Conditions: Attention Deficit Disorder With Hyperactivity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled, parallel-group study of NFC-1 versus placebo in adolescents with ADHD who have genetic disorders impacting mGluRs.

Detailed description:
This is a randomized, double-blind, placebo-controlled, parallel-group study of adolescents with ADHD who have genetic disorders impacting mGluRs. Approximately 90 subjects will receive randomized treatment with NFC-1 or placebo. Dosing will be optimized during the first 4 weeks of treatment, based on clinical response and tolerability, and maintained for an additional 2 weeks.

Arms:
arm 1: Doses of NFC-1 will be administered as 100, 200, or 400 mg twice daily as capsules for oral administration. arm 2: Matching placebo capsules.

Interventions: intervention 1: NFC-1 intervention 2: Placebo
Intervention descriptions: intervention 1: NFC-1 is supplied as size 2 hard gelatin capsules. intervention 2: Matching placebo capsules

Protocol document:
Prot_000.pdf: 




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2. SYNOPSIS 
PRODUCT NAME 
NFC-1 (fasoracetam monohydrate) 
PROTOCOL NUMBER 
MDGN-NFC1-ADHD-201 
DEVELOPMENT 
PHASE 
Phase 2 
PROTOCOL TITLE 
A Multicenter, 6-Week, Double-blind, Randomized, Placebo-controlled, Parallel-
design Study to Assess the Efficacy and Safety of NFC-1 in Adolescents 
(Ages 12-17 Years) with Genetic Disorders Impacting Metabotropic Glutamate 
Receptors and Attention Deficit Hyperactivity Disorder 
INDICATION 
Genetic disorders impacting metabotropic glutamate receptors (mGluRs) in subjects 
with Attention Deficit Hyperactivity Disorder (ADHD) 
OBJECTIVES 
The objectives of this study are: 
 
To assess the efficacy of NFC-1 relative to placebo in reducing the severity of 
symptoms associated with ADHD in adolescents with genetic disorders 
impacting mGluRs. 
 
To obtain additional safety data following exposure to NFC-1 in this 
population. 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, parallel-group study of 
adolescents with ADHD who have genetic disorders impacting mGluRs.  
Approximately 90 subjects will receive randomized treatment with NFC-1 or placebo.  
Dosing will be optimized during the first 4 weeks of treatment, based on clinical 
response and tolerability, and maintained for an additional 2 weeks when the primary 
assessments of efficacy and tolerability will be performed.  A follow-up telephone 
call will be performed at Week 7. 
PLANNED NUMBER 
OF SUBJECTS 
Ninety subjects are planned to be enrolled.  It is anticipated that this will yield 
80 subjects who will complete the study as planned. 
STUDY ENTRY 
CRITERIA 
Inclusion criteria: 
Subjects must fulfill all of the following requirements to enter the study: 
1. 
Subject is male or female, ≥ 12 to ≤ 17 years of age. 
2. 
Subject has a body mass index in the range of ≥ 15 to ≤ 35 kg/m2. 
3. 
Subject has ADHD as defined by the Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition (DSM-5) and Version 5 of the Attention Deficit 
Hyperactivity Disorder Rating Scale (ADHD-RS-5)  28 at Baseline with or 
without conventional ADHD therapy. 
4. 
Subject has an intelligence quotient (IQ) > 79, based on the Wechsler 
Abbreviated Scale of Intelligence, second edition (WASI-II). 
5. 
Subject has been genotyped previously and determined to have disruptive 
mutations in genes within the glutamate receptor metabotropic (GRM)-network 
as determined by the presence of copy number variations (CNVs) (GRM 
biomarker-positive subjects). The confirmation of a subject’s positive status 
will be provided by the sponsor.  
6. 
Subject is a non-smoker and/or has not used nicotine or nicotine-containing 
products on a weekly or more frequent basis for at least approximately 
6 months. 
7. 
Subject is judged to be in general good health, other than having ADHD, based 
on medical history, physical examination, vital signs measurements, laboratory 
safety tests, and the Columbia Suicide Severity Rating Scale (C-SSRS) 


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performed at the Screening Visit and/or prior to administration of 
investigational product (IP). 
8. 
Female subjects of reproductive potential will have a negative pregnancy test at 
Screening (serum) and prior to drug administration (urine).  If sexually active, 
female subjects agree to use (and/or have her partner use) 2 acceptable methods 
of birth control beginning at least 2 weeks prior to administration of IP and 
throughout the study.  Acceptable methods of birth control are abstinence or 
2 of the following: intrauterine device, diaphragm, spermicides, cervical cap, 
contraceptive sponge, and condoms. 
9. 
Subject has no clinically significant abnormality on electrocardiogram (ECG) 
performed at the Screening Visit and/or prior to administration of IP such as 
serious arrhythmia, bradycardia, tachycardia, cardiac conduction problems, or 
other abnormalities deemed to be a potential safety issue. 
10. Parent/legal guardian and subject understand the study procedures and agree to 
the subject’s participation in the study as indicated by parental/legal guardian 
signature on the subject informed consent form and subject signature on the 
assent form. 
Exclusion criteria: 
The presence of any of the following criteria excludes a subject from participating in 
the study: 
1. 
Subject or parent/legal guardian is in the opinion of the investigator mentally or 
legally incapacitated, has significant emotional problems at the time of the 
Screening Visit or during the conduct of the study. 
2. 
Subjects with a current or relevant history of comorbid major psychiatric 
disorders (ie, aside from ADHD), including major depression, bipolar disease, 
schizophrenia, pervasive development disorder, and intellectual disability. 
3. 
Subject is currently taking a prohibited medication and/or is unwilling to wean 
off current ADHD medication to participate in the study 
4. 
Subject has a history of any illness that in the opinion of the study investigator 
might confound the results of the study or poses an additional risk to the subject 
by his or her participation in the study. 
5. 
Subject has a history of any clinically significant disease that is not currently 
stable.  Subjects with a history of uncomplicated kidney stones may be enrolled 
in the study at the discretion of the investigator. 
6. 
Subject has a known history or presence of syncope, cardiac conduction 
problems (eg, clinically significant heart block), exercise-related cardiac events 
including syncope and pre-syncope, or clinically significant bradycardia. 
7. 
Subject has a history of stroke, chronic seizures, or major neurological disorder 
which, in the opinion of the investigator, would interfere with the subject’s 
ability to participate and/or be evaluated in the study. 
8. 
Subject is pregnant or a nursing mother. 
9. 
Subject has a history of aversion to blood draws that in the opinion of the 
investigator or parents would result in compromising the study conduct. 
10. Subject has a history of physiologic difficulty in venous access that in the 
opinion of the investigator and parent/legal guardian would compromise study 
conduct. 
11. Subject has a history of inability to swallow whole unadulterated capsules, 
which in the opinion of the investigator or parent/legal guardian would 
compromise study conduct. 
12. Subject has a systolic or diastolic blood pressure ≥ the 95th percentile for his or 
her age. 


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13. Subject consumes any alcoholic beverages on a regular basis (weekly or more 
often). 
14. Subject consumes excessive amounts of caffeine, defined as greater than 
4 servings (1 serving is approximately equivalent to 120 mg of caffeine) of 
coffee, tea, cola, or other caffeinated beverages per day. 
15. Subject has a history of significant multiple and/or severe allergies, or has had 
an anaphylactic reaction or significant intolerability to prescription of 
nonprescription drugs or food. 
16. Subject is currently a regular user (including “recreational use”) of any illicit 
drugs (including marijuana) or has a history of drug (including alcohol) abuse. 
17. Subject has had surgery, lost more than 5 mL/kg of blood, or participated in 
another investigational drug trial within 4 weeks prior to the Screening Visit. 
18. Subject has a clinical laboratory abnormality that indicates clinically significant 
hematologic, hepatobiliary, or renal disease: 
a 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
> 2.0-times the upper limit of normal 
b 
Alanine aminotransferase/serum glutamic pyruvic transaminase 
> 2.0-times the upper limit of normal 
c 
Total bilirubin > 2.0-times the upper limit of normal 
d 
Hemoglobin < 9 g/dL 
e 
White blood cell count < 1,000/mm3 
f 
Platelet count < 100,000/mm3 
g 
Creatinine kinase > 300 U/L for females and > 500 U/L for males 
CONCOMITANT 
TREATMENT 
All ADHD medications will be discontinued prior to starting this study.  There will be 
a wash-out phase of 5 days for stimulants and 14 days for atomoxetine and 
noradrenergic agonists.  Subjects will not start any new ADHD medication during the 
study.  Due to their potential to interfere with safety, efficacy, or tolerability 
assessments, the following medications are prohibited: norepinephrine reuptake 
inhibitors, anxiolytic or sedative hypnotic medications, antidepressants, clonidine, 
guanfacine, mood stabilizers (including lithium, anticonvulsants, and antipsychotics), 
antihypertensive agents, psychostimulants, sedating antihistamines, and 
investigational compounds. As NFC-1 is a potential inducer of cytochrome P450 3A4, 
2B6 and 2D6, medications that are metabolized by these enzymes are prohibited. 
INVESTIGATIONAL 
PRODUCT 
Name: NFC-1 (fasoracetam monohydrate), 
(5R)-5-(pyridine-1-carbonyl)-pyrrolidin-2-one monohydrate, 
NFC-1 will be provided as white opaque size 2 capsules containing 100 mg or 200 mg 
NFC-1; no excipients are used. 
Dose, route, and frequency: 100 mg, 200 mg, and 400 mg administered orally twice 
daily in the fed or fasting state. 
REFERENCE 
PRODUCT 
Name: Matching placebo containing microcellulose instead of NFC-1. 
Dose, route, and frequency: 100 mg, 200 mg, and 400 mg administered orally twice 
daily in the fed or fasting state. 
TREATMENT 
REGIMENS 
Subjects will receive randomized treatment with NFC-1 or placebo.  During the dose 
optimization phase, NFC-1 or placebo will be initiated at 100 mg twice daily and 
titrated weekly based on clinical response and tolerability up to a maximal dose of 
400 mg twice daily.  At the end of Week 4, subjects will continue with the optimized 
dose of NFC-1 at 100 mg, 200 mg, or 400 mg twice daily for an additional 2 weeks 
(maintenance phase). 


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COORDINATING 
PRINCIPAL 
INVESTIGATOR 
 
PLANNED STUDY 
SITES 
Approximately 35 sites in North America 
CRITERIA FOR 
EVALUATION 
Response to treatment will be assessed with tools commonly used in ADHD research.  
These include ADHD-RS-5, Adolescent Sleep Hygiene Scale (ASHS), Screen for 
Childhood Anxiety-related Emotional Disorders (SCARED), and Clinical Global 
Impression of Severity (CGI-S) and Improvement (CGI-I). 
Safety and tolerability will be assessed by the frequency and severity of adverse 
events (AEs) as well as the evaluation of changes in clinical laboratory values, vital 
signs, ECG recordings, and C-SSRS. 
STATISTICAL 
METHODS 
Efficacy: 
The primary endpoint for the assessment of efficacy will be the ADHD-RS-5 score.  
Secondary endpoints will include the CGI-S, ASHS, and SCARED.  The analysis will 
be based on changes from the baseline value and will test the hypothesis that there is 
no difference between the treatments (ie, that the difference is 0) against a 2-tailed 
alternative.  Further exploratory analyses may be performed that include additional 
independent factors (eg, age, gender, and/or maintenance dose of study drug) as well 
as covariates that are determined to be associated with the experimental results 
(eg, baseline value of the dependent variable).  All quantitative endpoints will be 
described with traditional summary statistics and tabulated by treatment group and 
visit. 
Safety: 
Adverse events will be coded with the Medical Dictionary for Regulatory Affairs 
(MedDRA) and tabulated by system organ class and preferred term.  Adverse events 
will be analyzed by frequency, severity, relationship to IP, and their effect on 
participation in the study. 
Clinical laboratory values will be compared to normal ranges and flagged for levels of 
clinical concern.  The analysis will focus on the frequencies of abnormal values as 
well as within-subject changes observed during the course of the study. 
Vital signs and ECG recordings will also be examined for changes during the study 
that may be attributed to exposure to IP. 
The C-SSRS will also be examined for changes that may be attributed to exposure to 
IP. 
SAMPLE SIZE 
DETERMINATION 
Enrollment of 90 subjects is expected to yield 80 subjects who complete the study as 
planned.  Assuming an effect size of 0.7, this number will provide approximately 
90% power to detect a significant difference between the treatments based on a 
2-tailed α = 0.05 comparison of mean change from Baseline. 
STUDY AND 
TREATMENT 
DURATION 
The sequence and maximum duration of the study periods will be as follows: 
 
Screening period: approximately 21 days. 
 
Wash-out period: if applicable, up to 14 days. 
 
Dose optimization phase: 28 days. 
 
Dose maintenance phase: 14 days. 
 
Follow-up: 7 days (+5 days) after the last dose of IP. 
 
The maximum study duration for each subject is approximately 70 days. 
 
The maximum treatment duration for each subject is 42 days. 
 


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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES .................................................................................................. 2 
2. 
SYNOPSIS .............................................................................................................................. 3 
3. 
TABLE OF CONTENTS ........................................................................................................ 7 
3.1 
List of Tables................................................................................................................ 11 
3.2 
List of Figures .............................................................................................................. 11 
REASONS FOR AMENDMENT ................................................................................................ 12 
SUMMARY OF AMENDED SECTIONS ................................................................................... 13 
AMENDED PROTOCOL ............................................................................................................ 15 
4. 
LIST OF ABBREVIATIONS................................................................................................ 16 
5. 
INTRODUCTION ................................................................................................................. 17 
5.1 
Background and Rationale ........................................................................................... 17 
5.2 
Clinical Experience ...................................................................................................... 17 
5.3 
Summary of Potential Risks and Benefits .................................................................... 19 
6. 
OBJECTIVES ........................................................................................................................ 19 
7. 
STUDY DESIGN .................................................................................................................. 19 
7.1 
Overall Study Design and Plan .................................................................................... 19 
7.2 
Discussion of Study Design ......................................................................................... 21 
7.3 
Study Site(s) ................................................................................................................. 21 
8. 
SUBJECT POPULATION .................................................................................................... 21 
8.1 
Selection of Study Population ...................................................................................... 21 
8.2 
Study Entry Criteria ..................................................................................................... 21 
8.2.1 Inclusion Criteria .............................................................................................. 21 
8.2.2 Exclusion Criteria ............................................................................................. 22 
8.3 
Premature Subject Withdrawal .................................................................................... 23 
8.4 
Subject Replacement Criteria ....................................................................................... 23 
9. 
TREATMENTS ..................................................................................................................... 24 
9.1 
Identification of Investigational Product(s) ................................................................. 24 
9.2 
Labeling and Packaging ............................................................................................... 24 
9.2.1 Labeling ............................................................................................................ 24 
9.2.2 Packaging ......................................................................................................... 24 
9.3 
Treatments Administered ............................................................................................. 24 
9.4 
Dispensing and Storage ................................................................................................ 25 
9.4.1 Interactive Web Response System for Investigational Product Management . 25 
9.5 
Method of Assigning Subjects to Treatment Groups ................................................... 25 
9.6 
Blinding and Unblinding Treatment Assignment ........................................................ 25 
9.7 
Selection of Doses in the Study ................................................................................... 26 


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9.8 
Selection of Timing of Dose for Each Subject............................................................. 26 
9.9 
Dose Adjustment Criteria ............................................................................................. 26 
9.10 Drug Accountability ..................................................................................................... 27 
9.11 Treatment Compliance ................................................................................................. 27 
9.12 Permitted and Prohibited Therapies ............................................................................. 28 
9.12.1 Permitted Therapies .......................................................................................... 28 
9.12.2 Prohibited Therapies ......................................................................................... 28 
9.13 Treatment after End of Study ....................................................................................... 29 
10. STUDY PROCEDURES ....................................................................................................... 29 
10.1 Study Periods and Visits .............................................................................................. 29 
10.1.1 Screening and Wash-out ................................................................................... 29 
10.1.1.1 Screening (Visit 1, Day -21 [± 2 days]) ................................................ 29 
10.1.1.2 Wash-out Period ................................................................................... 30 
10.1.2 Baseline (Visit 2, Day -1 [± 2 days]) ................................................................ 30 
10.1.3 Double-blind Treatment Period ........................................................................ 31 
10.1.3.1 Dose Optimization Phase (Visit 3, Day 7 [± 2 days], Visit 4, Day 14 [± 
2 days], Visit 5, Day 21 [± 2 days], and Visit 6, Day 28 [± 2 days]) ... 31 
10.1.3.2 Dose Maintenance Phase (Visit 7, Day 35 [± 2 days], Visit 8, Day 42 [± 
2 days], or Early Termination) Evaluation ........................................... 31 
10.1.4 7-day Follow-up Call ........................................................................................ 32 
10.2 Study Duration ............................................................................................................. 32 
10.3 Assessments ................................................................................................................. 32 
10.3.1 Screening .......................................................................................................... 32 
10.3.1.1 Kiddie Schedule for Affective Disorders and Schizophrenia – Present 
and Lifetime .......................................................................................... 32 
10.3.1.2 Wechsler Abbreviated Scale of Intelligence ......................................... 33 
10.3.2 Efficacy ............................................................................................................ 33 
10.3.2.1 Attention Deficit Hyperactivity Disorder Rating Scale Version 5 ....... 33 
10.3.2.2 Clinical Global Impression-Improvement and Severity Scales ............ 33 
10.3.2.3 Adolescent Sleep Hygiene Scale .......................................................... 34 
10.3.2.4 Screen for Childhood Anxiety-related Emotional Disorders ................ 34 
10.3.3 Safety ................................................................................................................ 35 
10.3.3.1 Clinical Laboratory Safety Assessments .............................................. 35 
10.3.3.2 Clinical Examinations ........................................................................... 36 
10.3.3.3 Columbia Suicide Severity Rating Scale .............................................. 36 
10.3.3.4 Adverse Events ..................................................................................... 36 
11. ADVERSE EVENTS............................................................................................................. 37 
11.1 Definitions .................................................................................................................... 37 


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11.1.1 Adverse Events ................................................................................................. 37 
11.1.2 Unexpected Adverse Event .............................................................................. 37 
11.1.3 Serious Adverse Events .................................................................................... 37 
11.1.4 Significant Adverse Events .............................................................................. 38 
11.1.5 Treatment-Emergent Adverse Events .............................................................. 38 
11.2 Management of Adverse Events .................................................................................. 38 
11.2.1 Collection ......................................................................................................... 38 
11.2.2 Evaluation ......................................................................................................... 38 
11.2.2.1 Severity of Adverse Events .................................................................. 38 
11.2.2.2 Seriousness ........................................................................................... 39 
11.2.2.3 Action(s) Taken .................................................................................... 39 
11.2.2.4 Outcome at the Time of Last Observation ............................................ 39 
11.2.2.5 Adverse Event Relationship to Investigational Product ....................... 39 
11.2.3 Documentation ................................................................................................. 40 
11.2.4 Treatment of Adverse Events ........................................................................... 40 
11.2.5 Follow-up ......................................................................................................... 41 
11.2.6 Notification ....................................................................................................... 41 
11.2.6.1 Serious Adverse Events ........................................................................ 41 
11.2.6.2 Non-serious Adverse Events ................................................................. 42 
11.3 Special Considerations ................................................................................................. 42 
11.3.1 Adverse Events of Special Interest ................................................................... 42 
11.3.2 Pregnancy ......................................................................................................... 42 
12. DATA SAFETY MONITORING BOARD .......................................................................... 42 
13. STATISTICS ......................................................................................................................... 42 
13.1 Study Endpoints ........................................................................................................... 42 
13.1.1 Primary Efficacy Endpoint ............................................................................... 42 
13.1.2 Secondary Efficacy Endpoints ......................................................................... 43 
13.1.3 Safety Endpoints ............................................................................................... 43 
13.2 Sample Size Determination .......................................................................................... 43 
13.3 Analysis Populations .................................................................................................... 43 
13.4 Statistical Analyses ...................................................................................................... 43 
13.4.1 Study Subjects and Demographics ................................................................... 43 
13.4.1.1 Disposition and Withdrawals ................................................................ 43 
13.4.1.2 Protocol Deviations .............................................................................. 44 
13.4.1.3 Demographics and Other Baseline Characteristics ............................... 44 
13.4.2 Exposure and Compliance ................................................................................ 44 
13.4.3 Efficacy Analyses ............................................................................................. 44 


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13.4.3.1 Primary Analysis .................................................................................. 44 
13.4.3.2 Secondary Analyses .............................................................................. 45 
13.4.4 Safety and Tolerability Analyses ..................................................................... 45 
13.4.4.1 Adverse Events ..................................................................................... 45 
13.4.4.2 Clinical Laboratory Evaluations ........................................................... 45 
13.4.4.3 Vital Signs and Electrocardiograms ..................................................... 45 
13.4.4.4 Columbia Suicide Severity Rating Scale .............................................. 45 
13.4.4.5 Physical Examination Findings ............................................................ 46 
13.4.5 Interim Analysis ............................................................................................... 46 
14. STUDY CONDUCT .............................................................................................................. 46 
14.1 Sponsor and Investigator Responsibilities ................................................................... 46 
14.1.1 Sponsor Responsibilities .................................................................................. 46 
14.1.2 Investigator Responsibilities ............................................................................ 46 
14.2 Site Initiation ................................................................................................................ 47 
14.3 Screen Failures ............................................................................................................. 47 
14.4 Study Documents ......................................................................................................... 47 
14.4.1 Investigator’s Regulatory Documents .............................................................. 47 
14.4.2 Electronic Case Report Forms .......................................................................... 47 
14.4.3 Source Documents ............................................................................................ 48 
14.5 Data Quality Control .................................................................................................... 48 
14.5.1 Monitoring Procedures ..................................................................................... 48 
14.5.2 Data Management ............................................................................................. 48 
14.5.3 Quality Assurance/Audit .................................................................................. 49 
14.6 Study Termination ........................................................................................................ 49 
14.7 Study Site Closure ........................................................................................................ 49 
14.7.1 Record Retention .............................................................................................. 49 
14.7.2 Sample Retention ............................................................................................. 50 
14.8 Changes to the Protocol ............................................................................................... 50 
14.9 Use of Information and Publication ............................................................................. 50 
15. ETHICAL AND LEGAL CONSIDERATIONS ................................................................... 50 
15.1 Declaration of Helsinki and Good Clinical Practice .................................................... 50 
15.2 Subject Information and Informed Consent ................................................................. 50 
15.3 Approval by Institutional Review Board ..................................................................... 50 
15.4 Finance and Insurance .................................................................................................. 51 
16. REFERENCES ...................................................................................................................... 52 
17. ATTACHMENTS .................................................................................................................. 53 
17.1 Schedule of Events ....................................................................................................... 53 


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17.2 Investigator’s Agreement ............................................................................................. 55 
APPENDICES .............................................................................................................................. 56 
A. 
Study-specific Requirements ....................................................................................... 57 
B. 
Regulations and Good Clinical Practice Guidelines .................................................... 58 
1. 
Regulations ....................................................................................................... 58 
2. 
Good Clinical Practice Guidelines ................................................................... 58 
3.1 
List of Tables 
Table 1: 
Clinical Studies Conducted by Nippon Shinyaku Co., Ltd. with NFC-1 ......... 18 
Table 2: 
Clinical Global Impression Scales ................................................................... 34 
3.2 
List of Figures 
Figure 7.1: 
Study Design .................................................................................................... 20 
 
 
 


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REASONS FOR AMENDMENT 
The protocol was amended due to receipt of in vitro data indicating the potential of NFC-1 to be 
an inducer of cytochrome P450 3A4, 2B6 and 2D6. As such, the concomitant administration of 
NFC-1 with drugs that are metabolized by CYP3A4, CYP2B6, or CYP2D6 could potentially 
reduce the therapeutic effect of those drugs. The following changes were made to the protocol: 
1. Medications that may potentially be impacted by the interaction with NFC-1 are now 
prohibited. 
2. The wording related to medication usage during the study to manage anxiety, mood 
disorders, ADHD, and symptoms of autism was removed as this information is repetitive 
with the bullet points that followed. 
 


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SUMMARY OF AMENDED SECTIONS 
The text below presents the amendments made to the protocol during revision. Simple 
corrections of typographical errors are not presented. 
 
Synopsis 
Concomitant Treatment 
Added: 
As NFC-1 is a potential inducer of cytochrome P450 3A4, 2B6 and 2D6, 
medications that are metabolized by these enzymes are prohibited. 
 
Section 9.12.1 
Permitted Therapies 
Text formerly read: 
The use of bronchodilators is allowed, if needed.  Antibiotics and OTC 
medications that do not affect blood pressure, heart rate, or the central 
nervous system, which are considered necessary for the subject’s welfare, 
may be administered at the discretion of the investigator.   
 
Now reads: 
The use of inhaled bronchodilators is allowed, if needed.  Antibiotics and 
OTC medications that do not affect blood pressure, heart rate, or the 
central nervous system, which are considered necessary for the subject’s 
welfare, may be administered at the discretion of the investigator.  
 
Section 9.12.2 
Prohibited Therapies 
 
Text formerly read: 
Medications used to manage anxiety or mood disorders, ADHD, and 
symptoms of autism are not allowed in the study, and new medications for 
these or other psychiatric symptoms cannot be initiated.  Rescue 
medications will not be authorized for study participants.  If subjects 
should require rescue medication to manage anxiety or mood disorders, 
ADHD, or autism spectrum disorders they will be discontinued from the 
study. 
 
 
All ADHD medications will be discontinued prior to starting this study.  
There will be a wash-out phase of 5 days for stimulants and 14 days for 
atomoxetine and noradrenergic agonists.  Study subjects will not start any 
new ADHD medication during the study.  All ADHD medications will be 
discontinued prior to starting this study.  Due to their potential to interfere 
with safety, efficacy, or tolerability assessments, the following 
medications are prohibited during the study: 
 
 Norepinephrine reuptake inhibitors. 
 Anxiolytic or sedative hypnotic medications. 
 
Text now reads: 
All ADHD medications will be discontinued prior to starting this study.  
There will be a wash-out phase of 5 days for stimulants and 14 days for 
atomoxetine and noradrenergic agonists.  Study subjects will not start any 
new ADHD medication during the study.  Due to their potential to 


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interfere with safety, efficacy, or tolerability assessments, the following 
medications are prohibited during the study: 
 
 Any medication which is a substrate of CYP3A4, CYP2B6 or 
CYP2D6.  
 Norepinephrine reuptake inhibitors. 
 Anxiolytic or sedative hypnotic medications. 
 
 


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AMENDED PROTOCOL 
The following are the amended protocol and appendices, including all revisions specified above. 
 
