A Phase 3, Double-blind, Randomized, Placebo-controlled, Multi-center, Fixed-dose, Parallel Group Efficacy and Safety in Pediatrics (6-17) With Attention-Deficit/Hyperactivity Disorder (ADHD) Using CTx-1301 (Dexmethylphenidate)
Phase: PHASE3
Conditions: ADHD, Attention Deficit Hyperactivity Disorder, ADHD - Combined Type, Attention Deficit Hyperactivity Disorder Combined, Attention-deficit Hyperactivity, Attention Deficit Hyper Activity
Sponsor: Cingulate Therapeutics

 
 
 
 
 
Protocol CTX-1301-005                              Version 6.0, Date: 13 OCT 2023 
        
              Page 1 of 76 
 
CONFIDENTIAL 
 
 
 
 
CLINICAL STUDY PROTOCOL 
A PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTI-
CENTER, FIXED-DOSE, PARALLEL GROUP EFFICACY AND SAFETY STUDY IN 
PEDIATRICS (6-17) WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER 
(ADHD) USING CTX-1301 (DEXMETHYLPHENIDATE)  
Study Number: CTx-1301-005 
Drug Development Phase: 
Phase 3 
Investigational Product: 
Dexmethylphenidate 
Indication: 
Attention-Deficit/Hyperactivity Disorder (ADHD) 
IND 
136674 
Lead Investigator:  
 
Sponsor: 
Cingulate Therapeutics 
 
 
Date: 
Version 6, 13 Oct 2023 
 
Conduct: In accordance with the ethical principles that originate from the Declaration of 
Helsinki and that are consistent with International Conference on Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable. 
 
 
 
 
 
 
 
Confidential Information 
This document is the sole property of Cingulate Therapeutics. This document and 
information contained herein must be considered and treated as strictly confidential. This 
document shall be used only for the purpose of the disclosure herein provided. No 
disclosure or publication shall be made without the prior written consent of Cingulate 
Therapeutics. 
 
 
 
 

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CONFIDENTIAL 
 
 
 
 
SUMMARY INFORMATION 
 
Title: 
A Phase 3, double-blind, randomized, placebo-
controlled, multi-center, fixed-dose, parallel group 
efficacy and safety in pediatrics (6-17) with Attention-
Deficit/Hyperactivity Disorder (ADHD) using CTx-1301 
(dexmethylphenidate)  
 
 
Protocol Number: 
 
CTx-1301-005 
 
 
Sponsor: 
 
Cingulate Therapeutics 
 
Primary Sponsor contact: 
 
 
 
 
 
 
  
 
 
Secondary Sponsor contact: 
 
 
 
 
 
 
  
 
 
Medical Monitor:  
 
 
 
 
 
 
 
 

Protocol CTx-1301-005                           Version 6.0   Date: 13 OCT 2023 
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CONFIDENTIAL 
SPONSOR PROTOCOL APPROVAL 
 
 
Protocol Title: 
A Phase 3, double-blind, randomized, placebo-controlled, 
multi-center, fixed-dose, parallel-group efficacy, and 
safety study with CTx-1301 in pediatrics (6-17) with 
Attention-Deficit/Hyperactivity Disorder (ADHD) using 
CTx-1301 (dexmethylphenidate) 
 
 
Protocol Number: 
 
CTx-1301-005 
 
Protocol Version: 
6.0 
 
Date of Version: 
13 Oct 2023  
 
Signed for approval by: 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 

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CONFIDENTIAL 
 
 
 
 
 
  
 
PROTOCOL SIGNATURE PAGE 
I have read and understand the contents of this clinical protocol for Study No. CTx-1301-005 
dated 13 OCT 2023 and agree to meet obligations of Cingulate Therapeutics as detailed in 
applicable regulations and guidelines. The signature of the Investigator below constitutes 
his/her approval of this protocol and provides the necessary assurances that this study will be 
conducted according to Good Clinical Practice (ICH 1996) and to stipulations, clinically and 
administratively, as stated in the protocol, including statements as to confidentiality. It is 
agreed that the conduct and results of this study will be kept confidential and that the case 
report forms, and other pertinent data, will become the property of Cingulate Therapeutics. 
 
It is agreed that the protocol contains necessary information required to conduct the study and 
that the study will not be initiated without the approval of an appropriate Institutional Review 
Board (IRB).  
It is agreed that participants, parents/guardian, and caregiver (if applicable) in this study will 
provide written informed consent and assent in accordance with the requirements specified in 
the Declaration of Helsinki 1964. Participants will also be informed that their medical records 
will be kept confidential except for review by study site personnel and appropriate IRB 
representatives and regulatory authorities. 
In some instances, a summary of the protocol and study results, along with the names of the 
principal Investigator from the study site, and details of the institution with which the 
Investigator is affiliated will be posted in one or more publicly accessible worldwide registers 
at any time after the commencement of the study. The signature of the Investigator below 
constitutes his/her consent to have his/her name and institution disclosed should this study be 
made publicly available on a register. In addition, to avoid confusing or conflicting information, 
the signature of the Investigator below constitutes his/her agreement not to post information 
about the study on any clinical trials registry without first obtaining the prior written consent of 
the Sponsor. 
 
Signed By: 
 
Principal Investigator  
 
 
 
 
Date of Signature 
 
_________________________ 
 

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CONFIDENTIAL 
 
Emergency Contact Information 
In the event of an SAE, the investigator must fax or e-mail the SAE Form within 24 hours to 
the 
 Pharmacovigilance Department. Applicable fax numbers and email address can 
be found on the SAE form. A copy of the SAE form must also be sent to the CRO/Medical 
Monitor by email using the following details. 
For protocol or safety-related issues during normal business hours (8am-5pm) eastern 
standard time, the investigator must contact the 
 Medical Monitor: 
 
Email Address: 
 
Please use the study identifier in the subject of your e-mail (and replies to e-mail); use the 
study-specific medical monitor e-mail and not individual e-mail addresses of medical monitors. 
The study e-mail address will distribute your e-mail automatically to back-up medical 
monitor(s), and ensure your e-mail will have a receiver, even if the lead medical monitor is out 
of the office. For urgent protocol or safety-related issues outside of normal business hours 
(8am-5pm) eastern standard time, the investigator must contact the 
 Medical Monitor: 
Phone: 
 
This phone number will connect you to a call center and an operator will ask you for your 
details and will connect you through to a 
 medical monitor. 
 
 
 

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CONFIDENTIAL 
TABLE OF CONTENTS 
 
SUMMARY INFORMATION ...................................................................................................... 2 
SPONSOR PROTOCOL APPROVAL ...................................................................................... 3 
ABBREVIATIONS ................................................................................................................... 18 
1 
PRODUCT BACKGROUND INFORMATION ................................................................. 24 
1.1 
INDICATION AND CURRENT TREATMENT OPTIONS ....................................... 24 
1.2 
OVERVIEW OF CLINICAL STUDIES WITH CTX-1301......................................... 25 
2 
STUDY PURPOSE AND OBJECTIVES ......................................................................... 26 
2.1 
STUDY DESIGN SCHEMATIC ............................................................................... 26 
2.2 
STUDY PURPOSE .................................................................................................. 26 
2.3 
PRIMARY OBJECTIVE ........................................................................................... 26 
2.4 
SECONDARY OBJECTIVE(S) ............................................................................... 26 
3 
INVESTIGATIONAL PLAN AND DESIGN ..................................................................... 27 
3.1 
STUDY DESIGN ...................................................................................................... 27 
3.2 
RATIONALE FOR STUDY DESIGN ....................................................................... 27 
4 
STUDY POPULATION .................................................................................................... 28 
4.1 
SOURCE AND NUMBER OF SUBJECTS ............................................................. 28 
4.2 
CRITERIA FOR EVALUATION ............................................................................... 28 
4.3 
INCLUSION CRITERIA ........................................................................................... 28 
4.4 
EXCLUSION CRITERIA .......................................................................................... 29 
4.5 
SUBJECT WITHDRAWAL CRITERIA ................................................................... 31 
4.6 
SUBJECT REPLACEMENT.................................................................................... 31 
4.7 
TREATMENT AND SUBJECT RESTRICTIONS.................................................... 31 
4.7.1 MEDICATIONS AND TREATMENTS ................................................................. 31 
4.7.2 ALLOWED TREATMENTS: ................................................................................. 33 
4.7.3 PROTOCOL DEVIATIONS .................................................................................. 33 
5 
STUDY TREATMENTS: ASSIGNMENT & SUPPLY MANAGEMENT ......................... 33 
5.1 
STUDY TREATMENTS ........................................................................................... 33 
5.1.1 IDENTITY OF STUDY TREATMENTS ............................................................... 33 
5.1.2 SELECTION OF DOSES ..................................................................................... 34 
5.1.3 ADMINISTRATION .............................................................................................. 34 
5.1.4 DOSE SCHEDULE .............................................................................................. 35 
5.1.5 DOSE MODIFICATION ....................................................................................... 35 
5.1.6 TREATMENT COMPLIANCE .............................................................................. 35 
5.1.7 OVERDOSAGE ................................................................................................... 36 
5.1.8 RESCUE THERAPY ............................................................................................ 36 
5.1.9 RISKS................................................................................................................... 36 
5.2 
STUDY TREATMENT ASSIGNMENT .................................................................... 38 
5.2.1 ENROLLMENT PROCEDURE ............................................................................ 38 
5.2.2 BLINDING PROCEDURE AND CODE BREAKS................................................ 38 

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CONFIDENTIAL 
5.3 
STUDY TREATMENT SUPPLIES MANAGEMENT ............................................... 39 
5.3.1 INTERACTIVE RESPONSE TECHNOLOGY (IRT) FOR INVESTIGATIONAL 
PRODUCT MANAGEMENT ............................................................................................ 39 
5.3.2 SHIPPING, MANUFACTURE, PACKAGING, AND LABELING ......................... 39 
5.3.3 ACCOUNTABILITY OF STUDY SUPPLIES ....................................................... 40 
5.3.4 STORAGE OF STUDY TREATMENT SUPPLIES .............................................. 41 
6 
METHODS, MEASUREMENTS, EVALUATIONS, AND STUDY-RELATED 
PROCEDURES ........................................................................................................................ 41 
6.1 
PARENTAL PERMISSION AND INFORMED CONSENT ..................................... 41 
6.2 
ADHD DIAGNOSIS AND CONFIRMATION ........................................................... 42 
6.3 
DEMOGRAPHICS ................................................................................................... 42 
6.4 
MEDICAL HISTORY................................................................................................ 43 
6.5 
PRIOR AND CONCOMITANT TREATMENTS ...................................................... 43 
6.6 
PRIOR ADHD MEDICATION QUESTIONNAIRE................................................... 43 
6.7 
PHYSICAL AND NEUROLOGICAL EXAMINATIONS .......................................... 43 
6.8 
HEIGHT, WEIGHT, AND BODY MASS INDEX (BMI) ........................................... 44 
6.9 
VITAL SIGNS........................................................................................................... 44 
6.10 
TABLET SWALLOWING TEST .............................................................................. 45 
6.11 
CLINICAL LABORATORY TESTS ......................................................................... 45 
6.12 
PHARMACOKINETIC BLOOD SAMPLING ........................................................... 46 
6.13 
ECG .......................................................................................................................... 48 
6.14 
C-SSRS .................................................................................................................... 48 
6.15 
STUDY EVALUATIONS AND EFFICACY ASSESSMENTS ................................. 49 
6.15.1 ADHD-RS-5.......................................................................................................... 49 
6.15.2 CGI-S ................................................................................................................... 49 
6.15.3 CGI-I ..................................................................................................................... 49 
6.15.4 MINI-KID .............................................................................................................. 49 
6.16 
DESCRIPTION OF OTHER STUDY PROCEDURES ............................................ 50 
6.16.1 DRUG ACCOUNTABILITY AND COMPLIANCE ................................................ 50 
6.16.2 BLOOD SAMPLING ............................................................................................. 50 
6.16.3 STUDY COMPLETION/MEDICAL SIGN-OFF .................................................... 50 
6.17 
DURATION OF THE STUDY .................................................................................. 50 
7 
STUDY SCHEDULE ........................................................................................................ 51 
7.1 
SCREENING (DAYS -30 TO -1) ............................................................................. 51 
7.1.1 VISIT 1 (SCREENING VISIT) .............................................................................. 51 
7.1.2 WASHOUT CALL ................................................................................................. 52 
7.1.3 VISIT 2 ................................................................................................................. 52 
7.1.4 VISIT 3 ................................................................................................................. 53 
7.1.5 VISIT 4 - VISIT 7 .................................................................................................. 54 
7.1.6 VISIT 8/ EARLY TERMINATION ......................................................................... 54 
7.1.7 VISIT 9 ................................................................................................................. 55 
7.2 
EARLY TERMINATION ........................................................................................... 55 

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CONFIDENTIAL 
7.3 
DISCONTINUATION OF STUDY INTERVENTION ............................................... 55 
7.4 
UNSCHEDULED VISITS ......................................................................................... 56 
7.5 
SUBJECTS LOST TO FOLLOW-UP ...................................................................... 56 
8 
SAFETY MEASUREMENTS AND EVALUATIONS ....................................................... 56 
8.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................... 56 
8.1.1 DEFINITIONS ...................................................................................................... 56 
8.1.2 REPORTING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......... 58 
8.1.3 ADVERSE EVENT GRADING AND ASSESSMENTS ....................................... 59 
8.2 
PREGNANCY .......................................................................................................... 62 
8.3 
LABORATORY EVALUATIONS RELATED TO SAFETY .................................... 63 
8.4 
VITAL SIGNS, PHYSICAL EXAM, ECGS, AND OTHER OBSERVATIONS 
RELATED TO SAFETY ....................................................................................................... 63 
9 
DATA MANAGEMENT AND STATISTICAL ANALYSIS METHODS ........................... 63 
9.1 
DATA COLLECTION............................................................................................... 63 
9.2 
CLINICAL DATA MANAGEMENT.......................................................................... 64 
9.3 
SAMPLE SIZE CALCULATION .............................................................................. 64 
9.4 
ANALYSIS POPULATIONS.................................................................................... 64 
9.5 
DATA ANALYSIS .................................................................................................... 64 
9.5.1 SUBJECT DISPOSITION .................................................................................... 64 
9.5.2 DRUG EXPOSURE AND COMPLIANCE ........................................................... 65 
9.5.3 DEMOGRAPHIC AND BASELINE CHARACTERISTICS................................... 65 
9.5.4 MEDICAL HISTORY ............................................................................................ 65 
9.5.5 PSYCHIATRIC HISTORY.................................................................................... 65 
9.6 
STATISTICAL CONSIDERATIONS ....................................................................... 65 
9.6.1 STATISTICAL APPROACH ................................................................................. 65 
9.6.2 PRIMARY EFFICACY ENDPOINT ANALYSIS ................................................... 66 
9.6.3 KEY SECONDARY EFFICACY ENDPOINT ANALYSIS .................................... 67 
9.7 
PK ANALYSIS ......................................................................................................... 67 
9.8 
SAFETY ................................................................................................................... 68 
9.9 
OTHER SECONDARY ENDPOINT ANALYSIS ..................................................... 68 
10 
ETHICAL AND REGULATORY ASPECTS ................................................................ 68 
10.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI ..................................... 68 
10.2 
INFORMED CONSENT ........................................................................................... 68 
10.3 
FDA .......................................................................................................................... 69 
10.4 
INSTITUTIONAL REVIEW BOARD (IRB) .............................................................. 69 
10.5 
FUNDING ................................................................................................................. 69 
11 
MONITORING OF THE STUDY .................................................................................. 70 
12 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING ............................... 70 
12.1 
INVESTIGATOR’S FILES/RETENTION OF DOCUMENTS .................................. 70 
12.2 
SOURCE DOCUMENTS/DATA .............................................................................. 70 

