, heterogeneous first-order autoregressive, 
heterogeneous compound symmetry, and compound symmetry; sandwich estimator will be 
utilized for each. 
Least squares (LS) means and differences across the 20 MI reps (see missing data imputation 
Section 8.3 below) will be combined using SAS procedure MIANALYZE (Rubin, 1976). 
Significance testing will be based on least-squares means and two-sided 95% confidence 
intervals (CIs) will be presented. 


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8.1.3. 
Sensitivity Analyses of the Dual Primary #1 Analysis 
The following sensitivity analyses will be performed: 
8.1.3.1. 
Multiple Imputation  Lost to Follow-
Random 
The primary analysis will be repeated using the same MI approach, but subjects that drop out 
with loss to follow-
ason will be grouped with LOE and AE 
dropouts in the imputation algorithm. 
8.1.3.2. 
Multiple Imputation  Baseline as reference distribution for Missing Not at 
Random 
The primary analysis will be repeated using the same MI approach, but subjects that drop out for 
LOE and AE will be imputed using the distribution of the baseline values. This investigates an 
alternative hypothetical strategy where instead of assuming the values will revert to the 
distribution in the placebo group, all subjects (placebo and active) are assumed to revert to the 
distribution of baseline values. 
8.1.3.3. 
Multiple Imputation Tipping Point 
A tipping point analysis will be performed using the above MI datasets and applying an 
increasing penalty delta (PERMP-C) to the active group until statistical significance is no longer 
achieved. The delta will only be applied to imputed values; this will be done in 5-point 
increments on the PERMP-C score. This will only be performed if the primary analysis is 
significant. This will test the overall robustness of the primary analysis. 
8.1.4. 
Secondary Analyses of the Dual Primary Endpoint #1 
The following secondary and supporting analyses will be performed: 
 PERMP-C will be analyzed at each visit comparing the within visit timepoints using the 
change from baseline to each time-matched value. These will be analyzed using a REML-
based MMRM with fixed effects for treatment group (NRCT-101SR and placebo), time 
point, the treatment-by-time point interaction; sex and baseline PERMP-C value will be 
included as a fixed covariate and site (possibly pooled) as a random effect. An 
unstructured within-subject covariance matrix will be utilized along with Kenward-
Rogers denominator degrees of freedom. Failure to converge will be handled as described 
in the primary analysis. 
Model results will be presented graphically with the LS means and 95% CIs from the 
model above plotted for each time point and treatment for Week 3 and Week 6 
separately. 
 In addition to the change from baseline to Week 6 in the PERMP-C score, the change 
from baseline at Week 3 will also be reported out of the primary MMRM model 
described in Section 8.1.2. 
 The primary analysis will be repeated on the mITT and PP populations. 


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 The primary analysis will be repeated including additional covariates as main effect and 
interactions with treatment in the primary analysis model. The LS means treatment 
difference, its 95% CI and p-value within each subgroup will be reported from the model.  
 
o 
 
o 
 
o 
 
 
o 
 
o 
 
8.2. 
Dual Primary Endpoint #2 
The second primary efficacy endpoint is the change in AISRS from Baseline to Week 6 in those 
receiving NRCT-101SR compared to those receiving placebo. The primary analysis population 
will be the ITT population. 
8.2.1. 
Computation of the Dual Primary Endpoint #2 
The AISRS is collected at baseline, Week 1, Week 3, and Week 6; at each visit, the change from 
baseline will be calculated as the score at the visit minus the baseline score. Because it is only 
collected once at each visit, no averaging across time points as described for the PERMP-C will 
be required. 
Missing data will be imputed as described in Section 8.3 below. 
8.2.2. 
Primary Analysis of the Dual Primary Endpoint #2 
Summary statistics (mean, SD, median, minimum, maximum) for the primary efficacy endpoint 
will be reported for the change from Baseline to Week 6 for each of the treatment groups. The 
primary efficacy endpoint will be analyzed using a REML-based MMRM with fixed effects for 
treatment group (NRCT-101SR and placebo), time (Week 1, Week 3, and Week 6), the 
treatment-by-visit interaction; sex and baseline AISRS value will be included as a fixed covariate 
and site (possibly pooled) as a random effect. The outcome variables will be the AISRS change 
from baseline to each timepoint; the primary comparison will be the contrast between treatment 
groups at Week 6. An unstructured within-subject covariance matrix will be utilized along with 
Kenward-Rogers denominator degrees of freedom. Should this fail to converge under the 
standard Newton-Raphson algorithm, the Fisher scoring method will be attempted, followed by 
alternative methodology given in Lu, Mehrotra (Lu and Mehrotra 2010). In the unlikely event 
that none of these converge, the following structures will be attempted in order with the first to 
converge being selected: first-order ante dependence, heterogeneous first-order autoregressive, 
heterogeneous compound symmetry, and compound symmetry; sandwich estimator will be 
utilized for each. 