 


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4. LIST OF ABBREVIATIONS 
ADHD 
attention deficit hyperactivity disorder 
ADHD-RS-5 
Attention Deficit Hyperactivity Disorder Rating Scale Version 5 
AE 
adverse event 
ANOVA 
analysis of variance 
ASHS 
Adolescent Sleep Hygiene Scale 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CNV 
copy number variation 
CRA 
clinical research associate 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
GRM 
glutamate receptor metabotropic 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IP 
investigational product 
IQ 
intelligence quotient 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system  
K-SADS-PL 
Kiddie Schedule for Affective Disorders and Schizophrenia - Present and 
Lifetime Version 
mGluRs 
metabotropic glutamate receptors 
OTC 
over-the-counter 
PK 
pharmacokinetic 
PP 
per-protocol 
SAE 
serious adverse event 
SCARED 
Screen for Childhood Anxiety-related Emotional Disorders 
Tmax 
time to maximum plasma concentration 
WASI-II 
Wechsler Abbreviated Scale of Intelligence, second edition 


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5. INTRODUCTION 
5.1 
Background and Rationale 
Several candidate genes related to dopamine and noradrenergic neurotransmitter systems are 
associated with attention deficit hyperactivity disorder (ADHD) severity and subtypes 
(persistence, comorbidity, functional impairment, and treatment effects), such as DAT1, DRD4, 
MAO-A, ADRA2A, ADRA2C, NET, and COMT.  Recently, a large-scale, genome-wide study 
comparing copy number variations (CNVs) in 3,500 ADHD cases versus approximately 
13,000 controls revealed that rare, recurring CNVs impacting specific glutamate receptor 
metabotropic (GRM) genes (ie, GRM1, GRM5, GRM7, and GRM8) were found in patients with 
ADHD at significantly higher frequencies compared to healthy controls. 
Originally developed by Nippon Shinyaku Co., fasoracetam monohydrate (NFC-1, previously 
referred to as NS-105) is an important candidate to explore for use in restoring metabotropic 
glutamate receptors (mGluRs) activity in patients with ADHD exhibiting mGluR hypofunction.  
It has been shown to improve symptoms of depression and memory/learning in animal models.  
The drug activity is based on regulating the intracellular adenylyl cyclase-activity stimulated by 
mGluRs and works by inhibiting the brain gamma-aminobutyric acid B (GABA) receptor 
stimulus response and enhancing the beta-adrenergic receptor response and the acetylcholine-
mediated neurologic system response (1). 
Data from animal models, pharmacotherapeutic interventions, and brain and genetic studies in 
humans implicate glutamatergic system involvement in ADHD pathophysiology.  Interventions 
specifically targeting this system remain to be developed even though a recent, large-scale, 
genome-wide study revealed that rare, recurring CNVs impacting genes in the glutamatergic 
network (ie, GRM1, GRM5, GRM7, and GRM8) were detected in approximately 10% of the total 
ADHD cases (2). 
Published preclinical studies indicate that NFC-1 exerts its bioactivity through mGluRs (3, 4, 5).  
NFC-1 was also found to be efficacious in ameliorating learning and memory impairment, which 
can be interpreted in the context of improved attention span, and in reducing locomotor activity, 
which is a correlate of hyperactivity (6).  Thus, NFC-1 may be a potentially effective therapeutic 
agent in the subgroup of patients with ADHD identified through genetic profiling with variants 
in the GRM network that the sponsor is leveraging as a biomarker indicative of the mGluR 
signaling pathway being disrupted. 
5.2 
Clinical Experience 
Previously, NFC-1 was in phase 3 development for adults with cerebrovascular diseases and 
dementia.  The previous sponsor (Nippon Shinyaku Co., Ltd.) performed the following studies: 
 
Phase 1 dose-finding and pharmacokinetic study in healthy volunteers. 
 
Phase 2 studies in subjects with residual symptoms following cerebral infarct or cerebral 
hemorrhage. 
 
Phase 3 study in subjects with cerebrovascular diseases and dementia. 
Exposure to NFC-1 in these studies is presented in Table 1. 
 


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Table 1: 
Clinical Studies Conducted by Nippon Shinyaku Co., Ltd. with NFC-1a 
Study 
Phase 
Study Population 
Number 
of 
Subjects 
Doses Tested 
Exposure 
Number of 
Treatment-
related 
SAEs 
Phase 1 
Healthy male 
adults 
30/6b 
25-800 mg  
single dose/ 
200 mg/day 
8 days 
0 
Phase 2 
Adults with 
cerebrovascular 
disease  
169 
75-450 mg/day 
8 weeks 
0 
Phase 2 
Adults with post 
cerebral infarct 
residual symptoms 
288 
150 and 
300 mg/day 
8 weeks 
0 
Phase 3 
Adults with 
cerebrovascular 
disease and 
dementia 
Not 
available 
300 mg/day 
6 months 
to 1 year 
2c 
Abbreviation: SAE = serious adverse event 
a Previously referred to as NS-105. 
b A total of 30 subjects were involved in dose finding at 25 – 800 mg, a further 6 subjects were tested at the 
recommended dose obtained during dose finding (200 mg). 
c Relationship to study treatment was categorized as unknown. 
 
Nippon Shinyaku terminated development because the phase 3 study failed to meet the defined 
efficacy endpoints.  Although a written report is unavailable, information in the Investigator’s 
Brochure (IB) (1) for this phase 3 study indicated that NFC-1 was well-tolerated over 8 weeks of 
continuous daily dosing at doses up to 450 mg/day.  The most frequently reported adverse events 
(AEs) were nausea (2% of subjects) and laboratory abnormalities including elevated liver 
function tests, including alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase (in 3% of the subjects each), and elevated creatinine kinase (in 1% of the subjects). 
Research has also been conducted on NFC-1 in adolescents with ADHD.  The recently 
completed NFC1-2014 trial was a 30-subject phase 1b study that evaluated adolescents with 
ADHD and disruptions in the mGluR gene network.  The objectives of the study were to 
evaluate the safety, tolerability, and single-dose pharmacokinetic (PK) profile of NFC-1 and to 
evaluate the effect of NFC-1 on ADHD during 4 weeks of continuous treatment (at doses up to 
400 mg twice daily) following 1 week of placebo therapy. 
The study was conducted at the Jefferson University Hospital in Philadelphia, Pennsylvania.  
Subjects were classified into three tiers, based on their mGluR mutations.  During the dose 
escalation phase of this study, NFC-1 was well tolerated with no treatment-related serious 
adverse events (SAEs) reported.  All AEs were mild to moderate, and the most frequently 
reported treatment-emergent adverse events (TEAEs) were headaches in 17/30 subjects (56.7%), 


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fatigue in 9/30 subjects (30.0%), upper abdominal pain in 7/30 subjects (23.3%), and irritability 
in 6/30 subjects (20.0%). 
In addition to several exploratory measures, efficacy was assessed using the Clinical Global 
Impression of Severity (CGI-S) and Improvement (CGI-I) scales, and the Vanderbilt Parent 
Assessment Score.  Clinical improvement, based on the CGI-S, CGI-I, and Vanderbilt scores, 
was demonstrated in analyses of all subjects.  Improvement in the mean scores after 4 weeks of 
active treatment was observed as follows: CGI-S scores decreased from 3.97 to 3.00 (P < 0.001), 
CGI-I scores decreased from 3.83 to 2.24 (P < 0.001), and the Vanderbilt score decreased from 
29.1 to 22.5 (P < 0.001).  Improvement was greatest in the Tier-1/Tier-2 mGluR mutation 
positive subjects (P < 0.001).  In this group, 80% of the subjects were deemed to be responders 
(defined as at least a 25% improvement in the Vanderbilt Score).  Approximately half of the 
participants opted to participate in the currently ongoing open-label extension study of NFC-1. 
5.3 
Summary of Potential Risks and Benefits 
The potential benefits of study participation are that mGluRs mutation-positive subjects with 
ADHD (1) may experience a reduction in symptoms as a result of treatment with NFC-1 and 
(2) will understand that they are contributing to the scientific knowledge that may lead to 
expansion of the treatment options for patients with genetic disorders impacting mGluRs 
together with ADHD.  No other benefits of participation are anticipated. 
The potential risks of study participation include those associated with exposure to NFC-1 and 
the risks of medical evaluation, including venipuncture. 
A summary of the pharmaceutical properties and known potential risks of NFC-1 is provided in 
the current version of the IB (1).  The investigator must become familiar with all sections of the 
NFC-1 IB before the start of the study. 
6. OBJECTIVES 
The objectives of this study are: 
 
To assess the efficacy of NFC-1 relative to placebo in reducing the severity of symptoms 
associated with ADHD in adolescents with genetic disorders impacting mGluRs. 
 
To obtain additional safety data following exposure to NFC-1 in this population. 
7. STUDY DESIGN 
7.1 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, parallel-group phase 2 study of 
adolescents to compare the safety and efficacy of NFC-1 with that of placebo.  Approximately 
90 male and female subjects will receive randomized treatment with NFC-1 or placebo to obtain 
80 subjects that complete the study as planned.  Subjects must be ≥ 12 to ≤ 17 years of age and 
have ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
(DSM-5) and Version 5 of the Attention Deficit Hyperactivity Disorder Rating Scale 
(ADHD-RS-5) > 28 at Baseline with or without conventional ADHD therapy. 
Subjects will not be eligible if they are mentally or legally incapacitated, have significant 
emotional problems, have a prior diagnosis of co-morbid major psychiatric disorders or any 
clinically significant medical condition that would interfere with the conduct of study 
evaluations, are pregnant or nursing, and/or have abnormal laboratory values that indicate 
clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, 
immunological, renal, respiratory, or genitourinary abnormalities or diseases. 


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As shown in Figure 7.1, subjects will be randomly assigned to receive either NFC-1 or placebo 
on Day -1 and will start taking the investigational product (IP) at a dose of 100 mg twice daily on 
Day 1.  Dosing will be optimized to 100 mg, 200 mg, or 400 mg twice daily, as appropriate, over 
the 4 weeks of treatment (dose optimization phase), based on clinical response and tolerability.  
If the subject tolerates a dose well, the dose will be maintained for an additional 2 weeks (dose 
maintenance phase) when the primary assessments of efficacy and tolerability will be performed.  
A follow-up telephone call will be performed at Week 7. 
Approximately 45 subjects will be randomly assigned to each treatment group.  The duration of 
study participation is expected to be 70 days. 
Efficacy will be assessed by the ADHD-RS-5 score, CGI-I, CGI-S, Adolescent Sleep Hygiene 
Scale (ASHS), and Screen for Childhood Anxiety-related Emotional Disorders (SCARED). 
Safety will be assessed by evaluating AEs, physical examination findings, vital sign 
measurements, electrocardiograms (ECGs), clinical laboratory test results, and Columbia Suicide 
Severity Rating Scale (C-SSRS) scores. 
All AEs observed by the study personnel or reported by the subject during the study (from the 
time of the signing of the informed consent through the posttreatment visit) will be documented. 
 
Figure 7.1: 
Study Design 
 
Abbreviation: ET = early termination 
 


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7.2 
Discussion of Study Design 
The randomized, double-blind, parallel group design chosen for this study is standard for the 
head-to-head comparison of treatments.  After assessing the baseline status of the disease (in the 
absence of study drug), the 4-week dose titration paradigm allows for individualized dose 
optimization.  This is the norm for pharmacological interventions in neuropsychiatric indications.  
The subsequent 2-week maintenance period will allow stabilization of drug effect(s) prior to 
assessing the disease status at the end of the treatment (ie, the primary endpoint in this study). 
7.3 
Study Site(s) 
The study will take place at approximately 35 sites in the United States.  Each site is anticipated 
to screen a sufficient number of subjects to be able to randomize approximately 2-3 subjects.  
A study site with a high recruitment rate may be allowed to recruit more subjects if other sites 
have slow enrollment. 
8. SUBJECT POPULATION 
8.1 
Selection of Study Population 
Approximately 90 subjects will be randomized.  It is anticipated that this will yield 80 subjects 
who will have completed the study as planned.  Justification of this sample size is presented in 
Section 13.2. 
A screening log of potential study candidates and an enrollment log of enrolled subjects must be 
maintained at each study site. 
8.2 
Study Entry Criteria 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if the subject meets all of the following criteria: 
1. 
Subject is male or female, ≥ 12 to ≤ 17 years of age. 
2. 
Subject has a body mass index in the range of ≥ 15 to ≤ 35 kg/m2. 
3. 
Subject has ADHD as defined by DSM-5 and ADHD-RS-5  28 at Baseline with or 
without conventional ADHD therapy. 
4. 
Subject has an intelligence quotient (IQ) > 79, based on the Wechsler Abbreviated Scale of 
Intelligence, second edition (WASI-II). 
5. 
Subject has been genotyped previously and determined to have disruptive mutations in 
genes within the GRM-network as determined by the presence of CNVs (GRM biomarker-
positive subjects). The confirmation of a subject’s positive status will be provided by the 
sponsor. 
6. 
Subject is a non-smoker and/or has not used nicotine or nicotine-containing products on a 
weekly or more frequent basis for at least approximately 6 months. 
7. 
Subject is judged to be in general good health, other than having ADHD, based on medical 
history, physical examination, vital signs measurements, laboratory safety tests, and the 
C-SSRS performed at the Screening Visit and/or prior to administration of IP. 
8. 
Female subjects of reproductive potential will have a negative pregnancy test at Screening 
(serum) and prior to drug administration (urine).  If sexually active, female subjects agree 
to use (and/or have her partner use) 2 acceptable methods of birth control beginning at least 
2 weeks prior to administration of IP and throughout the study.  Acceptable methods of 


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birth control are abstinence or 2 of the following: intrauterine device, diaphragm, 
spermicides, cervical cap, contraceptive sponge, and condoms. 
9. 
Subject has no clinically significant abnormality on ECG performed at the Screening Visit 
and/or prior to administration of IP such as serious arrhythmia, bradycardia, tachycardia, 
cardiac conduction problems, or other abnormalities deemed to be a potential safety issue. 
10. 
Parent/legal guardian and subject understand the study procedures and agree to the 
subject’s participation in the study as indicated by parental/legal guardian signature on the 
subject informed consent form and subject signature on the assent form. 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if the subject meets any of the following criteria: 
1. 
Subject or parent/legal guardian is in the opinion of the investigator mentally or legally 
incapacitated, has significant emotional problems at the time of the Screening Visit or 
during the conduct of the study. 
2. 
Subjects with a current or relevant history of comorbid major psychiatric disorders (ie, 
aside from ADHD), including major depression, bipolar disease, schizophrenia, pervasive 
development disorder, and intellectual disability. 
3. 
Subject is currently taking a prohibited medication and/or is unwilling to wean off current 
ADHD medication to participate in the study. 
4. 
Subject has a history of any illness that in the opinion of the study investigator might 
confound the results of the study or poses an additional risk to the subject by his or her 
participation in the study. 
5. 
Subject has a history of any clinically significant disease that is not currently clinically 
stable.  Subjects with a history of uncomplicated kidney stones may be enrolled in the 
study at the discretion of the investigator. 
6. 
Subject has a known history or presence of syncope, cardiac conduction problems 
(eg, clinically significant heart block), exercise-related cardiac events including syncope 
and pre-syncope, or clinically significant bradycardia. 
7. 
Subject has a history of stroke, chronic seizures, or major neurological disorder which, in 
the opinion of the investigator, would interfere with the subject’s ability to participate 
and/or be evaluated in the study. 
8. 
Subject is pregnant or a nursing mother. 
9. 
Subject has a history of aversion to blood draws that in the opinion of the investigator or 
parents would result in compromising the study conduct. 
10. 
Subject has a history of physiologic difficulty in venous access that in the opinion of the 
investigator and parent/legal guardian would compromise study conduct. 
11. 
Subject has a history of inability to swallow whole unadulterated capsules, which in the 
opinion of the investigator or parent/legal guardian would compromise study conduct. 
12. 
Subject has a systolic or diastolic blood pressure ≥ the 95th percentile for his or her age. 
13. 
Subject consumes any alcoholic beverages on a regular basis (weekly or more often). 
14. 
Subject consumes excessive amounts of caffeine, defined as greater than 4 servings 
(1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other 
caffeinated beverages per day. 


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15. 
Subject has a history of significant multiple and/or severe allergies, or has had an 
anaphylactic reaction or significant intolerability to prescription of nonprescription drugs 
or food. 
16. 
Subject is currently a regular user (including “recreational use”) of any illicit drugs 
(including marijuana) or has a history of drug (including alcohol) abuse. 
17. 
Subject has had surgery, lost more than 5 mL/kg of blood, or participated in another 
investigational drug trial within 4 weeks prior to the Screening Visit. 
18. 
Subject has a clinical laboratory abnormality that indicates clinically significant 
hematologic, hepatobiliary, or renal disease: 
a 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase > 2.0-times the 
upper limit of normal 
b 
Alanine aminotransferase/serum glutamic pyruvic transaminase > 2.0-times the 
upper limit of normal 
c 
Total bilirubin > 2.0-times the upper limit of normal 
d 
Hemoglobin < 9 g/dL 
e 
White blood cell count < 1,000/mm3 
f 
Platelet count < 100,000/mm3 
g 
Creatinine kinase > 300 U/L for females and > 500 U/L for males 
8.3 
Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice.  Every reasonable attempt should be made by the 
investigator to keep subjects in the study; however, subjects must be withdrawn from the study if 
they withdraw consent to participate.  Investigators must attempt to contact subjects who fail to 
attend scheduled visits by telephone or other means to exclude the possibility of an AE being the 
cause of withdrawal.  Should this be the cause, the AE must be documented, reported, and 
followed as described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol violations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate electronic case report form (eCRF).  
Whenever possible and reasonable, the evaluations that were to be conducted at the completion 
of the study should be performed at the time of premature discontinuation. 
8.4 
Subject Replacement Criteria 
Once randomized, subjects who discontinue from the study will not be replaced. 


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9. TREATMENTS 
9.1 
Identification of Investigational Product(s) 
The following IPs will be used in this study: 
 
NFC-1 will be provided as white opaque size-2 capsules containing 100 mg or 200 mg 
NFC-1; no excipients are used. 
 
Dose, route, and frequency (NFC-1): 100 mg, 200 mg, and 400 mg administered orally 
twice daily in the fed or fasting state. 
 
Matching placebo will be provided as white opaque size-2 capsules containing 
microcellulose instead of NFC-1. 
 
Dose, route, and frequency: Placebo for 100 mg, 200 mg, and 400 mg administered orally 
twice daily in the fed or fasting state. 
9.2 
Labeling and Packaging 
All packaging and labelling operations will be performed by the sponsor according to Good 
Manufacturing Practice and Good Clinical Practice (GCP) rules.  The IP will be sent to the study 
site by the sponsor or designee.  Labelling will be in local language and dependent upon local 
regulations. 
9.2.1 Labeling 
The bottle will have affixed a label that meets the applicable regulatory requirements and may 
include the following: subject identifier, name of compound or placebo, dosage strength, lot 
identifier, protocol number, specified number of capsules, caution statement (“New Drug – 
Limited by United States Law to Investigational Use”), storage conditions, and sponsor 
identification. 
The investigator will be asked to save all empty packaging or packaging containing unused 
capsules for final disposition by the sponsor. 
9.2.2 Packaging 
NFC-1 and placebo will be supplied by the sponsor.  NFC-1 will be packaged in high-density 
polyethylene bottles of 20 capsules. NFC-1 and placebo will be packaged so that the investigator, 
the study clinic personnel, and subjects are blinded to study treatment. 
9.3 
Treatments Administered 
Eligible subjects will be randomized to either NFC-1 or placebo for 6 weeks of treatment; a 
4-week stepwise dose-optimization period will be followed by a 2-week maintenance period. 
NFC-1 or placebo will be administered twice daily for a maximum of 6 weeks.  At Baseline, 
randomized subjects will receive blinded IP to begin treatment the following day at a dose of 
100 mg twice daily.  Doses will be optimized to 100 mg, 200 mg, or 400 mg twice daily over the 
following 4 weeks as determined by the investigator’s assessment of clinical response and 
tolerability to IP.  Additional dose adjustments will not be allowed after Week 4, and if well 
tolerated, subjects will be maintained at their Week-4 dose. 
The objective of this period is to ensure subjects are titrated to an optimal dose of IP based upon 
the investigator’s review of efficacy, AEs, and clinical judgment. 


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9.4 
Dispensing and Storage 
The IP supplied by Medgenics is to be used exclusively in this clinical study according to the 
instructions of this protocol.  The investigator is responsible for dispensing the IP according to 
the dosage scheme and for ensuring proper storage of the IP. 
The investigator must confirm the receipt of the IP with his/her signature.  A copy of this receipt 
must be kept by the investigator, and another copy will be stored at Medgenics and/or 
 
.  Until the IP is dispensed to the subjects, it must be stored at 20-25°C and in a dry 
place in a securely locked area that is not generally accessible. 
The key to the storage area is to be kept by the investigator or designee responsible for the IP.  
The storage area will be accessible only to those persons authorized by the investigator to 
dispense the IP. 
9.4.1 Interactive Web Response System for Investigational Product Management 
An Interactive Web Response System (IWRS) will be employed in this study to register and 
randomize subjects, maintain the blind during the study, provide a mechanism for unblinding, 
dispense and manage investigational product, and track final subject disposition (ie, study 
completion or discontinuation). 
A user manual with specific functions and instructions for the IWRS will be provided to the site. 
9.5 
Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria will be randomly 
assigned in a 1:1 ratio to NFC-1 or placebo.  The randomization schedule will be computer-
generated using a permuted block algorithm and will randomly allocate IP to randomization 
numbers.  The randomization numbers will be assigned sequentially through the central IWRS as 
subjects are entered into the study. 
The randomization schedule will be prepared by 
 in advance of study initiation.  
All efforts will be made to ensure the integrity of the study blind up until the final database has 
been locked.  No one involved in study conduct will have access to the randomization schedule 
prior to that event.  No subject will be randomized into this study more than once. 
9.6 
Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment with the exception of a specified 
unblinded statistician from 
 who will have access to the randomization code.  
The unblinded study personnel will not otherwise participate in study procedures or data analysis 
prior to unblinding of the study data to all study related personnel. 
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in 
the conduct of the study.  Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency.  
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. Unblinding should be discussed in advance with the medical 
monitor if possible.  For emergency unblinding, study personnel will access the IWRS 
unblinding module.  If the investigator is not able to discuss treatment unblinding in advance, 
then he/she must notify the medical monitor as soon as possible about the unblinding incident 
without revealing the subject’s treatment assignment.  The investigator or designee must record 
the date and reason for study discontinuation on the appropriate eCRF for that subject.  In all 


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cases that are not emergencies, the investigator should discuss the event with the medical 
monitor prior to unblinding the subject’s treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study.  Thus, the overall study blind will not be compromised.  If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study.  The investigator will make this decision after consultation with the medical monitor. 
9.7 
Selection of Doses in the Study 
Doses of 100 mg, 200 mg, or 400 mg twice daily will be administered in this study.  These doses 
were found to be safe and well tolerated in a phase 1 study of adolescents with ADHD. 
Previous PK studies in both healthy adults (aged 26 to 48 years) and young adults (aged 20 to 
32 years) showed an elimination half-life (t½) of about 4 hours.  In view of the short half-life, 
twice daily dosing is expected to provide a more consistent pharmacologic effect throughout the 
day. 
Administration of single oral doses of 100 mg NFC-1 after a meal to young adults (aged 20 to 
32 years) showed rapid absorption (time to maximum plasma concentration [Tmax] from 0.6 to 
1.5 hours), dose-proportional increases in exposure, and a t½ of 3.7 to 4.4 hours in healthy male 
adults.  Comparison of doses administered under fed and fasted conditions to healthy male adults 
showed that food caused slower absorption (Tmax of 1.5 versus 0.7 hours) and decreased the 
maximum observed plasma concentration (Cmax) (4.14 versus 5.65 μg/mL), but no difference in 
the area under the plasma concentration-time curve extrapolated from time 0 to infinity (AUC0-∞) 
(29.3 versus 31.3 μg h/mL) and t½ (4.2 versus 4.3 hours).  In separate studies, similar 
PK parameters were obtained following administration of 100 mg NFC-1 to healthy male adults 
and young adults, respectively, with Tmax of 1.0 versus 1.2 hours, Cmax of 2.57 versus 
2.14 μg/mL, AUC0-∞ of 17.0 versus 14.0 μg h/mL, and t½ of 4.4 versus 4.4 hours. 
Preliminary evaluation of PK data from the recent adolescent PK study is consistent with 
previous PK data and demonstrated a linear dose/concentration profile with a t½ of 
approximately 4 hours. 
9.8 
Selection of Timing of Dose for Each Subject 
NFC-1 or matching placebo is to be taken orally twice daily during the treatment period (in the 
morning upon awakening [7:00 a.m.to 9:00 a.m.] and in the mid-afternoon [between 3:00 p.m.to 
5:00 p.m.]) and can be taken in the fed or fasting state. 
9.9 
Dose Adjustment Criteria 
The duration of the dose-optimization period is 4 weeks to allow for up-titration to the highest 
dose and no more than one down-titration to the previous dose, if necessary. 
Subjects will be instructed to take NFC-1 or placebo each morning upon awakening (at 7:00 a.m. 
to 9:00 a.m.) and in the mid-afternoon (3:00 p.m. to 5:00 p.m.).  On Day 1, all subjects will begin 
taking NFC-1 or placebo and will be evaluated after 7 days (± 2 days) for tolerability and 
effectiveness.  Subjects may be titrated weekly to the next available dose strength after 7 days 
(± 2 days) on the previous dose, based on the overall response of the subject.  Additionally, if 
needed, a subject may be down-titrated to the previous dose level in order to optimize tolerability 
and efficacy.  Subject response will be categorized by the investigator as 1 of 3 conditions and 
associated actions, with titration continuing until an “acceptable response” is achieved.  These 
conditions are defined as follows: 


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Intolerable response (ie, intolerable side effects):  Requires the subject to be tapered to a lower 
dose of NFC-1 (if available).  However, if this lower dose produces an intolerable response as 
well, the subject should be discontinued from the study. 
Ineffective response:  The subject is not showing a significant reduction in symptoms, and 
requires increasing titration of NFC-1 to the next available dose strength, provided tolerability is 
acceptable, followed by weekly evaluation. 
Acceptable response:  A response is defined as acceptable if it shows a significant reduction in 
symptoms with tolerable side effects.  Subjects categorized as “acceptable” may be maintained at 
their current dose for the remainder of the optimization period. Subjects who are tolerating study 
medication at the highest available dose but do not achieve an acceptable response should 
continue in the trial at that dose. 
Further, if the “acceptable” dose is well tolerated and, in the opinion of the investigator, the 
subject would potentially receive additional symptom reduction, the dose may be increased to the 
next higher dose level. 
If the subject experiences unacceptable intolerability, in the opinion of the investigator, the dose 
may be reduced (if available) by 1 dose level (to the previous dose).  If the subject tolerates the 
dose reduction well and maintains symptom control, the subject may be maintained at that 
reduced dose for the remainder of the optimization period (through Visit 6). 
Only 1 dose reduction is permitted during the optimization period.  Visit 5 will be the last visit at 
which titration can occur.  Once a subject has reached an optimal dose, this dose will be 
maintained for the remainder of the dose-optimization phase of the study (through Visit 6).  
Subjects who are unable to tolerate the IP will be discontinued.  After the dose optimization 
period, subjects will continue to receive the current optimized dose of IP for an additional 
2 weeks.  A 7-day follow-up call will occur after discontinuing study treatment. 
Subjects who discontinue because they are unable to tolerate the IP must complete all early 
termination (ET) visit assessments required during the last study visit. These subjects will also 
receive a 7-day follow-up call after discontinuing study treatment. 
9.10 Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IP including the date, quantity, batch or code number, and identification of 
subjects (subject number and initials) who received the IP.  The investigator will not supply the 
IP to any person except those named as subinvestigators on the US Food and Drug 
Administration (FDA) Form FDA 1572, designated study personnel, and subjects in this study.  
The investigator will not dispense the IP from any study sites other than those listed on Form 
FDA 1572.  IP(s) may not be relabeled or reassigned for use by other subjects.  If any of the IP is 
not dispensed; is lost, stolen, spilled, unusable, or is received in a damaged container, this 
information must be documented and reported to Medgenics and appropriate regulatory agencies, 
as required. 
Upon completion of the study, the IP (partly used, unused, and empty packaging [eg, bottles]) 
must be left in the original packaging and returned to the sponsor or designee for destruction. 
9.11 Treatment Compliance 
Treatment compliance with IP regimens will be assessed by study personnel via capsule counts 
of returned medication and by questioning the subject, if necessary, at every post-baseline visit.  
A subject who is not compliant (taken < 80% or > 100% of IP) will be counseled at each visit on 


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the importance of taking IP as instructed.  A subject who is noncompliant on 3 consecutive visits 
will be discharged from the study. 
9.12 Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter [OTC] medications) will be 
recorded in the source document and on the appropriate eCRF. 
9.12.1 Permitted Therapies 
Ongoing behavioral therapies, including individual cognitive behavioral therapy, group cognitive 
behavioral therapy, social effectiveness training, ADHD behavioral therapy, or applied 
behavioral analysis are allowed and must be maintained at the same frequency/intensity as at 
Screening.  The initiation of new behavioral therapies is not allowed. 
The use of inhaled bronchodilators is allowed, if needed.  Antibiotics and OTC medications that 
do not affect blood pressure, heart rate, or the central nervous system, which are considered 
necessary for the subject’s welfare, may be administered at the discretion of the investigator.   
The administration of all such medication must be recorded in the appropriate section of the 
source documentation and eCRF.  Non-sedating antihistamines such as Allegra® are allowed, as 
are OTC non-stimulant cold remedies such as guaifenesin. 
The use of inhaled steroids (corticosteroids) for asthma is allowed. 
9.12.2 Prohibited Therapies 
All ADHD medications will be discontinued prior to starting this study.  There will be a wash-
out phase of 5 days for stimulants and 14 days for atomoxetine and noradrenergic agonists.  
Study subjects will not start any new ADHD medication during the study.  Due to their potential 
to interfere with safety, efficacy, or tolerability assessments, the following medications are 
prohibited during the study: 
 
Any medication which is a substrate of CYP3A4, CYP2B6 or CYP2D6.  
 