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CONFIDENTIAL 
12.3 
ELECTRONIC CASE REPORT FORMS ................................................................ 70 
12.4 
CONTROLLED SUBSTANCE REGULATIONS AND LEGISLATION .................. 71 
13 
PROCESS FOR AMENDING THE PROTOCOL ........................................................ 71 
14 
CONDITIONS FOR TERMINATING THE STUDY ..................................................... 71 
15 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT RECORDS .......... 72 
16 
AUDITS/INSPECTIONS .............................................................................................. 72 
17 
DISCLOSURE OF INFORMATION............................................................................. 72 
18 
REFERENCES ............................................................................................................ 74 
 
 
 
 

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CONFIDENTIAL 
STUDY SYNOPSIS 
 
Title 
A Phase 3, randomized, double-blind, placebo-controlled, multi-center, fixed-
dose, parallel-group efficacy, and safety study in a pediatric population (6-17) 
with Attention-Deficit/Hyperactivity Disorder (ADHD) using CTx-1301 (d-MPH) 
Sponsor 
Cingulate Therapeutics 
Short 
Title/Acronym 
A Phase 3, Fixed-Dose, Pediatric Efficacy and Safety Study 
Protocol Number 
CTx-1301-005 
Investigational 
Product 
CTx-1301, a novel, trimodal, extended-release dexmethylphenidate tablet (d-
MPH) 
Proposed 
Indication 
Attention Deficit Hyperactivity Disorder (ADHD) 
Route/Dosage 
Form 
Oral, trimodal, extended-release tablet  
Name of Active 
Ingredient 
Dexmethylphenidate HCl (d-MPH) 
Planned Efficacy 
Study Period 
Approximately 5 weeks (excluding screening)  
Full Study Period 
Approximately 10 weeks (including screening and safety follow up) 
Objective(s) 
Primary objective: 
• 
To evaluate the efficacy of a fixed dose of CTx-1301 compared to 
placebo in treating pediatric subjects with ADHD using the ADHD-RS-5 
Total Score 
Key Secondary objective: 
• 
To evaluate the efficacy of a fixed dose of CTx-1301 compared to 
placebo in treating pediatric subjects with ADHD using the CGI-S score 
Other Secondary objectives: 
• 
To determine safety and tolerability of a fixed dose of CTx-1301 
compared to placebo  
• 
To evaluate the PK levels of dexmethylphenidate after a single dose  
• 
To evaluate the PK levels of dexmethylphenidate at steady state 
• 
To evaluate the PK/PD correlation of dexmethylphenidate at steady 
state 
• 
To evaluate the CGI-I score at the end of treatment 

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CONFIDENTIAL 
Study Design and 
Methodology 
A multi-center, double-blind, randomized, placebo-controlled, fixed-dose, 
parallel efficacy, and safety study with CTx-1301 in children (6-17) with ADHD 
confirmed by an ADHD-RS-5 score of at least 28 and CGI-S score of at least 4 
(moderately ill) at baseline. The study will be comprised of a screening period, 
a double-blind randomized phase, and a safety follow-up visit.  
 
The Study will be comprised of 3 periods: 
• 
Screening Period (Day -30 to Day -1): Subjects will undergo a Screening 
Visit (Visit 1) up to 30 days prior to entering the randomized treatment 
period. Only subjects that meet inclusion and no exclusion criteria at 
screening may be considered for entry/randomization into the study. A 
reminder telephone call will be completed 5 days prior to Day 0 (Visit 2) to 
ensure 
washout 
of 
current 
prohibited 
medications, 
to 
confirm 
inclusion/exclusion criteria, and to confirm date of next visit. 
 
• 
Randomized Treatment Period (Day 0 to Day 35 ± 3 days): Subjects will 
be randomized on Day 0 to active or placebo (placebo, CTx-1301 18.75 mg, 
CTx-1301 25 mg, or CTx-1301 37.5 mg). Subjects randomized to the active 
dose will have a starting dose of 12.5 mg on Day 0. Each subject randomized 
to an active dose will be titrated (increased) weekly until they reach their 
assigned fixed dose; subjects must be on their assigned fixed dose a 
minimum of 2 sequential weeks prior to the primary efficacy assessment at 
Week 5/Visit 8. Subjects will be instructed to take their dose every morning 
at-home upon waking, no later than 8:00 am. 
 
• 
Safety Follow-Up Phone Call (Day 42 ± 5 days): Subjects will be 
evaluated for safety after washout of medication. 
Number of 
Subjects/Number 
of Sites 
Approximately 77 subjects per treatment group (CTx-1301 18.75 mg, 25 mg, 
37.5 mg, and placebo) would provide 90% power at 2-sided significance level 
of 0.017 based on a two-sample t test with effect size 0.60 after Bonferroni 
correction (nQuery Version 8.4.1.0), which results in a total sample size of 308. 
Assuming a drop-out rate of 20%, approximately 385 subjects will be enrolled. 
The study will take place at approximately 25 sites in the United States.  
Diagnosis and 
Main Inclusion 
Criteria  
Healthy male and female subjects aged 6 to 17 years old, inclusive, diagnosed 
with ADHD and who are unsatisfied with their current pharmacological therapy 
for ADHD or are not currently receiving pharmacological therapy for ADHD will 
be entered into the study.   

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CONFIDENTIAL 
Study Product 
and Planned Use 
The active investigational product is a trimodal, extended-release 
dexmethylphenidate (d-MPH) tablet (CTx-1301). Each tablet will contain a 
specified dose of d-MPH in the following strengths: 
 
• 
12.5 mg (starting dose only) 
• 
18.75 mg (randomized fixed dose) 
• 
25.0 mg (randomized fixed dose) 
• 
37.5 mg (randomized fixed dose) 
 
CTx-1301 is a novel, trimodal, modified, extended-release tablet which provides 
an efficient use of d-MPH over the course of the day. The first release (35% of 
dose) consists of an immediate release (IR) with an onset of action within 30 
minutes, the second release (45% of dose) is a sustained-release at 
approximately 3-4 hours (releasing over 60 – 90 minutes), and the third and final 
release (20% of dose) is an immediate release around 7-8 hours. 
 
 
  
The study drug should be administered at-home upon wakening in the morning, 
no later than 8:00 am, due to the extended efficacy of the investigational 
product. Dosing is one tablet per day. Study drug must be taken orally with 
approximately 240 mL (1 cup) of water. Study drug must be swallowed whole 
without any modification to the tablet (no crushing, chewing, or manipulating the 
tablet in any manner). Study drug may be taken with or without food (defined as 
food taken within one hour of study drug administration). 
Reference 
therapy 
The comparator product is a matching placebo tablet. 
ADHD 
Severity/Efficacy 
Evaluation 
Criteria 
 
The following scales will be used during the study to assess weekly the severity 
of ADHD as well as the eligibility of each subject: 
• 
ADHD-Rating Scale-5 (ADHD-RS-5) 
• 
Clinical Global Impression-Severity (CGI-S) 
• 
Clinical Global Impression-Improvement (CGI-I) 
• 
MINI International Neuropsychiatric Interview of Children and 
Adolescents (MINI-KID) 
Safety Evaluation 
Criteria 
Adverse events, vital signs, height, and weight (z-scores), sleep and appetite 
evaluation, physical examinations, ECGs, clinical laboratory measurements, 
and C-SSRS scores will be evaluated for safety. 

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CONFIDENTIAL 
Population PK 
and Sparse 
Sampling 
Population PK analysis can be used to derive patient PK exposure metrics that 
can be used to conduct sequential exposure-response analyses. Population PK 
models can predict individual patient exposures at specific time points 
regardless of the spread in sampling times (e.g., trough concentrations can be 
predicted for subjects). Population PK analysis is especially appropriate in 
children because it allows the use of infrequent (i.e., sparse) sampling 
compared to the rich sampling associated with traditional PK analyses, thus 
minimizing the total volume of blood sampled. Sampling windows in pediatric 
studies are generally expected to be wider than those of adult studies, because 
of the limited number of blood samples obtained from pediatric patients.  
 
Sparse PK sampling will be conducted after a single dose and at steady state 
from the patient population with special attention given to the time the sample is 
obtained post-dose. These analyses will inform strategies that manage dosing 
and detail administration for a given subpopulation, planned subsequent 
studies, and support labeling. 
PK Sampling 
PK samples will be obtained on Day 1 (post-dose) and Week 5 (post-dose) 
recording the time the sample is obtained post-dose at each timepoint. 
 
Collection times at Day 1 (Visit 3) and Week 5 (Visit 8) will be 0.5 to 5 hours 
post-dose, 5-6.5 hours post-dose, and 6.5 to 8 hours post-dose. Collection times 
at Day 1 and Week 5 will be different for each subject (i.e., if assigned 0.5-5 
hours post dose on Day 1, they will be assigned 5 to 6.5 hours or 6.5 to 8 hours 
post-dose at Week 5). Collection times will be assigned via automated IRT to 
ensure an approximately equal distribution among the 6 different combinations 
of timepoints. With 385 subjects at single dose (Day 1) and at least 308 subjects 
at Week 5, this should provide an adequate distribution to demonstrate Pop PK 
measurements.  
Duration of 
Subject 
Participation and 
Duration of Study 
Treatment 
Subjects will participate in the study as outpatients for up to approximately 10 
weeks (including screening); a 30-day screening period, a 5-week double-blind 
randomized period, and a 1-week follow-up safety visit.  
 
Completion of the study will be defined as completion of the last subject, last 
visit (LSLV) at Visit 9.  
 
Subjects will be randomized at baseline to CTx-1301 or placebo (CTx-1301 
18.75 mg, CTx-1301 25 mg, CTx-1301 37.5 mg, or placebo). Starting dose for 
subjects randomized to active treatment is 12.5 mg. These subjects will then be 
titrated up to their assigned fixed dose (18.75, 25, or 37.5 mg) for the last two 
weeks of the study period. Subjects randomized to placebo will receive placebo 
treatment for the full 5 weeks of the study.  
Medication 
Restrictions  
Subjects meeting eligibility requirements and enrolled into the study will be 
subject to medication restrictions during the trial: 
 

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CONFIDENTIAL 
• 
ADHD stimulant medications (except for study drug CTx-1301), 
including herbal medications, are prohibited from 5 days prior to 
Baseline (Visit 2) and through the end of the study (Visit 9). These 
medications include, but are not limited to, methylphenidate and 
amphetamine isomers and prodrugs.  
 
• 
ADHD non-stimulant medications are prohibited from 21 days prior to 
Baseline (Visit 2) and through the end of the study (Visit 9). These 
medications include, but are not limited to atomoxetine, guanfacine, 
clonidine, SSRIs such as fluoxetine, paroxetine and viloxazine.  
 
• 
The following medications are prohibited from 21 days prior to Baseline 
(Visit 2) and through the end of the study (Visit 9) or early termination 
visit *: 
 
o Tricyclic antidepressants 
o Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., fluoxetine, 
paroxetine) 
o Benzodiazepines 
o Monoamine oxidase inhibitors (MAOIs) 
o Mood stabilizers (e.g., lithium, valproate, quetiapine) 
o Antipsychotics (e.g., risperidone, olanzapine) 
o Coumadin anticoagulants 
o Anticonvulsants 
o Halogenated anesthetics 
o Phenylbutazone 
o Any medication not described in this protocol at the discretion of 
the Investigator 
 
*Note: These medications may signal that an exclusionary diagnosis is present. 
The medical monitor should be consulted before instructing a subject to 
discontinue any of these medication for this study. 
 
• 
Sedative hypnotics / sedative antihistamines (e.g., hydroxyzime, 
Diphenhydramine (three brand names: Benadryl, Nytol, Sominex), sleep 
enhancers (except for melatonin) are prohibited from 14 days prior to 
Baseline (Visit 2) and through the end of the study (Visit 9) or early 
termination visit*  
• 
The Investigator, and CRO Medical Monitor, will evaluate the impact of 
the underlying medical reason, for cold or allergy antihistamines 
medications, taken on an as needed (ex. PRN use) frequency. 
 

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CONFIDENTIAL 
*Note: These medications may signal that an exclusionary diagnosis is present. 
The medical monitor should be consulted before instructing a subject to 
discontinue any of these medication for this study. 
 
• 
Melatonin, up to a maximum of 10 mg per day, is allowed if subjects 
have taken the medication for more than 30 days prior to screening and 
are on a stable dose for the entire duration of the study. Otherwise, 
melatonin is prohibited from 5 days prior to Baseline (Visit 2) and through 
the end of the study (Visit 9) or early termination visit.  
 
Medications allowed during the study include the following:  
 
Nasal steroids, melatonin (if stable for 30 days prior to screening), thyroid 
medication (if stable for at least 90 days prior to screening), bronchodilators (if 
stable for at least 30 days prior to screening), hormonal contraceptives for 
females (if stable for 30 days prior to screening), acetaminophen, nonsteroidal 
anti-inflammatory 
medications, 
non-sedating 
antihistamines 
(cetirizine, 
loratadine, fexofenadine, etc.), mometasone, approved course(s) of prescription 
and nonprescription medications for the treatment of acute illnesses. Any other 
medication not specified in this protocol, but is considered necessary for the 
subject’s welfare, may be allowed if it is jointly approved by the Investigator, 
Sponsor, and Medical Monitor.  
 
Subjects are allowed to continue cognitive and/or behavioral therapy if they 
have been receiving therapy for at least 90 days prior to screening. 
 
Investigative site should attempt to obtain medical records for each subject. 
Criteria for 
Pharmacokinetics 
Evaluation 
The pharmacokinetic samples collected will be used to model and simulate the 
following pharmacokinetic parameters:  
 
Maximum Concentration (Cmax), Time of Maximum Concentration (Tmax), 
terminal elimination constant (K), lag time (Tlag), Half Life (T1/2), Area Under the 
Curve from time 0 to 28 hrs (AUClast), Area Under the Curve from time 0 to 
infinity (AUC0-¥), and partial areas AUC0-3, AUC3-6, AUC3-7, AUC6-9, AUC7-12, 
AUC9-12, and AUC12-16. Additional measures may be evaluated if deemed 
necessary. 
Statistical Methods  
Analysis 
Populations 
Intent-To-Treat (ITT) Population: Subjects who are randomized. 
 
Safety (SAF) Population: Subjects who have received at least one dose of 
study drug. 
 

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Modified ITT (mITT) Population: Subjects in the ITT population and have at 
least one post-baseline ADHD-RS-5 assessment. 
 