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LS means and differences across the 20 MI reps (see missing data imputation in Section 8.3 
below) will be combined using SAS procedure MIANALYZE (Rubin, 1976). Significance 
testing will be based on LS means and two-sided 95% CIs will be presented. 
8.2.3. 
Sensitivity Analyses of the Dual Primary #2 Analysis 
The following sensitivity analyses will be performed: 
8.2.3.1. 
Multiple Imputation  Lost to Follow-
Random 
The primary analysis will be repeated using the same MI approach, but subjects that drop out 
with loss to follow-
LOE and AE 
dropouts in the imputation algorithm.   
8.2.3.2. 
Multiple Imputation  Baseline as reference distribution for Missing Not at 
Random 
The primary analysis will be repeated using the same MI approach, but subjects that drop out for 
LOE and AE will be imputed using the distribution of the baseline values. This investigates an 
alternative hypothetical strategy where instead of assuming the values will revert to the 
distribution in the placebo group, all subjects (placebo and active) are assumed to revert to the 
distribution of baseline values. 
8.2.3.3. 
Multiple Imputation Tipping Point 
A tipping point analysis will be performed using the above MI datasets and applying an 
increasing penalty delta AISRS to the active group, until statistical significance is no longer 
achieved. The delta will only be applied to imputed values; this will be done in 1-point 
increments on the AISRS score. This will only be performed if the primary analysis is 
significant. This will test the overall robustness of the primary analysis. 
8.2.4. 
Secondary Analyses of the Dual Primary Endpoint #2 
The following secondary and supporting analyses will be performed: 
 In addition to the change from baseline to Week 6 in the AISRS score, the change from 
baseline at Week 1 and Week 3 will also be reported out of the primary MMRM model 
described in Section 8.2.2. 
 The primary analysis of AISRS will be repeated on the mITT and PP populations. 
 The primary analysis will be repeated including additional covariates as main effect and 
interactions with treatment in the primary analysis model. The LS means treatment 
p-value within each subgroup will be reported from the 
model. 
 
o 
 
o 
 


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o 
 
 
o 
 
o 
 
8.3. 
Missing Data Imputation 
Missing data will be imputed for the dual primary endpoints as well as the key secondary 
endpoints. 
For PERMP endpoints taken at multiple time points within a visit, the visit value will be the 
average of the values for that visit, as long as at least three post-dose assessments are performed; 
missing values within a visit will be assumed to be missing at random. 
Missing values for subjects in the ITT population will be imputed via MI. When the study 
medication is discontinued due to LOE or due to an AE, missing values will be imputed drawing 
from the placebo distribution at the matching time points, conditioned on the observed data 
under the assumption that they are missing not at random (MNAR), with a covariate for sex. If 
the study medication was discontinued for any other reason (including impacts from the 
COVID-19 pandemic), values will be imputed within treatment group using MI, under the 
assumption that they are missing at random (MAR), with covariates sex and observed values 
recorded at each time point. For the purposes of the imputation algorithm, AE discontinuations 
due solely to COVID and COVID sequelae will be included in the MAR imputation grouping. 
Subjects that withdraw due to COVID and have an independent, unrelated AE that also results in 
study discontinuation will be included in the MNAR imputation grouping (with all other AE 
withdrawals other than the aforementioned COVID exclusion). The MAR approach will also be 
applied for sporadic missing values (prior to discontinuation). The MI process will use 20 repeats 
in the analysis datasets generated. 
The steps will be as follows: 
1. 
Intermittent missing values for both completers and dropouts prior to discontinuation will 
be imputed using the Markov Chain Monte Carlo (MCMC) method implemented with the 
SAS MI procedure. 
2. 
For subjects that do not discontinue for LOE or AEs, a MAR imputation will be applied: 
the monotone missing values will be imputed with the SAS MI procedure using the 
monotone regression method. Baseline and the post-baseline scores at each visit will be 
included as covariates as well as sex; imputation will be done within treatment group. 
This will also apply for subjects that complete, but have their final value missing. 
3. 
For subjects that discontinue for LOE or AEs, values will be imputed using the placebo 
group as reference. Missing values will be imputed with the SAS MI procedure using the 
monotone regression method. Baseline and the post-baseline scores at each visit will be 
included as covariates 
. 
Subjects that discontinue study drug or early terminate from the study but provide data will have 
all observed data used. 