Norepinephrine reuptake inhibitors. 
 
Anxiolytic or sedative hypnotic medications. 
 
Antidepressants, tricyclic antidepressants , selective serotonin reuptake inhibitors (SSRI), 
selective norepinephrine reuptake inhibitors including atomoxetine (Strattera). 
 
Clonidine. 
 
Guanfacine. 
 
Mood stabilizers (including lithium, anticonvulsants, and antipsychotics). 
 
Antihypertensive agents. 
 
Psychostimulants. 
 
Sedating antihistamines. 
 
Investigational compounds. 
 
All herbal preparations. 
 
Cough/cold preparations containing stimulants. 
Subjects receiving excluded therapies will be ineligible for study enrollment or for continuation 
in the study, at the discretion of the investigator and sponsor. 


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9.13 Treatment after End of Study 
After the end of the study, each subject will be treated according to standard clinical practice.  In 
order to support a subject’s transition from the clinical trial, after care and medical oversight will 
be covered in the amount of $250.00 per month for a total of up to 3 months. Payment will be 
made to the site to ensure appropriate medical oversight of the subject during titration and to 
cover costs for prescribed medication within the allotted total. 
10. STUDY PROCEDURES 
Subjects will provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the schedule of 
events (Section 17.1).  Throughout the study, every reasonable effort should be made by study 
personnel to follow the timing of assessments and procedures in the schedule of events for each 
subject.  If a subject misses a study visit for any reason, the visit should be rescheduled as soon 
as possible, ideally within 2 days of the originally scheduled date. 
10.1 Study Periods and Visits 
10.1.1 Screening and Wash-out 
10.1.1.1 Screening (Visit 1, Day -21 [± 2 days]) 
The subject must be screened within 21 days [± 2 days] before enrollment in the study.  The 
following procedures will be performed at Screening: 
1. 
Obtain written informed consent/assent. 
2. 
Perform a psychiatric evaluation Kiddie Schedule for Affective Disorders and 
Schizophrenia - Present and Lifetime Version (K-SADS-PL). 
3. 
Conduct the WASI-II brief IQ test (IQ should be > 79). 
4. 
Conduct ADHD-RS-5 evaluation. 
5. 
Conduct CGI-S evaluation. 
6. 
Review inclusion/exclusion criteria. 
7. 
Collect demographic information. 
8. 
Record medical and medication history including confirmation from the sponsor that each 
subject has been determined to have disruptive mutations in genes within the GRM-
network as determined by the presence of CNVs (GRM biomarker-positive subjects).  
9. 
Perform a physical examination including vital signs (resting blood pressure, heart rate, 
and respiratory rate), weight, and height. 
10. 
Collect blood and urine for clinical laboratory tests: hematology, serum chemistry, and 
urinalysis. 
11. 
Perform 12-lead ECG. 
12. 
Perform a serum pregnancy test (for females of childbearing potential only). 
13. 
Perform urine drug test. 
14. 
Conduct C-SSRS evaluation. 
15. 
Access IWRS. 
16. 
Assess and record concomitant medication and ongoing AEs. 


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If more than 23 days have elapsed between the Screening Visit and the Baseline Visit the 
following procedures must be repeated and the results available and reviewed prior to proceeding 
with the Baseline Visit: 
 Collect blood and urine for clinical laboratory tests: hematology, serum chemistry, and 
urinalysis. 
 Perform a serum pregnancy test (for females of childbearing potential only). 
 Measure vital signs (resting blood pressure, heart rate, and respiratory rate) and weight. 
 Perform 12-lead ECG. 
 Perform urine drug test. 
 
10.1.1.2 Wash-out Period 
Caregivers will receive a telephone call no later than at Day -14 (± 2 days) before the scheduled 
day of treatment initiation to confirm that stimulant and/or non-stimulant therapies for ADHD 
are being washed out. 
The following details will be recorded: 
1. 
Review inclusion/exclusion criteria. 
2. 
Assess and record concomitant medication and newly occurring AEs since the last 
evaluation. 
Subjects who do not require a washout call must still be contacted by phone prior to the Baseline 
visit being conducted.  
10.1.2 Baseline (Visit 2, Day -1 [± 2 days]) 
Subjects will attend a baseline visit (Day -1) on the day before starting study treatment (Day 1).  
Subjects who remain eligible for the study will be given blinded IP at the initial dose 
(100 mg twice daily) to begin treatment the following day (Day 1). 
The following procedures will be performed at Visit 2: 
1. 
Review inclusion/exclusion criteria. 
2. 
The subject will be randomized to NFC-1 or placebo via IWRS. 
3. 
Measure vital signs (resting blood pressure, heart rate, and respiratory rate) and weight. 
4. 
Perform 12-lead ECG. 
5. 
Perform a urine pregnancy test (for females of childbearing potential only). 
6. 
Conduct ADHD-RS-5 evaluation. 
7. 
Conduct CGI-S evaluation. 
8. 
Conduct ASHS evaluation. 
9. 
Conduct SCARED evaluation. 
10. 
Conduct C-SSRS evaluation. 
11. 
Access IWRS. 
12. 
Dispense IP at initial dose level of 100 mg twice daily with instructions to begin taking the 
IP the following day. 
13. 
Assess and record concomitant medication and newly occurring AEs since the last 
evaluation. 


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10.1.3 Double-blind Treatment Period 
The double-blind treatment period will comprise a dose optimization phase of 28 days and a 
subsequent dose maintenance phase of 14 days. 
10.1.3.1 Dose Optimization Phase (Visit 3, Day 7 [± 2 days], Visit 4, Day 14 [± 2 days], 
Visit 5, Day 21 [± 2 days], and Visit 6, Day 28 [± 2 days]) 
Subjects will take 100 mg NFC-1 or placebo twice daily from Study Day 1.  During the 4-week 
dose-optimization phase, subjects will be administered 100 mg, 200 mg, or 400 mg IP twice 
daily based on dose assessments performed by the investigator. 
Subjects will attend a visit for evaluation by the investigator on the last day of each week of 
treatment during the optimization phase.  Subjects will undergo the same evaluations at the end 
of each of the 4 weeks of the dose-optimization phase.  During these visits, the investigator will 
assess the tolerability and efficacy of the subject’s current IP dose, and categorize their response 
as intolerable, ineffective, or acceptable.  Based on this categorization, the subjects will be 
dispensed the next appropriate dose of the IP, to begin taking at the next scheduled dosing 
timepoint (see Section 9.9 for the definition of the dose adjustment criteria). 
The following procedures will be performed at Visit 3 (Day 7 [± 2 days]), Visit 4 (Day 14 
[± 2 days]), Visit 5 (Day 21 [± 2 days]), and Visit 6 (Day 28 [± 2 days]): 
1. 
Measure vital signs (resting blood pressure, heart rate, and respiratory rate) and weight. 
2. 
Collect blood and urine for clinical laboratory tests: hematology, serum chemistry, and 
urinalysis (at Visit 3 only). 
3. 
Perform 12-lead ECG. 
4. 
Perform a urine pregnancy test (for females of childbearing potential only). 
5. 
Conduct ADHD-RS-5 evaluation. 
6. 
Conduct CGI-I evaluation. 
7. 
Conduct C-SSRS evaluation. 
8. 
Access IWRS. 
9. 
Conduct dose assessment and dispense the IP at the appropriate dose level, with 
instructions to begin taking the provided IP at the next scheduled dosing timepoint. 
10. 
Subject returns unused IP. 
11. 
Assess subject compliance using returned IP. 
12. 
Assess and record concomitant medication and newly occurring AEs since the last 
evaluation. 
10.1.3.2 Dose Maintenance Phase (Visit 7, Day 35 [± 2 days], Visit 8, Day 42 [± 2 days], or 
Early Termination) Evaluation 
At Day 35 and Day 42 or ET of the study, the following procedures will be performed: 
1. 
Perform a physical examination and measure height (at Visit 8/ET only). 
2. 
Measure vital signs (resting blood pressure, heart rate, and respiratory rate) and weight. 
3. 
Collect blood and urine for clinical laboratory tests: hematology, serum chemistry, and 
urinalysis (at Visit 8/ET only). 
4. 
Perform 12-lead ECG. 
5. 
Perform a urine pregnancy test (for females of childbearing potential only). 


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6. 
Conduct ADHD-RS-5 evaluation. 
7. 
Conduct CGI-S evaluation (at Visit 8/ET only). 
8. 
Conduct CGI-I evaluation. 
9. 
Conduct ASHS evaluation (at Visit 8/ET only). 
10. 
Conduct SCARED evaluation (at Visit 8/ET only). 
11. 
Conduct C-SSRS evaluation. 
12. 
Access IWRS. 
13. 
Subject returns unused IP. 
14. 
Assess subject compliance using returned IP. 
15. 
Assess and record concomitant medication and newly occurring AEs since the last 
evaluation. 
10.1.4 7-day Follow-up Call 
At Day 49 (+ 5 days), caregivers will receive a telephone call to assess and record concomitant 
medication and newly occurring AEs since the last evaluation. 
10.2 Study Duration 
The overall study duration is expected to be 70 days (including up to 21 days of screening 
inclusive of a maximum 14 days of wash-out, approximately 42 days of treatment, and a follow-
up period of approximately 7 days). 
The planned sequence and maximum duration of the study periods will be as follows: 
1. 
Screening period: approximately 21 days. 
2. 
Wash-out period: if applicable, up to 14 days. 
3. 
Dose optimization phase: 28 days. 
4. 
Dose maintenance phase: 14 days. 
5. 
Follow-up: 7 days (+5 days) after the last dose of IP. 
The maximum study duration for each subject is approximately 70 days. 
The maximum treatment duration for each subject is 42 days. 
10.3 Assessments 
10.3.1 Screening 
10.3.1.1 Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime 
The K-SADS-PL is a semi-structured diagnostic interview designed to assess current and past 
episodes of psychopathology in children and adolescents according to Diagnostic and Statistical 
Manual of Mental Disorders, 3rd Edition, Revised (DSM-III-R) and Diagnostic and Statistical 
Manual of Mental Disorders, 4th Edition (DSM-IV) criteria.  Probes and objective criteria are 
provided to rate individual symptoms. 
The primary diagnoses assessed with the K-SADS-PL include, but are not limited to: major 
depression, dysthymia, mania, bipolar disorders, schizoaffective disorders, panic disorder, 
agoraphobia, separation anxiety disorder, avoidant disorder of childhood and adolescence, 
simple phobia, social phobia, overanxious disorder, generalized anxiety, obsessive compulsive 
disorder, ADHD, conduct disorder, and oppositional defiant disorder. 


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The K-SADS-PL will be administered by the investigator, by interviewing the parent or 
caregiver, the child, and finally achieving summary ratings, which include all sources of 
information (parent or legal caregiver, child, school, chart, and other). 
Time of administration: 90 minutes 
10.3.1.2 Wechsler Abbreviated Scale of Intelligence 
The WASI-II is administered by the investigator.  It comprises a 4 sub-test form (vocabulary, 
similarities, block design, matrix reasoning) and yields 3 scales: 
 
Full Scale IQ-4 score: estimate of generalized cognitive ability. 
 
Verbal Comprehension Index score: measure of crystallized abilities. 
 
Perceptual Reasoning Index score: measure of nonverbal fluid abilities and 
visuomotor/coordination skills. 
Time of administration: 30 minutes 
10.3.2 Efficacy 
All scales included in Section 10.3.2 that are described as “clinician rated” are to be completed 
by the principal investigator or a delegated subinvestigator who is a licensed clinician. A 
licensed clinician is defined as a doctor of medicine, doctor of osteopathic medicine, or licensed 
psychologist with a PhD or another individual that is approved by the sponsor or designee. All 
raters are to be approved by the sponsor or designee. 
10.3.2.1 Attention Deficit Hyperactivity Disorder Rating Scale Version 5 
The ADHD-RS-5 (7) will be used as the primary measure.  This parent-reported clinician-rated 
scale will be administered at each visit, beginning at Screening to capture the ADHD symptoms 
within each study week.  The ADHD-RS-5 is a parent-reported/clinician-rated scale that was 
developed to measure the behaviors of children with ADHD, and comes in a Home Version and 
a School Version, with separate forms for children (ages 5-10 years) and adolescents (11-17 
years); it consists of 18 items designed to reflect the symptomatology of ADHD based on the 
Diagnostic and Statistical Manual of Mental Disorders (DSM) DSM-5  criteria.  Each item will 
be scored on a range of 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total 
scores ranging from 0-54. The 18 items may be grouped into 2 subscales: inattention and 
hyperactivity/impulsivity.  The Inattention subscale raw score is computed by summing the item 
scores for Items 1–9.  The Hyperactivity–Impulsivity subscale raw score is computed by 
summing the item scores for Items 10–18. Additionally, the ADHD-RS-5 incorporates 2 
impairment scales keyed to the inattention and hyperactivity–impulsivity dimensions, which 
allow the clinician to assess the extent to which ADHD-related problems adversely affect the 
home and/or school functioning of children and adolescents 
Time of administration: 10-15 minutes 
10.3.2.2 Clinical Global Impression-Improvement and Severity Scales 
The CGI-I and CGI-S scales will be used as a secondary outcome measure for estimating level of 
functioning in response to NFC-1 treatment.  These scales record the investigator’s global 
assessment of the severity of the symptoms and changes in symptoms from Baseline based on 
reports from parents, subject, and minimal direct observation (8).  This assessment will guide the 
investigator during dosing adjustments. 


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A CGI-S scale captures the severity of a subject’s condition on a 7-point scale ranging from 
1 (normal, not at all ill) to 7 (among the most extremely ill subjects) (Table 2) on Baseline 
(Visit 2) and at Visit 8/ET. 
At each visit from Visit 3 to Visit 8/ET, the investigator will assess the improvement of the 
subject’s illness severity on the 7-point CGI-I scale ranging from 1 (very much improved) to 
7 (very much worse) (Table 2). 
The CGI-based assessments have been used to evaluate efficacy of ADHD medications (9), 
where they have general consistency and reliability.   
Time of administration: 10-20 minutes. 
 
Table 2: 
Clinical Global Impression Scales 
SEVERITY – CGI-S 
 
 IMPROVEMENT – CGI-I 
 
Normal, not at all ill 
1 
 Very much improved 
1 
Borderline mentally ill 
2 
 Much improved 
2 
Mildly ill 
3 
 Minimally improved 
3 
Moderately ill 
4 
 No change 
4 
Markedly ill 
5 
 Minimally worse 
5 
Severely ill 
6 
 Much worse 
6 
Amongst the most extremely ill patients 
7 
 Very much worse 
7 
Abbreviations: CGI-I = Clinical Global Impression of Improvement, CGI-S = Clinical Global Impression of 
Severity 
10.3.2.3 Adolescent Sleep Hygiene Scale 
The ASHS is a self-report questionnaire assessing sleep practices theoretically important for 
optimal sleep in adolescents aged ≥ 12 years of age.  It assesses physiological (eg, evening 
caffeine consumption), cognitive (eg, thinking about things that need to be done at bedtime), 
emotional (eg, going to bed feeling upset), sleep environment (eg, falling asleep with the lights 
on), sleep stability (eg, different bedtime/wake time pattern on weekdays and at weekends), 
substance use (eg, evening alcohol use), daytime sleep (eg, napping), and having a bedtime 
routine. 
The ASHS will be assessed at Baseline (Visit 2) and Visit 8/ET. 
Time of administration: 10 minutes. 
10.3.2.4 Screen for Childhood Anxiety-related Emotional Disorders 
The SCARED is a child self-report instrument for ages 8-18 years used to screen for childhood 
anxiety disorders including general anxiety disorder, separation anxiety disorder, panic disorder, 
and social phobia.  In addition, it assesses symptoms related to school phobias. 
The SCARED consists of 41 items and 5 factors that parallel the DSM-IV classification of 
anxiety disorders.  The scale has good internal consistency, test-retest reliability, and 
discriminant validity, and it is sensitive to treatment response. 
The SCARED will be assessed at Baseline (Visit 2) and Visit 8/ET. 
Time of administration: 10 minutes. 


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10.3.3 Safety 
Safety and tolerability assessments will include the frequency and severity of AEs as well as the 
evaluation of changes in clinical laboratory values, vital signs, ECG recordings, and C-SSRS. 
10.3.3.1 Clinical Laboratory Safety Assessments 
10.3.3.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following clinical laboratory tests will be collected at the time points specified in 
the schedule of events (Section 17.1). 
Hematology 
Hemoglobin, hematocrit, red blood cell count, red blood cell indices, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, platelet count (or estimate), white blood cell count 
including differential. 
Serum chemistry 
Albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, creatinine, creatine kinase, glucose, sodium, potassium, 
chloride, bicarbonate, lactate dehydrogenase, uric acid. 
Urinalysis 
pH, specific gravity, blood, glucose, protein, ketones. 
[Urine/serum] 
pregnancy test 
For women of childbearing potential only. 
Urine drug screen 
Amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, cannabinoids, propoxyphene and methadone. 
Blood samples will be collected as specified in the study laboratory manual. 
Laboratory specimens will be analyzed at the central laboratory as specified in the study 
laboratory manual. 
10.3.3.1.2 Biological Markers 
Not applicable. 
10.3.3.1.3 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products.  Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens 
in both the clinic and laboratory settings.  Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples.  Procedures and regulations for the packaging and 
shipping of infectious samples are outlined in the study laboratory manual.  The investigator is 
responsible for ensuring that all study samples that are to be transported to another location are 
appropriately packed and shipped according to the applicable regulations. 
10.3.3.1.4 Evaluation of Laboratory Values 
The normal ranges of values for the laboratory assessments in this study will be provided by the 
responsible laboratory and submitted to Medgenics, Inc. prior to the beginning of the study.  
They will be regarded as the reference ranges on which decisions will be made. 


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If a laboratory value is out of the reference range, it is not necessarily clinically relevant.  The 
investigator must evaluate the out-of-range values and record his/her assessment of the clinical 
relevance in the appropriate eCRF. 
All laboratory values which, in the investigator’s opinion, show clinically relevant or 
pathological changes during or after termination of the treatment are to be discussed with the 
medical monitor and reported as AEs and followed, as described in Section 11.2.5. 
All measurements described in this section are recognized standard methods. 
10.3.3.2 Clinical Examinations 
10.3.3.2.1 Vital Signs 
Vital signs, including heart rate, respiratory rate, and systolic and diastolic blood pressure will be 
measured after the subject has been in a sitting position for 5 minutes. 
10.3.3.2.2 Electrocardiogram 
A standard 12-lead ECG will be performed after the subject has been supine for at least 
5 minutes.  All ECG recordings will be identified with the subject number, subject initials, date, 
and time of the recording and will be attached to the subject’s eCRF. 
All ECG values which, in the investigator’s opinion, show clinically relevant or pathological 
changes during or after termination of the treatment are to be discussed with the medical monitor 
and reported as AEs and followed, as described in Section 11.2.5. 
10.3.3.2.3 Physical Examination 
A complete physical examination (excluding the genitourinary examination) will be performed at 
Visit 1 before potential exposure to the IP and at Visit 8 at the completion of exposure. 
10.3.3.3 Columbia Suicide Severity Rating Scale 
The C-SSRS (10) is a semi-structured interview that captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviors during the assessment period.  The interview 
includes definitions and suggested questions to solicit the type of information needed to 
determine if a suicide-related thought or behavior has occurred.  The interview and rating for the 
C-SSRS must be completed by a licensed clinician and is medically responsible for the subject.  
A licensed clinician is defined as a doctor of medicine, doctor of osteopathic medicine, or 
licensed psychologist with a PhD.  The C-SSRS has a “baseline” version which will be 
completed at Screening (Visit 1) and a “Since Last Visit” version that will be completed at all 
subsequent visits.  There are a maximum of 19 items to be completed: 7 that are required, 
10 potential additional items if there is a positive response to a required item, and 2 items for 
suicide/suicide behavior present during the interview.  The C-SSRS uses dichotomous scales 
(ie, yes or no), Likert scales, and text or narrative to further describe the thoughts or behaviors. 
Time of administration = 10 minutes. 
10.3.3.4 Adverse Events 
The definitions and management of and special considerations for AEs are provided in 
Section 11. 


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11. ADVERSE EVENTS 
11.1 Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with the product.  An AE can therefore be any unfavorable and unintended sign 
(including a new, clinically important abnormal laboratory finding), symptom, or disease, 
temporally associated with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition (worsening of a 
pre-existing condition is considered an AE). 
Events occurring in subjects treated with placebo or during treatment-free periods of the study 
are also considered AEs. 
11.1.2 Unexpected Adverse Event 
An expected AE is one for which the nature or severity is consistent with the known AE profile 
of the product.  For an IP, the known information is contained in the IB.  For a marketed product, 
the known information is contained in the current package insert for the product. 
An unexpected AE is one for which the specificity or severity is not consistent with the current 
IB.  For example, hepatic necrosis would be unexpected (greater severity) if the IB only listed 
elevated hepatic enzymes or hepatitis.  Likewise, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (greater specificity) if the IB only listed cerebral vascular 
accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, 
already documented adverse reaction constitute unexpected events.  Examples would be (a) acute 
renal failure as an expected adverse reaction with a subsequent new occurrence of interstitial 
nephritis (interstitial nephritis would be unexpected) and (b) hepatitis with a first occurrence of 
fulminant hepatitis (fulminant hepatitis would be unexpected). 
11.1.3 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
 
Results in death. 
 
Is life-threatening. 
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 
which hypothetically might have caused death if it were more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay.  
An elective hospital admission to treat a condition present before exposure to the test 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE. Further, an overnight stay in the hospital that is only due 
to transportation, organization, or accommodation problems and without medical 
background does not need to be considered an SAE. 
 
Results in persistent or significant disability/incapacity. 


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 
Is a congenital anomaly. 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE.  However, a newly diagnosed pregnancy in a subject that 
has received an IP is not considered an SAE unless it is suspected that the IP(s) 
interacted with a contraceptive method and led to the pregnancy. 
 
Is an important medical event. 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  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. 
11.1.4 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.1.5 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first 
administration of IP (NFC-1 or placebo) and not more than 7 days after the last administration of 
IP. 
11.2 Management of Adverse Events 
Adverse events will be collected from the time of signing informed consent form (ICF) through 
the Follow-up Visit or Early Termination Visit, whichever occurs first. 
11.2.1 Collection 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously.  At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation.  The investigator will 
then monitor and/or ask about or evaluate AEs using nonleading questions, such as: 
 
“How are you feeling?” 
 
“Have you experienced any issues since your last visit?” 
 
“Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
Mild: 
Usually transient and may require only minimal treatment or therapeutic 
intervention.  The event does not generally interfere with usual activities of 
daily living. 
Moderate: 
Usually alleviated with additional specific therapeutic intervention.  The 
event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 


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Severe: 
Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs.  Severity is a classification of 
intensity whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.3. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.3. 
11.2.2.3 Action(s) Taken 
Action(s) taken may consist of: 
Dose increased: 
An indication that a medication schedule was modified by addition; 
either by changing the frequency, strength or amount. 
Dose not changed: 
An indication that a medication schedule was maintained. 
Dose reduced: 
An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength or amount. 
Drug interrupted: 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug withdrawn: 
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication. 
Not applicable: 
Determination of a value is not relevant in the current context. 
Unknown: 
Not known, not observed, not recorded, or refused. 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
 
Recovered/resolved. 
 
Recovered/resolved with sequelae. 
 
Recovering/resolving. 
 
Not recovered/not resolved. 
 
Fatal*. 
 
Unknown. 
*Only select fatal as an outcome when the AE results in death.  If more than one AE is possibly 
related to the subject’s death, the outcome of death should be indicated for each such AE.  
Although “fatal” is usually an event outcome, events such as sudden death or unexplained death 
should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP.  The categories 
for classifying the investigator’s opinion of the relationship are listed below. 
Not related: 
An AE with sufficient evidence to accept that there is no causal 
relationship to IP administration (eg, no temporal relationship to drug 
administration, because the drug was administered after onset of event; 


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investigation shows that the drug was not administered; another cause was 
proven). 
Unlikely related: 
An AE, including laboratory test abnormality, with a temporal 
relationship to IP administration that makes a causal relationship 
improbable, and in which other drugs, events or underlying disease 
provide plausible explanations. 
Possibly related: 
An AE with a reasonable time sequence to administration of the IP, but 
which could also be explained by concurrent disease or other drugs or 
events.  Information on drug withdrawal may be lacking or unclear. 
Related: 
An AE occurring in a plausible time relationship to IP administration, and 
which cannot be explained by a concurrent disease or other drugs or 
events. The response to withdrawal of the drug (dechallenge) is clinically 
reasonable. 
The AE relationship to IP will be assessed separately by the investigator and Medgenics. 
11.2.3 Documentation 
All AEs occurring within the period of observation for the study must be documented in the 
eCRF with the following information, where appropriate.  The period of observation for the 
study is described in Section 11.2. 
 
AE name or term. 
 
When the AE first occurred (start date and time). 
 
When the AE stopped (stop date and time or an indication of “ongoing”). 
 
Severity of the AE. 
 
Seriousness (hospitalization, death, etc.). 
 
Actions taken. 
 
Outcome. 
 