Per Protocol (PP) Population: Subjects in the ITT population who have 
completed Baseline and Visit 8 efficacy assessments, demonstrate at least 
80% medication compliance, and have no major protocol deviations that 
interfere with the primary efficacy analysis. The PP Population will be 
determined in a blinded manner prior to database lock. 
Study Endpoints 
Primary efficacy endpoint: change of the ADHD-RS-5 Total Score from 
Baseline (Visit 2) to Week 5 (Visit 8) 
 
Key secondary efficacy endpoint: change of the CGI-S Score from Baseline 
(Visit 2) to Week 5 (Visit 8) 
 
Safety endpoints: the occurrence of TEAEs, systolic and diastolic blood 
pressure, pulse, and weight, height, BMI, ECG, and C-SSRS 
 
PK 
endpoints: 
Maximum Concentration 
(Cmax), 
Time 
of Maximum 
Concentration (Tmax), terminal elimination constant (K), lag time (Tlag), Half Life 
(T1/2), Area Under the Curve from time 0 to 28 hrs (AUClast), Area Under the 
Curve from time 0 to infinity (AUC0-¥), and partial areas AUC0-3, AUC3-6, AUC3-
7, AUC6-9, AUC7-12, AUC9-12, and AUC12-16. Additional measures may be 
evaluated if deemed necessary. 
Efficacy Analyses 
The hypotheses of the primary efficacy analysis will be the following: 
 
• 
Null hypothesis: There is no difference in the mean change of ADHD-
RS-5 total scores from Baseline (Visit 2) to Week 5 (Visit 8) between 
CTx-1301 fixed doses (18.75, 25.0, 37.5 mg) and placebo. 
 
• 
Alternative hypothesis: There is a difference in the mean change of 
ADHD-RS-5 total scores from Baseline (Visit 2) to Week 5 (Visit 8) 
between any CTx-1301 fixed dose (18.75, 25.0, or 37.5 mg) and 
placebo. 
 
The primary efficacy analysis will be conducted in the ITT population using 
mixed-effects model for repeated measures (MMRM) with treatment group, 
visit, age group and the interaction of treatment group with visit as factors and 
Baseline ADHD-RS-5 Total Score as a covariate. Missing data will be imputed 
using multiple imputation. Sensitivity analysis will be conducted in the mITT 
and PP population if appropriate. 
 
The key secondary efficacy endpoint, CGI-S will be analyzed similarly as the 
primary efficacy endpoint using the same analysis method (MMRM). The 
Baseline CGI-S score will be used as the covariate. Missing data will be 

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CONFIDENTIAL 
imputed using multiple imputation. Sensitivity analysis will be conducted in the 
mITT and PP population if appropriate.  
To protect the study-wide Type I error at the 2-sided 0.05 level for testing 
across multiple dosage groups on the primary endpoint (ADHD-RS-5 Total 
Score), Bonferroni correction is applied so that the hypothesis in each dose 
group is tested at alpha = 0.017. The subsequent key secondary endpoint 
(CGI-S) in each dose group will be analyzed following a hierarchical testing 
procedure. If the hypothesis is significant for the primary endpoint at the 2-
sided 0.017 significance level, the key secondary endpoint will be analyzed. 
Both tests in the sequence are based on the MMRM.  
Safety 
Safety data will be summarized by treatment group and age group in the Safety 
population . Exposure to investigational product will be summarized.  
 
Adverse events will be coded using MedDRA. The number and percent of 
subjects with Treatment emergent AEs will be calculated for each system 
organ class, by preferred term, treatment group and age group. The severity 
of the TEAEs, the relationship to the investigational product, TEAEs causing 
study discontinuation, and serious AEs will also be summarized. 
 
Vital signs (systolic and diastolic blood pressure, and pulse), weight  (z-scores), 
height, BMI, ECGs, clinical laboratory measurements, and C-SSRS results will 
be summarized by treatment and visit.  
Pharmacokinetics 
Pharmacokinetic parameters will be summarized descriptively by time 
collected, treatment group, and age groups as appropriate.  

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ABBREVIATIONS 
 
ADHD 
  
Attention Deficit Hyperactivity Disorder 
ADHD-RS-5   
ADHD Rating Scale Version 5 
ADME 
  
Absorption, Distribution, Metabolism and Excretion 
AE 
  
Adverse Event 
ALT 
  
Alanine Aminotransferase 
ANCOVA 
  
Analysis of Covariance  
AST 
  
Aspartate Aminotransferase 
AUC 
  
Area Under the Curve 
AV 
  
Assessment Visit 
BMI 
  
Body Mass Index 
bpm 
  
Beats Per minute 
CGI-I 
 
 Clinical Global Impressions-Improvement 
CGI-S 
 
 Clinical Global Impressions-Severity 
CNS  
 
 Central Nervous System 
CRF 
  
Case Report Form 
CRO 
 
 Clinical Research Organization 
CSR 
 
 Clinical Study Report 
CS 
 
 Clinically Significant 
C-SSRS 
 
 Columbia Suicide Severity Rating Scale 
CTx 
 
 Cingulate Therapeutics 
CTMS  
 
 Clinical Trial Management system 
cm 
 
 Centimeters 
d-MPH 
 
 Dexmethylphenidate 
DA  
 
 Dopamine 
DO 
 
 Dose Optimization 
DMDD  
 
 Disruptive Mood Dysregulation Disorder 
DSM-5 
 
 Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
FSFV 
  
First Subject First Visit 
ECG 
 
 Electrocardiogram 
eCRF 
 
 Electronic Case Report Form 
EDC 
 
 Electronic Data Capture 
ENT  
 
 Ears, Nose, Throat 
EOS 
  
End of Study 
ET 
  
Early Termination 
FDA 
  
Food and Drug Administration 

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GCP 
  
Good Clinical Practice 
GGT 
  
Gamma-Glutamyl transpeptidase 
GI 
  
Gastrointestinal 
Hb  
 
 Hemoglobin 
Hct  
 
 Hematocrit 
hCG 
 
 Human Chorionic Gonadotropin 
hr  
 
 Hour(s) 
HR 
 
 Heart Rate 
ICH  
  
International Conference on Harmonization 
IEC 
  
Independent Ethics Committee 
IP 
  
Investigational Product 
IR 
  
Immediate Release 
IRB 
  
Institutional Review Board 
IRT 
  
Interactive Response Technology 
ITT 
  
Intent-To-Treat 
 
 
 
kg 
  
Kilograms 
L 
  
Liter 
LLN 
  
Lower Limit of Normal 
LSLV 
  
Last Subject Last Visit 
m 
  
Meter 
MAOIs 
  
Monoamine Oxidase Inhibitors 
MAS  
  
Mixed Amphetamine Salts 
MCH 
  
Mean Cell Hemoglobin 
MCHC 
  
Mean Corpuscular Hemoglobin Concentration 
MCV 
  
Mean Cell Volume 
MedDRA 
  
Medical Dictionary for Regulatory Activities 
mg 
  
Milligram(s) 
min 
  
Minute 
mL 
 
 Milliliter(s) 
MMRM 
  
Mixed-Effect Model Repeated Measure 
mmHg 
  
Millimeters of Mercury 
MPH 
  
Methylphenidate 
MPV 
  
Mean Platelet Volume 
ms 
  
Millisecond 
mSv 
  
Millisieverts 
NCS  
 
 Not Clinically Significant 
NMS  
 
 Neuroleptic Malignant Syndrome 

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NE  
 
 Norepinephrine 
POC 
 
 Proof of Concept 
PP 
 
 Per Protocol 
PK 
 
 Pharmacokinetic 
RBC 
  
Red Blood Cell 
R 
  
Randomized Period 
RS 
  
Randomized Safety 
S 
  
Safety Period 
SAE 
  
Serious Adverse Event 
SAP 
  
Statistical Analysis Plan 
SAR 
  
Serious Adverse Reaction 
SOC 
  
System Organ Class 
SOP 
  
Standard Operating Procedure 
SSRIs  
  
Selective Serotonin Reuptake Inhibitors 
SUSAR 
 
 Suspected Unexpected Serious Adverse Reaction 
TMF  
 
 Trial Master File 
TSH 
  
Thyroid Stimulating Hormone 
ULN  
  
Upper Limit of Normal 
URTI 
  
Upper Respiratory Tract Infection 
WBC 
  
White Blood Cell 
 
WHO 
  
World Health Organization 
WHO-DD 
  
World Health Organization Drug Dictionary 
 

 
 
 
 
 
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CONFIDENTIAL 
 
Table 1 Schedule of Assessments 
 
Procedure / 
Assessments 
 
 
Screening/ 
Washout 
Washout Phone 
Call 
 
Baseline 
 
Day 1 
Week 1 
( 3 days) 
Week 2 
( 3 days) 
Week 3 
( 3 days) 
Week 4 
( 3 days) 
Week 5e 
( 3 days) 
Week 6  
Phone Call 
( 5 days) 
Study Day 
-30 to -1 Days 
Day -5  
0 
1 
7 ( 3 days) 
14 ( 3 days) 
21 ( 3 days) 
28 ( 3 days) 
35 ( 3 days) 
42 ( 5 days) 
Visit Number 
1 
N/A 
2 
3 
4 
5 
6 
7 
8 
9 
Parental 
Permission/ 
Written Assent 
✓ 
 
 
 
 
 
 
 
 
 
ADHD Diagnosis 
and Confirmation 
✓a 
 
✓a 
 
 
 
 
 
 
 
Tablet Swallowing 
Test 
✓ 
 
 
 
 
 
 
 
 
 
Inclusion & 
Exclusion Criteria 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
Demographics 
✓ 
 
 
 
 
 
 
 
 
 
Medical History 
✓ 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
✓ 
 
✓ 
 
 
 
 
 
✓ 
 
Body Weight, 
Height, BMIb 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
12-Lead ECG 
✓c 
 
✓c 
 
 
 
 
 
✓ 
 
Vital Signs 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Chemistry, 
Hematology,  
Urinalysis 
✓ 
 
 
 
 
 
 
 
✓ 
 
Serology 
✓ 
 
 
 
 
 
 
 
 
 
PK Blood 
Sampling 
 
 
 
✓ 
 
 
 
 
✓ 
 
Serum hCGf 
✓ 
 
 
 
 
 
 
 
✓ 
 
Urine hCGfg 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓  
 
TSH 
✓ 
 
 
 
 
 
 
 
 
 
Urine Screen for 
Methylphenidate 
✓ 
 
✓ 
 
 
 
 
 
 
 

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Procedure / 
Assessments 
 
 
Screening/ 
Washout 
Washout Phone 
Call 
 
Baseline 
 
Day 1 
Week 1 
( 3 days) 
Week 2 
( 3 days) 
Week 3 
( 3 days) 
Week 4 
( 3 days) 
Week 5e 
( 3 days) 
Week 6  
Phone Call 
( 5 days) 
Study Day 
-30 to -1 Days 
Day -5  
0 
1 
7 ( 3 days) 
14 ( 3 days) 
21 ( 3 days) 
28 ( 3 days) 
35 ( 3 days) 
43 ( 5 days) 
Visit Number 
1 
N/A 
2 
3 
4 
5 
6 
7 
8 
9 
Urine Screen for 
Drugs of Abuse  
✓ 
 
✓ 
 
 
 
 
 
✓ 
 
C-SSRS 
Screeningh 
✓ 
 
 
 
 
 
 
 
 
 
C-SSRSh           
(Since Last Visit) 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
MINI-KID 
✓ 
 
 
 
 
 
 
 
 
 
ADHD-RS-5a 
✓a 
 
✓a 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
CGI-Sa 
✓a 
 
✓a 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
CGI-I 
 
 
 
 
 
 
 
 
✓ 
 
Prior Medication 
Questionnaire 
 
 
✓ 
 
 
 
 
 
 
 
AE Assessmentd 
✓ 
✓  
✓  
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Randomization 
 
 
✓ 
 
 
 
 
 
 
 
Dispense Double-
Blind Study Drug 
Administration 
 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
 
Drug 
Accountability & 
Compliance 
Assessment 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Collect/Distribute 
Dosing Diary 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Concomitant 
Medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Study 
Completion/Medic
al Sign-Off 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 

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a. Subjects must meet inclusion criteria prior to randomization at Baseline/Visit 2. The Eligibility/Baseline ADHD-RS-5, and CGI-S must be assessed after appropriate washout from ADHD medications 
(stimulants and non-stimulants). If able to complete at Screening Visit, these assessments do not need to be repeated at Visit 2. If unable to complete at Screening Visit due to washout requirement, this may be 
taken at Visit 2.   
b. Height and weight will be measured without shoes and with light clothing using a calibrated stadiometer and scale.   
c. The Eligibility/Baseline ECG must be assessed after appropriate washout from ADHD medications (stimulants and non-stimulants). If able to complete at Screening Visit, these assessments do not need to be 
repeated at Visit 2. If unable to complete at Screening Visit due to washout requirement, this may be taken at Visit 2.   
d. AEs will be assessed throughout the study; AEs will be collected from time the informed consent is signed until end of the study. Any AEs occurring between visits should be attributed to the next study visit 
(or unscheduled visit) but the dates of the AE must be recorded as occurred. AEs occurring during the washout may be reported via phone or at the following visit. 
e.  Early Termination Visits should follow the Visit 8/Week 5 visit study assessment schedule.  
f.  Females of childbearing potential. 
g. A positive urine hCG test will be confirmed with a serum hCG. A positive pregnancy test before the last dose of study drug will exclude a subject from further participation in the study.  
h. Columbia Suicide Severity Rating Scale (C-SSRS): The “Baseline” version will be assessed at Screening and “Since Last Visit’ at Visits 2-9 and at Early Termination. Subjects who have, in the opinion of the 
Investigator, clinically significant suicidal ideation/behavior, based on history of attempted suicide and the C-SSRS assessment at Screening or at any time before the last dose of study drug, will be excluded 
from further participation in the study.  
 