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8.4. 
Secondary Endpoints 
All secondary efficacy analyses will be based on the ITT population.   
8.4.1. 
 Key Secondary Endpoints 
There will be two key secondary endpoints: 
8.4.1.1. 
Behavior Rating Inventory of Executive Function  Adult Version (BRIEF-A) 
The BRIEF-A will be collected at Baseline, Week 1, Week 3, and Week 6. Summary statistics 
(mean, SD, median, minimum, maximum) will be reported for the values and the changes from 
Baseline to Week 6 for each of the treatment groups.  
The change from baseline will be modeled in an MMRM identical to that described for the dual 
primary endpoints. No imputation will be performed; however, the MMRM model will return 
unbiased estimates under the assumption that data are missing at random. 
LS means, standard errors, and 95% CIs will be reported for each treatment and visit as well as 
the difference between treatments at each visit. The primary visit of interest is Week 6. 
8.4.1.2. 
Hospital Anxiety and Depression Scale (HADS) 
The HADS will be collected at Baseline, Week 1, Week 3, and Week 6. For each domain 
(anxiety and depression), summary statistics (mean, SD, median, minimum, maximum) will be 
reported for the values and the change from Baseline to Week 6 for each of the treatment groups.  
The change from baseline for each domain will be modeled in an MMRM identical to that 
described for the dual primary endpoints. No imputation will be performed; however, the 
MMRM model will return unbiased estimates under the assumption that data are missing at 
random. 
LS means, standard errors, and 95% CIs will be reported for each treatment and visit, as well as 
the difference between treatments at each visit. The primary visit of interest is Week 6. 
8.4.2. 
Additional Secondary Endpoints and Other Endpoints 
8.4.2.1. 
Continuous Secondary Endpoints 
Each of the following continuous endpoints will be summarized: 
 Change from Baseline in the Clinical Global Impression  Severity (CGI-S) 
 Change from Baseline in the Adult ADHD Quality of Life scale (AAQoL) 
 Change from Baseline in the AISRS Expanded Version 
 Change from Baseline in the Work Productivity and Activity Impairment questionnaire 
(WPAI) 
For each of the above, summary statistics (mean, SD, median, minimum, maximum) for the 
primary efficacy endpoint will be reported for the change from the Baseline to Week 6 for each 




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9. 
SAFETY EVALUATION 
9.1. 
Overview of Safety Analysis Methods 
All safety analyses will be completed for the Safety Population. All safety data will be tabulated 
and listed. No formal statistics or imputation will be performed for the safety analysis. Safety 
and tolerability will be assessed by: 
 Incidence of AEs and serious adverse events (SAEs) throughout the entire duration of 
the study 
 Changes from baseline in electrocardiogram (ECG) results 
 Changes from baseline in clinical laboratory test results 
 Changes from baseline in vital signs 
 Indications of increased suicidal ideation or behavior as assessed by the Columbia 
Suicide Severity Rating Scale (C-SSRS) 
9.2. 
Adverse Events 
All AEs will be coded using MedDRA version 25.0. 
A treatment-emergent AE (TEAE) is defined as any AE that has an onset on or after the dose of 
study drug, or any pre-existing condition that has worsened on or after the first dose of study 
drug. 
An AE summary table will present totals for the following: 
 All TEAEs 
 TEAEs by severity (mild, moderate, severe, life threatening, death) 
 TEAEs leading to study discontinuation  
 TEAEs by relationship (unrelated, related, see below) 
 SAEs 
The incidence of TEAEs (number and percentage of subjects reporting the AE at least once 
during the study), SAEs and TEAEs related to study drug will be summarized by treatment. 
The incidence of TEAEs and study drug administration-related TEAEs will also be summarized 
by maximum severity and most-related relationship to study drug by MedDRA primary SOC and 
PT. The summary will include the total number and percentage of subjects reporting an event. 
An AE is said to be study drug administration-related 
 