Investigator opinion regarding the AE relationship to the IP. 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject may continue in 
the study/should be withdrawn from the study and the reason must be documented in the eCRF.  
The decision about whether the subject may continue in the study will be made by the sponsor 
after consultation with the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, or for which continued administration of IP is not 
reasonable in view of the potential benefit to subject, the investigator must decide whether to 
stop the study and/or treat the subject.  Special procedures may be recommended for the specific 
IP, such as the collection of a serum sample for blood concentrations of IP, specific tapering 
procedures, or treatment regimens, as appropriate. 
For double- or triple-blinded studies, it is not necessary to unblind a subject’s treatment 
assignment in most circumstances, even if an SAE has occurred.  If unblinding is necessary, see 
Section 9.6 for a description of the unblinding procedures. 


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11.2.5 Follow-up 
Any AE will be followed (up to a maximum of 7 days after the last dose of the IP) to a 
satisfactory resolution, until it becomes stable, or until it can be explained by another known 
cause(s) (ie, concurrent condition or medication) and clinical judgment indicates that further 
evaluation is not warranted.  All findings relevant to the final outcome of an AE must be reported 
in the subject’s medical record and recorded on the appropriate eCRF. 
11.2.6 Notification 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to 
 within 24 hours 
of first becoming aware of the event by completing, signing, and dating the SAE pages, verifying 
the accuracy of the information recorded on the SAE pages with the corresponding source 
documents and eCRF, and sending the SAE pages to the 
 Pharmacovigilance 
Department by one of the following methods: 
 
Email: 
. 
 
FAX number: 
 
The written report should be submitted on the SAE form provided for this purpose.  At the time 
of first notification, the investigator or designee should provide the following information, if 
available: 
 
Protocol number. 
 
Reporter (study site and investigator). 
 
Subject’s study number. 
 
Subject’s year of birth. 
 
Subject’s gender. 
 
Date of first dose of IP. 
 
Date of last dose of IP, if applicable. 
 
Adverse event term. 
 
Date of occurrence of the event. 
 
A brief description of the event, outcome to date, and any actions taken. 
 
The seriousness criteria(on) that were met. 
 
Concomitant medication at onset of the event. 
 
Relevant past history information. 
 
Relevant laboratory test findings. 
 
Investigator’s opinion of the relationship to IP(s) (“Is there a reasonable possibility that the 
IP caused the SAE? Yes or No?”). 
 
Whether and when the investigator was unblinded as to the subject’s treatment assignment. 
Any missing or additional relevant information concerning the SAE should be provided to the 
recipient(s) of the initial information as soon as possible on a follow-up SAE Report Form 
together with the following information: AE, date of occurrence, subject ID, study ID, IP, and 
site number.  This will allow the follow-up information to be linked to the initial SAE report. 


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Specific information may be requested by the 
 Pharmacovigilance Department 
using a follow up request form.  The investigator is required to comply with applicable 
regulations (including local laws and guidances) regarding the notification of his/her health 
authorities, institutional review boards (IRBs), principal and coordinating investigators, study 
investigators, and institutions. 
11.2.6.2 Non-serious Adverse Events 
Nonserious AEs will be recorded in the eCRF and reported by 
 to Medgenics. 
11.3 Special Considerations 
11.3.1 Adverse Events of Special Interest 
The following events will be considered as AEs of special interest during this study: 
 
Psychosis. 
 
Suicidal ideation. 
Based on the population under study, and their age, suicidal ideation will be considered as an AE 
of special interest. 
11.3.2 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
study participation.  Women should be instructed to contact the investigator or study staff 
immediately if pregnancy occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of IP on every woman of 
childbearing potential.  A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
A woman who becomes pregnant during IP treatment or within 30 days of discontinuing the IP 
will be immediately discontinued from study participation.  The investigator must report the 
pregnancy within 24 hours of learning of the pregnancy to 
 Pharmacovigilance 
using the Pregnancy Data Collection Form via the same fax and email address as for SAE 
reporting.  The investigator should contact the designated individual(s) who receive SAE 
notification and record information related to the pregnancy on an Exposure in Utero form/other 
designated form provided by the sponsor or its designee. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy.  The investigator is also responsible for following the pregnancy until delivery or 
termination.  These findings must be reported on the Exposure in Utero Form/other designated 
form and forwarded to the designated individual(s).  The event meets the SAE criterion only if it 
results in a spontaneous abortion or a congenital anomaly. 
12. DATA SAFETY MONITORING BOARD 
No Data Safety Monitoring Board will be required. 
13. STATISTICS 
13.1 Study Endpoints 
13.1.1 Primary Efficacy Endpoint 
The primary endpoint for the assessment of efficacy will be the ADHD-RS-5 score.  The analysis 
will be based on changes from the baseline value and will test the hypothesis that there is no 
difference between the treatments (ie, that the difference is 0) against a 2-tailed alternative. 


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13.1.2 Secondary Efficacy Endpoints 
Secondary endpoints will include the CGI-I, CGI-S, and other assessment scales.  Further 
exploratory analyses will examine the effect of covariates such as dose-level and age.  All 
quantitative endpoints will be described with traditional summary statistics and tabulated by 
treatment group and visit. 
13.1.3 Safety Endpoints 
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Affairs (MedDRA) and tabulated by system organ class and preferred term.  Adverse 
events will be analyzed by frequency, severity, relationship to IP, and their effect on 
participation in the study. 
Clinical laboratory values will be compared to normal ranges and flagged for levels of clinical 
concern.  The analysis will focus on the frequencies of abnormal values as well as within-subject 
changes observed during the course of the study. 
Vital signs and ECG recordings will also be examined for changes during the study that may be 
attributed to exposure to IP. 
The C-SSRS will also be examined for changes that may be attributed to exposure to IP. 
13.2 Sample Size Determination 
Enrollment of 90 subjects is expected to yield 80 subjects who complete the study as planned.  
Assuming an effect size of 0.7, this number will provide approximately 90% power to detect a 
significant difference between the treatments based on a 2-tailed α = 0.05 comparison of mean 
change from Baseline. 
13.3 Analysis Populations 
The design of this study yields 3 main populations of scientific interest. 
The Safety Population will consist of all subjects who are randomized into the study and receive 
any amount of IP. 
The Intent-to-Treat (ITT) Population will be composed of all subjects who are randomized into 
the study. 
The occurrence of significant protocol deviations may lead to the exclusion of some subjects 
from specific analyses, thereby yielding a Per-protocol (PP) Population. 
Specific subgroups of these populations may also be evaluated as warranted by the experimental 
results. 
Membership in the analysis populations will be determined prior to unblinding. 
13.4 Statistical Analyses 
This section presents a summary of the planned statistical analyses.  Additional details regarding 
data handling, analytical methods, and presentation of results will be found in the Statistical 
Analysis Plan for this study.  The Statistical Analysis Plan will be finalized prior to database 
lock. 
13.4.1 Study Subjects and Demographics 
13.4.1.1 Disposition and Withdrawals 
The disposition of all subjects enrolled in this study will be fully described with respect to their 
randomization status and ultimate discontinuation.  Subjects who discontinue the study will be 
summarized with the reason for discontinuation. 


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13.4.1.2 Protocol Deviations 
All subject data will be reviewed for the occurrence of protocol deviations.  Prior to database 
lock, all protocol deviations will be reviewed in a blinded fashion and classified with respect to 
the potential to influence experimental outcomes.  The results of this review may lead to 
enumeration of a PP Population, as described in Section 13.3. 
13.4.1.3 Demographics and Other Baseline Characteristics 
The analysis of demographic and baseline data will be performed for all study populations. 
Demographic variables include age, gender, race, ethnicity, height, and weight.  Baseline subject 
characteristics to be summarized will include medical history, physical examination, 
ECG assessment, C-SSRS evaluation, an IQ test (WASI-II), and clinical laboratory tests. 
Prior and concomitant medications will be summarized by treatment group and by the number 
and percentage of subjects taking each medication.  Medications will be coded according to the 
World Health Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical 
(ATC) classes and preferred terms. 
13.4.2 Exposure and Compliance 
Exposure to IP will be summarized for all participating subjects.  Subjects will be described with 
respect to cumulative exposure as well as categorized by the highest dose received. 
Compliance with study medication will be determined for each subject.  Based on capsule 
counts, the number of doses administered will be expressed as the proportion of doses scheduled.  
Compliance will be assessed independently for each phase of the study (ie, dose optimization 
and maintenance). 
13.4.3 Efficacy Analyses 
All efficacy measures will be described with standard summary statistics.  Continuous variables 
will be summarized by N, mean, and standard deviation, and categorical variables by the number 
and percent of subjects in each category.  Where appropriate, estimates will be presented with 
95% confidence intervals. 
Efficacy analyses will attempt to quantify the effects of treatment with NFC-1 relative to 
placebo.  The null hypothesis of no difference between active and placebo will be tested against 
a 2-tailed alternative with a type-I error rate of 0.05. 
13.4.3.1 Primary Analysis 
The primary analysis will focus on the effect of treatment on ADHD, as indicated by the 
ADHD-RS-5.  The change in ADHD-RS-5 will be derived as the difference between the last 
post-treatment value and that recorded at the Baseline visit.  The analysis of the change will 
employ a 1-way analysis of variance (ANOVA) model with a term for treatment (active or 
placebo).  Depending on the fit of the single-factor model, subsequent exploratory analyses may 
be performed that include additional independent factors (eg, age, gender, and/or maintenance 
dose of study drug) as well as covariates that have been determined to be associated with 
experimental results (eg, baseline value of the dependent variable).  Results of these exploratory 
analyses will be presented as estimates for all factors included in the model with corresponding 
95% confidence intervals and associated levels of statistical significance. 
This analysis will be performed with primary focus on the ITT Population. 


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13.4.3.2 Secondary Analyses 
Secondary efficacy analyses will examine the effects of the treatment on changes observed in 
other efficacy measures (ie, CGI-S, ASHS, and SCARED).  These analyses will model the 
overall or total scale scores and will employ the same general approach as for the primary 
analysis.  All secondary efficacy measures will be treated as continuous measurement scales and 
analyzed by the ANOVA methods described above. 
Results of the CGI-I assessment will also be dichotomized and presented for each week of 
treatment.  CGI-I scores of 1 or 2 will be combined into a single group labelled “Improved” and 
scores of 3 to 7 will be combined and labelled “No Improvement.”  The observed proportions of 
“Improved” subjects will be compared between treatment groups at each week of the study. 
In addition, analysis of the weekly results from ADHD-RS-5 and CGI-I will be evaluated for 
evidence of trend over time.  This analysis will employ a linear mixed-effects model with 
repeated measures on each subject.  Terms for the model will be selected as described for the 
primary analysis. 
Secondary analyses will focus on the ITT Population.  However, analyses of the PP Population 
may be performed if warranted by the data. 
13.4.4 Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 13.3).  Safety variables include treatment-emergent adverse events (TEAEs), clinical 
laboratory values, vital signs, ECG results, C-SSRS, and physical examination results.  No 
formal inferential analyses will be conducted for safety variables, unless otherwise noted. 
13.4.4.1 Adverse Events 
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Treatment-emergent AEs will be summarized by system 
organ class (SOC) and preferred term.  Treatment-emergent AEs will be presented as the number 
and proportion of subjects reporting each event.  Similar summaries will be produced for post-
treatment AEs, SAEs, AEs leading to termination, and AEs with at least a possible relationship 
to the IP.  The intensity of AEs and the relationship to the IP will also be summarized for each 
SOC and preferred term. 
13.4.4.2 Clinical Laboratory Evaluations 
Descriptive summaries of actual (absolute) values and changes from baseline values will be 
presented by treatment group for each study visit. 
The number of subjects with clinical laboratory values below, within, or above normal ranges, at 
each study visit will be tabulated (shift tables) for each clinical laboratory analyte by treatment 
group. 
13.4.4.3 Vital Signs and Electrocardiograms 
Vital signs (systolic and diastolic blood pressure, pulse, and respiratory rate), and ECG results 
will be summarized by visit and treatment group using appropriate descriptive statistics.  The 
number and percentage of subjects with abnormal ECG findings will be summarized by 
treatment group for each study visit. 
13.4.4.4 Columbia Suicide Severity Rating Scale 
The C-SSRS score will be summarized by visit and treatment group using descriptive statistics. 


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13.4.4.5 Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group. 
13.4.5 Interim Analysis 
No interim analysis is planned for this study. 
14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel prior to the study, periodic monitoring visits, and meticulous data management. 
14.1 Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 15).  The sponsor reserves the right to withdraw a subject from the study (Section 8.3), 
to terminate participation of a study site at any time (Section 14.7), and/or to discontinue the 
study (Section 14.6). 
Medgenics agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement in Section 17.2, the investigator indicates that she/he 
has carefully read the protocol, fully understands the requirements, and agrees to conduct the 
study in accordance with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including and in accordance with the 
April 1996 International Conference on Harmonisation (ICH) Guidance for Industry E6 GCP and 
in agreement with the 1996 Version of the Declaration of Helsinki.  While delegation of certain 
aspects of the study to subinvestigators and study coordinators is appropriate, the investigator 
will remain personally accountable for closely overseeing the study and for ensuring compliance 
with the protocol and all applicable regulations and guidelines.  The investigator is responsible 
for maintaining a list of all persons that have been delegated study-related responsibilities 
(eg, subinvestigators and study coordinators) and their specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, IPs, and their specific 
duties within the context of the study.  Investigators are responsible for providing Medgenics 
with documentation of the qualifications, GCP training, and research experience for themselves 
and their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person.  
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 


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14.2 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site.  The study site 
will not be authorized for study initiation until: 
1. 
The study site has received the appropriate IRB approval for the protocol and the 
appropriate ICF. 
2. 
All regulatory documents have been submitted to and approved by the sponsor or its 
designee. 
3. 
The study site has a Clinical Trial Agreement in place. 
4. 
Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3 Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study upon 
agreement with the medical monitor. 
14.4 Study Documents 
All documentation and material provided by Medgenics for this study are to be retained in a 
secure location and treated as confidential material. 
14.4.1 Investigator’s Regulatory Documents 
The regulatory documents are listed in the Study Manual. 
The regulatory documents must be received from the investigator and reviewed and approved by 
Medgenics or its designee before the study site can initiate the study and before Medgenics will 
authorize shipment of IP to the study site.  Copies of the investigator’s regulatory documents 
must be retained at the study site in a secure location.  Additional documents, including a copy of 
the protocol and applicable amendment(s), the NFC-1 IB, eCRF completion guidelines, copies of 
regulatory references, copies of IRB correspondence, and IP accountability records should also 
be retained as part of the investigator’s regulatory documents.  It is the investigator’s 
responsibility to ensure that copies of all required regulatory documents are organized, current, 
and available for inspection. 
14.4.2 Electronic Case Report Forms 
By signing the Investigator’s Agreement in Section 17.2, the investigator agrees to complete the 
eCRFs and maintain source documentation as part of the case histories for all subjects who sign 
an ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly.  The sponsor or its designee will provide the necessary training on the use of the 
specific eCRFs used during the study to ensure that the study information is captured accurately 
and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit.  All requested information must be entered in the eCRF according to the 
completion guidelines provided by the sponsor or its designee. 
The eCRFs may be signed by the investigator or a subinvestigator.  These signatures serve to 
attest that the information contained in the eCRF is accurate and true. 


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14.4.3 Source Documents 
All information recorded in the eCRF must be supported by corresponding source 
documentation.  Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
During the study, select eCRF data may be used as original data collection tools as long as a 
description of this documentation process is maintained in the investigator’s study files. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central laboratory to the sponsor or its designee.  A paper copy of the laboratory results will be 
provided to the study site and should be retained with each subject’s source data. 
14.5 Data Quality Control 
Medgenics and its designees will perform quality control checks on this clinical study. 
14.5.1 Monitoring Procedures 
Medgenics and/or designee will conduct site visits to monitor the study and ensure compliance 
with the protocol, GCP, and applicable regulations and guidelines.  The assigned clinical 
research associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals and 
maintain periodic communication.  The investigator agrees to allow the CRA(s) and other 
authorized Medgenics personnel access.  The CRA(s) will maintain current personal knowledge 
of the study through observation, review of study records and source documentation, and 
discussion of the conduct of the study with the investigator and staff.  While on site, the CRA(s) 
will review: 
 
Regulatory documents, directly comparing entries in the eCRF with the source documents. 
 
Consenting procedures. 
 
AE procedures. 
 
Storage and accountability of IP and study materials. 
The CRA will ask for clarification and/or correction of any noted inconsistencies.  Procedures 
for correcting eCRF are described in the study manual.  As representatives of the sponsor, CRAs 
are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement in Section 17.2, the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed, to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area, and to assist the monitors in their activities, if requested.  Further, the investigator 
agrees to allow Medgenics or designee auditors or inspectors from regulatory agencies to review 
records and to assist the inspectors in their duties, if requested. 
14.5.2 Data Management 
Medgenics or designee will be responsible for activities associated with the data management of 
this study.  The standard procedures for handling and processing records will be followed per 
GCP and 
 standard operating procedures.  A comprehensive data 
management plan will be developed including a data management overview, database contents, 
annotated eCRF, pre-entry review list, self-evident correction conventions, query contacts, and 
consistency checks. 


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Study site personnel will be responsible for providing resolutions to all data queries.  The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the study manual. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Medgenics or designee.  The audits will be undertaken to 
check compliance with GCP guidelines and will include a minimum of: 
 
In-house study file audit. 
 
Audit of computer database quality control. 
 
Audit of clinical report quality control. 
Medgenics or designee may conduct additional audits on a selection of study sites, requiring 
access to subject notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities according 
to GCP guidelines.  The investigator agrees to cooperate with the auditor during the visit and will 
be available to supply the auditor with eCRFs or other files necessary to conduct that audit.  Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Medgenics immediately. 
14.6 Study Termination 
The study may be terminated at Medgenics’ discretion at any time and for any reason. 
14.7 Study Site Closure 
At the end of the study, all study sites will be closed.  Medgenics may terminate participation of 
a study site at any time.  Examples of conditions that may require premature termination of a 
study site include, but are not limited to, the following: 
 
Noncompliance with the protocol and/or applicable regulations and guidelines. 
 
Inadequate subject enrollment. 
14.7.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until 
 
At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
 
At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of her/his intent to 
destroy all such material.  The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 


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14.7.2 Sample Retention 
Not applicable.  
14.8 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Medgenics.  The protocol amendment must be signed by the 
investigator and approved by the IRB before it may be implemented.  Protocol amendments will 
be filed with the appropriate regulatory agency(ies) having jurisdiction over the conduct of the 
study. 
14.9 Use of Information and Publication 
All information concerning NFC-1, Medgenics’ operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information supplied by 
Medgenics or designee to the investigator and not previously published, is considered 
confidential and remains the sole property of Medgenics.  Case report forms also remain the 
property of Medgenics.  The investigator agrees to use this information for purposes of study 
execution through finalization. 
The information developed in this study will be used by Medgenics in connection with the 
continued development of NFC-1 and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
The information generated by this study is the property of Medgenics.  Publication or other 
public presentation of NFC-1 data resulting from this study requires prior review and written 
approval of Medgenics.  Abstracts, manuscripts, and presentation materials should be provided 
to Medgenics for review at least 30 days prior to the relevant submission deadline. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until Medgenics has reviewed and commented on 
such a presentation or manuscript for publication. 
15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1 Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the protocol, the April 1996 ICH Guidance for 
Industry E6 GCP (including archiving of essential study documents), the 1996 Version of the 
Declaration of Helsinki, and the applicable regulations of the country(ies) in which the study is 
conducted. 
See Appendix B for regulations and guidelines. 
15.2 Subject Information and Informed Consent 
A properly constituted, valid IRB must review and approve the protocol, the investigator’s 
informed consent document, and related subject information and recruitment materials before the 
start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
15.3 Approval by Institutional Review Board 
For Investigational New Drug (IND) studies, the minimum standards of conduct and 
requirements for informed consent are defined in the FDA regulations. 
A valid IRB must review and approve this protocol before study initiation.  Written notification 
of approval is to be submitted by the investigator to the Medgenics monitor before shipment of 


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investigational drug supplies and will include the date of the committee’s approval and the 
chairperson’s signature.  This written approval must consist of a completed Medgenics, 
IRB Approval Form, or written documentation from the IRB containing the same information. 
Until written approval by the IRB has been received by the investigator, no subject may undergo 
any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB.  Written approval from 
the IRB, or a designee, must be received by Medgenics before implementation.  This written 
approval will consist of a completed IRB approval form or written documentation from the IRB 
containing the same information. 
15.4 Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the 
investigator and Medgenics. 


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16. REFERENCES 
1. 
NFC-1 Investigator’s Brochure, 2015. 
2. 
Elia J, Glessner JT, Wang K, et al. Genome-wide copy number variation study associates 
metabotropic glutamate receptor gene networks with attention deficit hyperactivity 
disorder. Nat Genet. 2011;44(1):78-84. 
3. 
Oka M, Itoh Y, Tatsumi, S, Ma FH, Ukai Y, Yoshikuni Y, Kimura KA. A novel cognition 
enhancer NS-105 modulates adenylate cyclase activity through metabotropic glutamate 
receptors in primary neuronal culture. Naunyn Schmiedebergs Arch Pharmacol. 
1997;356(2):189-96. 
4. 
Oka M, Itoh Y, Shimidzu T, Ukai Y, Yoshikuni Y, Kimura K. Involvement of 
metabotropic glutamate receptors in Gi- and Gs-dependent modulation of adenylate 
cyclase activity induced by a novel cognition enhancer NS-105 in rat brain. Brain Res. 
1997;754(1-2):121-30. 
5. 
Hirouchi M, Oka M, Itoh Y, Ukai Y, Kimura K. Role of metabotropic glutamate receptor 
subclasses in modulation of adenylyl cyclase activity by a nootropic NS-105. Eur J 
Pharmacol. 2000;387(1):9-17. 
6. 
Ogasawara T, Itoh Y, Tamura M, Mushiroi T, Ukai Y, Kise M, Kimura K. Involvement of 
cholinergic and GABAergic systems in the reversal of memory disruption by NS-105, a 
cognition enhancer. Pharmacol Biochem Behav. 1999;64(1):41-52. 
7. 
DuPaul GJ, Power TJ, Anastopoulos AD, and Reid R. ADHD Rating Scale—5 for 
Children and Adolescents Checklists, Norms, and Clinical Interpretation. Guildford 
Press. 2016. 
8. 
Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a Research Tool 
in Clinical Practice. Psychiatry (Edgmont). 2007;4(7):28-37. 
9. 
Goodman DW. Lisdexamfetamine dimesylate (vyvanse), a prodrug stimulant for attention-
deficit/hyperactivity disorder. PT. 2010;35(5):273-87. 
10. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
 


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17. ATTACHMENTS 
17.1 Schedule of Events 
 
Visit 
Screening 
Wash-out 
Call 
Baseline 
Treatment Period 
7-day 
Follow-up 
Calla 
Dose Optimization 
Dose Maintenance 
1 
No Visit 
2 
3 
4 
5 
6 
7 
8/ET 
No Visit 
Assessment Day 
-21 
-14 
-1 
7 
14 
21 
28 
35 
42 
49 
Visit Window 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
+ 5 days 
Informed consent/ 
assentb 
 
 
 
 
 
 
 
 
 
 
Psychiatric evaluation  
(K-SADS-PL) 
 
 
 
 
 
 
 
 
 
 
WASI-II (brief IQ test) 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
 (review) 
 (review) 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
Medical and medication 
historyc 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
Vital signs (resting blood 
pressure, heart rate, and 
respiratory rate) 
g 
 
 
 
 
 
 
 
 
 
Height (calibrated 
stadiometer) 
 
 
 
 
 
 
 
 
 
 
Weight (calibrated scale) 
g 
 
 
 
 
 
 
 
 
 
Clinical laboratory test 
g 
 
 
 
 
 
 
 
 
 
12-lead ECG 
g 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(females of childbearing 
potential) 
g 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(females of childbearing 
potential) 
 
 
 
 
 
 
 
 
 
 
Urine drug test 
g 
 
 
 
 
 
 
 
 
 
Investigator dose 
assessment 
 
 
 
 
 
 
 
 
 
 


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Visit 
Screening 
Wash-out 
Call 
Baseline 
Treatment Period 
7-day 
Follow-up 
Calla 
Dose Optimization 
Dose Maintenance 
1 
No Visit 
2 
3 
4 
5 
6 
7 
8/ET 
No Visit 
Assessment Day 
-21 
-14 
-1 
7 
14 
21 
28 
35 
42 
49 
Visit Window 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 days 
+ 5 days 
ADHD-RS-5 
 
 
 
 
 
 
 
 
 
 
CGI-Sd 
 
 
 
 
 
 
 
 
 
 
CGI-Ie 
 
 
 
 
 
 
 
 
 
 
ASHS 
 
 
 
 
 
 
 
 
 
 
SCARED 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
Access IWRSf 
 
 
 
 
 
 
 
 
 
 
Study drug dispensed 
 
 
 
 
 
 
 
 
 
 
Study drug returned 
 
 
 
 
 
 
 
 
 
 
Compliance 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ADHD-RS-5 = Attention Deficit Hyperactivity Disorder Rating Scale Version 5, ASHS = Adolescent Sleep Hygiene Scale, 
CGI-I = Clinical Global Impression of Improvement, CGI-S = Clinical Global Impression of Severity, C-SSRS = Columbia Suicide Severity Rating Scale, 
ECG = electrocardiogram, ET = early termination, IQ = intelligence quotient, IWRS = interactive web response system, K-SADS-PL = Kiddie Schedule for 
Affective Disorders and Schizophrenia - Present and Lifetime Version, SCARED = Screen for Childhood Anxiety-related Emotional Disorders, 
WASI-II = Wechsler Abbreviated Scale of Intelligence, second edition 
a Caregivers will receive a follow-up telephone call from a study staff member 7 days after the last visit to collect information about any ongoing AEs and 
concomitant medication. 
b Informed consent to be completed by a duly authorized subject representative.  Assent is to be provided by subject where required. 
c Medical and medication history including confirmation from the sponsor that each subject has been determined to have disruptive mutations in genes within 
the GRM-network as determined by the presence of CNVs (GRM biomarker-positive subjects).  
d The CGI–S rates illness severity on the following 7-point scale: 1 = normal, not at all ill, 2 = borderline mentally ill, 3 = mildly ill, 4 = moderately ill, 
5 = markedly ill, 6 = severely ill, and 7 = among the most extremely ill subjects. 
e The CGI-I requires the investigator to assess how much the subject’s illness has improved or worsened: 1 = very much improved, 2 = much improved, 
3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. 
f 
IWRS will assign treatment numbers and will also manage all logistical aspects of treatments (eg, drug resupply and expiry dates). 
g If more than 23 days have elapsed between the Screening Visit and the Baseline Visit clinical laboratory tests, serum pregnancy test, vital signs and weight, 
urine drug test, and ECG must be repeated and the results available and reviewed prior to proceeding with the Baseline Visit.  


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17.2 Investigator’s Agreement 
PROTOCOL NUMBER: 
MDGN-NFC1-ADHD-201 
PROTOCOL TITLE: 
A Multicenter, 6-Week, Double-blind, Randomized, Placebo-
controlled, Parallel-design Study to Assess the Efficacy and 
Safety of NFC-1 in Adolescents (Ages 12-17 Years) with 
Genetic Disorders Impacting Metabotropic Glutamate Receptors 
and Attention Deficit Hyperactivity Disorder 
FINAL PROTOCOL: 
27 Oct 2016 
 
I have read this protocol and agree to conduct this clinical trial as outlined herein.  I will ensure 
that all subinvestigators and other study staff members have read and understand all aspects of 
this protocol.  I agree to cooperate fully with Medgenics and 
 during the study.  
I will adhere to all FDA, ICH, and other applicable regulations and guidelines regarding clinical 
trials on an IP during and after study completion. 
Principal Investigator: 
 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 


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APPENDICES 
A. 
Study-specific Requirements 
B. 
Regulations and Good Clinical Practice Guidelines 
 


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A. Study-specific Requirements 
All diagnostic scales are available under license at the study centers. 