 
 
 
 
 
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1 
PRODUCT BACKGROUND INFORMATION 
 
Methylphenidate (d,l-MPH) products have been an important treatment for ADHD for more 
than 70 years. The primary pharmacological effect of d,l-MPH is to increase the level of 
dopamine (DA) and norepinephrine (NE) in the extraneuronal space by binding to DA and NE 
transporters (DAT and NET, respectively) on presynaptic nerve terminals and inhibiting the 
reuptake of these neurotransmitters.10,26 
 
Clinically used MPH formulations contained a racemic (1:1) mixture of d-threo-(R,R)-MPH and 
l-threo-(R,R)-MPH 
isomers 
until 
the 
enantiopure 
d-MPH 
(d-threo-(R,R)-MPH, 
dexmethylphenidate,) was introduced in 2002.7 The development of enantiopure d-MPH was 
based on the findings that similar improvement on sustained attention was achieved after 
treatment with d-equivalent doses of d-MPH and d,l-MPH, but not after l-MPH.8 Clinical 
efficacy was highly correlated with plasma concentrations of d-MPH. The elimination of the l-
isomer does not diminish the efficacy of an acute dose of methylphenidate.9 The efficacy of 
the d-isomer was equivalent to the racemic preparation in ameliorating the target symptoms 
of ADHD and increasing academic productivity. Thus, it was thought that the efficacy of MPH 
resides in the d-isomer.8,10,11,12 
 
The short acting form of d-MPH was released to the market13 and demonstrated clinical 
efficacy lasting slightly over 5 hours in open-label studies.14 Long-acting forms were released 
to the market and demonstrated clinical efficacy lasting up to 12 hours; however, a major 
drawback to most long-acting stimulant products currently on the market is that they do not 
remain therapeutically effective more than 12 hours after administration. For many patients 
this duration in coverage is not sufficiently long. Furthermore, as blood levels drop 
precipitously during the latter portions of the day, patients also may experience a crash or 
rebound effect, which often manifests in adverse effects such as irritability, mood changes, 
and worsening of clinical presentations.25 
 
To alleviate the need for a mid-day dose (thereby eliminating problems related to dispensing 
the medication at school), a long-acting formulation of d-MPH (CTx-1301) was developed that 
could be administered once a day.14  
 
CTx-1301 is a trimodal, extended-release tablet which provides an efficient use of d-MPH over 
the course of the day. The first release (35% of dose) consists of an immediate release (IR) 
within 30 minutes, the second release (45% of dose) is a sustained-release at approximately 
3-4 hours (releasing over 60 – 90 minutes), and the third and final release (20% of dose) is an 
immediate release around 7-8 hours. 
 
 
 
1.1 
INDICATION AND CURRENT TREATMENT OPTIONS 
 
Attention-Deficit/Hyperactivity Disorder (ADHD) is the most prevalent psychiatric condition in 
children. It affects approximately 5-10% of school-aged children.1,2,3 The hallmark set of 
symptoms of ADHD include inattention, hyperactivity, and impulsivity. Although ADHD was at 

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CONFIDENTIAL 
one time considered a childhood illness that resolved in adolescence, it is estimated that up 
to 50% of children’s symptoms persist into adolescence and beyond.4  
 
Stimulants have been considered the mainstay of pharmacological treatment of ADHD for over 
seventy years. Their effect on disruptive behavior was discovered in 1937, when these drugs 
proved to increase compliance, improve academic performance, and reduce motor activity in 
hyperactive children.5 Methylphenidate (MPH) is the most frequently prescribed among 
stimulant agents. It has proven efficacy on ADHD symptoms.6,7 In addition to methylphenidate 
products, amphetamine products such as mixed amphetamine salts (MAS) and isolated 
dextroamphetamine are also commonly used to treat ADHD.27 Finally, non-stimulant 
medications are also used to manage ADHD symptoms. Non-stimulant medications such as 
atomoxetine, clonidine, and guanfacine may be useful in patients who cannot tolerate 
stimulants or who may benefit from a combination of stimulant and non-stimulant combination 
therapy.28 
 
Refer to the latest version of the CTx-1301 Investigational Brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy, and safety. 
 
1.2 
OVERVIEW OF CLINICAL STUDIES WITH CTX-1301 
 
As part of the initial development of CTx-1301, the Sponsor conducted a proof of concept 
(POC) study in Scotland. The POC study was a randomized, three-arm, open-label crossover 
PK study in 15 healthy volunteers with a preliminary formulation. The primary objectives were 
to confirm the time and site of radiolabel release of the second and third doses of CTx-1301 
and to provide PK data on blood plasma levels of d-MPH. Secondary objectives of this study 
were to compare the PK profiles of the LD, Focalin XR®, to CTx-1301, and to determine the 
gastrointestinal transit parameters of CTx-1301. Each subject received one dose of 10 mg 
Focalin XR®, (Treatment A) and two doses of 12.5 mg CTx-1301, one with a radiolabeled 
second dosage layer (Treatment B) and one with a radiolabeled core dosage layer (Treatment 
C). 
 
 
 
 
The sponsor also conducted CTx-1301-001, the pivotal comparative BA study, which 
demonstrated bridging to the LD (Focalin XR®,) and allows reliance on the previous findings 
of the LD for safety. The comparative BA study evaluated the lowest dose of Focalin XR®, (5 
mg) to the lowest dose of CTx-1301 (6.25 mg) and the highest dose of Focalin XR®, (40 mg) 
to the highest dose of CTx-1301 (50.0 mg). This study was completed with 39 ADHD patients 
and each patient received 4 doses. The primary objectives of this study were to compare the 
bioavailability of the listed drug, Focalin XR®, to CTx-1301 in a fasted state as well as to 
evaluate dose proportionality of CTx-1301. Secondary objectives were to characterize the PK 
of d-MPH blood plasma levels after dosing as well as to evaluate safety. 
 
 
 
 
 
 

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2 
STUDY PURPOSE AND OBJECTIVES  
 
2.1 
STUDY DESIGN SCHEMATIC  
 
 
 
2.2 
STUDY PURPOSE 
 
The purpose of this study is to evaluate the efficacy and safety of a fixed dose of CTx-1301 
for treatment of ADHD in a pediatric population including children ages 6-17 years. Results 
from prior studies of CTx-1301 demonstrate that it is well tolerated. This study will provide 
additional data regarding the safety and efficacy of three fixed doses over 5 weeks.  
 
2.3 
PRIMARY OBJECTIVE 
 
• 
To evaluate the efficacy of three fixed doses of CTx-1301 compared to placebo in 
treating pediatric patients with ADHD utilizing the ADHD-RS-5. 
 
2.4 
SECONDARY OBJECTIVE(S) 
 
• 
To evaluate the efficacy of a fixed dose of CTx-1301 compared to placebo in treating 
pediatric patients with ADHD utilizing the CGI-S. 
• 
To determine safety and tolerability of a fixed dose of CTx-1301 compared to placebo  
• 
To evaluate the PK levels of dexmethylphenidate after a single dose 
• 
To evaluate the PK levels of dexmethylphenidate at steady state 
• 
To evaluate the PK/PD correlation of dexmethylphenidate at steady state 
• 
To evaluate the CGI-I score at the end of treatment 
 
 
 

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3 
INVESTIGATIONAL PLAN AND DESIGN 
3.1 
STUDY DESIGN 
 
The study design is a double-blind, randomized, placebo-controlled, fixed-dose, parallel-group 
efficacy, and safety study with CTx-1301 in children (6-17) with ADHD confirmed by an ADHD-
RS-5 score of at least 28 at baseline. The study will be comprised of a 30-day screening 
period, a 5-week randomized period, and a 1-week safety follow-up period.  
 
The Study will be comprised of 3 periods:  
• 
Screening Period (Day -30 to Day -1): Subjects will undergo a Screening Visit (Visit 1) 
up to 30 days prior to entering the 5-week randomization period. Only subjects that meet 
inclusion and no exclusion criteria at screening may be considered for enrollment in the 
randomized portion of the study. 
 
• 
Double-Blind Randomized Period (Day 0 - Day 35 ± 3 days): During the 5-week 
randomized period (Visits 2-8), subjects will have weekly visits to assess safety and 
efficacy. Eligible subjects will be randomized at Visit 2. Subjects randomized to active 
will have a starting dose of 12.5 mg and will be titrated up (increased) to their assigned 
fixed dose of CTx-1301 (18.75, 25, or 37.5 mg); subjects randomized to placebo will 
receive placebo throughout the entire randomized period. Each subject is required to be 
on their assigned fixed dose a minimum of 2 sequential weeks prior to the final efficacy 
assessment at Visit 8 (Week 5).  
 
• 
Safety Follow-Up Phone Call (Days 36 - Day 42 ± 5 days): Subjects will washout after 
the efficacy assessment at Visit 8 and have a follow-up phone call (Visit 9) to ensure 
safety of subjects.  
 
3.2 
RATIONALE FOR STUDY DESIGN 
 
The purpose of this study is to evaluate the safety and efficacy of a fixed dose of CTx-1301 in 
a pediatric population (6-17) in randomized, double-blind, fixed-dose study using the ADHD-
RS-5.  
 
Dose selection was chosen to obtain safety and efficacy data across the range of doses (low, 
medium, and highest proposed dose for the age groups). Given traditional dosing regimens 
for dexmethylphenidate, the randomized active doses selected (18.75 mg, 25 mg, and 37.5 
mg) will be the best range for the treatment groups (with a lead-in dose of 12.5 mg for active 
arms). Equivalent doses are being used in clinical practice to treat children and adolescents. 
 
The lead-in dose of 12.5 mg for active arms is considered safe and tolerable in the selected 
patient population due its release profile 
 
 
 
 
 
 

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4 
STUDY POPULATION 
 
4.1 
SOURCE AND NUMBER OF SUBJECTS 
 
The study site will recruit potential subjects from its database and via local advertising and 
school and medical referrals if required.  
 
Assuming a dropout rate of 20%, 385 subjects will be required to enter the randomized period 
of the study to achieve the target of approximately 308 subjects (154 in each subgroup) to 
complete the study (approximately 77 per treatment arm in each subgroup). 
 
4.2 
CRITERIA FOR EVALUATION 
 
Eligibility of subjects for study enrollment will be based on the results of a Screening medical 
history, tablet swallowing test, physical examination, mental state examinations, vital signs 
(blood pressure and pulse), the inclusion/exclusion criteria as described below, and clinical 
laboratory tests. Screening tests will be performed and assessed by qualified study staff. The 
nature of any conditions present at the time of the physical and mental state examinations at 
screening and any pre-existing conditions will be documented as medical history. 
 
4.3 
INCLUSION CRITERIA  
 
1. 
Male or female subjects between 6 and 17 years of age (inclusive) at the time of 
Randomization (Visit 2). Subjects who are expected to turn 18 years of age during the 
trial will not be allowed. 
2. 
Subject must have a body weight between the 5th and 95th percentile (≥5th percentile and 
≤95th percentile) for their respective age and sex. 
3. 
Subject is unsatisfied with his/her current pharmacological therapy for treatment of 
ADHD or not currently receiving pharmacological therapy for ADHD. Inclusion of subjects 
who are naïve to pharmacological therapy for ADHD is permitted. 
4. 
Subjects of child-bearing potential at screening or that become of child-bearing potential 
during the study must agree to remain abstinent or agree to use a highly effective, 
medically acceptable form of birth control for the time of written assent and for at least 
30 days after the last dose of study drug has been taken (females). Male subjects with 
female partners must agree at Screening to remain abstinent or agree to use an effective 
and medically acceptable form of birth control from Screening to 90 days after the last 
dose of study drug. Child-bearing potential is defined as any female who has had their 
first period or is 12 years or older (or will be 12 while in the study). 
5. 
Subject must be in general good health defined as absence of any clinically relevant 
abnormalities as determined by the Investigator based on physical and neurological 
examinations, vital signs, ECGs (QTc less than or equal to 460 milliseconds), medical 
history, and laboratory values (hematology, chemistry, serology, TSH, or urinalysis) at 
Screening. If any of the exams or values are not within the laboratory reference range, 
the Investigator must review range and determine if clinically relevant. If clinically 
relevant, the subject is not eligible for the study.  

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CONFIDENTIAL 
6. 
Subject’s intellectual function is at an age-appropriate level, as deemed by the 
Investigator. 
7. 
Subject must meet Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
(DSM-5) criteria for the primary diagnosis of ADHD or any of the three presentations 
(combined, inattentive, or hyperactive/impulsive presentation) upon clinical evaluation 
and confirmed by the MINI International Neuropsychiatric Interview of Children and 
Adolescents (MINI-KID). The MINI should also be used to evaluate any other psychotic 
disorders. 
8. 
Subject must score 28 or higher on the ADHD-RS-5 scale at the Baseline visit (Visit 2).  
9. 
Subject must have a score of 4 (moderately ill) or higher on the clinician-administrated 
Clinical Global Impressions-Severity (CGI-S) scale at Baseline (Visit 2).  
10. Subject must be able and willing to wash out of stimulant ADHD medications (except 
study drug as indicated per protocol), including herbal medication, from 5 days prior to 
the start of the randomized phase (Visit 2) and for the duration of the entire study, defined 
as completion of the safety follow-up visit (approximately 1.25 months, excluding 
screening). Additionally, subject must be able and willing to wash out from non-stimulant 
ADHD medications 21 days prior to the start of the randomized phase (Visit 2) and for 
the duration of the entire study (approximately 1.25 months, excluding screening), 
defined as completion of the safety follow-up visit. 
11. Subject and parent/legal guardian, and/or caregiver (if applicable) must be able to read, 
write, speak, and understand English and be able to communicate with the Investigator 
and study coordinator in a satisfactory fashion and complete any study-related materials. 
Subject and parent/legal guardian, and/or caregiver (if applicable) must plan to be 
available for the entire duration of the study.  
12. One or more of the parents/legal guardians/caregivers of the subject must voluntarily 
give written permission for him/her to participate in the study. 
13. Subject must provide written assent prior to study participation.  
14. Subject, subject’s parent/legal guardian, and/or caregiver (if applicable) must understand 
and be willing and able to comply with study procedures as well as the visit schedule. If 
the subject is cared for by a caregiver for relevant portions of the day, the caregiver may 
be more suitable for certain assessments, and the caregiver will need to agree to the 
applicable procedures and visits.  
15. Subject must be able to swallow the CTx-1301 tablet as evidenced by ability to swallow 
a similar size tablet (placebo) at screening.  
 