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In recording events, a continuous event, i.e., reported more than once and which did not cease, 
will be counted only once; non-continuous AEs reported several times by the same subjects will 
be recorded as multiple events. However, for reporting, each subject will be counted only once 
within each summation level (SOC and PT). If a subject experiences more than one TEAE within 
each summation level, the TEAE with the strongest relationship or the maximum severity, as 
appropriate, will be included in the summaries by relationship and severity. 
All AEs will be presented in a listing. 
These summaries will include SAEs; additionally, they will be presented separately (see below). 
9.3. 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
Summaries of incidence rates (frequencies and percentages) of individual SAEs by MedDRA 
SOC and PT will be presented, as well as SAEs related to study drug. Additionally, SAEs will be 
listed separately. 
TEAEs leading to discontinuation of study will be analyzed and presented in a manner identical 
to the SAEs. 
All deaths will be reported in a listing.  
9.4. 
Clinical Laboratory Evaluation 
Mean changes from baseline at each post-baseline time point for each numeric laboratory 
variable will be presented. In addition, each reading will be classified as below, within, or above 
normal range, based on ranges supplied by the laboratory used. Shift from baseline tables for the 
follow-up measurements will be presented. 
Laboratory values will be displayed in the data listings with their corresponding normal ranges, 
and those values that are outside the normal range will be flagged. 
Results of urine drug screens and pregnancy tests will be presented in listings. 
 
 
9.5. 
Vital Signs, ECGs, Physical Findings, and Other Observations 
Related to Safety 
9.5.1. 
Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point will be reported for vital signs including 
weight (kg), BMI (kg/m2), body temperature (°F), heart rate (beats/min), respiratory rate 
(breaths/min), systolic blood pressure (mmHg) and diastolic blood pressure (mmHg). Vital sign 
values, including abnormal values, will be listed. 


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9.5.2. 
ECGs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point will be reported for the following ECG 
parameters: 
 Heart Rate (beats/min) 
 PR Interval (msec) 
 QT Interval (msec) 
 QTcF (msec) 
 QRS Duration (msec) 
 RR Interval (msec) 
The ECG interpretation will be in the CRF as normal, abnormal but not clinically significant, or 
abnormal and clinically significant. The number and percentage of subjects in each category will 
be reported at each visit. The ECG cardiac rhythm will be collected in the CRF as regular or 
irregular. The number and percentage of subjects in each category will be reported at each visit. 
ECG values, including interpretation and cardiac rhythm, will be listed. 
9.5.3. 
Physical Examinations 
Physical examination data will be presented in a data listing. 
9.5.4. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS findings at all visits will be presented in a listing for any subject with emergent increase 
in ideation or any suicidal behavior. 
9.5.5. 
Pregnancy Reporting 
Any data relating to pregnancies reported during the study will be provided in a data listing. 
 


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10. 
OTHER ANALYSES 
10.1. 
Exploratory Analyses 
Additional subgroups may be investigated using the primary analysis approach for each 
endpoint, performed within the given subgroup. These analyses are purely exploratory and may 
not be performed if insufficient subjects are available in a subgroup of interest. 
Exploratory covariate analyses may be performed for endpoints in addition to the dual primary 
endpoints. 
10.2. 
PK Analysis 
At Week 3, PK sampling will be completed pre-dose, 4- and 7-hours post-dose with a 30-minute 
window for completion of sampling. Descriptive statistics will be reported for the concentrations 
for each analyte and each timepoint for the subjects in the active group. In addition to the 
standard descriptive statistics, geometric means and geometric SDs will be reported. Individual 
subjects may be excluded from these analyses in the case that they accidentally dose prior to the 
visit. Likewise, individual time point values may be excluded if they are biologically 
implausible.  
Mean concentration curves will be displayed graphically on both the natural and log scale.   


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11. 
INTERIM ANALYSES  
No interim analyses are planned. 
 


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12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
The protocol stated that clinically significant vital sign changes would be summarized; clinical 
significance was not collected for vital signs. 
The primary models included site as a fixed effect; this has been updated to be a random effect 
and details on site pooling (if necessary) have been added. 
Additional details of the sensitivity and covariate analyses have been added. 


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13. 
REFERENCES 
ICH Topic E3 Structure and Content of Clinical Study Reports. July 1996. 
 
ICH Topic E9 Statistical Principles for Clinical Trials. September 1998. 
 
Lu K. and Mehrotra D.V. Specification of covariance structure in longitudinal data analysis for 
randomized clinical trials. Statistics in Medicine 2010 Feb 20; 29(4):474-88. 
 
, Biometrika, 63, 581 592. 
 
 






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4195486 
4222382 
3418814 
2867763 
8995736 
5775152 
These will generally be used in order for the primary analysis, then secondary endpoints and 
sensitivity analyses. For cases where identical code may be applied to more than one outcome or 
a sensitivity analysis that uses a minor variation on the primary code, the second to last digit will 
be incremented by 1 to produce new seeds for the subsequent outcome/analysis. If a single 
dataset requires more than the 10 seeds above, additional seeds will be generated by 
incrementing the last digit by 1. All seeds used will be documented in the programming 
specifications and the programs themselves. 


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15. 
ATTACHMENTS 
N/A