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B. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
 
FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
 
FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
 
FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/products/guidelines.html 
 

SAP_001.pdf: 


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DOCUMENT HISTORY
Version
Date
Author
Description
0.1
17-JUN-2016 
 
Initial Draft
0.2
06-JUL-2016 
 
Updated Draft from sponsor 
review comments
0.3
15-JUL-2016 
 
Updated CMH to Chi-Square 
analyses, Updated Changes to 
planned Analysis Section, Added 
Dose group on several tables, Re-
ordered tables and updated titles, 
Other minor updates 
1.0
18-JUL-2016 
 
Updated Version numbering, 
included signature page at end of 
document 
2.0
30-NOV-2016 
 
Updated to include response and 
remission criteria. Removed PCI 
analysis for labs. Removed 
Temperature from PCI vitals, as 
this is not collected




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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................2 
SIGNATURE PAGE AND APPROVALS ......................................................................3 
TABLE OF CONTENTS ..................................................................................................4 
ABBREVIATIONS ............................................................................................................6 
1 
OVERVIEW ...........................................................................................................7 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................7 
2.1 
Study Objectives ..........................................................................................7 
2.1.1 Primary Objective ............................................................................7 
2.1.2 Study Endpoints ...............................................................................7 
3 
OVERALL STUDY DESIGN AND PLAN .........................................................8 
4 
ANALYSIS AND REPORTING ........................................................................11 
4.1 
Interim Analysis .........................................................................................11 
4.2 
Final Analysis ............................................................................................11 
5 
ANALYSIS POPULATIONS .............................................................................11 
5.1 
Sample Size ................................................................................................11 
6 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................11 
6.1 
General Statistical Methodology................................................................11 
6.2 
Data Adjustments, Handling, Conventions ................................................12 
6.3 
Derived and Computed Variables ..............................................................13 
6.4 
Adjustment for multiple comparisons ........................................................14 
7 
STUDY PATIENTS/SUBJECTS AND DEMOGRAPHICS ...........................15 
7.1 
Disposition of Subjects and Withdrawals ..................................................15 
7.2 
Protocol Deviations ....................................................................................15 
7.3 
Demographics and Other Baseline Characteristics ....................................15 
7.4 
Baseline Disease Characteristics ................................................................16 
8 
EFFICACY ANALYSIS ......................................................................................16 
8.1 
Primary Analysis ........................................................................................16 
8.2 
Secondary Analysis ....................................................................................16 
9 
SAFETY AND TOLERABILITY ANALYSIS .................................................17 
9.1 
Adverse Events ..........................................................................................17 
9.1.1 Adverse Events Leading to Early Termination ..............................18 
9.1.2 Deaths ............................................................................................18 


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9.2 
Clinical Laboratory Evaluations ................................................................18 
9.3 
Vital Signs ..................................................................................................18 
9.4 
Electrocardiograms ....................................................................................19 
9.5 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................19 
9.6 
Physical Examination Findings..................................................................19 
9.7 
Concomitant Medication ............................................................................20 
9.8 
Exposure and Compliance .........................................................................20 
10 
CHANGES FROM PLANNED ANALYSIS .....................................................20 
11 
REFERENCES .....................................................................................................21 
APPENDIX A – TABLES, LISTINGS, AND FIGURE SHELLS ..............................22 
11.1 
Standard Layout for all Tables, Listings, and Listing ................................24 
11.2 
Planned Table Shells ..................................................................................25 
11.3 
Planned Listing Shells................................................................................27 


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ABBREVIATIONS
ABBREVIATION
DEFINITION OR DESCRIPTION
ADHD
Attention Deficit Hyperactivity Disorder
ADHD-RS-5
Attention Deficit Hyperactivity Disorder Rating Scale Version 5
ANCOVA
Analysis of covariance
ASHS
Adolescent Sleep Hygiene Scale
CGI-I
Clinical Global Impression of Improvement
CGI-S
Clinical Global Impression of Severity
CI
Confidence Interval
CNV
Copy Number Variant
C-SSRS
Columbia Suicide Severity Rating Scale
CSR
Clinical Study Report
CV
Coefficient of Variation
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
Electrocardiogram
ET
Early Termination
eCRFs
Electronic Case Report Forms
EMA
European Medicines Agency
FAS
Full Analysis Set Population
FDA
Food and Drug Administration
GRM
Glutamate Receptors, Metabotropic
ICH
International Conference on Harmonisation
IP
Investigational Product
IQ
Intelligence Quotient
IWRS
Interactive Web Response System
K-SADS-PL
Kiddie Schedule for Affective Disorders and Schizophrenia - Present and 
Lifetime Version
LLOQ
Lower Limit of Quantitation
LOCF
Last Observation Carried Forward
LOD
Limit of Detection
MAR
Missing-At-Random
mGluR
Metabotropic Glutamate Receptors
MMRM
Mixed-Effect Model Repeated Measure
PCI
Potentially Clinically Important
SAP
Statistical Analysis Plan
SCARED
Screen for Childhood Anxiety-related Emotional Disorders
SD
Standard Deviation
ULOQ
Upper Limit of Quantitation
WASI-II
Wechsler Abbreviated Scale of Intelligence, 2nd edition


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1
OVERVIEW
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Medgenics, 
Inc. Protocol MDGN-NFC1-ADHD-201(A Multicenter, 6-Week, Double-blind, Randomized, 
Placebo-controlled, Parallel-design Study to Assess the Efficacy and Safety of NFC-1 in 
Adolescents (Ages 12-17 Years) with Genetic Disorders Impacting Metabotropic Glutamate 
Receptors and Attention Deficit Hyperactivity Disorder), Final Version 4.0 dated 27-OCT-2016. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials [1]. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association [2] and the Royal Statistical 
Society [3], for statistical practice. 
The planned analysis identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analysis 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 addition to the study protocol, the following documents were reviewed in preparation of this 
SAP:
x
The electronic case report forms (eCRFs) for this Protocol. 
x
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 related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis.
2
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective
The primary objectives of this study are:
x
To assess the efficacy of NFC-1 relative to placebo in reducing the severity of symptoms 
associated with Attention Deficit Hyperactivity Disorder (ADHD) in adolescents with 
genetic disorders impacting mGluRs.
x
To obtain additional safety data following exposure to NFC-1 in this population. 
2.1.2
Study Endpoints
The primary endpoint for the assessment of efficacy will be the Attention Deficit Hyperactivity 
Disorder Rating Scale Version 5 (ADHD-RS-5) score. The analysis will be based on the changes 
from the baseline value and will test the hypothesis that there is no difference between the 
treatments (i.e., that the difference is 0) against a 2-tailed alternative.


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Additionally, secondary endpoints of efficacy will include the CGI-I, CGI-S, ASHS, SCARED
scales, and Response and Remission criteria using the ADHD-RS-5 and CGI-I [4]. Further 
analyses will examine effect of gender and dose level. All quantitative endpoints will be 
described with traditional summary statistics and tabulated by treatment group and visit.
3
OVERALL STUDY DESIGN AND PLAN
This is a randomized, double-blind, placebo-controlled, parallel-group phase 2 study of 
adolescents to compare the safety and efficacy of NFC-1 with that of placebo. Approximately 90 
male and female subjects will receive randomized treatment with NFC-1 or placebo to obtain 80 
VXEMHFWV WKDW FRPSOHWH WKH VWXG\ DV SODQQHG 6XEMHFWV PXVW EH   WR   \HDUV RI DJH DQG KDYH
ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
(DSM-5) and an ADHD-RS-5 > 28 at Baseline. The study will take place in approximately 25 
sites in the United States.  
The overall maximum study duration for an individual subject is expected to be 70 days with
maximum treatment duration of 42 days. As per the schedule of events below (Table 1), subjects 
will be randomly assigned in a 1:1 ratio to receive either NFC-1 or placebo on Day -1 and will 
start taking investigational product (IP) at a dose of 100 mg twice daily on Day 1. Dosing will be 
optimized to 100 mg, 200 mg, or 400 mg twice daily as appropriate, over the 4 weeks of 
treatment (dose optimization phase), based on clinical response and tolerability. If the subject 
tolerates their final optimized dose well, the dose will be maintained for an additional 2 weeks 
(dose maintenance phase) when the primary assessments of efficacy and tolerability will be 
performed. A follow-up telephone call will be performed 7 days after the last visit. 


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Table 1. Schedule of Events


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4
ANALYSIS AND REPORTING
4.1
Interim Analysis 
No interim analysis is planned for this study.
4.2
Final Analysis 
All final, planned analysis identified in the protocol and in this SAP will be performed after the 
study database has been locked and treatment code has been unblinded.
Any post-hoc, exploratory analysis 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. 
5
ANALYSIS POPULATIONS
The following analysis populations are planned for this study:
x
Safety Population (SAFETY): The Safety Population includes all subjects who are 
randomized into the study and receive any amount of Investigational Product (IP). 
x
Intent-To-Treat Population (ITT): The ITT Population includes all subjects who are 
randomized into the study. 
x
Per-Protocol Population (PP): The PP Population includes all randomized subjects who do 
not have any significant protocol deviations defined as a major protocol deviation. Major 
protocol deviations are listed in section 7 (below). Membership in the PP population will be 
determined by a blinded review of patient data prior to database lock.
5.1
Sample Size
Enrollment of 90 subjects is expected to yield 80 subjects who complete the study as planned.  
Assuming an effect size of 0.7, this number will provide approximately 90% power to detect a 
significant difference between the treatments based on a 2-WDLOHG Į = 0.05 comparison of mean 
change from baseline.
6
GENERAL ISSUES FOR STATISTICAL ANALYSIS
6.1
General Statistical Methodology 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed using SAS® Software (release 9.3 or higher) for 
Windows, unless otherwise specified. 
Continuous (quantitative) variables will be summarized using descriptive statistics including 
number of non-missing values, mean, standard deviation (SD), median, minimum, and 
maximum. Where appropriate, estimates will be presented with 95% confidence intervals (CIs).   
Categorical (qualitative) variables will be summarized using the number and proportion of each 
possible value. In general, the denominator for the percentage calculation will be based upon the 
total number of subjects in the study population for the treatment group. 95% CIs of proportions 
may also be presented for selected endpoints where applicable. Zero-count levels of variables 
will not display a percentage. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the raw data. Measures of location (mean and median) will be 


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reported to 1 degree of precision more than the raw data and measures of spread (standard 
deviation) will be reported to 2 degrees of precision more than the raw data. 
All statistical tests will be conducted at the 0.05 significance level using 2-tailed tests, and P-
values will be reported. Assessments done on unscheduled visits will not be summarized but will 
be listed.
In general, baseline and safety tables will be completed for the Safety Population unless 
otherwise specified. Efficacy tables for primary and secondary endpoints will be presented for 
the ITT Population. However, analyses of the PP Population may be performed if warranted by 
the data.  These potential PP tables are not present in the table index.
All final, planned analyses identified in the protocol and in this SAP will be performed after all 
relevant study data have been processed and integrated into the analysis database, analysis 
populations have been finalized, and the database has been locked. Any post-hoc, exploratory 
analysis completed to support planned study analyses, which were not identified in this SAP, will 
be documented and reported in Section 9.8 of the Clinical Study Report (CSR). Any results from 
these unplanned analyses (post-hoc) will also be clearly identified as such in the text of the CSR.
6.2
Data Adjustments, Handling, Conventions
All collected data will be presented in listings. Data not subject to analyses according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
Adverse events will be coded using the MedDRA (version 19.0).  Concomitant and Prior 
medications will be coded using WHO-DD (version March 1, 2016).
If partial dates occur, the convention for replacing missing dates for the purpose of calculating 
derived variables is as follows: 
For partial start dates:
x
If the year is unknown, then do not impute the date but assign a missing value. 
x
If the month is unknown, then: 
o
If the year matches the year of the randomization date, then impute the month and 
day of the randomization date. 
o
Otherwise, assign 01 January
x
If the day is unknown, then: 
o
If the month and year match the month and year of the randomization date, then 
impute the day of the first dose date. 
o
Otherwise, assign 01. 
For partial end dates: 
x
If the year is unknown, then do not impute the date but assign a missing value.
x
If the month is unknown, then assign the last day of the year 31 December. 
x
If the day is unknown, then assign the last day of the month. 
If an AE has a missing severity, it will be imputed as 'Severe'; any missing relationship to study 
drug of an AE will be imputed as 'Related'.


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For the primary endpoint, ADHD-RS-5, missing observations will be imputed by the LOCF 
method (as described in section 8, below).  Other ADHD-RS-5 subscales will impute the value 
of a missing result if enough data is present (as described in section 6.3). 
No other missing data will be imputed.
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(LLOQ) or limit of detection (LOD), one-half of the reported value (i.e., LLOQ, LOD) will be 
used for analysis.
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the reported value (i.e., ULOQ) will be used for analysis. 
For analysis purposes, repeat laboratory test results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non-missing repeat 
laboratory value will be used for data analysis.
6.3
Derived and Computed Variables
x
Baseline = the last non-missing measurement/assessment before the date of first dose will 
be flagged.  Typically, this will be the value recorded on Day -1. 
x
Study Day = Assessment Date - Date of Randomization + 1 
x
Change from Baseline = Value at Post-Baseline - Value at Baseline
x
% Change from Baseline = 100 * Change from Baseline / Value at Baseline
x
"Screen Failure" is a patient who has not met eligibility criteria, or otherwise chose not to 
participate in the study prior to randomization 
x
ADHD-RS-5 subscales – if at least 80% of the questions needed to calculate a scale or 
subscale score have valid responses, then that score will be computed as the sum of all 
non-missing items divided by the percentage of items in that scale or subscale present. If 
fewer than 80% of items have valid responses, then that score will be assigned as 
missing.
x
ADHD-RS-5 Inattention subscale is computed by summing the first 9 item scores for 
Question 4 – Question 12. 
x
ADHD-RS-5 Hyperactivity-Impulsivity subscale is computed by summing the second 9 
item scores for Question 19 – Question 27. 
x
ADHD-RS-5 Total Score is based on 18 items designed to reflect the symptomatology of 
ADHD based on the DSM-5 criteria.  Each item is scored on a 0 (reflecting no 
symptoms) to 3 (reflecting severe symptoms) and then added for a total score ranging 
from 0-54. 
x
ASHS Physiological factor is the mean of Questions 6, 13, 15, 21, and 22. 
x
ASHS Behavioral Arousal Factor is the mean of Questions 14, 16, and 31. 
x
ASHS Cognitive/Emotional Factor is the mean of Questions 12, 17, 18, 19, 20, and 32.  
x
ASHS Sleep Environment Factor is the mean of Questions 23, 24, 25, 26, and 27. 
x
ASHS Sleep Stability Factor is the mean of Questions 33, 37, and 39. 
x
ASHS Daytime Sleep Factor is the mean of Questions 4, and 7. 
x
ASHS Substances Factor is the mean of Questions 9, and 10. 
x
ASHS Bedtime Routine Factor is the value for Question 30. 
x
ASHS Total Score is the mean of all 8 subscales, with a higher score indicating better 
success on each of the dimensions of sleep hygiene.


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x
SCARED Panic Disorder is the summation of Questions 1, 6, 9, 12, 15, 18, 19, 22, 24, 
27, 30, 34, and 38. 
x
SCARED Generalized Anxiety is the summation of Questions 5, 7, 14, 21, 23, 28, 33, 35, 
and 37. 
x
SCARED Separation Anxiety is the summation of Questions 4, 8, 13, 16, 20, 25, 29, and 
31.
x
SCARED Social Anxiety is the summation of Questions 3, 10, 26, 32, 39, 40 and 41. 
x
SCARED Significant School Avoidance is the summation of questions 2, 11, 17, and 36. 
x
SCARED Total Score is the summation of all 41 questions, each scored from 0 to 2 scale. 
x
C-SSRS Suicidal Ideation is an indicator of any subject who experience any one of the 
five suicidal ideation events at least once (Questions 4, 6, 8, 10, and 12) 
x
C-SSRS Suicidal Behavior is an indicator of any subject who experience any one of the 
suicidal behavior events at least once (Questions 22, 26, 29, 32, and 35) 
x
C-SSRS composite endpoint of Suicidal Ideation or Behavior is an indicator of any 
subject who experiences any one of the ten suicidal ideation or behavior events at least 
once.
x
TEAE - An AE is defined as treatment emergent if the first onset or worsening is after the 
first administration of IP (NFC-1 or placebo) and not more than 7 days after the last 
administration of IP
x
For the tabulation of TEAE’s that are related to study drug, these are defined as any 
TEAE which is determined by the investigator as ‘possibly related’ or ‘related’. 
x
Post-Treatment AE is an AE that has started more than 7 days after last administration of 
IP.
x
Prior medications are defined as medications or therapies initiated prior to date of first 
dose of IP and terminating prior to date of first dose of IP.  Medications that are started 
prior to the date of first dose of IP and are continuing after the first dose of IP are 
considered to be both prior and concomitant medications
x
Concomitant medication is defined as any medication a subject received concurrently 
with study treatment. 
x
Post-treatment medication is defined as any medication that has started more than 7 days 
after the last administration of IP.
x
Compliance (OveUDOO   ,QGLYLGXDO :HHN &RPSOLDQFH  7LPH-Weight)) * 100.  A 
subject is non-compliant if they take < 80% or > 120% of IP.
- Individual Week Compliance is defined as the number of capsules taken at a particular 
week divided by the expected number of capsules taken at a particular week.  Given that 
a subject will be dose optimized, the number of expected capsules will vary according to 
which dose the subject is currently on for each day. 
- Time-Weight is the fraction of x/y where x is the number of days in the week the 
subject is expected to be on dose and y is the whole treatment duration defined as first 
dose – last dose + 1.  
6.4
Adjustment for multiple comparisons
There will be no adjustments for multiple comparisons in the analysis. 


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7
STUDY PATIENTS/SUBJECTS AND DEMOGRAPHICS
7.1
Disposition of Subjects and Withdrawals
All subjects who provide informed consent will be accounted for in this study. The number of 
subjects screened, randomized, completing, and withdrawing from the study, as well as reason 
for withdrawal, will be summarized by treatment group, dose, and overall. Additionally, the 
number of subjects in each population will be displayed. All disposition information will be 
included in a listing.
7.2
Protocol Deviations 
Protocol deviations will be collected by the clinical team and provided to 
 biostatistics 
prior to database lock.  Protocol deviations will be reviewed and on a case-by-case basis to be 
classified and minor or major by the project team prior to database lock.
The categories of protocol deviations which will be reviewed and classified as major/minor 
include: 
x
Informed Consent/Assent 
x
Inclusion/Exclusion Criteria
x
Concomitant Medication
x
Use of prohibited medication 
x
Laboratory Assessment
x
Study Assessments/Procedures
x
Investigational Product 
x
Overdose/Misuse 
x
Visit Window
x
Non-compliance
x
Other
7.3
Demographics and Other Baseline Characteristics
Descriptive summaries of the demographic and other baseline characteristics will be completed 
for all patients in the Safety population by treatment group, dose, and overall. These tabulations 
will include the following variables:
x
Demographics (age, gender, race, ethnicity, height, weight, and BMI) 
x
IQ test (WASI-II)
x
K-SADS-PL
Prior medication: The frequency and percentage of all prior medications will be summarized by 
Anatomical Therapeutic Chemical (ATC) classification level 3 and preferred term for all patients 
in the Safety population by treatment group and overall. 
Medical History: Incidences of medical history will be listed by reported term for all patients in 
the Safety population. 
All demographic and other baseline characteristics will be presented in subject listings.


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7.4
Baseline Disease Characteristics
Descriptive summaries of baseline disease characteristics will be provided for all patients in the 
ITT population by treatment group and overall. These tabulations will include the following 
variables:
x
ADHD Subtype
x
Age at Diagnosis 
x
Time Since ADHD Diagnosis
x
ADHD-RS-5 Baseline Score (Overall and sub-scales)
x
CGI-S Score at baseline
8
EFFICACY ANALYSIS
8.1
Primary Analysis 
The primary efficacy endpoint will be the change in ADHD-RS-5 total score from Baseline to 
the end of treatment (e.g., Visit 8).  For any subjects who discontinue the study prior to Visit 8, 
their last treated value of the ADHD-RS-5 will be used.  That is, the LOCF method of imputation 
will be employed. The analysis will be performed on the ITT population using an analysis of 
covariance (ANCOVA) model. The model will use a residual (restricted) maximum likelihood 
(REML) estimation method and a standard variance components (VC) covariance structure, with 
treatment group (NFC-1 or placebo) as a fixed factor and baseline ADHD-RS-5 total score as a 
covariate.  The null hypothesis is that there are no differences between the means of the two 
treatment groups. The hypothesis will be tested at a two-tailed alpha of 0.05.  This analysis will 
be repeated for each of the scheduled visits for ADHD-RS-5 and summarized within the table.  
Descriptive summaries for actual and change from baseline values will be displayed along with 
the LS means, LS mean treatment difference, and 95% CIs of the treatment difference, and p-
values by visit.
8.2
Secondary Analysis 
Secondary analysis endpoints will include the following measurements (ASHS and SCARED 
treated as continuous measures):
x
Improvement in CGI-I/CGI-S 
x
Change from baseline in ASHS total score
x
Change from baseline in SCARED total score
When appropriate, the analysis for these endpoints will employ the same model and approach as 
in the primary analysis using an ANCOVA as specified above. Additionally, any subscales for 
the above primary/secondary endpoints will be included on their corresponding table for the total 
score (i.e. ADHD-RS-5 Inattention subscale, SCARED Generalized Anxiety, etc.). Please see 
Section 6.3 for a complete list of derived subscales and composite scores. 
Results of the CGI-I assessment will be dichotomized and presented by count and frequency for 
each week of treatment. CGI-I scores of 1 (very much improved) or 2 (much improved)will be 
combined into a single category labeled 'Improved', and all other scores (3 [minimally improved] 
to 7 [very much worse]) will be combined into a single category labeled 'Not Improved'. The 


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observed frequencies of 'Improved' subjects will be compared using a chi-square analysis to test 
the hypothesis of no association between Improvement and Treatment at type I error rate of 5%.   
The CGI-S assessment will be presented similarly. CGI-S scores of 1 (Normal, not at all ill) or 2 
(Borderline mentally ill) will be combined into a single category labeled ‘Normal or Borderline 
mentally ill’, and all other scores (3 [Mildly Ill] to 7 [Among the most extremely ill patients]) 
will be combined into a single category labeled ‘Mentally ill’.
As to measure treatment response and remission of subjects, three criteria will be defined for 
each [4]. For response, the criteria are (A) a change in ADHD-RS-5 total score from baseline of 
30% or more, (B) a CGI-I score of 1 (very much improved) or 2 (much improved) relative to 
baseline, and (C) a composite requiring both (A) and (B) to be met. For remission, the criteria are 
(A) ADHD-RS-5 total score of 18 or less at post-baseline visits, (B) a CGI-I score of 1, and (C) a 
composite of (A) and (B) to be met. The observed frequency and percentage of subjects in each 
category will be presented and will be compared using a chi-square analysis to test the 
hypothesis of no association between response/remission and treatment for each category.
9
SAFETY AND TOLERABILITY ANALYSIS 
The analysis of safety assessments in this study will include summaries of the following 
categories of safety and tolerability data collected for each subject:
x
Adverse Events
ƒ
Summary of all Adverse Events
ƒ
treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) 
ƒ
TEAEs leading to early termination
ƒ
TEAEs by severity
ƒ
TEAEs deemed related to the IP
ƒ
TEAEs occurring in more than 5% of subjects
ƒ
Post-treatment AEs
ƒ
Any deaths
x
Clinical Laboratory Investigations(chemistry, Hematology, Urinalysis) 
x
Vital Signs (systolic and diastolic blood pressure, pulse, respiratory rate, height, weight, and 
BMI) 
x
Electrocardiograms (ECG)
x
C-SSRS Score
x
Concomitant Medications
x
Post-treatment Medications
x
Study Drug Exposure and Treatment Compliance
All tabulations and summaries for these categories will be performed on the Safety population 
unless otherwise noted. 
9.1
Adverse Events
The causal relationship of the AE to the study drug is determined by the investigator as 'not 
related', 'unlikely/remotely related', 'possibly related', or 'related'. Any AE determined as 


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'possibly related' or 'related' will be considered 'potentially related' to study drug for purposes of 
analysis of these events.
Missing and partially missing AE start and/or stop dates will be imputed for the purpose of 
statistical analysis, according to the specifications described in Section 6.2. 
Summaries of incidence rates (frequencies and percentages) of individual TEAEs by MedDRA 
SOC and preferred term will be prepared. Such summaries will be displayed for TEAEs, SAEs, 
TEAEs leading to early termination, TEAEs by relationship to study drug, TEAEs by severity,
TEAEs occurring in more than 5% of subjects, and Post-treatment AEs.
Each patient/subject will be counted only once within each preferred term If a subject 
experiences more than one TEAE within a preferred term only the TEAE with the strongest 
relationship or the maximum intensity, as appropriate, will be included in the summaries of 
relationship and intensity.  
Subject listings of all AEs and SAEs, will be presented. 
9.1.1
Adverse Events Leading to Early Termination 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to early 
termination of study drug, by treatment group and overall, SOC, and preferred term, will be 
prepared for the Safety Population. 
A listing of TEAEs leading to early termination will also be provided, displaying details of the 
event(s) captured on the CRF. 
9.1.2
Deaths
A summary and data listing of deaths that occurred will be provided, displaying details of the 
event(s) captured on the CRF. 
9.2
Clinical Laboratory Evaluations 
Descriptive summaries of actual (absolute) values and changes from baseline will be presented 
for Chemistry, Hematology, and Urinalysis analytes. These tables will be grouped by treatment 
group, and by visit.  Summaries will be displayed in conventional units.  
The number and proportion of subjects with clinical laboratory values below, within, or above 
normal ranges, at each study visit will be tabulated (shift tables) for each clinical laboratory 
analyte by treatment group. Normal ranges for lab results will be provided by the Central 
laboratory used in this study (i.e., Eurofins).
Laboratory values will be displayed in the data listings and those that are outside the normal 
range will be flagged, along with corresponding normal ranges.   
9.3
Vital Signs
Descriptive summaries of actual (absolute) values and changes from baseline will be presented 
for systolic and diastolic blood pressure, pulse, respiratory rate, and BMI.  These tables will be 
grouped by treatment group, and by visit. 
Additionally, the frequency and percentage of subjects with values of Potential Clinical 
Importance (PCI) will be summarized in shift tables, by treatment group and overall for each 
study visit. Criteria for assigning PCI to vital signs are as follows:


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Criteria for PCI Vital Signs and Change in Body Weight
Measurement
Lower Criterion
Upper Criterion
Systolic BP
< 90 mmHg
>120 mmHg
Diastolic BP
< 50 mmHg
>80 mmHg
Pulse Rate
  ESP
  ESP
Respiration Rate
< 10 breaths/minute
>20 breaths/minute
Body Weight Change
  GHFUHDVH
  LQFUHDVH
Vital signs and weight/height measurements will also be presented in a subject listing.   
9.4
Electrocardiograms
ECG results will be summarized in three ways, as follows: 
1. A summary of Central ECG results that presents the number and percent of results that 
are deemed normal, abnormal, and missing.   
2. A summary providing N and % of evaluations that are interpreted by each investigative 
site as Normal, Abnormal NCS, Abnormal CS, and missing.  
3. Tabulation of ECG results that are of potential clinical importance.  Criteria for assigning 
PCI to ECG results are as follows:
Criteria for PCI categories to ECG Results
ECG Parameter
Lower Criterion
Upper Criterion
Heart Rate
 0 bpm
  ESP
PR Interval
None
  PVHF
QRS Interval
None
  PVHF
QT Interval
None
  PVHF
QTcB
None
  PVHF
QTcF
None
  PVHF
Change in Heart Rate
  bpm 
with decrease > 5 bpm
None
Change in QTcB
None
  PVHF
Change in QTcF
None
 30 msec
Depending on the incidence of abnormal ECG results, some of these displays might not be 
needed.
ECG results will also be displayed in a separate subject listing.
9.5
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS score will be summarized by treatment group and overall for each study visit it is 
measured.  These C-SSRS evaluations will be presented in a subject listing.
9.6
Physical Examination Findings 
Abnormal physical examination findings at screening and indications of clinically significant 
abnormal findings that were newly diagnosed or worsened since the screening visit will be 
provided in a subject listing. 