4.4 
EXCLUSION CRITERIA 
 
1. 
If female and of child-bearing potential, the subject must not be pregnant or 
breastfeeding at any time during the study or for 30 days following the completion of the 
study, defined as completion of safety visit at the end of study (Visit 9). If of child-bearing 
potential, urine hCG tests will be administered at protocol-specified time points. Any 
positive pregnancy test during the study will exclude them from further participation in 
the study. 
2. 
Subject has any psychiatric diagnosis of bipolar I or II disorder, major depressive 
disorder, conduct disorder, disruptive mood dysregulation disorder (DMDD), intellectual 
disability, obsessive-compulsive disorder, eating disorder, anxiety disorder (including 
generalized anxiety disorder), any history of psychosis, autism spectrum disorder, a 

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history of motor or vocal tics or Tourette’s Syndrome, confirmed genetic disorder with 
cognitive and/or behavioral disturbances, or any other diagnosis/significant medical 
history that at the discretion of the Investigator excludes the subject from entry into the 
study. 
3. 
Subject has evidence of any chronic disease of the central nervous system (CNS) such 
as tumors, inflammation, seizure disorder, vascular disorder, potential CNS-related 
disorders that might occur in childhood, or history of persistent neurological symptoms 
related to a serious head injury. 
4. 
Subject has any clinically significant and/or unstable/uncontrolled medical abnormality 
or chronic medical condition, persistent neurological symptoms, history of cardiovascular 
abnormality, abnormalities of respiratory, hepatic, gastrointestinal, renal, or any disorder 
or history of a condition that would impact or interfere with drug absorption, distribution, 
metabolism, or excretion during the study or may interfere with the participants ability to 
participate in the study. 
5. 
Subject has family history of early cardiovascular disease or sudden death. 
6. 
Subject has any history of attempted suicide or clinically significant suicidal ideation 
based on the Columbia Suicide Severity Rating Scale (C-SSRS) assessment, or 
answers “yes” to “Suicidal Ideation” item 4 or 5 of any lifetime history on the C-SSRS 
Children’s Lifetime/Recent assessment at screening. 
7. 
Subject has history of seizures, excluding febrile seizures.  
8. 
Subject has a known primary sleep disorder (e.g., sleep apnea, narcolepsy, etc.) 
9. 
If the subject’s blood pressure is < 90th percentile for their age, sex, and height, the single 
read is sufficient. If the subject’s blood pressure is ≥ 90th percentile, two additional reads 
will be taken, and the three reads will be averaged. If the average of the three readings 
is ≥ 95th percentile at screening they will be excluded. 
10. Subject is considered treatment refractory by the Investigator or is intolerant to stimulant 
ADHD mediation. 
11. Any use of anticonvulsants currently or within the past 2 years. 
12. Uncontrolled thyroid disorder indicated by thyroid stimulating hormone (TSH) ≤0.8 x the 
lower limit of normal (LLN) or ≥ 1.25 x the upper limit of normal (ULN) from the reference 
laboratory.  
13. Subject has first-degree relatives (biological parent or sibling) with a history of 
schizophrenia, schizoaffective disorder, bipolar I disorder, or bipolar II disorder. 
14. Subject has history of substance abuse or shows evidence of substance use or has a 
positive urine drug screen at Screening or Baseline. Subjects with positive drug screens 
may be allowed to continue in the study if the result of the positive drug screen is from 
prescribed medications and the subject is willing to washout of the medication as 
required per protocol. 
15. Previous treatment experience/exposure to CTx-1301. 
16. Subject has a history of allergic reaction or sensitivity to methylphenidate, 
dexmethylphenidate, or any other substance contained in CTx-1301 or the placebo drug. 
17. Subject has participated in any other clinical study with an investigational drug/product 
within 30 days prior to Screening or is currently participating in another clinical study. 
18. Subject’s family anticipates a move outside the geographic range of the investigative site 
during the duration of the study period or plans on travel that would not allow compliance 
to the protocol during the study period. 

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19. Subject is unsuitable in any other way, to participate in the study, as determined by the 
Investigator. 
20. Subject is a family member of an employee at the study center, of the investigator, or 
those with direct involvement in the proposed study under the direction of that 
investigator or study center. 
 
4.5 
SUBJECT WITHDRAWAL CRITERIA 
 
Subjects have the right to withdraw from the study at any time for any reason. The Investigator 
also has the right to withdraw subjects from the study in the event of intercurrent illness, 
adverse events (AEs) or treatment failure after a prescribed procedure, protocol deviations, 
administrative, or other reasons. It is understood by those concerned that an excessive rate 
of withdrawals can render the study data uninterpretable; therefore, unnecessary withdrawal 
of subjects should be avoided.  
 
Should a subject decide to withdraw, efforts should be made to complete and report the 
observations as thoroughly as possible. Regardless of the reason for withdrawal, a complete 
final evaluation should be attempted at the time of withdrawal including an explanation of why 
the subject is withdrawing from the study. The early termination visit should follow the Visit 8 
schedule of events along with a final ECG.  
 
The primary reason for removal or withdrawal of a subject from the study must be recorded 
on the electronic case report form (eCRF). If the reason for removal of a subject from the study 
is an AE or an abnormal laboratory test result, the principal specific event or test should also 
be recorded on the eCRF. Any AEs ongoing at the final visit will be followed up until resolved, 
the condition stabilizes, is otherwise explained, or the subject is lost to follow-up. 
 
4.6 
SUBJECT REPLACEMENT 
 
Subjects may be rescreened once for participation if the screen fail reason is resolved and is 
not related to non-qualifying ADHD-RS-5 or CGI-S score at Baseline Visit (Visit 2). Subjects 
who are rescreened will receive a new Subject ID; however, their original Subject ID and 
screen fail reason must be documented. Subjects are allowed to be rescreened a maximum 
of 1 time. Any subject who received any dose of study drug and/or are terminated early, 
withdraw early, or are not eligible to continue into the double-blind, randomization phase, are 
not allowed to be rescreened. Drop-outs will not be replaced. 
 
4.7 
TREATMENT AND SUBJECT RESTRICTIONS 
4.7.1 MEDICATIONS AND TREATMENTS 
 
Subjects meeting eligibility requirements and who are enrolled in the study will be subject to 
medication restrictions during the trial: 
 

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• 
ADHD stimulant medications (except for study drug), including herbal medications, are 
prohibited from 5 days prior to Visit 2 to the end of the study (Visit 9) or early termination 
visit. These include but are not limited to methylphenidate and amphetamine isomers and 
prodrugs.  
 
• 
ADHD non-stimulant medications are prohibited from 21 days prior to Visit 2 to the end 
of the study (Visit 9) or early termination visit. These include, but are not limited to, 
atomoxetine, guanfacine, clonidine, and SSRIs such as fluoxetine and paroxetine. 
 
• 
The following medications are prohibited from 21 days prior to Visit 2 to the end of the 
study (Visit 9) or early termination visit*: 
 
o 
Tricyclic antidepressants 
o 
Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., fluoxetine, paroxetine) 
o 
Monoamine oxidase inhibitors (MAOIs) 
o 
Benzodiazepines 
o 
Mood stabilizers (e.g., lithium, valproate, quetiapine) 
o 
Antipsychotics (e.g., risperidone, olanzapine) 
o 
Coumadin anticoagulants 
o 
Anticonvulsants 
o 
Halogenated anesthetics 
o 
Phenylbutazone 
o 
Any medication which would make subject excluded from study (see exclusion 
criteria) 
 
*Note: These medications may signal that an exclusionary diagnosis is present. The medical 
monitor should be consulted before instructing a subject to discontinue any of these 
medications for this study. 
 
• 
Sedative hypnotics / sedative antihistamines (e.g., hydroxyzime, Diphenhydramine (three 
brand names: Benadryl, Nytol, Sominex), sleep enhancers (except for melatonin) are 
prohibited from 14 days prior to Baseline (Visit 2) and through the end of the study (Visit 
9) or early termination visit* 
 
• 
The Investigator, and CRO Medical Monitor, will evaluate the impact of the underlying 
medical reason, for cold or allergy antihistamines medications, taken on an as needed 
(ex. PRN use) frequency. 
 
*Note: These medications may signal that an exclusionary diagnosis is present. The medical 
monitor should be consulted before instructing a subject to discontinue any of these 
medication for this study. 
 

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• 
Melatonin, up to 10 mg per day, is allowed if subjects have taken the medication for more 
than 30 days prior to screening and are on a stable dose. Otherwise, melatonin is 
prohibited from 5 days prior to Visit 2 to the end of the study (Visit 9) or early termination 
visit.  
 
4.7.2 ALLOWED TREATMENTS: 
 
Medications allowed during the course of the study include the following: nasal steroids, 
melatonin (if stable for 30 days prior to screening), thyroid medication (if stable for at least 90 
days prior to screening), bronchodilators (if stable for at least 30 days prior to screening), 
hormonal contraceptives for females (if stable for 30 days prior to screening), acetaminophen, 
nonsteroidal 
anti-inflammatory 
medications, 
non-sedating 
antihistamines 
(cetirizine, 
loratadine, fexofenadine, etc.), mometasone, approved course(s) of prescription and 
nonprescription medications for the treatment of acute illnesses. Any other medication not 
specified in this protocol, but is considered necessary for the subject’s welfare, may be allowed 
if it is jointly approved by the Investigator, Sponsor, and Medical Monitor.  
 
Subjects are allowed to continue cognitive and/or behavioral therapy if they have been 
receiving therapy for at least 30 days prior to screening. 
 
4.7.3 PROTOCOL DEVIATIONS 
 
Subjects, parent/legal guardians, and/or caregivers (if applicable) will be questioned on 
compliance with restrictions during Screening, prior to and during the double-blind, 
randomization phase, and the safety follow up. The Investigator will determine whether a 
deviation from the restrictions warrants the subject’s withdrawal from the study. Deviations 
should be documented in the appropriate database such as a Clinical Trial Management 
system (CTMS). 
 
Medications will be coded using World Health Organization Drug Dictionary (WHO-DD). 
Information on the format and version of the coding dictionary will be provided in the data 
management plan and the statistical analysis plan. 
 
5 
STUDY TREATMENTS: ASSIGNMENT & SUPPLY MANAGEMENT 
5.1 
STUDY TREATMENTS 
5.1.1 IDENTITY OF STUDY TREATMENTS  
 
The active investigational product is a trimodal, modified-release dexmethylphenidate (d-
MPH) tablet (CTx-1301). Each tablet will contain a specified dose of d-MPH in the following 
strengths: 
 
 

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• 
12.5 mg (titration only) 
• 
18.75 mg (randomized fixed dose) 
• 
25.0 mg (randomized fixed dose) 
• 
37.5 mg (randomized fixed dose) 
 
CTx-1301 is a trimodal, modified-release tablet, which provides d-MPH in 3 releases over the 
course of the day. The first release (35% of dose) consists of an immediate release (IR) with 
an onset of action within 30 minutes, the second release (45% of dose) is a sustained-release 
at approximately 3-4 hours (releasing over 60 – 90 minutes), and the third and final release 
(20% of dose) is an immediate release around 7-8 hours. 
 
 
 
5.1.2 SELECTION OF DOSES 
 
Subjects will be randomized to active or placebo drug by the IRT according to the subject 
randomization created by the unblinded statistician that was imported into the IRT. Those 
subjects that are assigned to active drug will be titrated to a randomly assigned fixed dose by 
the IRT; subjects’ starting dose on active drug will begin with 12.5 mg and will titrate up weekly 
to one of three possible fixed dose drug levels 18.75 mg, 25 mg, or 37.5 mg. Each subject is 
expected to stay on their assigned fixed dose for at least 2 sequential weeks prior to Week 5 
(Visit 8).  
 
Possible assigned fixed doses are: 18.75, 25.0, 37.5 mg of CTx-1301, or placebo.  
 
5.1.3 ADMINISTRATION 
 
Under supervision from the subject’s parent/legal guardian, and/or caregiver (if applicable), 
subject will self-administer the study drug daily on an outpatient basis for the full duration of 
the study, beginning on the day after Visit 2 and ending at Visit 8; between Visit 8 and Visit 9, 
a washout of study drug is required.  
 
• 
Study drug (1 tablet per day) should be taken orally, upon wakening, at approximately the 
same time each day, and prior to 8:00 am.  
 
• 
Study drug may be taken with or without food. For the purpose of this study, taken with 
food will be described as food taken within one hour of study drug administration. 
 
• 
Study drug will be given orally with approximately 240 mL (1 cup) of water.  
 
• 
The tablet is to be swallowed whole; no alteration of the tablet is allowed (crushing, 
chewing, dividing, etc.).  

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If a subject forgets to take a dose prior to 8:00 am, the subject should skip the dose and 
resume taking the medication the following day. Subject should not make up a missed dose 
by taking more than one tablet/day; medication is restricted to a single dose/tablet each day. 
 
5.1.4 DOSE SCHEDULE 
 
It is recommended that dosing takes place upon wakening, and no later than 8:00 am in the 
morning due to the extended efficacy of the investigational product. Subject should take dose 
for entire randomized efficacy assessment period (Visit 2 through Visit 8). 
 
5.1.5 DOSE MODIFICATION 
 
No alteration of the tablet is allowed (crushing, chewing, dividing, etc.) at any time during the 
study. Subjects will be randomized on Day 0 to active or placebo (placebo, CTx-1301 18.75 
mg, CTx-1301 25 mg, or CTx-1301 37.5 mg). Subjects randomized to the active dose will have 
a starting dose of 12.5 mg on Day 0. Each subject randomized to an active dose, will be titrated 
up to their randomly assigned fixed dose at weekly increasing dose intervals by the IRT until 
they reach their assigned fixed dose (example titration increase possibilities: 12 to 18.75 mg, 
or 12 to 18.75 to 25 mg, or 12 to 18.75 to 25 to 37.5 mg); subjects must be on their assigned 
fixed dose for a minimum of 2 sequential weeks prior to the primary efficacy assessment at 
Week 5/Visit 8. Subjects will be instructed to take their dose every morning at-home upon 
waking, no later than 8:00 am. 
 
5.1.6 TREATMENT COMPLIANCE 
 
Subjects must agree to take the study medication daily at-home as detailed per the protocol. 
Subjects and their parents/legal guardians, and/or caregivers (if applicable) will be instructed 
to complete at-home dosing diary entry with each dose and bring diary with them to each visit. 
 
Compliance with the study drug will be monitored and determined at each visit. Subjects and 
their parent/legal guardian, and/or caregiver (if applicable) will be instructed to bring unused 
study drug with them to each visit. Compliance will be assessed by counting tablets and 
dividing the actual number of doses taken (per tablet count) by the number of doses the subject 
should have taken within a visit period and multiplying by 100. Subjects who miss more than 
25% of scheduled doses or taken more than 125% of scheduled doses will be considered non-
compliant and will be reviewed and evaluated by the Investigator. Evidence of non-compliance 
must be immediately reported to the Sponsor or Sponsor’s designee (i.e., Medical Monitor). 
Noncompliance issues will be discussed with the subjects and their parent/legal guardian, 
and/or caregiver (if applicable) and at the Investigator’s discretion, may result in termination 
from the study. Subjects and their parent/legal guardian, and/or caregiver (if applicable) will 
be reminded of the importance of strict compliance with taking study drug for the effectiveness 
of treatment, safety of the patient, and successful outcomes of the study. 
 

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5.1.7 OVERDOSAGE 
 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol. For the purposes of this clinical trial, overdosage is defined as the 
administration of a supratherapeutic dose, a daily dose of the study drug which is larger than 
the highest dose used in the study, i.e., 37.5 mg. Notifications of subjects taking more than 
one tablet of study drug per day (irrespective of dose size) will be provided by each study site 
to the Sponsor or Sponsor’s representative before the end of the next business day after 
learning of the discrepancy. The Sponsor will review with the Medical Monitor and investigator 
to determine if subject can continue in the study. Overdose per se is not an AE; however, any 
clinical sequelae of an overdose should be reported as an AE (and an SAE, if appropriate). 
See Section 8.1.2 for reporting instructions.  
 
Known signs and symptoms after acute overdosage of d-MPH, resulting primarily from 
overstimulation of the central nervous system and from excessive sympathomimetic effects 
include: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be 
followed by a coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, 
headache, hyperpyrexia, tachycardia, palpitations, cardiac arrythmias, hypertension, 
mydriasis, and dryness of mucous membranes (Focalin XR® Package Insert 2019). 
 
5.1.8 RESCUE THERAPY 
 
No rescue therapy is applicable for this study. 
 
5.1.9 RISKS 
 
The perceived risks involved in this study relate to: 
 
Drug 
 
Inclusion/exclusion criteria have been included to minimize possible risks in relation to 
administration of CTx-1301 (d-MPH). 
 
The most common adverse reactions after taking d-MPH (Focalin XR®) capsules (at least 5% 
and twice the incidence among placebo-treated patients) are dry mouth, dyspepsia, headache, 
and anxiety for adult patients. Any adverse reactions to CTx-1301 are expected to be similar 
to those of Focalin XR®. 
 