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9.7
Concomitant Medication
Concomitant medications will be analyzed the same way as prior medications as noted in Section 
7.3. The frequency and percentage of all concomitant medications will be summarized by ATC
classification level 3 and preferred term for all patients in the Safety population by treatment 
group and overall. Similarly to previous, post-treatment medications will be analyzed the same 
way as prior medications as noted in Section 7.3. 
A subject listing of all medications will be provided. 
9.8
Exposure and Compliance
For each subject, treatment compliance will be calculated at each visit and summarized for the 
entire study. Overall compliance will be summarized by treatment group. Compliance is defined 
in Section 6.3. Drug Accountability/Exposure and Treatment compliance will also be provided in 
a subject listing.
10 CHANGES FROM PLANNED ANALYSIS
Below are the major changes and/or updates from the protocol planned analysis: 
x
The SAP has ANCOVA with LOCF as the primary endpoint but this was noted as 
ANOVA in the protocol
x
CGI-I and CGI-S were originally going to be analyzed by ANOVA, but will be analyzed 
by a Chi-Square test
x
PCI analyses has been added for ECG, Vitals
x
Post-treatment AEs and Post-treatment medications have been added
x
Several tables now include dose group summaries instead of NFC-1 vs. Placebo 


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11 REFERENCES
US Federal Register. (1998) International Conference on Harmonization; Guidance on Statistical 
Principles for Clinical Trials. Department of Health and Human Services: Food and Drug 
Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, pages 
49583-49598. September 16, 1998. 
ASA. (1999) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, August 7, 1999. http://www.amstat.org/about/ethicalguidelines.cfm
RSS. (1993) The Royal Statistical Society: Code of Conduct, April 1993.
http://www.rss.org.uk/main.asp?page=1875. 
Waxmonsky JG, et. al. Prediction of Placebo Response Rates in 2 Clinical Trials of 
Lisdexamfetamine Dimesylate for the Treatment of ADHD. J Clin Psych 72:10, October 2011. 
Am J Psychiatry. (2007) Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA.  The 
worldwide prevalence of ADHD: a systematic review and metaregression analysis.  164:942–
948, 2007. 
Neurotherapeutics. (2012)Willcutt EG.The Prevalence of DSM-IV Attention-
Deficit/Hyperactivity Disorder: A Meta-Analytic Review.  9:490–9, 2012. 


Protocol: MDGN-NFC1-ADHD-201 
 
Page 22 of 88 
SAP FINAL Version 2.0 
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30-NOV-2016 
AD-ST-33.03 16 Mar 2012  
APPENDIX A – TABLES, LISTINGS, AND FIGURE SHELLS
This section presents the shells for the planned Tables, Listings and Graphs to be programmed in 
support of the planned analyses identified in the SAP.  This section is intended to support the 
SAP and provides guidance on the programming specifications (shells) for the planned outputs
and may be updated, independent of the SAP, with any updates appropriately documented, 
reviewed, and approved. 
The following reporting conventions will be adopted for the presentation of study data.  These 
conventions will enhance the review process and help to standardize the presentation with 
common notations. 
       General Reporting Conventions
x
All tables and data listings will be developed in landscape orientation. 
x
Specialized text styles, such as bolding, italics, borders, shading, superscripted and 
subscripted text will not be used in tables and data listings unless they add significant 
value to the table, figure, or data listing.  
x
Only standard keyboard characters should be used in tables and data listings.  Special 
characters, such as nonprintable control characters, printer-specific characters, or font 
specific characters, will not be used on a table, figure, or data listing.  Hexadecimal 
character representations are allowed (e.g., P, D, E).
x
All titles will be centered on a page.  The ICH numbering convention is to be used for all 
outputs.
x
All footnotes will be left justified and at the bottom of a page.  
x
Missing values for both numeric and character variables will be presented as blanks in a 
table or data listing.  A value of zero may be used if appropriate to identify when the 
frequency of a variable is not observed. 
x
All date values will be presented as ddmmmyyyy (e.g., 29AUG2011) format.  A 4-digit 
year is preferred for all dates.
x
If applicable, all observed time values will be presented by using a 24-hour clock 
HH:MM:SS format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they 
were measured as part of the study. 
x
All tables and data listings will have the name of the program, the location, and a date 
stamp on the bottom of each output.  
Population Summary Conventions 
x
Population sizes may be presented for each classification factor as totals in the column 
header as (N=xxxx), where appropriate. 
x
Population sizes shown with summary statistics are the samples sizes (n) of subjects with 
non-missing values.  
x
All population summaries for categorical variables will include all categories that were 
planned and for which the subjects may have had a response.  Percentages corresponding 
to null categories (cells) will be suppressed, however counts and percentages of missing 
values may be needed. 


Protocol: MDGN-NFC1-ADHD-201 
 
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x
All population summaries for continuous variables will include: N, mean, SD, minimum, 
and maximum.  Other summaries (e.g., number missing, geometric mean, median, 
quartiles, 95% CIs, and coefficient of variation (CV) or % CV) may be used as 
appropriate.  
x
All percentages are rounded and reported to a single decimal point (xx.x %).  A 
percentage of 100% will be reported as 100%.  No value of 0% will be reported.  Any 
computation of percent that results in 0% is to be presented as a blank.  
x
Population summaries that include P-values will report the P-value to 4 decimal places 
with a leading zero (0.0001).  All P-values reported on default output from statistical 
software (i.e., SAS® Software) may be reported at the default level of precision.  P-values 
<0.0001 should be reported as <0.0001 not 0.0000. 


Protocol: MDGN-NFC1-ADHD-201 
 
Page 24 of 88 
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11.1
Standard Layout for all Tables, Listings, and Listing
The following standard layout will be applied to all Tables, Listings, and Listings in support of this study. Note that programming 
notes may be added if appropriate after each TLF shell.  These notes are noted within brackets and will not appear on the output "{}".
Medgenics, Inc.
Page 1 of x 
 
Protocol: MDGN-NFC1-ADHD-201 
<version> 
<Table, Listing, Figure> xx.x.x
<Title of Table Listing or Figure> 
<Study Population and if applicable subgroup Description>
____________________________________________________________________________________________________________
Body of Table, Listing or Figure 
___________________________________________________________________________________________________________
Note: <Note: If directly Applicable>
(Running Footnote for all tables, place after last ‘Note:’ present)  Note:  All treatments were administered BID.
[1] Footnote 1 <if applicable>
[2] Footnote 2 <if applicable>
[n] Footnote n <if applicable>
T:\Medgenics\NFC-1\ADHD-201\...\xxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYY


Protocol: MDGN-NFC1-ADHD-201 
 
SAP FINAL Version 2.0 
CONFIDENTIAL                                                                                                       30-NOV-2016 
AD-ST-33.03 16 Mar 2012 
11.2
Planned Table Shells
Table 
Table Title 
Topline 
14.1.1 
Disposition of Study Population by Optimized Dose and Randomized Treatment (ITT 
Population) 
x 
14.1.2 
Major Protocol Deviations (ITT Population) 
 
14.1.3 
Demographics and Baseline Characteristics by Optimized Dose and Randomized 
Treatment (Safety Population) 
x 
14.1.4 
Disease Characteristics at Baseline by Optimized Dose and Randomized Treatment (Safety 
Population) 
x 
14.1.5 
Summary of Prior Medications by Randomized Treatment (Safety Population) 
 
14.2.1.1 
Analysis of Change from Baseline in ADHD-RS-5:  Total Score and Subscales, by Study Visit 
(ITT Population) 
x 
14.2.1.2 
Summary of Change from Baseline in ADHD-RS-5 Score and Subscales by Actual Dose and 
Randomized Treatment, by Study Visit (ITT Population) 
 
14.2.2.1 
Chi-Square Analysis of CGI-I Improvement, by Study Visit (ITT Population) 
x 
14.2.2.2 
Summary of Categorical and Continuous CGI-I Scores by Randomized Treatment Group 
and Study Visit (ITT Population) 
x 
14.2.2.3 
Summary of CGI-I Improvement by Optimized Dose and Randomized Treatment, by Study 
Visit (ITT Population) 
 
14.2.3.1 
Chi-Square Analysis of CGI-S Improvement, by Study Visit (ITT Population) 
 
14.2.3.2 
Summary of Categorical and Continuous CGI-S Scores by Randomized Treatment Group 
and Study Visit (ITT Population) 
 
14.2.3.3 
Summary of CGI-S Improvement by Optimized Dose and Randomized Treatment, by Study 
Visit (ITT Population) 
 
14.2.4.1 
Analysis of Change from Baseline in ASHS Total Score and Factors, by Study Visit (ITT 
Population) 
 
14.2.4.2 
Summary of Change from Baseline in ASHS Total Score and Factors by Randomized 
Treatment, by Study Visit (ITT Population) 
 
14.2.5.1 
Analysis of Change from Baseline in SCARED Score and Factors, by Study Visit (ITT 
Population) 
 
14.2.5.2 
Summary of Change from Baseline in SCARED Score and Factors by Randomized 
Treatment, by Study Visit (ITT Population) 
 
14.2.6.1 
Chi-Square Analysis of Response and Remission Criteria, at End of Study (ITT Population) 
x 
14.3.1.1 
Summary of TEAEs by Dose at Onset (Safety Population) 
 
14.3.1.2 
Incidence of TEAEs by Dose at Onset and Randomized Treatment (Safety Population) 
x 
14.3.1.3 
Incidence of TEAEs occurring in more than 5% of subjects by  Randomized Treatment 
(Safety Population) 
 


Protocol: MDGN-NFC1-ADHD-201 
 
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14.3.1.4 
Incidence of Post-Treatment AE's by Randomized Treatment (Safety Population) 
 
14.3.1.5 
Incidence of SAE's by Randomized Treatment (Safety Population) 
 
14.3.1.6 
Incidence of TEAEs Leading to Early Termination by Randomized Treatment (Safety 
Population) 
 
14.3.1.7 
Incidence of Deaths by Randomized Treatment (Safety Population) 
 
14.3.1.8 
Incidence of TEAEs by Relationship to Study Drug by Randomized Treatment (Safety 
Population) 
 
14.3.1.9 
Incidence of TEAEs by Maximum Severity by Randomized Treatment (Safety Population) 
 
14.3.2 
Summary of Exposure to Study Drug and Compliance by Actual Dose and Randomized 
Treatment (Safety Population) 
 
14.3.3.1 
Summary of Clinical Laboratory Data:  Clinical Chemistry by Randomized Treatment by 
Study Visit (Safety Population) 
 
14.3.3.2 
Summary of Clinical Laboratory Data:  Hematology by Randomized Treatment by Study 
Visit (Safety Population) 
 
14.3.3.3 
Summary of Clinical Laboratory Data:  Urinalysis by Randomized Treatment by Study Visit 
(Safety Population) 
 
14.3.3.4 
Shifts from Baseline of Clinical Laboratory Data: Clinical Chemistry by Randomized 
Treatment (Safety Population) 
 
14.3.3.5 
Shifts from Baseline of Clinical Laboratory Data:  Hematology by Randomized Treatment 
(Safety Population) 
 
14.3.3.6 
Shifts from Baseline of Clinical Laboratory Data: Urinalysis by Randomized Treatment 
(Safety Population) 
 
14.3.4.1 
Summary of Vital Signs by Randomized Treatment by Study Visit (Safety Population) 
 
14.3.4.2 
Potentially Clinically Important Vital Signs by Randomized Treatment (Safety Population) 
 
14.3.5.1 
Incidence of Abnormal ECG Findings: based on Site Interpretations by Randomized 
Treatment by Study Visit (Safety Population) 
 
14.3.5.2 
Incidence of Abnormal ECG Findings:  based on Central Reading by Randomized 
Treatment by Study Visit (Safety Population) 
 
14.3.5.3 
Potentially Clinically Important ECG Results by Randomized Treatment (Safety Population) 
 
14.3.6 
Summary of C-SSRS Assessments by Randomized Treatment (Safety Population) 
 
14.3.7 
Summary of Concomitant Medications by Randomized Treatment (Safety Population)  
 
14.3.8 
Summary of Post-Treatment Medications by Randomized Treatment (Safety Population) 
 


Protocol: MDGN-NFC1-ADHD-201 
 
SAP FINAL Version 2.0 
CONFIDENTIAL                                                                                                       30-NOV-2016 
AD-ST-33.03 16 Mar 2012 
11.3
Planned Listing Shells
Listing 
Listing Title 
16.2.1.1 
Analysis Populations and Treatment (All Subjects) 
16.2.1.2 
Subject Disposition (Safety Population) 
16.2.1.3 
Inclusion/Exclusion Criteria (All Subjects) 
16.2.2 
Major and Minor Protocol Deviations (Safety Population) 
16.2.3.1 
Demographics and Other Baseline Characteristics (Safety Population) 
16.2.3.2 
Prior, Concomitant, and Post-treatment Medications (Safety Population) 
16.2.3.3 
Behavioral Therapies (Safety Population) 
16.2.3.4 
Medical History (Safety Population) 
16.2.4.1 
Study Drug Exposure (Safety Population) 
16.2.4.2 
Study Drug Accountability and Compliance (Safety Population) 
16.2.4.3 
Investigator Dose Assessment (Safety Population) 
16.2.5.1.1 
Attention Deficit Hyperactivity Disorder Rating Scale Version 5 (ADHD-RS-5), part 1 (ITT 
Population) 
16.2.5.1.2 
Attention Deficit Hyperactivity Disorder Rating Scale Version 5 (ADHD-RS-5), part 2 (ITT 
Population) 
16.2.5.2 
Clinical Global Impression of Improvement (CGI-I) and Clinical Global Impression of Severity (CGI-
S)  (ITT Population) 
16.2.5.3.1 
Adolescent Sleep Hygiene Scale (ASHS), part 1 (ITT Population) 
16.2.5.3.2 
Adolescent Sleep Hygiene Scale (ASHS), part 2 (ITT Population) 
16.2.5.3.3 
Adolescent Sleep Hygiene Scale (ASHS), part 3 (ITT Population) 
16.2.5.3.4 
Adolescent Sleep Hygiene Scale (ASHS), part 4 (ITT Population) 
16.2.5.4.1 
Screen for Childhood Anxiety-related Emotional Disorders (SCARED), part 1 (ITT Population) 
16.2.5.4.2 
Screen for Childhood Anxiety-related Emotional Disorders (SCARED), part 2 (ITT Population) 
16.2.5.4.3 
Screen for Childhood Anxiety-related Emotional Disorders (SCARED), part 3 (ITT Population) 
16.2.5.4.4 
Screen for Childhood Anxiety-related Emotional Disorders (SCARED), part 4 (ITT Population) 
16.2.5.5 
WASI-II (brief IQ test) (ITT Population) 
16.2.5.6.1 
Kiddie Schedule for Affective Disorders (K-SADS-PL), part 1 (ITT Population) 
16.2.5.6.2 
Kiddie Schedule for Affective Disorders (K-SADS-PL), part 2 (ITT Population) 
16.2.5.6.3 
Kiddie Schedule for Affective Disorders (K-SADS-PL), part 3 (ITT Population) 
16.2.5.6.4 
Kiddie Schedule for Affective Disorders (K-SADS-PL), part 4 (ITT Population) 
16.2.6.1 
Adverse Events (Safety Population) 
16.2.6.2 
Serious Adverse Events (Safety Population) 
16.2.6.3 
Adverse Events leading to Early Termination (Safety Population) 
16.2.6.4 
Listing of Deaths (All Subjects) 
16.2.7.1 
Clinical Laboratory Data: Chemistry (Safety Population) 


Protocol: MDGN-NFC1-ADHD-201 
 
SAP FINAL Version 2.0 
CONFIDENTIAL                                                                                                       30-NOV-2016 
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16.2.7.2 
Clinical Laboratory Data: Hematology (Safety Population) 
16.2.7.3 
Clinical Laboratory Data: Urinalysis (Safety Population) 
16.2.7.4 
Pregnancy Tests (Safety Population) 
16.2.7.5 
Urine Drug Screen (Safety Population) 
16.2.8 
Vital Signs (Safety Population) 
16.2.9 
Electrocardiograms (ECGs), Site Interpretation (Safety Population) 
16.2.10 
Electrocardiograms (ECGs), Central Reading (Safety Population) 
16.2.11 
Physical Examinations (Safety Population) 
16.2.12 
Columbia Suicide Severity Rating Scale (C-SSRS) (Safety Population) 


Protocol: MDGN-NFC1-ADHD-201 
 
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Medgenics, Inc. 
 
 
 
Page 1 of x
Protocol: MDGN-NFC1-ADHD-201
Final
Table 14.1.1
Disposition of Study Population by Optimized Dose and Randomized Treatment
Intent-To-Treat Population
Disposition
100mg 
NFC-1 
(N=xx)
200mg 
NFC-1 
(N=xx)
400mg 
NFC-1 
(N=xx)
All Doses
NFC-1 
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
Screened for Eligibility
xx
xx
xx
xx
xx
xx
Screen Failure [1]
xx
xx
xx
xx
xx
xx
Randomized
xx
xx
xx
xx
xx
xx
Intent-To-Treat Population [2]
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
Safety Population [3]
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
Per-Protocol Population [4]
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
Completed Study
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
xx (xx x %)
xx (xx.x %)
Completed Follow-Up Phone Call
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
xx (xx x %)
xx (xx.x %)
Discontinued Early
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
Adverse Event
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
Lack of Efficacy
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
xx (xx x %)
xx (xx.x %)
Non-compliance/Protocol Violation
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
Subject Withdrawal of Consent
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
Lost to Follow up
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
Other
xx (xx.x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx x %)
xx (xx.x %)
Note:  Percentages are 100*n/N.  
[1] Subjects who have not met eligibility criteria, or otherwise chose not to participate in the study.
[2] The ITT Population includes all subjects who are randomized into the study.
[3] The Safety Population includes all subjects who are randomized into the study and receive any amount of IP.
[4] The Per-Protocol Population includes all subjects who do not have any significant protocol deviations.
Source: Listing 16.2.1.2
T:\Medgenics\NFC-1\ADHD-201\...\xxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY


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Page 1 of x
Protocol: MDGN-NFC1-ADHD-201
Final
Table 14.1.2
Major Protocol Deviations
Intent-To-Treat Population
Major Protocol Deviation Category
NFC-1
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
Subjects with any Major Deviation
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Deviation 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Deviation 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Deviation 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
...
{Continue for all major deviations}
Note:  Percentages are 100*n/N. Subjects may be counted under multiple major deviation categories.
Source: Listing 16.2.2
T:\Medgenics\NFC-1\ADHD-201\...\xxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY


Protocol: MDGN-NFC1-ADHD-201 
 
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Page 1 of x
Protocol: MDGN-NFC1-ADHD-201
Final
Table 14.1.3
Demographics and Baseline Characteristics by Optimized Dose and Randomized Treatment
Safety Population
Parameter
Category
100mg 
NFC-1 
(N=xx)
200mg 
NFC-1 
(N=xx)
400mg 
NFC-1 
(N=xx)
All Doses
NFC-1 
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
Age (years)
n   
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx xx
xx.xx
xx xx
xx xx
Standard Deviation
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx xx
xx.xx
xx xx
xx xx
Minimum, Maximum
(x.x, x x)
(x x, x x)
(x x, x x)
(x x, x.x)
(x.x, x x)
(x x, x x)
Gender
Male
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Female
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Ethnicity
Hispanic or Latino
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Not Hispanic or Latino
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Not Reported
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Unknown
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Race
American Indian or Alaska Native
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
Asian
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Black or African American
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
Native Hawaiian or Other Pacific Islander
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
White
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Other
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Note:  Percentages are 100*n/N. K-SADS-PL = Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime Version. WASI-II = Wechsler 
Abbreviated Scale of Intelligence, 2nd edition. 
Source:  Listing 16.2.3.1, 16.2.5.5, 16.2.5.6.1, 16.2.5.6.2, 16.2.5.6.3, 16.2.5.6.4
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Protocol: MDGN-NFC1-ADHD-201
Final
Table 14.1.3
Demographics and Baseline Characteristics by Optimized Dose and Randomized Treatment
Safety Population
Parameter
Category
100mg 
NFC-1 
(N=xx)
200mg 
NFC-1 
(N=xx)
400mg 
NFC-1 
(N=xx)
All Doses
NFC-1 
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
Height (cm)
n   
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Minimum, Maximum
(x x, x x)
(x.x, x x)
(x x, x.x)
(x x, x x)
(x x, x x)
(x x, x.x)
Weight (kg)
n   
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Minimum, Maximum
(x x, x x)
(x.x, x x)
(x x, x.x)
(x x, x x)
(x x, x x)
(x x, x.x)
BMI (kg/m^2)
n   
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Minimum, Maximum
(x x, x x)
(x.x, x x)
(x x, x.x)
(x x, x x)
(x x, x x)
(x x, x.x)
Note:  Percentages are 100*n/N. K-SADS-PL = Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime Version. WASI-II = Wechsler 
Abbreviated Scale of Intelligence, 2nd edition. 
Source:  Listing 16.2.3.1, 16.2.5.5, 16.2.5.6.1, 16.2.5.6.2, 16.2.5.6.3, 16.2.5.6.4
T:\Medgenics\NFC-1\ADHD-201\...\xxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY


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Page 3 of x
Protocol: MDGN-NFC1-ADHD-201
Final
Table 14.1.3
Demographics and Baseline Characteristics by Optimized Dose and Randomized Treatment
Safety Population
Parameter
Category
100mg 
NFC-1 
(N=xx)
200mg 
NFC-1 
(N=xx)
400mg 
NFC-1 
(N=xx)
All Doses
NFC-1 
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
WASI-II
FSIQ-4 Composite Score
n
xx
xx
xx
xx
xx
xx
Mean
xx.xx
xx xx
xx.xx
xx xx
xx xx
xx xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx.xxx
Median
xx.xx
xx xx
xx.xx
xx xx
xx xx
xx xx
Minimum, Maximum
(x x, x.x)
(x x, x x)
(x.x, x x)
(x x, x x)
(x.x, x x)
(x x, x.x)
Verbal Comprehension
n
xx
xx
xx
xx
xx
xx
Mean
xx.xx
xx xx
xx.xx
xx xx
xx xx
xx xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx xxx
xx xxx
xx.xxx
Median
xx.xx
xx xx
xx.xx
xx xx
xx xx
xx xx
Minimum, Maximum
(x x, x.x)
(x x, x x)
(x.x, x x)
(x x, x x)
(x.x, x x)
(x x, x x)
Perceptual Reasoning Comprehension
n
xx
xx
xx
xx
xx
xx
Mean
xx.xx
xx xx
xx.xx
xx xx
xx xx
xx xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx xxx
xx xxx
xx.xxx
Median
xx.xx
xx xx
xx.xx
xx xx
xx xx
xx xx
Minimum, Maximum
(x x, x.x)
(x x, x x)
(x.x, x x)
(x x, x x)
(x.x, x x)
(x x, x x)
Note:  Percentages are 100*n/N. K-SADS-PL = Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime Version. WASI-II = Wechsler 
Abbreviated Scale of Intelligence, 2nd edition. 
Source:  Listing 16.2.3.1, 16.2.5.5, 16.2.5.6.1, 16.2.5.6.2, 16.2.5.6.3, 16.2.5.6.4
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Final
Table 14.1.3
Demographics and Baseline Characteristics by Optimized Dose and Randomized Treatment
Safety Population
Parameter
Category
100mg 
NFC-1 
(N=xx)
200mg 
NFC-1 
(N=xx)
400mg 
NFC-1 
(N=xx)
All Doses
NFC-1 
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
K-SADS-PL
Probable Diagnosis
Major Depressive Episode
Yes
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
No
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Dysthymia
Yes
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
No
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
Unspecified Depressive Disorder
Yes
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
No
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
{Continue for all K-SADS-PL parameters}
Note:  Percentages are 100*n/N. K-SADS-PL = Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime Version. WASI-II = Wechsler 
Abbreviated Scale of Intelligence, 2nd edition. 
Source:  Listing 16.2.3.1, 16.2.5.5, 16.2.5.6.1, 16.2.5.6.2, 16.2.5.6.3, 16.2.5.6.4  
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Final
Table 14.1.4
Disease Characteristics at Baseline by Optimized Dose and Randomized Treatment
Safety Population
Parameter
Category
100mg 
NFC-1 
(N=xx)
200mg 
NFC-1 
(N=xx)
400mg 
NFC-1 
(N=xx)
All Doses
NFC-1 
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
ADHD Subtype
Combined
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
Inattentive
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
Impulsive/Hyperactive
xx (xx x%)
xx (xx.x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
Age at Diagnosis (years)
n
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Minimum, Maximum
(x x, x x)
(x.x, x x)
(x x, x.x)
(x x, x x)
(x x, x x)
(x x, x.x)
Time Since ADHD Diagnosis (years)
n
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Minimum, Maximum
(x x, x x)
(x.x, x x)
(x x, x.x)
(x x, x x)
(x x, x x)
(x x, x x)
CGI-S at Baseline
1 = Normal, not at all ill
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
2 = Borderline mentally ill
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
3 = Mildly ill
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
4 = Moderately ill
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
5 = Markedly ill
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
6 = Severely ill
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
7 = Among the most extremely ill patients
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
Note:  Percentages are 100*n/N.  
Source:  Listing 16.2.3.1 
 
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Final
Table 14.1.4
Disease Characteristics at Baseline by Optimized Dose and Randomized Treatment
Safety Population
Parameter
Category
100mg 
NFC-1 
(N=xx)
200mg 
NFC-1 
(N=xx)
400mg 
NFC-1 
(N=xx)
All Doses
NFC-1 
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
ADHD-RS-5 Total Score at Baseline
n
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Minimum, Maximum
(x x, x x)
(x.x, x x)
(x x, x.x)
(x x, x x)
(x x, x x)
(x x, x.x)
ADHD RS-5 Inattention subscale at Baseline
n
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Minimum, Maximum
(x x, x x)
(x.x, x x)
(x x, x.x)
(x x, x x)
(x x, x x)
(x.x, x x)
ADHD RS-5 Hyperactivity-Impulsivity subscale at 
Baseline
n
xx
xx
xx
xx
xx
xx
Mean
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
Median
xx xx
xx xx
xx.xx
xx xx
xx xx
xx.xx
Minimum, Maximum
(x x, x x)
(x.x, x x)
(x x, x.x)
(x x, x x)
(x x, x x)
(x.x, x x)
Note:  Percentages are 100*n/N.  
Source:  Listing 16.2.3.1 
 
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Final
Table 14.1.5 
Summary of Prior Medications by Randomized Treatment
Safety Population
ATC
Preferred Term [1]
NFC-1
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
Number of Subjects with at least one prior medication
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<ATC 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<ATC 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<ATC 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
Note:  Percentages are 100*n/N. Subjects were counted only once for each Anatomical Therapeutic Chemical (ATC) or Preferred 
Term. Prior medications are defined as medications or therapies initiated prior to date of first dose and terminating prior to date 
of first dose.  Mediations that are started prior to the date of first dose of IP and are continuing after the first dose of IP are 
considered to be both prior and concomitant medications.
[1] Medications were coded using WHO-DD (Enhanced version xxxx) and summarized at ATC Level 3.
Source:  Listing 16.2.3.2
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Final
Table 14.2.1.1
Analysis of Change from Baseline in ADHD-RS-5:  
Total Score and Subscales, by Study Visit
Intent-To-Treat Population
Variable
Visit
Statistic [1]
NFC-1 
(N=xx)
Placebo
(N=xx)
ADHD-RS-5
Visit 3
LS Mean (SE)
x xx (x xxx)
x.xx (x.xxx)
       (95% CI for LS Mean)
(x xx, x xx)
(x xx, x xx)
LS Mean Difference from Placebo (SE)
x xx (x xxx)
(95% CI for Mean Difference from Placebo)
(x xx, x xx)
p-value vs. Placebo [2]
0 xxxx
{Continue for all scheduled post-baseline visits and 
subscales}
Note:  ADHD-RS-5 = Attention Deficit Hyperactivity Disorder Rating Scale Version 5; CI = Confidence Interval; LS = Lease-
squares; SE = Standard error.
[1] Estimates are from an analysis of covariance (ANCOVA) model. The model uses a residual (restricted) maximum likelihood 
(REML) estimation method and a standard variance components (VC) covariance structure, with treatment group (NFC-1 or 
placebo) as a fixed factor and baseline ADHD-RS-5 total score (or appropriate subscale) as a covariate.
[2] P-value for testing if the mean change from baseline for NFC-1 versus Placebo at the specified timepoint is zero.
Source: Listing 16.2.5.1.1, 16.2.5.1.2
 
 
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Final
Table 14.2.1.2
Summary of Change from Baseline in 
ADHD-RS-5 Score and Subscales by Actual Dose and Randomized Treatment, by Study Visit 
Intent-To-Treat Population
NFC1 100mg
(N=xx)
NFC1 200mg
(N=xx)
NFC1 400mg
(N=xx)
All NFC1 Doses
(N=xx)
Placebo
(N=xx)
Variable
Visit
Statistic [1]
Value
Change 
From 
Baseline
Value
Change 
From 
Baseline
Value
Change 
From 
Baseline
Value
Change 
From 
Baseline
Value
Change 
From 
Baseline
ADHD-RS-5
Baseline
n
xx
--
xx
--
xx
--
xx
--
xx
--
Mean
xx.xx
--
xx xx
--
xx xx
--
xx xx
--
xx xx
--
Standard Deviation
xx xxx
--
xx.xxx
--
xx.xxx
--
xx xxx
--
xx xxx
--
Median
xx.xx
--
xx xx
--
xx xx
--
xx xx
--
xx xx
--
Minimum, Maximum
(x x, x.x)
--
(x x, x.x)
--
(x x, x x)
--
(x x, x x)
--
(x.x, x x)
--
Visit 3
n
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
Mean
xx.xx
xx xx
xx xx
xx xx
xx xx
xx.xx
xx xx
xx xx
xx xx
xx xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx.xxx
Median
xx.xx
xx xx
xx xx
xx xx
xx xx
xx.xx
xx xx
xx xx
xx xx
xx xx
Minimum, Maximum
(x x, x.x)
(x x, x x)
(x x, x.x)
(x.x, x x)
(x x, x x)
(x x, x.x)
(x x, x x)
(x x, x.x)
(x.x, x x)
(x x, x x)
Visit 4
n
xx
xx
xx
xx
xx
xx
xx
xx
xx
xx
Mean
xx.xx
xx xx
xx xx
xx xx
xx xx
xx.xx
xx xx
xx xx
xx xx
xx xx
Standard Deviation
xx xxx
xx xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx xxx
xx.xxx
xx xxx
xx.xxx
Median
xx.xx
xx xx
xx xx
xx xx
xx xx
xx.xx
xx xx
xx xx
xx xx
xx xx
Minimum, Maximum
(x x, x.x)
(x x, x x)
(x x, x.x)
(x.x, x x)
(x x, x x)
(x x, x.x)
(x x, x x)
(x x, x.x)
(x.x, x x)
(x x, x x)
{Continue for all scheduled post-
baseline visits and subscales}
Source:  Listing 16.2.5.1.1, 16.2.5.1.2
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Final
Table 14.2.2.1
Chi-Square Analysis of CGI-I Improvement, by Study Visit
Intent-To-Treat Population
Variable
Visit
Statistic
NFC-1 
(N=xx)
Placebo
(N=xx)
CGI-I Improvement [1] 
Visit 3
n
xx
xx
Improved
xx (xx x%)
xx (xx.x%)
95% CI
xx x%, xx x%
xx x%, xx.x%
p-value [2]
0 xxxx
Visit 4
n
xx
xx
Improved
xx (xx x%)
xx (xx.x%)
95% CI
xx x%, xx x%
xx x%, xx.x%
p-value [2]
0 xxxx
Visit 5
n
xx
xx
Improved
xx (xx x%)
xx (xx.x%)
95% CI
xx x%, xx x%
xx x%, xx.x%
p-value [2]
0 xxxx
{Continue for all scheduled post-baseline visits}
Note:  CGI-I = Clinical Global Impression of Improvement. 
[1] Improvement defined as achieving a CGI-I score of 1 or 2, scores of 3 to 7 or missing are defined as Not Improved.
[2] P-value for comparison of the frequency of ‘Improved’ versus ‘No Improvement’ between the NFC-1 and Placebo treatment. The 
analysis is from a Chi-Square test of association at alpha = 0.05.
Source:  Listing 16.2.5.2 
 
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Final
Table 14.2.2.2
Summary of Categorical and Continuous CGI-I Scores by Randomized Treatment Group and Study Visit
Intent-To-Treat Population
Variable
Visit
Score
NFC-1 
(N=xx)
Placebo
(N=xx)
CGI-I score 
Visit 3
1)
Very Much Improved, n (%)
xx (xx x%)
xx (xx.x%)
2)
Much Improved, n (%)
xx (xx x%)
xx (xx.x%)
3)
Minimally Improved, n (%)
xx (xx x%)
xx (xx.x%)
4)
No Change, n (%)
xx (xx x%)
xx (xx.x%)
5)
Minimally Worse, n (%)
xx (xx x%)
xx (xx.x%)
6)
Much Worse, n (%)
xx (xx x%)
xx (xx.x%)
7)
Very Much Worse, n (%)
xx (xx x%)
xx (xx.x%)
8)
Missing
xx (xx x%)
xx (xx.x%)
n
xx
xx
Mean
xx.xx
xx xx
Standard Deviation
xx xxx
xx xxx
Median
xx.xx
xx xx
Minimum, Maximum
(x x, x.x)
(x.x, x x)
{Continue for all scheduled post-baseline visits}
Note:  CGI-I = Clinical Global Impression of Improvement. 
Source:  Listing 16.2.5.2
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Final
Table 14.2.2.3
Summary of CGI-I Improvement by Optimized Dose and Randomized Treatment, by Study Visit 
Intent-To-Treat Population
Variable
Visit
Statistic
NFC-1
100mg
(N=xx)
NFC-1
200mg
(N=xx)
NFC-1
400mg
(N=xx)
All
NFC-1 
(N=xx)
Placebo
(N=xx)
CGI-I Response [1]
Visit 3
n
xx
xx
xx
xx
xx
Improved
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Not Improved
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Missing
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Visit 4
n
xx
xx
xx
xx
xx
Improved
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Not Improved
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Missing
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Visit 5
n
xx
xx
xx
xx
xx
Improved
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Not Improved
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Missing
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
{Continue for all scheduled post-baseline visits}
Note:  CGI-I = Clinical Global Impression of Improvement. 
[1] Improved is defined as a CGI-I scores of 1 or 2. Scores of 3 to 7 are defined as Not Improved.
Source:  Listing 16.2.5.2
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Table 14.2.3.1
Chi-Square Analysis of CGI-S Improvement, by Study Visit
Intent-To-Treat Population
{Similar shell as Table 14.2.2.1; Source: Listing 16.2.5.2} 
{Update footnote to replace CGI-I with CGI-S acronym}
{Update footnote for categorization: CGI-S scores of 1 (Normal, not at all ill) or 2 (Borderline mentally ill) are combined into a single category labeled ‘Normal 
or Borderline mentally ill’, and all other scores (3 [Mildly Ill] to 7 [Among the most extremely ill patients]) are combined into a single category labeled 
‘Mentally ill’.
Table 14.2.3.2
Summary of Categorical and Continuous CGI-S Scores by Randomized Treatment Group and Study Visit 
Intent-To-Treat Population
{Similar shell as Table 14.2.2.2; Source: Listing 16.2.5.2} 
{Update footnote to replace CGI-I with CGI-S acronym}
{Update row labels to corresponding CGI-S levels}
Table 14.2.3.3
Summary of CGI-S Improvement by Optimized Dose and Randomized Treatment, by Study Visit
Intent-To-Treat Population
{Similar shell as Table 14.2.2.3; Source: Listing 16.2.5.2} 
{Update footnote to replace CGI-I with CGI-S acronym}
{Update footnote for categorization: CGI-S scores of 1 (Normal, not at all ill) or 2 (Borderline mentally ill) are combined into a single category labeled ‘Normal 
or Borderline mentally ill’, and all other scores (3 [Mildly Ill] to 7 [Among the most extremely ill patients]) are combined into a single category labeled 
‘Mentally ill’.


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Table 14.2.4.1
Analysis of Change from Baseline in 
ASHS Total Score and Factors, by Study Visit
Intent-To-Treat Population
{Similar shell as Table 14.2.1.1; Source: Listing 16.2.5.3.1, 16.2.5.3.2, 16.2.5.3.3, 16.2.5.3.4}
{Update footnote to replace ADHD-RS-5 with ASHS acronym}
Table 14.2.4.2
Summary of Change from Baseline in 
ASHS Total Score and Factors by Randomized Treatment, by Study Visit 
Intent-To-Treat Population
{Similar shell as Table 14.2.1.2; Source: Listing 16.2.5.3.1, 16.2.5.3.2, 16.2.5.3.3, 16.2.5.3.4} 
{Update footnote to replace ADHD-RS-5 with ASHS acronym}
Table 14.2.5.1
Analysis of Change from Baseline in 
SCARED Score and Factors, by Study Visit
Intent-To-Treat Population
{Similar shell as Table 14.2.1.1; Source: Listing 16.2.5.4.1, 16.2.5.4.2, 16.2.5.4.3, 16.2.5.4.4} 
{Update footnote to replace ADHD-RS-5 with SCARED acronym}
Table 14.2.5.2
Summary of Change from Baseline in 
SCARED Score and Factors by Randomized Treatment, by Study Visit 
Intent-To-Treat Population
{Similar shell as Table 14.2.1.2; Source: Listing 16.2.5.4.1, 16.2.5.4.2, 16.2.5.4.3, 16.2.5.4.4} 
{Update footnote to replace ADHD-RS-5 with SCARED acronym}


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Table 14.2.6.1
Chi-Square Analysis of Response and Remission Criteria, at End of Study  
Intent-To-Treat Population
Endpoint
Definition
Statistic
NFC-1 
(N=xx)
Placebo
(N=xx)
Response[1]
Definition A
n
xx
xx
Response
xx (xx x%)
xx (xx.x%)
95% CI
xx x% - xx x%
xx x% -xx x%
p-value [3]
0 xxxx
Definition B
n
xx
xx
Response
xx (xx x%)
xx (xx.x%)
95% CI
xx x% - xx x%
xx x% -xx x%
p-value [3]
0 xxxx
Definition C
n
xx
xx
Response
xx (xx x%)
xx (xx.x%)
95% CI
xx x% - xx x%
xx x% -xx x%
p-value [3]
0 xxxx
{Repeat for Remission definitions A, B, and C}
Note:  ADHD-RS-5 = Attention Deficit Hyperactivity Disorder Rating Scale Version 5, CGI-I = Clinical Global Impression of Improvement.
Percentages are 100*n/N, where N is the number of non-missing values for corresponding treatment.
[1] Response is defined as: (A) a change in ADHD-RS-5 total score from baseline of 30% or more, (B) a CGI-I score of 1 (very much improved) 
or 2 (much improved) relative to baseline, and (C) a composite requiring both (A) and (B) to be met. 
[2] Remission is defined as: (A) ADHD-RS-5 total score of 18 or less at post-baseline visits, (B) a CGI-I score of 1, and (C) a composite of (A) 
and (B) to be met
[3] P-value for comparison of the frequency of Response versus No Response between the NFC-1 and Placebo treatment. The analysis is from a 
Chi-Square test of association at alpha = 0.05.
Source:  Listing 16.2.5.1.1, 16.2.5.1.2, 16.2.5.2
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Table 14.3.1.1
Summary of TEAEs by Dose at Onset
Safety Population
Category
NFC-1
100mg
(N=xx)
NFC-1
200mg
(N=xx)
NFC-1
400mg
(N=xx)
All
NFC-1 
(N=xx)
Placebo
(N=xx)
Subjects with at least one:
Treatment-Emergent Adverse Event
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
TEAE Related to Study Drug [1]
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
Serious Adverse Event
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
TEAE Leading to Study Drug Discontinuation
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
Adverse Event Leading to Death
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
Note:  Percentages are 100*n/N. TEAE = Treatment-Emergent Adverse Event
[1] Any AE determined by the investigator as ‘possibly related’ or ‘related’ is considered related for purposes of analysis.
Source:  Listing 16.2.6.1, 16.2.6.2, 16.2.6.3, 16.2.6.4
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Table 14.3.1.2
Incidence of TEAEs by Dose at Onset and Randomized Treatment
Safety Population
SOC
Preferred Term [1]
NFC-1
100mg
(N=xx)
NFC-1
200mg
(N=xx)
NFC-1
400mg
(N=xx)
NFC-1 
(N=xx)
Placebo
(N=xx)
Number of Subjects with at Least One AE
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<SOC 1>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 1>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 2>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 3>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<SOC 2>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 1>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 2>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 3>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<SOC 3>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 1>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 2>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
<Event 3>
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
Note:  Percentages are 100*n/N. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  TEAE is defined as AEs occurring or 
worsening with an onset at the time of or following the start of treatment with study medication.  TEAE = Treatment-Emergent Adverse Event.
[1] Adverse Events were coded from MedDRA (version xx x).
Source:  Listing 16.2.6.1
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Table 14.3.1.3 
Incidence of TEAEs occurring in more than 5% of subjects by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.1.2; Source: Listing 16.2.6.1} 
{Update footnote to add definition of TEAE, update first row of table} 
Table 14.3.1.4
Incidence of Post-Treatment AEs by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.1.2; Source: Listing 16.2.6.1} 
{Update footnote to add definition of TEAE, update first row of table} 
Table 14.3.1.5 
Incidence of SAEs by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.1.2; Source: Listing 16.2.6.2} 
{Update footnote to add definition of SAE, update first row of table} 
Table 14.3.1.6 
Incidence of TEAEs Leading to Early Termination by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.1.2; Source: Listing 16.2.6.3} 
{Update update first row of table} 
Table 14.3.1.7
Incidence of Deaths by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.1.2; Source: Listing 16.2.6.1} 
{Update update first row of table} 


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Table 14.3.1.8 
Incidence of TEAEs by Relationship to Study Drug by Randomized Treatment
Safety Population
SOC
Preferred Term [1]
Causality
NFC-1 
(N=xx)
Placebo
(N=xx)
Number of Subjects with at least one TEAE
xx (xx.x%)
xx (xx.x%)
Potentially Related
xx (xx x%)
xx (xx.x%)
Not Related
xx (xx x%)
xx (xx.x%)
<SOC 1>
xx (xx x%)
xx (xx.x%)
Potentially Related
xx (xx x%)
xx (xx.x%)
Not Related
xx (xx x%)
xx (xx.x%)
<Event 1>
xx (xx x%)
xx (xx.x%)
Potentially Related
xx (xx x%)
xx (xx.x%)
Not Related
xx (xx x%)
xx (xx.x%)
<Event 2>
xx (xx x%)
xx (xx.x%)
Potentially Related
xx (xx x%)
xx (xx.x%)
Not Related
xx (xx x%)
xx (xx.x%)
<Event 3>
xx (xx x%)
xx (xx.x%)
Potentially Related
xx (xx x%)
xx (xx.x%)
Not Related
xx (xx x%)
xx (xx.x%)
Note:  Percentages are 100*n/N. Subjects were counted only once for each System Organ Class (SOC) or Preferred Term.  If a 
subject experiences the same event, the event which most related to study drug is used.  Any AE determined by the investigator
as ‘possibly related’ or ‘related’ is considered potentially related for purposes of analysis.
[1] Adverse Events were coded from MedDRA (version xx x).
Source:  Listing 16.2.6.1 
 
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Table 14.3.1.9 
Incidence of TEAEs by Maximum Severity by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.1.8; Source: Listing 16.2.6.1} 
{Update update first row of table, nest Severity within each category.} 


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14.3.2
Summary of Exposure to Study Drug and Compliance by Actual Dose and Randomized Treatment
Safety Population
Variable
Statistic
NFC-1
100mg
(N=xx)
NFC-1
200mg
(N=xx)
NFC-1
400mg
(N=xx)
All
NFC-1 
(N=xx)
Placebo
(N=xx)
Total Drug Exposure (mg)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx x
xx x
xx x
--
Standard Deviation
xx xx
xx.xx
xx.xx
xx xx
--
Median
xx.x
xx x
xx x
xx x
--
Minimum, Maximum
(x, x)
(x, x)
(x, x)
(x, x)
--
Treatment Duration (days) [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx x
xx x
xx x
xx.x
Standard Deviation
xx xx
xx.xx
xx.xx
xx xx
xx xx
Median
xx.x
xx x
xx x
xx x
xx.x
Minimum, Maximum
(x, x)
(x, x)
(x, x)
(x, x)
(x, x)
Compliance [2]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx x
xx x
xx x
xx.x
Standard Deviation
xx xx
xx.xx
xx.xx
xx xx
xx xx
Median
xx.x
xx x
xx x
xx x
xx.x
Minimum, Maximum
(x, x)
(x, x)
(x, x)
(x, x)
(x, x)
[1] Treatment Duration is defined as Date of Last Dose – Date of First Dose + 1.
[2] A subject is non-compliant if they take < 80% or > 100% of IP. Compliance (Overall) = (sum of (Individual Week Compliance) * (Time-Weight)) * 
100.  Individual Week Compliance is defined as the number of capsules taken at a particular week divided by the expected number of capsules taken at a 
particular week.  Given that a subject will be dose optimized, the number of expected capsules will vary according to which dose the subject is currently 
on for each day. Time-Weight is the fraction of x/y where x is the number of days in the week the subject is expected to be on dose and is the whole 
treatment duration.
Source:  Listing 16.2.4.1, 16.2.4.2
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Table 14.3.3.1
Summary of Clinical Laboratory Data: Clinical Chemistry
by Randomized Treatment by Study Visit
Safety Population
Analyte
Visit
Statistic
NFC-1 
(N=xx)
Placebo
(N=xx)
<Analyte (unit)>
Baseline
n
xx
xx
Mean
xx xx
xx xx
Standard Deviation
xx.xxx
xx xxx
Median
xx xx
xx xx
Minimum, Maximum
(x x, x x)
(x x, x x)
Visit 3
n
xx
xx
Mean
xx xx
xx xx
Standard Deviation
xx.xxx
xx xxx
Median
xx xx
xx xx
Minimum, Maximum
(x x, x x)
(x x, x x)
{Continue for all scheduled post-baseline visits and all analytes.  Start a new 
page for every additional analyte}
Source: Listing 16.2.7.1
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Table 14.3.3.2
Summary of Clinical Laboratory Data: Hematology
by Randomized Treatment by Study Visit  
Safety Population
{Similar shell as Table 14.3.3.1; Source: Listing 16.2.7.2} 
Table 14.3.3.3
Summary of Clinical Laboratory Data: Urinalysis
by Randomized Treatment by Study Visit  
Safety Population
{Similar shell as Table 14.3.3.1; Source: Listing 16.2.7.3} 


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Table 14.3.3.4
Shifts from Baseline of Clinical Laboratory Data: Clinical Chemistry by Randomized Treatment
Safety Population
Analyte
Visit [1]
Category
NFC-1
(N=xx)
Placebo
(N=xx)
Missing
Low
Normal
High
Missing
Low
Normal
High
<Analyte (unit)>
Visit 3
Missing
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Low
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Normal
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
High
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
Visit 4
Missing
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Low
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
Normal
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
High
xx (xx.x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
xx (xx x%)
xx (xx x%)
xx (xx.x%)
xx (xx x%)
{Continue for all scheduled post-
baseline visits and all analytes.  Start 
a new page for every additional 
analyte}
Note: Percentages are 100*n/N. A low value is a result less than the lower normal reference range; A high value is a result greater than the normal reference range; A normal 
value is a result which falls between the low and high normal reference ranges.
[1] Baseline value is on the column, post-baseline value is on the row.
Source: Listing 16.2.7.1
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Table 14.3.3.5
Shifts from Baseline of Clinical Laboratory Data: Hematology by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.3.4; Source: Listing 16.2.7.2} 
Table 14.3.3.6
Shifts from Baseline of Clinical Laboratory Data: Urinalysis by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.3.4; Source: Listing 16.2.7.3} 
Table 14.3.4.1
Summary of Vital Signs by Randomized Treatment by Study Visit
Safety Population
{Similar shell as Table 14.3.3.1; Source: Listing 16.2.8} 


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Table 14.3.4.2
Potentially Clinically Important Vital Signs by Randomized Treatment
Safety Population
Parameter
Visit
Category
NFC-1 
(N=xx)
Placebo
(N=xx)
Temperature (ºF)
Baseline
n
xx
xx
< 96 ºF
xx (xx x%)
xx (xx x%)
  ºF DQG  ºF
xx (xx x%)
xx (xx x%)
> 102ºF
xx (xx x%)
xx (xx x%)
Missing
xx (xx x%)
xx (xx x%)
Visit 3
n
xx
xx
< 96 ºF
xx (xx x%)
xx (xx x%)
  ºF DQG  ºF
xx (xx x%)
xx (xx x%)
> 102ºF
xx (xx x%)
xx (xx x%)
Missing
xx (xx x%)
xx (xx x%)
{Continue for all scheduled post-baseline visits and all parameters.  Start a 
new page for every additional parameter, individual parameter ranges are 
given within the SAP text  Section 9.3}
Source: Listing 16.2.8
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Table 14.3.5.1
Incidence of Abnormal ECG Findings: based on Site Interpretations by Randomized Treatment by Study Visit
Safety Population
Visit
Category
NFC-1
(N=xx)
Placebo
(N=xx)
Baseline
n
xx
xx
Normal
xx (xx x%)
xx (xx.x%)
Abnormal – Not Clinically Significant
xx (xx x%)
xx (xx.x%)
Abnormal – Clinically Significant
xx (xx x%)
xx (xx.x%)
Unable To Be Evaluated
xx (xx x%)
xx (xx.x%)
Visit 3
n
xx
xx
Normal
xx (xx x%)
xx (xx.x%)
Abnormal – Not Clinically Significant
xx (xx x%)
xx (xx.x%)
Abnormal – Clinically Significant
xx (xx x%)
xx (xx.x%)
Unable To Be Evaluated
xx (xx x%)
xx (xx.x%)
Visit 4
n
xx
xx
Normal
xx (xx x%)
xx (xx.x%)
Abnormal – Not Clinically Significant
xx (xx x%)
xx (xx.x%)
Abnormal – Clinically Significant
xx (xx x%)
xx (xx.x%)
Unable To Be Evaluated
xx (xx x%)
xx (xx.x%)
{Continue for all scheduled post-baseline visits}
Note:  Percentages are 100*n/N. ECG = Electrocardiogram.
Source: Listing 16.2.9
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Table 14.3.5.2
Incidence of Abnormal ECG Findings:  based on Central Reading by Randomized Treatment by Study Visit
Safety Population
Visit
Category
NFC-1
(N=xx)
Placebo
(N=xx)
Baseline
n
xx
xx
Normal
xx (xx x%)
xx (xx.x%)
Abnormal 
xx (xx x%)
xx (xx.x%)
Unable To Be Evaluated
xx (xx x%)
xx (xx.x%)
Visit 3
n
xx
xx
Normal
xx (xx x%)
xx (xx.x%)
Abnormal 
xx (xx x%)
xx (xx.x%)
Unable To Be Evaluated
xx (xx x%)
xx (xx.x%)
Visit 4
n
xx
xx
Normal
xx (xx x%)
xx (xx.x%)
Abnormal 
xx (xx x%)
xx (xx.x%)
Unable To Be Evaluated
xx (xx x%)
xx (xx.x%)
{Continue for all scheduled post-baseline visits}
Note:  Percentages are 100*n/N. ECG = Electrocardiogram.
Source: Listing 16.2.10
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Table 14.3.5.3
Potentially Clinically Important ECG Results by Randomized Treatment
Safety Population
Parameter
Visit
Category
NFC-1 
(N=xx)
Placebo
(N=xx)
Heart Rate
Baseline
n
xx
xx
  ESP
xx (xx x%)
xx (xx x%)
> 50 bpm and < 130 bpm
xx (xx x%)
xx (xx x%)
  ESP
xx (xx x%)
xx (xx x%)
Unable To Be Evaluated
xx (xx x%)
xx (xx x%)
Visit 3
n
xx
xx
  ESP
xx (xx x%)
xx (xx x%)
> 50 bpm and < 130 bpm
xx (xx x%)
xx (xx x%)
  ESP
xx (xx x%)
xx (xx x%)
Unable To Be Evaluated
xx (xx x%)
xx (xx x%)
{Continue for all scheduled post-baseline visits and all parameters.  Start a 
new page for every additional parameter, individual parameter ranges are 
given within the SAP text  Section 9.4}
Source: Listing 16.2.9
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Final
Table 14.3.6
Summary of C-SSRS Assessments by Randomized Treatment
Safety Population
Category [1]
NFC-1
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
Suicidal Ideation (1-5)
xx (xx x%)
xx (xx x%)
xx (xx x%)
(1) Wish to be dead
xx (xx x%)
xx (xx x%)
xx (xx x%)
(2) Non-specific active suicidal thoughts
xx (xx x%)
xx (xx x%)
xx (xx x%)
(3) Active suicidal ideation with any methods (not plan) with intent to act
xx (xx x%)
xx (xx x%)
xx (xx x%)
(4) Active suicidal ideation with some intent to act, without specific plan
xx (xx x%)
xx (xx x%)
xx (xx x%)
(5) Active suicidal ideation with specific plan and intent
xx (xx x%)
xx (xx x%)
xx (xx x%)
Suicidal Behaviour (6-10)
xx (xx x%)
xx (xx x%)
xx (xx x%)
(6) Preparatory acts or behaviour
xx (xx x%)
xx (xx x%)
xx (xx x%)
(7) Aborted attempt
xx (xx x%)
xx (xx x%)
xx (xx x%)
(8) Interrupted attempt
xx (xx x%)
xx (xx x%)
xx (xx x%)
(9) Non-fatal suicide attempt
xx (xx x%)
xx (xx x%)
xx (xx x%)
(10) Completed suicide
xx (xx x%)
xx (xx x%)
xx (xx x%)
Suicidal Ideation or Behaviour (1-10)
xx (xx x%)
xx (xx x%)
xx (xx x%)
Note:  Percentages are 100*n/N. For the composite endpoint of suicidal ideation (1-5), n and (%) refer to the number and percent of patients who experience any one 
of the five suicidal ideation events at least once. For the composite endpoint of suicidal behavior (6-10), n and (%) refer to the number and percent of patients 
who experience any one of the five suicidal behavior events at least once. For the composite endpoint of suicidal ideation or behavior (1-10), n and (%) refer to 
the number and percent of patients who experience any one of the ten suicidal ideation or behavior events at least once.
[1] Results are calculated at any point during the study for each subject and reflect any positive response to these questions.  For example, if a subject answered Yes to 
(1) and (2) on two separate visits, both of those values would be shown instead of just one or the other.
Source: Listing 16.2.11
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Final
Table 14.3.7
Summary of Concomitant Medications by Randomized Treatment
Safety Population
ATC
Preferred Term [1]
NFC-1
(N=xx)
Placebo
(N=xx)
Overall
(N=xx)
Number of Subjects with at least one concomitant 
medication
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<ATC 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<ATC 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<ATC 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 1>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 2>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
<Medication 3>
xx (xx x%)
xx (xx x%)
xx (xx.x%)
Note:  Percentages are 100*n/N. Subjects were counted only once for each Anatomical Therapeutic Chemical (ATC) or Preferred 
Term. Concomitant medications are defined as any medication a subject received concurrently with study treatment.
[1] Medications were coded using WHO-DD (Enhanced version xxxx) ATC Level 3.
Source:  Listing 16.2.3.2
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Table 14.3.8
Summary of Post-Treatment Medications by Randomized Treatment
Safety Population
{Similar shell as Table 14.3.7; Source: Listing 16.2.3.2} 
{Update footnote and first row label accordingly}