Table 2 shows the treatment-emergent adverse events resulting from a placebo-controlled, 
double-blind-group study in pediatrics with ADHD at a flexible Focalin XR® dose of 5-30 mg 
per day. Only events that occurred in 5% or more of the patients treated with Focalin XR® were 
at least twice the incidence in placebo-treated patients. 
 
 
 

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Table 2 Treatment-Emergent Adverse Events Occurring during Double-Blind 
Treatment (Pediatrics) 
 
 
The following adverse reactions may also occur: 
 
Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia  
 
Gastrointestinal: abdominal pain, nausea  
 
Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative 
dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and 
thrombocytopenic purpura  
 
Metabolism/Nutrition: anorexia, weight loss during prolonged therapy  
 
Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette’s 
syndrome, toxic psychosis  
 
Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion  
 
Although a definite causal relationship has not been established, the following have been 
reported in patients taking methylphenidate:  
 
Blood/Lymphatic: leukopenia and/or anemia  
 
Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma  
 
Psychiatric: transient depressed mood, aggressive behavior, libido changes 
 
Skin/Subcutaneous: scalp hair loss  

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Urogenital: priapism 
 
Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most 
of these, patients were concurrently receiving therapies associated with NMS. 
 
Further information can be found in the Focalin XR® Extended-Release Package Insert. 
 
5.2 
STUDY TREATMENT ASSIGNMENT  
 
Subjects randomized to active treatment will have a starting dose of 12.5 mg; they will then be 
titrated up to their assigned fixed dose (18.75 mg, 25 mg, or 37.5 mg) by the IRT . An IRT 
system will be used to track each subject’s dose of drug during the titration phase as well as 
track that they are on their assigned fixed dose for the last 2 weeks of the randomized efficacy 
period.  
 
Treatment (active or placebo), given to individual subjects during the double-blind, 
randomized, efficacy period of the study, is determined by a randomization schedule; the 
randomization schedule will randomly assign eligible subjects to 1 of 4 treatment groups (A, 
B, C, or D) and be in an allocation ratio of 1:1:1:1 (active 18.75 mg: active 25 mg: active 37.5 
mg: placebo). The actual treatment assigned to each subject is executed by an IRT system 
utilizing the randomization schedule. Subjects will be stratified by age groups (6-12) and (13-
17). Investigational products (active and placebo) will appear identical to ensure blinding. 
 
5.2.1 ENROLLMENT PROCEDURE 
 
Subjects who meet inclusion and none of the exclusion criteria at Screening and at Baseline 
(Visit 2) may be enrolled into the double-blind, randomized study. Subjects will be randomized 
via IRT to active or placebo 1:1:1:1 stratified by each age group (6-12 and 13-17) at Visit 2. 
 
5.2.2 BLINDING PROCEDURE AND CODE BREAKS 
 
Study drug (CTx-1301 and placebo) is identical in color, shape, size, and packaging to 
maintain the blind. 
 
Subjects, Sponsor personnel, Investigator staff, and Sponsor representatives involved in the 
daily operations of the study will remain blinded to the identity of the treatment from time of 
randomization until database lock and subsequent unblinding by using the following methods:  
 
1) 
Randomization data are kept strictly confidential until the time of unblinding and will not 
be accessible by anyone else involved in the study except for the unblinded Biostatistician 
and the Clinical Trials Material Management Personnel 
 

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2)  The identity of the treatments will be concealed using study drugs (active/placebo) that are 
identical in packaging, labeling, schedule of administration, and appearance.  
 
If breaking of the blind may be essential to permit appropriate treatment of a subject’s medical 
condition: 
 
• 
The Investigator should contact the Medical Monitor by phone to discuss 
• 
The Medical Monitor will provide their recommendation to unblind or not to unblind via the 
Emergency Unblinding Authorization Form 
• 
Ultimately, the Investigator will make the final determination whether to unblind the 
treatment allocation for the welfare of the subject 
 
• 
If unblinding is deemed necessary, the Investigator should consult with the appropriate 
unblinded study personnel. 
• 
Every effort should be made to ensure that unblinding information is not shared with 
blinded study team members 
 
Please refer to CRO unblinding procedure.  
 
5.3 
STUDY TREATMENT SUPPLIES MANAGEMENT 
5.3.1 INTERACTIVE RESPONSE TECHNOLOGY (IRT) FOR INVESTIGATIONAL 
PRODUCT MANAGEMENT  
 
An IRT will be utilized during this study to manage the tracking and confirmation of shipment, 
supply, inventory, ordering, expiration, site-assignments, subject randomizations, returns, and 
emergency unblinding of the investigational product. 
 
An IRT user manual and training will be provided to each site, detailing instructions for use on 
IRT. 
 
Questions can be directed to the 
 Customer Care Team at: 
 
Or 
 
 
5.3.2 SHIPPING, MANUFACTURE, PACKAGING, AND LABELING 
 
Manufacturing of study treatments will be carried out by the CDMO vendor according to 
internal SOPs and approved manufacturing procedures. The CDMO vendor will ship study 
drug to the packaging facility for subsequent packaging, labeling, and shipping to the sites. 
 

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The packaged tablets will be shipped and stored in a secured, temperature-monitored 
environment between 20 – 25 °C (68 – 77°F). Excursions are permitted from 15-30°C (59-
86°F) if the excursion does not exceed 24 hours; excursions exceeding 24 hours must be 
reported immediately to the CRO. Deviations from the storage requirements must be 
documented and reported to the CRO and Sponsor. Investigational product must be 
quarantined and not used until Sponsor reviews the deviation and provides documentation if 
it is permissible to use the study drug. 
 
The study drug will be shipped in 10-ct bottles. The labels will include, but will not be limited 
to, the following information: study number, quantity, dosing instructions, and precautionary 
labeling as required by FDA on investigational drugs per CFR 21 Subpart A, Section 312.6. 
 
5.3.3 ACCOUNTABILITY OF STUDY SUPPLIES 
 
Enough of the Investigational Product (IP) for the study will be provided to the site. The 
investigator or qualified designee will acknowledge receipt of the IP investigational product 
and document the content of the shipment including quantity, temperature, and condition. The 
Investigator or designee will maintain a full record of study treatment accountability. An 
Investigational Product Dispensing and Accountability Log should be kept up to date with the 
following information: 
 
• 
The identification of the subject number to whom the study treatment was dispensed.  
• 
The date and time the study treatment was dispensed to the subject.  
• 
Any deviations from the IP dispensing (if applicable).  
 
Study supplies should be reconciled with this record and the shipping quantities. IP must be 
accounted for via documentation that accurately records IP that is received, dispensed, 
administered, returned to site, and returned to Sponsor (or Sponsor representative). Any 
unused materials must be returned as per Sponsor requirements.  
 
It is ultimately the Investigator’s responsibility to dispense and administer (when applicable) 
IP. These tasks may be assigned to a qualified designee who has been sufficiently trained 
and works closely under the direct supervision of the Investigator. This delegation must be 
documented in the applicable study delegation of authority form. The Investigator or designee 
will dispense the IP only to the designated parent/legal guardian, and/or caregiver (if 
applicable) of the subject. Subjects will receive enough IP to last them until the next in-clinic 
visit. Subjects must return unused study drug to the site at their next scheduled visit. 
Dispensing and return of study drug will be recorded on the CRFs and Dispensing and 
Accountability Log.  
 
The Investigator or designee will be required to have a valid DEA Form 223 certificate of 
registration for Scheduled II Controlled Substances for the duration of the study and be able 
to order and distribute Scheduled II Controlled Substances via a valid DEA Form 222. 
 

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No IP supplied by the Sponsor (stock product or returned from subject) may be removed from 
the site where originally shipped without the knowledge and approval of the Sponsor. If 
transfer of IP is approved by the Sponsor, the site must document the transfer and follow local, 
state, and national laws regarding shipment of Scheduled II Controlled Substances.  
 
At the end of the study, or as instructed by the Sponsor, unused stock, subject-returned IP, 
and empty/used IP packaging are to be sent to a Sponsor representative or nominated 
contractor. Investigational products being returned to the sponsor’s designated contractors 
must be counted and verified by clinical site personnel and the Sponsor (or CRO). If there is 
unused supply in which the original packaging is verified as intact, the bottle should not be 
opened and the amount on the label will be used instead of a physical count. Prior to shipment, 
the Sponsor and/or Sponsor contractor should be contacted for authorization to return any IP. 
Shipment of IP must follow local, state, and national laws regarding shipment of Scheduled II 
Controlled Substances. The drug accountability forms maintained by the site will allow for 
reconciliation of IP, both used and returned. The Sponsor should be notified immediately if 
there is any discrepancy involving IP accountability. 
 
5.3.4 STORAGE OF STUDY TREATMENT SUPPLIES 
 
Study drug must be stored in compliance with the label requirements and in a secure place 
with limited and controlled access.  
 
Throughout the duration of the study, the temperature of the storage locations will be 
monitored and recorded daily. The packaged tablets will be stored in a secured, temperature-
monitored environment between 20 – 25 °C (68 – 77°F). Excursions are permitted from 15-
30°C (59-86°F) if the excursion does not exceed 24 hours; excursions exceeding 24 hours 
must be reported immediately to the CRO. Deviations from the storage requirements must be 
documented and reported to the CRO and Sponsor. Investigational product must be 
quarantined and not used until Sponsor reviews the deviation and provides documentation if 
it is permissible to use the study drug. 
 
6 
METHODS, 
MEASUREMENTS, 
EVALUATIONS, 
AND 
STUDY-RELATED 
PROCEDURES 
6.1 
PARENTAL PERMISSION AND INFORMED CONSENT 
 
The Investigator, or designated study staff, must obtain written (signed and dated) parental 
permission and informed consent from the parent/legal guardian, and/or caregiver (if 
applicable) prior to their participation in this study. Informed consent will be obtained after full 
explanation of the aims, methods, objectives, and potential hazards of the study. There must 
also be written (signed and dated) assent indication that the subject is aware of the 
investigational nature of the study, and the required procedures and restrictions, prior to the 
performance of any study-related procedures. 
 
The Investigator, or designated study staff, must also explain to the subjects, parent/legal 
guardian, and/or caregiver (if applicable) that they are completely free to refuse to enter the 
study or to withdraw from it at any time. Appropriate forms for documenting a written consent 
and assent must be obtained prior to any study procedures being conducted. The Investigator, 

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or designated study staff, should sign and date the consent and assent form to confirm that 
the consent process was completed correctly and the subject, parent/legal guardian, and/or 
caregiver (if applicable) has fully understood the objectives of the study as well as the risks.  
 
The subject, legal guardian, and/or caregiver (if applicable) will be provided with a copy of their 
signed and dated consent and assent form, along with any other written information, which 
they should be instructed to retain. The original will be stored with the subject’s source 
documents. 
 
If, during participation in the trial, any new information becomes available that may affect the 
subjects, parent/legal guardians, and/or caregivers (if applicable) willingness to participate in 
the study, each ongoing subject should receive a copy of this new information and be re-
consented into the study. Subjects, parent/legal guardians, and/or caregivers (if applicable) 
should be provided with a copy of the signed and dated amended consent and assent form. 
 
A washout period may be required to discontinue any prohibited medication. A subject cannot 
be instructed to washout of any medication for this study until after the signed informed 
consent is obtained. 
 
Screening procedures may take place across multiple days to allow enough time to complete 
procedures and confirm subject eligibility. Screening procedures and dates should be 
documented in the source documents as well as in the eCRF’s.  
 
6.2 
ADHD DIAGNOSIS AND CONFIRMATION 
 
The investigator will confirm the subject meets the criteria for the primary diagnosis of ADHD 
(combined, inattentive, or hyperactive/impulsive presentation) per the Diagnostic and 
Statistical Manual of Mental Disorders – Fifth Edition (DSM-5) upon clinical evaluation and 
confirmed by the MINI International Neuropsychiatric Interview of Children and Adolescents 
(MINI-KID). In addition, the subject must score 28 or higher on the ADHD-RS-5 scale and a 4 
or higher on the clinician-administrated Clinical Global Impressions-Severity (CGI-S) scale at 
the Baseline Visit (Visit 2).  
 
Subjects must have adequate washout of ADHD medications prior to Visit 2. See 
inclusion/exclusion criteria for washout information (section 4.2). 
 
6.3 
DEMOGRAPHICS 
 
The Investigator, or designee, will record each subject's date of birth, sex (at birth), and race. 
 
 
 

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6.4 
MEDICAL HISTORY 
 
The Investigator, or designated study staff, will take a detailed medical history from each 
subject at Screening. Details of any relevant medical or surgical history, including allergies or 
drug sensitivity, will be recorded. Any concomitant medications will also be recorded. Other 
medications taken 30 days prior to the screening visit should be recorded with start and stop 
dates. Lifetime psychoactive medications and lifetime nonpharmacological interventions (e.g., 
cognitive, or behavioural therapy) should be recorded. A diagnosis of ADHD is an inclusion 
criterion and should be recorded as part of the Subject’s Medical History in the eCRFs. 
 
6.5 
PRIOR AND CONCOMITANT TREATMENTS 
 
Non-study treatment including but not limited to herbal treatments, vitamins, prescription 
medication, nonpharmacological treatment (e.g., cognitive, or behavioral therapy), received 
within 30 days prior to screening will be recorded as a prior medication on the appropriate 
eCRF page. Any treatments received between screening and the EOS (Visit 9) will be 
recorded as a concomitant medication on the appropriate eCRF page. If a treatment is 
received both within the 30 days prior to screening and between screening and EOS, it should 
be recorded as both a prior and concomitant treatment. 
 
The subject’s lifetime ADHD medication history and the subject’s lifetime nonpharmacological 
interventions (e.g., cognitive and/or behavioral therapy) for ADHD will be documented. 
 
6.6 
PRIOR ADHD MEDICATION QUESTIONNAIRE  
 
The site, in consultation with the subject, parents/legal guardians, and/or caregivers (if 
applicable), will be asked about prior medical history and response utilizing stimulant 
medications (including sleep and appetite evaluation) at the Baseline Visit 2.  
 
6.7 
PHYSICAL AND NEUROLOGICAL EXAMINATIONS 
 
The investigator, or medically qualified designee, will perform the physical examination at the 
protocol specified times, which will include assessments of the following body systems:  
 
• 
General appearance 
• 
Skin 
• 
Head, Eyes, Ears, Nose and Throat 
• 
Neck and Spine 
• 
Psychiatric 
• 
Respiratory 
• 
Cardiovascular 
• 
Gastrointestinal 

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• 
Musculoskeletal 
• 
Central Nervous System (CNS)/Neurological  
• 
Hematopoietic/lymphatic 
• 
Endocrine/metabolic 
 
The outcome of these assessments will be documented in the source. Pre-treatment findings 
or clinically significant abnormalities should be noted as medical history and post treatment 
findings or clinically significant abnormalities should be added as adverse events.  
Abnormalities should be described. Changes in physical exam from the Screening visit will be 
recorded as an AE, if deemed clinically significant by the Investigator. See Section 8.1.2 for 
AE reporting. 
 
6.8 
HEIGHT, WEIGHT, AND BODY MASS INDEX (BMI) 
 
Body weight and height will be recorded at the protocol-specified times within the Vital Signs 
eCRF. Weight will be measured in kilograms (kg) while wearing light clothing and without 
shoes. Weight measurements should be taken with the same calibrated scale and recorded 
to the nearest tenth of a kilogram. Subject must have a body weight between the 5th and 95th 
percentile (≥5th percentile and ≤95th percentile) for their respective age and sex at screening 
to be eligible. 
Height will be measured in centimeters (cm) without shoes. Height measurements should be 
taken with the same calibrated stadiometer and recorded to the nearest centimeter. (See 
Table 1 for schedule of assessments).  
Any clinically significant changes in height, weight, or BMI from screening will be recorded as 
an AE, if deemed clinically significant by the Investigator. See Section 8.1.2 for AE reporting. 
 
6.9 
VITAL SIGNS 
 
Arterial blood pressure, heart rate, and temperature will be recorded at screening and in-clinic 
study visits. Prior to obtaining blood pressure and heart rate measurements, the subject should 
be at rest for a minimum of 5 minutes. If the subject’s blood pressure is <90th percentile for 
their age, sex, and height, the single read is sufficient. If the subject’s blood pressure is ≥90th 
percentile, two additional reads will be taken, and the three reads averaged. If the average of 
the three reads is ≥95th percentile at screening they will be excluded. If the average of the 
three reads is ≥95th percentile after screening, it will be recorded as an AE. Vital signs will be 
checked at each in-clinic visit for clinical safety and recorded in the eCRF.  
 
The Investigator can interpret individual findings based on the subject’s age, physical state, 
and level of fitness. Subjects with readings marginally outside the normal range29,30 may be 
included in the study if, in the Investigator’s opinion, these are not clinically significant (NCS); 
this decision will be documented in the eCRF. Any clinically significant value observed after 
screening must be reported as an AE. See Section 8.1.2 for AE reporting. 
 
 
 

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6.10 
TABLET SWALLOWING TEST 
 
The subject will be administered a tablet (placebo) identical in size and shape to the study 
drug at screening to ensure the subject is able to easily swallow CTx-1301 for the duration of 
the study.  
 
6.11 
CLINICAL LABORATORY TESTS 
 
The Investigator, or appropriately trained study staff, will collect blood samples at screening 
for: serology, TSH, hematology, biochemistry, and a urine sample for urinalysis, and at Visit 8 
(or early termination) for: hematology, biochemistry, and urinalysis. Values for the laboratory 
safety tests (hematology, biochemistry, and urinalysis) must be within normal ranges, as 
defined by the accredited central laboratory facility, or considered not clinically significant by 
the Investigator at screening to be eligible. The results of these tests must be available before 
subjects are enrolled into the randomization phase. If additional clinical laboratory tests are 
performed in addition to the protocol-required tests, they must be recorded in the source 
documents and eCRF. 
 
If a lab test result is outside of normal range, the test may be repeated at the Investigator’s 
discretion. If a lab test result at Visit 8 has changed significantly from screening and is deemed 
clinically significant (CS) by the Investigator, it should be recorded as an AE. See Section 8.1.2 
for AE reporting. 
 
Subjects will be advised to follow up with their primary physician regarding any CS laboratory 
finding or other event of medical significance (as judged by the Investigator). 
 
The following tests will be carried out: 
 
Hematology 
White Blood Cell (WBC) and differential, Red Blood Cell (RBC), Hemoglobin (Hb), Hematocrit 
(Hct), Mean Cell Volume (MCV), Mean Cell Hemoglobin (MCH), Mean Platelet Volume (MPV), 
Mean corpuscular hemoglobin concentration (MCHC), platelets  
 
Biochemistry 
Sodium, potassium, chloride, BUN, creatinine, BUN/Creatinine ratio, alkaline phosphatase, 
bilirubin, albumin, calcium, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), glucose. 
 
Thyroid 
Thyroid Stimulating Hormone (TSH)  
 
 
 

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Serology 
Hep-B and Hep-C 
 
Urinalysis 
Color, Clarity, Bilirubin, urobilinogen, ketones, glucose, proteins, blood, nitrite, pH, specific 
gravity, and leukocytes.  
 
Urine Screen for Drugs of Abuse 
At Screening (Visit 1), Baseline (Visit 2), and Week 5 (Visit 8) urine samples will be tested for 
drugs of abuse (amphetamines, benzodiazepines, barbiturates, cannabinoids, cocaine, and 
opioids) per the study schedule (see Table 1).  
 
Urine samples will be tested for methylphenidate at screening and Day 0 Baseline (Visit 2). 
  
If the urine test is positive for drugs of abuse at Screening or Baseline (Visit 2), the subject 
must be excluded from study participation, except for the subject’s current ADHD medication 
(at Screening only). Subjects are required to washout of their ADHD medications prior to 
Baseline (Visit 2). 
 
The Investigator, in conjunction with the Sponsor and CRO Medical Monitor, will evaluate the 
potential impact of a positive urine drug screen on the continued participation of the subject. 
 
Pregnancy Test 
Pregnancy tests will be performed for female subjects of childbearing potential. A serum hCG 
pregnancy test will be performed at Visit 1 and Visit 8 (or early termination visit). A urine hCG 
will be performed at Visits 2, and 4-8 per the study schedule (see Table 1). A positive 
pregnancy test will exclude a subject from participation in the study. A positive urine hCG test 
will be confirmed with a serum hCG pregnancy test. 
 
“Childbearing potential” is defined as females under the age of 12 who have had their first 
period. Girls 12 years and older (including girls who will become 12 years or older during the 
study) will be considered of child-bearing potential, even if they have not had their first period. 
Irrespective of age, girls who have had their first period will be considered of child-bearing 
potential. 
 
6.12 
PHARMACOKINETIC BLOOD SAMPLING 
 
At Day 1 (Visit 3) and Week 5 (Visit 8) a single blood sample for pharmacokinetic (PK) 
assessment will be drawn by suitably trained site staff using an indwelling cannula or by 
venipuncture. The Week 5 PK draw will be combined with the safety lab draw at Week 5 to 
avoid separate draw. 
 

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The total blood volume taken for each blood sample will be approximately 5 mL per visit (4 mL 
sample volume and 1 mL of waste volume). The time of PK draw should be recorded at each 
of the two visits. Accordingly, if subject does not take dose the day of the PK draw, the PK 
draw should not be completed, and it should be recorded in the CRFs.  
 
There is a risk of bruising and fainting during the blood sampling procedure. See AE section 
for reporting procedure-related AEs. 
 
The PK blood samples should be collected in vacutainers containing K2-EDTA as the 
anticoagulant. Each blood tube will be labelled with the Subject Number and time collected 
post dose (ex. 3 hours post dose). Blood samples should be kept in ice/water bath until 
centrifugation. Blood samples should be centrifuged at 1,500 g for 10 minutes at 4°C  if a 
refrigerated centrifuge is available or non-refrigerated centrifuge can be used within 60 
minutes of collection. A minimum of 0.5 mL plasma should be aliquoted into two polypropylene 
tubes (Primary and Backup); if there is not sufficient plasma for both, preference should be 
given to the Primary sample. Each plasma sample should be kept in an ice/water bath 
environment until storage. Each plasma sample must be stored at -20ºC nominal within 30 
min of centrifuging.  
 
The analysis of these samples will be undertaken by a Sponsor-selected laboratory. Blood 
samples for PK determination will be processed, split, stored, and shipped according to the 
sample processing instructions supplied by the bioanalytical facility. Samples will be evaluated 
using a validated d-MPH method.  
  
The pharmacokinetic samples collected will be used to model and simulate the following 
pharmacokinetic parameters by population PK:  
 
Maximum Concentration (Cmax), Time of Maximum Concentration (Tmax), terminal elimination 
constant (K), lag time (Tlag), Half Life (T1/2), Area Under the Curve from time 0 to 28 hrs 
(AUClast), Area Under the Curve from time 0 to infinity (AUC0-¥), and partial areas AUC0-3, 
AUC3-6, AUC3-7, AUC6-9, AUC7-12, AUC9-12, and AUC12-16. Additional measures may be evaluated 
if deemed necessary. 
 
Collection times at Day 1 (Visit 3) and Week 5 (Visit 8) will be 0.5 to 5 hours post-dose, 5-6.5 
hours post-dose, and 6.5 to 8 hours post-dose. Collection times at Day 1 and Week 5 will be 
different for each subject (i.e., if assigned 0.5-5 hours post dose on Day 1, they will be 
assigned 5 to 6.5 hours or 6.5 to 8 hours post-dose at Week 5). Collection times will be 
assigned via automated IRT to ensure an approximately equal distribution among the 6 
different combinations of timepoints. With approximately 385 subjects at Day 1 and at least 
308 subjects at Week 5, this should provide an adequate distribution to demonstrate Pop PK 
measurements.  
 
 
 

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6.13 
ECG 
 
ECGs will be administered at Visit 1 and Visit 8 (or early termination visit). Visit 1 ECGs should 
be obtained when subject is not on ADHD medication and may be taken at Visit 2 if needed. 
ECGs will be recorded in triplicate and will be collected after the subject has been resting 
supine for at least 5 minutes. ECGs will be 12-lead with a 10-second rhythm strip and will be 
collected using recorder provided by the central ECG vendor/reader. ECGs should be 
recorded prior to drawing blood samples (if applicable to visit). Typical length between 
triplicate tracings is usually between 5 and 10 minutes.  
 
The initial read of the ECGs will be done immediately by the Investigator after collection to 
ensure the safety of subjects. The ECG tracings will be sent electronically to the central reader 
for analysis. The Investigator must review the central ECG provider report. If abnormal and 
significant results are observed following analysis by the central reader, the Investigator, in 
consultation with the CRO Medical Monitor, will reconfirm subject eligibility to continue. 
 
The central read will determine the eligibility of subjects for enrollment into the study (Visit 1). 
A final read for safety will occur at Visit 8. If a subject early terminates for any reason, an ECG 
should be conducted along with the other study procedures for Visit 8. 
 
The Standard 12-lead ECG will record heart rate (HR), PR interval, RR interval, QT interval, 
QTc with Bazett correction (QTcB) and QTc with Fredericia correction (QTcF) intervals, and 
QRS duration. 
 
6.14 
C-SSRS  
 
The C-SSRS is a tool designed to systemically assess and track suicidal AEs (suicidal 
behavior and suicidal ideation) throughout the study. The strength of this suicide classification 
system is in its ability to comprehensively identify suicidal events while limiting the over 
identification of suicidal behavior. The scale takes approximately 5 minutes to administer. The 
C-SSRS will be administered by a trained rater at the site. 
 
This study will utilize 2 versions of the C-SSRS. At the screening visit, the lifetime/recent 
version (Baseline) will be completed; for subsequent visits, the “Since Last Visit” version of 
the C-SSRS will be administered. The outcome of these assessments will be documented in 
the eCRF. 
 
Subjects who have significant findings for suicidal ideation upon completion of the C-SSRS 
during the study must be referred to the Investigator for assessment. If investigator defines as 
significant, the medical monitor should also be notified (through CRO email). Any potential 
subject deemed to be at risk will be excluded from the study. 
 
Any clinically significant value observed after screening must be reported as an AE. See 
Section 8.1.2 for AE reporting. 
 

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6.15 
STUDY EVALUATIONS AND EFFICACY ASSESSMENTS 
 
Rating scales and assessments completed for each individual subject, including the ADHD-
RS-5, CGI-S, CGI-I and MINI-KID should be completed by the same Investigator (or 
appropriate designee) and parent/legal guardian, and/or caregiver (if applicable) whenever 
possible. Clinicians who administer these scales and/or assessments will be trained, 
experienced with the scale/assessment, and approved by the Sponsor prior to administration.  
 
6.15.1 ADHD-RS-5  
 
The ADHD-RS-5 is an 18-item scale based on Diagnostic and Statistical Manual of Mental 
Disorders, 5th edition (DSM-5) (American Psychiatric Association 2013) criteria of ADHD that 
rates symptoms on a 4-point scale. Each item is scored using a combination of severity and 
frequency ratings from a range of 0 (reflecting no symptoms or a frequency of never or rarely) 
to 3 (reflecting severe symptoms or a frequency of very often), so that the total ADHD-RS-5 
scores range from 0 to 54. The 18 items can be divided into two 9-item subscales: One for 
hyperactivity/impulsivity and the other for inattentiveness. Scores will be obtained during a 
clinician-directed interview with the parent/legal guardian, and/or caregiver (if applicable) at 
each visit. The ADHD-RS-5 will be completed at every in-office visit or early termination visit, 
if applicable. The ADHD-RS-5 at the Baseline visit requires adequate washout of medication. 
 
6.15.2 CGI-S 
 
The CGI-S is a clinician-rated scale that evaluates the severity of psychopathology (ADHD 
symptoms in the study) on a scale from 1 (not at all ill) to 7 (among the most severely ill) 
(Busner and Targum 2007). The CGI-S will be completed at Visits 2, 4-8 or early termination 
visit, if applicable. CGI-S at the Baseline visit requires adequate washout of medication.  
 
6.15.3 CGI-I 
 
The CGI-I is a clinician-rated scale that is scored from 1 (very much improved) to 7 (very much 
worse). The CGI-I will be completed at Visit 8. 
 
6.15.4 MINI-KID  
 
The MINI International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) is 
a structured diagnostic interview for making diagnoses included in the Diagnostic and 
Statistical Manual of Mental Disorders and is an accurate structured psychiatric interview for 
multicenter clinical trials. The interview takes approximately 30 minutes to administer. The 
MINI-KID will be administered by a trained clinician at the site. 
 
The MINI-KID will be administered at Screening to confirm the diagnosis of ADHD in 
conjunction with the ADHD-RS-5 and CGI-S at the Baseline Visit (Visit 2). In addition, the 
interview can be used to identify any other presenting diagnosis which may be clinically 
significant and/or exclusionary. The outcome of these assessments will be documented in the 

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eCRF. Any potential subject deemed to be at risk for other exclusionary psychiatric diagnosis 
will be excluded from the study. 
 
6.16 
DESCRIPTION OF OTHER STUDY PROCEDURES 
6.16.1 DRUG ACCOUNTABILITY AND COMPLIANCE  
 
Compliance with the study drug will be monitored and determined at each in-office visit. 
Subjects and their parent/legal guardian, and/or caregiver (if applicable) will be instructed to 
bring unused study drug and used/empty packaging with them to each visit. Compliance will 
be assessed by counting tablets and dividing the actual number of doses taken (per tablet 
count) by the number of doses the subject should have taken within a visit period and 
multiplying by 100. Details of compliance assessments will be appropriately documented by 
designated site personnel. Subjects who miss more than 25% of scheduled doses or taken 
more than 125% of scheduled doses will be considered non-compliant and will be reviewed 
and evaluated by the Investigator. Evidence of non-compliance must be immediately reported 
to the Medical Monitor. Noncompliance issues will be discussed with the subjects and their 
parent/legal guardian, and/or caregiver (if applicable), and at the Investigator’s discretion, may 
result in termination from the study. Subjects and their parent/legal guardian, and/or caregiver 
(if applicable) will be reminded of the importance of strict compliance with taking study drug 
for the effectiveness of treatment, safety of the patient, and successful outcomes of the study. 
 