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Final
Listing 16.2.1.1
Analysis Populations and Treatment
All Subjects
Subject ID
Treatment
Treatment 
Start Date
Treatment
End Date
Randomization 
Number
Reason Excluded 
From Population
Analysis Population
Safety
ITT
Per-Protocol
xxxxxxxx
NFC-1
DDMMYYYY
DDMMYYYY
XXXXX
xxxxxxxxxxx
Yes
Yes
No
xxxxxxxx
NFC-1
DDMMYYYY
DDMMYYYY
XXXXX
Yes
Yes
Yes
xxxxxxxx
Placebo
DDMMYYYY
DDMMYYYY
XXXXX
xxxxxxxxxxxxx;
xxxxxxxx
No
Yes
No
xxxxxxxx
NFC-1
DDMMYYYY
DDMMYYYY
XXXXX
xxxxxx; 
xxxxxxxxx; 
xxxxx
No
No
No
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Final
Listing 16.2.1.2
Subject Disposition
Safety Population
Subject ID
Treatment
Completed
Study?
Follow-up
Phone Call?
Date of 
Discontinuation
Reason for Discontinuation
Date of Last Contact
xxxxxxxx
NFC-1
Yes
Yes
DDMMYYYY
xxxxxxxx
NFC-1
Yes
Yes
DDMMYYYY
xxxxxxxx
Placebo
No
No
DDMMYYYY
xxxxxxxxxxxx
DDMMYYYY
xxxxxxxx
NFC-1
No
No
DDMMYYYY
Other; xxxxxxx xxxxxxx
DDMMYYYY
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{If subject discontinued due to reason = ‘Other’, concatenate discontinuation reason field with Other with a ‘;’, as per the example above}


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Final
Listing 16.2.1.3
Inclusion/Exclusion Criteria
All Subjects
Treatment: XXXXX
Subject ID
Were all Inclusion Criteria 
Met?
Category Not Met
Criteria Not Met
xxxxxxxx
No
Inclusion
INCL01; INCL04; INCL10
xxxxxxxx
Yes
xxxxxxxx
Yes
xxxxxxxx
No
Inclusion; Exclusion
INCL02; INCL03; EXCL15; EXCL18G
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Final
Listing 16.2.2
Major and Minor Protocol Deviations
Safety Population
Treatment: XXXXX
Subject ID
Event Date
Event Report Date
Event Category
Event Type
Description
xxxxxxxx
DDMMYYYY
DDMMYYYY
Major
Informed Consent/Assent
xxxxxxxxxxxxxxxxxxxxxxxx; xxxxxxxxxxxxxx xxxx 
xxxx
DDMMYYYY
DDMMYYYY
Major
Concomitant  Medication
xxxxxxxxxxxxxxxxxxxx
DDMMYYYY
DDMMYYYY
Minor
Other
xxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxx 
xxxxxxxxxxxxx
xxxxxxxx
DDMMYYYY
DDMMYYYY
Minor
Study 
Assessments/Procedures
xxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxx
DDMMYYYY
DDMMYYYY
Minor
Inclusion/Exclusion Criteria
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxxxx
DDMMYYYY
DDMMYYYY
Major
Laboratory Assessment
xxxxxxxxxxxxxxxxxxx
DDMMYYYY
DDMMYYYY
Major
Laboratory Assessment
xxxxxxxx
xxxxxxxx
DDMMYYYY
DDMMYYYY
Major
Other
xxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxx xxxxxxx
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Protocol: MDGN-NFC1-ADHD-201
Final
Listing 16.2.3.1
Demographics and Other Baseline Characteristics
Safety Population
Treatment: XXXXXX
Subject ID
Previous 
Subject ID 
from 
ADHD-001
Date of Parental 
Informed Consent
Date of 
Informed 
Assent
Date of Birth
Age
(yrs)/ 
Gender
CB
Ethnicity
Race
ADHD Diagnosis Date
(Age  at Onset) (yrs)
xxxxxxxx
xxxxxxxx
DDMMYYYY
DDMMYYYY
DDMMYYYY
xx/F
No
xxxxxxxxxx
White
DDMMYYYY (13)
xxxxxxxx
xxxxxxxx
DDMMYYYY
DDMMYYYY
DDMMYYYY
xx/M
No
xxxxx
Asian
DDMMYYYY (8)
xxxxxxxx
xxxxxxxx
DDMMYYYY
DDMMYYYY
DDMMYYYY
xx/F
Yes
xxxxxxxxxxx
White
DDMMYYYY (10)
xxxxxxxx
xxxxxxxx
DDMMYYYY
DDMMYYYY
DDMMYYYY
xx/F
Yes
xxxxxxxxxxx
Black or African 
American
DDMMYYYY (14)
Note: NA = not applicable. yrs = Years. CB = If Female, is She of Childbearing Potential.
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Protocol: MDGN-NFC1-ADHD-201
Final
Listing 16.2.3.2
Prior, Concomitant, and Post-treatment Medications
Safety Population
Treatment: XXXXXX
Subject ID
Any 
Meds?
Concomitant/
Prior/Both
Anatomic Therapeutic Class/
Preferred Term/
Verbatim Term
Start Date/
End Date
Indication
Dose (unit)/
Route/
Frequency
xxxxxxxx
Yes
P
xxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxxxx
xxxx (xxxx)/
xxxxxxxxxx/
xxxxxxxxxxxx
P
xxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxx
DDMMYYY/
ONGOING
xxxxxxxxxxxxx
xxxx (xxxx)/
xxxxxxxxxx/
xxxxxxxxxxxx
C
xxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxxxx
xxxx (xxxx)/
xxxxxxxxxx/
xxxxxxxxxxxx
xxxxxxxx
Yes
B
xxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxxxx
xxxx (xxxx)/
xxxxxxxxxx/
xxxxxxxxxxxx
B
xxxxxxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxxxx
xxxx (xxxx)/
xxxxxxxxxx/
xxxxxxxxxxxx
Note: Medications were coded using WHO-DD (Enhanced version xxxxxx), Anatomic Therapeutic Class (ATC), level 4. B = Both, C = Concomitant, P = Prior.
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Protocol: MDGN-NFC1-ADHD-201
Final
Listing 16.2.3.3
Behavioral Therapies
Safety Population
Treatment: XXXXXX
Subject ID
Any 
Therapies?
Type of Therapy
Start Date/
End Date
Frequency
xxxxxxxx
Yes
xxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxx
xxxxxxxxxxxxxxxxxx
DDMMYYY/
ONGOING
xxxxxxxxxxxxxxx
xxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxxxxx
xxxxxxxx
Yes
xxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxx
xxxxxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxxxxxxxx
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Protocol: MDGN-NFC1-ADHD-201
Final
Listing 16.2.3.4
Medical History
Safety Population
Treatment: XXXXXX
Subject ID
Any 
History?
Verbatim Term
Start Date/
End Date
xxxxxxxx
Yes
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxxxxxxxxxxxxxxx
DDMMYYY/
ONGOING
xxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxx
Yes
xxxxxxxxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
DDMMYYY/
DDMMYYY
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Final
Listing 16.2.4.1
Study Drug Exposure
Safety Population
Treatment: XXXXXX
Subject ID
Dose (mg)
Start Date
(Study Day) [1]
End Date 
(Study Day) [1]
Treatment Duration (days) [2]
xxxxxxxx
xxx
DDMMYYYY
DDMMYYYY
x
xxx
DDMMYYYY
DDMMYYYY
x
xxx
DDMMYYYY
DDMMYYYY
xx
xxx
DDMMYYYY
DDMMYYYY
xx
xxx
DDMMYYYY
DDMMYYYY
xx
xxxxxxxx
xxx
DDMMYYYY
DDMMYYYY
x
xxx
DDMMYYYY
DDMMYYYY
x
xxx
DDMMYYYY
DDMMYYYY
xx
xxx
DDMMYYYY
DDMMYYYY
xx
xxx
DDMMYYYY
DDMMYYYY
xx
xxxxxxxx
xxx
DDMMYYYY
DDMMYYYY
x
xxx
DDMMYYYY
DDMMYYYY
x
xxx
DDMMYYYY
DDMMYYYY
xx
xxxxxxxx
xxx
DDMMYYYY
DDMMYYYY
x
xxx
DDMMYYYY
DDMMYYYY
x
xxx
DDMMYYYY
DDMMYYYY
xx
xxx
DDMMYYYY
DDMMYYYY
xx
xxx
DDMMYYYY
DDMMYYYY
xx
[1] Study Day is calculated relative to the date of the first dose of study drug.
[2] Treatment Duration is defined as Date of Last Dose – Date of First Dose + 1 for the specified Dose level.
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Final
Listing 16.2.4.2
Study Drug Accountability and Compliance
Safety Population
Treatment: XXXXXX
Subject ID
Visit
Bottles 
dispensed at 
this visit
Date Bottle 
Dispensed
Date Bottle 
Returned
Capsules 
Returned
Compliance [1]
By Week
Overall
xxxxxxxx
Visit 3
xx
DDMMYYYY
xx x%
Visit 4
xx x%
Visit 5
xx x%
Visit 6
DDMMYYYY
xx
xx x%
xx x%
xxxxxxxx
Visit 3
xx
DDMMYYYY
xx x%
Visit 4
xx x%
Visit 5
xx x%
Visit 6
DDMMYYYY
xx
xx x%
Visit 7
xx x%
Visit 8/ET
DDMMYYYY
xx
xx x%
xx x%
[1] A subject is non-compliant if they take < 80% or > 100% of IP. Compliance (Overall) = (sum of (Individual Week Compliance) * (Time-
Weight)) * 100.  Individual Week Compliance is defined as the number of capsules taken at a particular week divided by the expected number of 
capsules taken at a particular week.  Given that a subject will be dose optimized, the number of expected capsules will vary according to which dose 
the subject is currently on for each day.  Time-Weight is the fraction of x/y where x is the number of days in the week the subject is expected to be 
on dose and is the whole treatment duration. 
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Final
Listing 16.2.4.3
Investigator Dose Optimization
Safety Population
Treatment: XXXXXX
Subject ID
Dose (mg)
Investigator 
Assess Efficacy 
of Current Dose?
Date of Dose 
Assessment 
Response 
Categorization
Dose Optimization – 
Action Taken
xxxxxxxx
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
No
xxx
Yes
DDMMYYYY
Acceptable
DOSE MAINTAINED
xxxxxxxx
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
No
xxx
Yes
DDMMYYYY
Acceptable
DOSE MAINTAINED
xxxxxxxx
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Ineffective
DOSE MAINTAINED
xxxxxxxx
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Acceptable
DOSE INCREASED
xxx
Yes
DDMMYYYY
Ineffective
DOSE DECREASED
xxx
Yes
DDMMYYYY
Intolerable
IP DISCONTINUED
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Final
Listing 16.2.5.1.1
Attention Deficit Hyperactivity Disorder Rating Scale Version 5 (ADHD-RS-5), part 1
Intent-To-Treat Population
Treatment: XXXXXX
Subject 
ID
Visit
Performed?
Date
Performed
Q4
Q5
Q6
Q7
Q8
Q9
Q10
Q11
Q12
Q13
Q14
Q15
Q16
Q17
Q18
Q19
Q20
xxxxxxxx
Screening
Yes
DDMMYYYY
Y
Y
Y
Y
N
Y
Y
N
Y
0
0
0
0
0
0
1
2
Baseline
Yes
DDMMYYYY
Y
Y
Y
Y
N
Y
Y
N
Y
1
0
0
1
0
0
3
1
Visit 3
Yes
DDMMYYYY
Y
Y
Y
Y
N
Y
Y
N
N
0
0
0
0
0
0
1
2
Visit 4
Yes
DDMMYYYY
Y
Y
Y
Y
N
Y
Y
N
N
1
0
0
1
0
0
3
1
Visit 5
No
Visit 6
Yes
DDMMYYYY
Y
Y
Y
Y
Y
Y
Y
N
N
0
0
0
0
0
0
1
2
Visit 7
Yes
DDMMYYYY
Y
Y
Y
Y
Y
Y
Y
N
Y
1
0
0
1
0
0
3
1
Visit 8/ET
Yes
DDMMYYYY
Y
Y
Y
Y
N
Y
Y
N
N
1
0
0
1
0
0
3
1
Note: Y = Yes, N = No. For Questions 13 – 18: 0 – Never or Rarely, 1 – Sometimes, 2 – Often, 3 – Very often.  For Questions 19-33: 0 – No problem, 1 – Minor 
problem, 2 –Moderate Problem, 3 – Severe Problem
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Listing 16.2.5.1.2
Attention Deficit Hyperactivity Disorder Rating Scale Version 5 (ADHD-RS-5), part 2
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1, using Questions 21 – 33 and Inattention Subscale, Hyperactivity/Impulsivity Subscale, and ADHD RS-5 Total Score}


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Final
Listing 16.2.5.2
Clinical Global Impression of Improvement (CGI-I) and Clinical Global Impression of Severity (CGI-S)
Intent-To-Treat Population
Treatment: XXXXXX
Subject 
ID
Visit
Performed CGI-I/ 
Performed CGI-S
Date
Performed
CGI-I
CGI-S
xxxxxxxx
Screening
NA/Yes
DDMMYYYY
Normal, not at all ill
Baseline
NA/Yes
DDMMYYYY
Borderline mentally ill
Visit 3
Yes/NA
DDMMYYYY
No change
Visit 4
Yes/NA
DDMMYYYY
Minimally worse
Visit 5
Yes/NA
DDMMYYYY
Minimally improved
Visit 6
Yes/NA
DDMMYYYY
Much improved
Visit 7
Yes/NA
DDMMYYYY
Much improved
Visit 8/ET
Yes/Yes
DDMMYYYY
Very much Improved
Normal, not at all ill
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Listing 16.2.5.3.1
Adolescent Sleep Hygiene Scale (ASHS), part 1
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1} 
{Include questions 4-15, add footnote regarding decode values, see eCRF}
Listing 16.2.5.3.2
Adolescent Sleep Hygiene Scale (ASHS), part 2
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1} 
{Include questions 16-25, add footnote regarding decode values, see eCRF}
Listing 16.2.5.3.3
Adolescent Sleep Hygiene Scale (ASHS), part 3
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1}
{Include questions 26-40, add footnote regarding decode values, see eCRF}
Listing 16.2.5.3.4
Adolescent Sleep Hygiene Scale (ASHS), part 4
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1} 
{Include factors for ASHS and total score, add footnote regarding decode values, see eCRF}
Listing 16.2.5.4.1
Screen for Childhood Anxiety-related Emotional Disorders (SCARED), part 1
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1}
{Include questions 1-15, add footnote regarding decode values, see eCRF}
Listing 16.2.5.4.2
Screen for Childhood Anxiety-related Emotional Disorders (SCARED), part 2
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1} 
{Include questions 16-25, add footnote regarding decode values, see eCRF}


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Listing 16.2.5.4.3
Screen for Childhood Anxiety-related Emotional Disorders (SCARED), part 3
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1} 
{Include questions 26-41, add footnote regarding decode values, see eCRF}
Listing 16.2.5.4.4
Screen for Childhood Anxiety-related Emotional Disorders (SCARED), part 4
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1} 
{Include factors for SCARED and total score, add footnote regarding decode values, see eCRF}
Listing 16.2.5.5 
WASI-II (brief IQ test)
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1} 
Listing 16.2.5.6.1
Kiddie Schedule for Affective Disorders (K-SADS-PL), part 1
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1,
{Include questions 4-20, add footnote regarding decode values, see eCRF} 
Listing 16.2.5.6.2
Kiddie Schedule for Affective Disorders (K-SADS-PL), part 2
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1,
{Include questions 21-37, add footnote regarding decode values, see eCRF} 
Listing 16.2.5.6.3
Kiddie Schedule for Affective Disorders (K-SADS-PL), part 3
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1,
{Include questions 38-55, add footnote regarding decode values, see eCRF} 


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Listing 16.2.5.6.4
Kiddie Schedule for Affective Disorders (K-SADS-PL), part 4
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1, 
{Include questions 56-60, add footnote regarding decode values, see eCRF} 


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Final
Listing 16.2.6.1
Adverse Events
Safety Population
Treatment: XXXXXX
Subject ID
Any 
AEs?
System Organ Class/
Preferred Term/
Verbatim Term
TEAE?
Start Datetime/
End Datetime
Severity/
Relationship to IP
Outcome/
Study Drug 
Action Taken
SE
IME/CA/SD/ 
DE/HO/LT/
xxxxxxxx
Yes
xxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxxx
Yes
DDMMYYY:HH:MM/
DDMMYYY:HH:MM
xxxxxxxx/
xxxxxx
xxxxxxxx/
xxxxxx  xxxxx
No
No/No/No
No/No/No
xxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxxxxxx/
xxxxxxxx
Yes
DDMMYYY:HH:MM /
ONGOING
xxxxxxx/
xxxx
xxxxxxx/
xxxxxxxxxxx
No
No/No/No
No/No/No
xxxxxxxxxxxxxx/
xxxxxxx/
xxxxxxxxxxxxxxxx
No
DDMMYYY:HH:MM/
DDMMYYY:HH:MM
xxxxxxxx/
xxxxx
xxxxxxxx/
xxxxxxxxxxxx
Yes
Yes/Yes/No/
Yes/No/No
xxxxxxxx
Yes
xxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxx
Yes
DDMMYYY:HH:MM/
DDMMYYY:HH:MM
xxxxxx/
xxxx
xxxxxx/
xxxxxxxx
Yes
No/No/No/
Yes/No/No
xxxxxxxxxxxxxxxxxxxxxxxx/
xxxxxxxxxxxxxxxxx/
xxxxxxx
Yes
DDMMYYY:HH:MM/
DDMMYYY:HH:MM
xxxxxxx/
xxxxx
xxxxxxx/
xxxxx
No
No/No/No
No/No/No
Note: Adverse Events were coded using MedDRA version xx x.  CA = Congenital Anomaly; DE = Results in Death; HO = Hospitalization; IME = Important Medical Event; 
IP = Investigational Product; LT = Life Threatening; SD = Results in Persistent or Significant Disability/Incapacity; SE = Serious Event; TEAE = Treatment-Emergent 
Adverse Event
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Listing 16.2.6.2
Serious Adverse Events
Safety Population
{Similar shell as Listing 16.2.6.1, remove Any AEs column} 
Listing 16.2.6.3
Adverse Events leading to Early Termination
Safety Population
{Similar shell as Listing 16.2.6.1, remove Any AEs column} 
Listing 16.2.6.4
Listing of Deaths
All Subjects
{Similar shell as Listing 16.2.6.1, remove Any AEs column} 


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Final
Listing 16.2.7.1
Clinical Laboratory Data: Chemistry
Safety Population
Treatment: XXXXXX
Subject ID
Laboratory Test (unit)
Visit
Collection Date
Test Result
Reference Range Low
Reference Range High
Flag [1]
xxxxxxxx
xxxxxxxxxxxxxx
Screening
DDMMMYYYY
xx.xx
xxx
xxx
H
Baseline
DDMMMYYYY
xx.xx
xxx
xxx
Visit 3
DDMMMYYYY
xx.xx
xxx
xxx
P; L
Visit 4
DDMMMYYYY
xx.xx
xxx
xxx
Visit 5
DDMMMYYYY
xx.xx
xxx
xxx
Visit 6
DDMMMYYYY
xx.xx
xxx
xxx
L
Visit 7
DDMMMYYYY
xx.xx
xxx
xxx
Visit 8/ET
DDMMMYYYY
xx.xx
xxx
xxx
xxxxxxxxxxxxxx
Screening
DDMMMYYYY
xx.xx
xxx
xxx
P
Baseline
DDMMMYYYY
xx.xx
xxx
xxx
Visit 3
DDMMMYYYY
xx.xx
xxx
xxx
Visit 4
DDMMMYYYY
xx.xx
xxx
xxx
P; H
Visit 5
DDMMMYYYY
xx.xx
xxx
xxx
Visit 6
DDMMMYYYY
xx.xx
xxx
xxx
H
Visit 7
DDMMMYYYY
xx.xx
xxx
xxx
H
Visit 8/ET
DDMMMYYYY
xx.xx
xxx
xxx
{Repeat for all scheduled analytes}
[1] H = High, L = Low, P = Potential Clinical Importance.
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Listing 16.2.7.2
Clinical Laboratory Data: Hematology
Safety Population
{Similar shell as Listing 16.2.7.1}
Listing 16.2.7.3
Clinical Laboratory Data: Urinalysis
Safety Population
{Similar shell as Listing 16.2.7.1}
Listing 16.2.7.4
Pregnancy Tests
Safety Population
{Similar shell as Listing 16.2.7.1, limit to only female subjects, remove flag column} 
Listing 16.2.7.5
Urine Drug Screen
Safety Population
{Similar shell as Listing 16.2.7.1, remove reference limit columns and flag column} 


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Protocol: MDGN-NFC1-ADHD-201
Final
Listing 16.2.8
Vital Signs
Safety Population
Treatment: XXXXXX
Subject ID
Visit
Vital Signs 
Collected?
Date of
Measurement
Height 
(cm)
Weight 
(kg)
Heart Rate
(beats/min)
Respiratory 
Rate 
(breaths/min)
Systolic 
Blood 
Pressure 
(mmHg)
Diastolic
Blood 
Pressure 
(mmHg)
BMI 
(kg/m^2)
xxxxxxxx
Screening
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x
Baseline
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x
Visit 3
Yes
DDMMYYYY
xx x
xx x*
xxx
xxx
xx
xx
xx x
Visit 4
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x
Visit 5
Yes
DDMMYYYY
xx.x
xx.x
xxx
xxx^
xx
xx
xx x
Visit 6
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx*
xx x
Visit 7
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x
Visit 8/ET
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x^
xxxxxxxx
Screening
Yes
DDMMYYYY
xx x
xx.x
xxx*#
xxx
xx
xx
xx x
Baseline
Yes
DDMMYYYY
xx x
xx x^#
xxx
xxx
xx
xx
xx x
Visit 3
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x
Visit 4
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx*
xx
xx
xx x
Visit 5
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x
Visit 6
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x^
Visit 7
Yes
DDMMYYYY
xx x
xx.x
xxx*
xxx
xx
xx
xx x
Visit 8/ET
Yes
DDMMYYYY
xx x
xx.x
xxx
xxx
xx
xx
xx x
Note: * = High, ^ = Low, # = Potential Clinical Significance.
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Protocol: MDGN-NFC1-ADHD-201
Final
Listing 16.2.9
Electrocardiograms (ECGs), Site Interpretation
Safety Population
Treatment: XXXXXX
Subject ID
Visit
ECG 
Collected?
Datetime of
Measurement
Investigator Interpretation
xxxxxxxx
Screening
Yes
DDMMYYYY:HH:MM
Normal
Baseline
Yes
DDMMYYYY:HH:MM
Normal
Visit 3
Yes
DDMMYYYY:HH:MM
Normal
Visit 4
Yes
DDMMYYYY:HH:MM
Abnormal – Not clinically significant
Visit 5
Yes
DDMMYYYY:HH:MM
Normal
Visit 6
Yes
DDMMYYYY:HH:MM
Normal
Visit 7
Yes
DDMMYYYY:HH:MM
Normal
Visit 8/ET
Yes
DDMMYYYY:HH:MM
Unable to be evaluated
xxxxxxxx
Screening
Yes
DDMMYYYY:HH:MM
Normal
Baseline
Yes
DDMMYYYY:HH:MM
Normal
Visit 3
Yes
DDMMYYYY:HH:MM
Normal
Visit 4
Yes
DDMMYYYY:HH:MM
Normal
Visit 5
Yes
DDMMYYYY:HH:MM
Normal
Visit 6
No
Unscheduled
Yes
DDMMYYYY:HH:MM
Normal
Visit 7
Yes
DDMMYYYY:HH:MM
Normal
Visit 8/ET
Yes
DDMMYYYY:HH:MM
Abnormal – Clinically significant
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Listing 16.2.10
Electrocardiograms (ECGs), Central Reading
Safety Population
{Similar shell as Listing 16.2.9}


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Protocol: MDGN-NFC1-ADHD-201
Final
Listing 16.2.11
Physical Examination
Safety Population
Treatment: XXXXXX
Subject ID
Visit
Physical 
Examination 
Performed
Date of
Measurement
Body 
System
Abnormal Finding
xxxxxxxx
Screening
Yes
DDMMYYYY
System 1
xxxxxxxxxxxx
System 2
xxxxxxxxxxxxxxxxx
System 3
xxxxxxxxxxxxxxxxxxxxx
Visit 8/ET
Yes
DDMMYYYY
xxxxxxxx
Screening
Yes
DDMMYYYY
System 1
xxxxxxxxxxx
Visit 8/ET
Yes
DDMMYYYY
xxxxxxxx
Screening
Yes
DDMMYYYY
Visit 8/ET
Yes
DDMMYYYY
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Listing 16.2.12
Columbia Suicide Severity Rating Scale (C-SSRS)
Intent-To-Treat Population
{Similar shell as Listing 16.2.5.1.1}