6.16.2 BLOOD SAMPLING 
 
Blood samples for safety will be taken at Screening for eligibility, and again at Week 5 (Visit 
8). Blood sample for pharmacokinetic assessments will be taken post-dose at Day 1 (Visit 3) 
and post-dose at Week 5 (Visit 8). There is a risk of bruising and fainting during blood 
sampling.  
 
6.16.3 STUDY COMPLETION/MEDICAL SIGN-OFF 
 
Completion of the study will be defined as completion of the last subject, last visit (LSLV) at 
the end of the safety follow-up visit (Visit 9). Following completion of Visit 9 (as defined 
previously), the Investigator will perform a medical sign-off for each subject.  
 
6.17 
DURATION OF THE STUDY 
 
Subjects will participate in the study as outpatients for approximately 10 weeks: a 30-day 
screening period, a 5-week, randomized, double-blind treatment period, and a 1-week follow-
up safety assessment visit (if applicable).  
 
Completion of the study will be defined as completion of the last subject, last visit (LSLV) at 
Visit 8 
. 
 
 
 

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The treatment duration is approximately 5 weeks.  
 
Subjects will receive a single, daily dose of CTx-1301 during the 5-week, double-blind, 
randomized, efficacy period of the study.  
 
7 
STUDY SCHEDULE 
7.1 
 SCREENING (DAYS -30 TO -1) 
 
After obtaining parental informed consent and child assent, subjects  will be evaluated at their 
Screening Visit to determine whether they are eligible to enroll into the study. Subjects who 
are adequately washed out of ADHD medications (stimulants and non-stimulants) will be 
administered the ADHD-RS-5, CGI-S and ECG. Subjects who are currently taking ADHD 
medications (stimulants and non-stimulants) will be instructed to washout and come back on 
Visit 2 to obtain the ADHD-RS-5, CGI-S, ECG for eligibility (after an adequate washout of 
ADHD medications is confirmed). These subjects will be deemed eligible or not eligible at Visit 
2. 
 
Subjects may be rescreened a maximum of 1 time when the subject may still be a suitable 
candidate for the study and the reason for screen failure may be resolved (e.g., out-of-range 
clinical laboratory results, insufficient medication washout, etc.). The previous subject number 
must be recorded in the subject’s study history. 
 
7.1.1 VISIT 1 (SCREENING VISIT) 
 
Subjects will be evaluated at the Screening Visit to determine their eligibility to enroll into the 
study. The following study-related procedures will be performed: 
 
• 
Obtain Parental Permission and Written Informed Consent Assent 
• 
Confirmation of ADHD Diagnosis utilizing ADHD-RS-5 (score of ≥ 28), and CGI-S (score 
of ≥4). This can be obtained at Visit 2 if washout from ADHD medications is needed 
• 
Administer the MINI-KID 
• 
Administer the C-SSRS (Baseline Version) 
• 
Confirm Inclusion and Exclusion Criteria 
• 
Collect Demographics 
• 
Collect Medical History, including Prior and Concomitant Medications 
• 
Perform Physical Examination 
• 
Collect Vital Signs (included on eCRF Body Weight, Height, and BMI) 
• 
Tablet Swallowing Test 
• 
Perform 12-Lead ECG. This can be obtained at Visit 2 if washout from ADHD medications 
is needed 

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• 
Collect Blood and Urine Samples for Chemistry, Hematology, TSH, Serology, and 
Urinalysis 
• 
Collect a urine sample for Drugs of Abuse 
• 
Collect a urine sample for Methylphenidate 
• 
Perform a Serum Screen for hCG in Females of Child-Bearing Potential 
• 
Assess for Adverse Events 
• 
Record Concomitant Medications 
• 
Remind Subjects that they must washout of ADHD medications prior to the start of the 
Randomized Phase (Visit 2).   
• 
Schedule next Day 0/ Study Visit 2 
 
Rating scales and assessments for each individual subject should be completed by the same 
Investigator (or appropriate designee) and parent/legal guardian, and/or caregiver (if 
applicable) whenever possible. 
 
7.1.2 WASHOUT CALL 
 
The washout phone call should be initiated after clinical lab test results and 12-lead ECG 
results from Screening have been received, reviewed, and subject is confirmed eligible if not 
on ADHD medications. Eligible subjects will be contacted by a member of the site staff and 
provided with instructions on discontinuing protocol-prohibited medications. During the 
washout, a subject’s current prohibited medications (if applicable) will be discontinued for a 
period of a minimum of 5 times the half-life of the medication. 
 
The site personnel should perform the following procedures on the washout call: 
 
• 
Schedule and/or confirm Visit 2 (Day 0)  
• 
Review Inclusion/Exclusion Criteria 
• 
Review concomitant medications. If new concomitant medications that require washout 
are reported, instructions for appropriate washout will be provided. 
• 
Provide/remind instructions on discontinuing any medication requiring washout 
• 
Determine if there have been any changes in medical history since Screening; Assess for 
Adverse Events since Screening 
 
7.1.3 VISIT 2 
 
The following study-related procedures will be performed: 
 
• 
Review and confirm that subject still meets Inclusion Criteria and No Exclusion Criteria 

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• 
Confirmation of ADHD Diagnosis utilizing ADHD-RS-5 (score of ≥ 28) and CGI-S (score 
of ≥4) if was not collected at Screening (Visit 1) 
• 
Perform 12-Lead ECG, if it was not collected at Screening (Visit 1) 
• 
Complete Prior Medication Questionnaire 
• 
Perform Physical Examination 
• 
Collect Vital Signs (included on eCRF Body Weight, Height, and BMI) 
• 
Collect a urine sample for Drugs of Abuse 
• 
Collect a urine sample for Methylphenidate for analysis by the central laboratory 
• 
Perform a Urine hCG in Females of Child-Bearing Potential 
• 
Administer the C-SSRS (Since Last Visit Version) 
• 
Record Concomitant Medications 
• 
Assess for Adverse Events 
• 
Randomize Subject 
• 
Dispense Study Drug (active or placebo, per IRT randomization) 
• 
Distribute Dosing Diary 
• 
Assign PK draw time for Day 1 (Visit 3) and Day 35 (Visit 8) (per IRT randomization) 
• 
Remind Subject to take their dose prior to 8:00 am each day and schedule the Day 1 Visit 
 
Rating scales and assessments for each individual subject should be completed by the same 
Investigator (or appropriate designee) and parent/legal guardian, and/or caregiver (if 
applicable) whenever possible. Efficacy assessments should be evaluated prior to any 
invasive study assessment. 
 
7.1.4 VISIT 3 
 
Drug Accountability and Compliance Assessments will begin at Visit 3 and continue at each 
Visit throughout the entire course of the study. Visit 3 will include the following study-related 
procedures: 
 
• 
Collect Vital Signs (included on eCRF Body Weight, Height, and BMI) 
• 
Record Concomitant Medications 
• 
Assess for Adverse Events 
• 
Drug Accountability and Compliance Assessment 
• 
Collect Dose Time of IP  
• 
Collect Blood Sample for Pharmacokinetic Assessment per PK Instructions 
• 
Remind Subject to take their dose prior to 8:00 am each day 
• 
Schedule or confirm upcoming study visits 4-8 
 

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7.1.5 VISIT 4 - VISIT 7 
 
Visit 4-7 will include the following study-related procedures: 
 
• 
Administer the ADHD-RS-5  
• 
Administer the CGI-S 
• 
Collect Vital Signs (included on eCRF Body Weight, Height, and BMI) 
• 
Perform a Urine hCG in females of childbearing potential 
• 
Administer the C-SSRS (Since Last Visit Version) 
• 
Drug Accountability and Compliance Assessment 
• 
Record Concomitant Medications 
• 
Assess for Adverse Events 
• 
Dispense Study Drug (must be at stable dose) 
• 
Collect/Distribute Dosing Diary 
• 
Remind Subject to Take Their Dose Prior to 8:00 am Each Day 
• 
Schedule or confirm upcoming study visits 4-8. At Visit 7, confirm Visit 8 date and time 
according to the assigned time window for PK draw 
 
Rating scales and assessments for each individual subject should be completed by the same 
Investigator (or appropriate designee) and parent/legal guardian, and/or caregiver (if 
applicable) whenever possible. Efficacy assessments should be evaluated prior to any 
invasive study assessment. 
 
7.1.6 VISIT 8/ EARLY TERMINATION 
 
Visit 8 will include the following study-related procedures: 
 
• 
Administer the ADHD-RS-5  
• 
Administer the CGI-S & CGI-I 
• 
Collect Vital Signs (included on eCRF Body Weight, Height, and BMI) 
• 
Perform Physical Examination 
• 
Collect a urine sample for Drugs of Abuse 
• 
Administer the C-SSRS (Since Last Visit Version) 
• 
Perform 12-Lead ECG 
• 
Collect Dose Time of IP Just Prior to Blood Draw 
• 
Collect Blood and Urine Samples for Chemistry, Hematology, and Urinalysis 
• 
Collect Blood Sample for Pharmacokinetic Assessment per PK instructions 

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• 
Perform a urine and serum screen for hCG in females of childbearing potential 
• 
Drug Accountability and Compliance Assessment 
• 
Collect/Review Dosing Diary 
• 
Record Concomitant Medications 
• 
Assess for Adverse Events 
• 
Schedule or confirm upcoming study visit 9 
 
Rating scales and assessments for each individual subject should be completed by the same 
Investigator (or appropriate designee) and parent/legal guardian, and/or caregiver (if 
applicable) whenever possible. Efficacy assessments should be evaluated prior to any 
invasive study assessment. 
 
7.1.7 VISIT 9  
 
Visit 9 is a safety follow-up phone call and subject will be washed out of drug. Visit 9 includes 
the following study-related procedures: 
 
• 
Assess for Adverse Events 
• 
Record Concomitant Medications 
 
7.2 
EARLY TERMINATION 
 
If possible, Early Termination Visits should follow the Visit 8 procedures. 
 
7.3 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from CTx-1301 does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol. If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine further or additional 
intervention with participant. Any new clinically relevant finding will be reported as an adverse 
event (AE) or SAE such as overdosage, etc.  
 
 
 

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7.4 
UNSCHEDULED VISITS 
 
Investigator may require a subject to undergo an unscheduled visit if required for safety and/or 
efficacy during the study. Subjects may contact the clinic and request an unscheduled visit to 
address safety and/or efficacy between scheduled visits, if necessary. Procedures conducted 
at an unscheduled visit must be recorded in the CRF.  
 
7.5 
SUBJECTS LOST TO FOLLOW-UP 
 
When a subject is lost to follow-up at any time during the study prior to the last scheduled visit 
(Visit 9), three attempts must be made to contact the subject. These attempts must be 
documented and at least one attempt must include communication in writing which asks the 
subject to return to the site to undergo EOS procedures and return any remaining 
investigational drug. The written communication will be sent to the subject’s address via mail 
or courier with an acknowledgment of receipt request. 
 
8 
SAFETY MEASUREMENTS AND EVALUATIONS 
8.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
The Investigator and site staff are responsible for detecting, documenting, and reporting 
events that meet the definition of an Adverse Event, Serious Adverse Event, or Suspected 
Unexpected Serious Adverse Reaction. 
 
8.1.1 
DEFINITIONS 
 
Adverse event 
 
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of an investigational product whether considered related 
to the investigational product. Symptoms of the disease under study should not be considered 
AEs if they are part of the expected vacillation/progression of the disease. However, significant 
worsening of the symptoms should be recorded as an AE. The Investigator should use 
professional judgement in deciding whether a symptom is a normal, expected event 
associated with the disease or is an AE. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding if collected after dosing), symptom, or disease (new or exacerbated) 
temporally associated with the use of an investigational product.  
 
AEs are collected from the time of the informed consent is signed until the end of the study. 
AEs must be followed to conclusion of the AE or no further improvement is expected.  
 
Events meeting the definition of an AE include, but are not limited to:  

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• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New condition(s) detected or diagnosed after investigational product administration even 
though it may have been present prior to the start of the study. A thorough medical history 
should be taken to limit observation of conditions that were present prior to dosing. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication (overdose per se should not be 
reported as an AE/SAE). 
 
Events that do not meet the definition of an AE include: 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience/prescheduled admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.  
 
Clinical AEs will be described by diagnosis and not by symptoms, when possible (e.g., upper 
respiratory tract infection (URTI), seasonal allergy, etc. instead of runny nose). 
 
Serious adverse event 
An SAE is any untoward medical occurrence that, at any dose: 
a) Results in death. 
b) 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. 
 
c) Requires hospitalization or prolongation of existing hospitalization. 
 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the Investigator’s office or out-patient 
setting. Complications that occur during hospitalization are considered AEs. If a complication 
prolongs hospitalization or fulfils any other serious criteria, the event is serious. When in doubt 
as to whether “hospitalization” occurred and/or was necessary, the AE should be considered 
serious. 

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Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline (Day 0) is not considered an AE. 
 
d) Results in disability/incapacity, or 
 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere or prevent everyday life 
functions but do not constitute a substantial disruption. 
 
e) Is a congenital anomaly/birth defect. 
 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, 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 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These should also be considered serious. Examples of such events are invasive or 
malignant cancers, 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 or reports of spontaneous abortion. 
 
8.1.2 REPORTING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
Time period for reporting adverse events and serious adverse events 
 
AEs will be collected from the time the subject signs the Informed Consent Form until the end 
of the study. 
 
SAEs will be collected over the same time as stated above for AEs and will be reported to the 
Sponsor within 24 hours of the Investigator or designee becoming aware of the situation. 
 
Medical conditions existing prior to consent should be recorded as part of the subject’s medical 
history. 
 
Reporting adverse events 
 
AEs will be recorded in detail on the AE source document and collected in the electronic data 
capture (EDC) system. 
 

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Medical conditions reported by the subject that meet the definition of an AE must also be 
recorded if not previously well-characterized by the Investigator in the subject’s medical 
history.  
 
Adverse events will be collected as reported by the subjects for the duration of the study. 
 
8.1.3 ADVERSE EVENT GRADING AND ASSESSMENTS 
 
Intensity grading 
 
AEs will be graded on a three-point scale and reported in detail as indicated on the eCRF: 
 
• 
Mild – easily tolerated, causing minimal discomfort, and not interfering with normal 
everyday activities 
 
• 
Moderate – sufficiently discomforting to interfere with normal everyday activities 
 
• 
Severe – incapacitating and/or prevents normal everyday activities 
 
Expectedness 
 
AEs must be assessed as to whether they are expected to occur or unexpected. The Medical 
Monitor must evaluate expectedness based on current knowledge as found in the protocol, 
the investigator brochure, product insert, or label of other methylphenidate drugs. 
 
• 
Unexpected –severity and nature of the event is not consistent with information about 
the condition under study or intervention in the protocol, consent form, product brochure, 
or investigator brochure. 
 
• 
Expected – event is known to be associated with the intervention or condition under 
study. 
 
Relationship assessment 
 
Study treatment relationship for each AE should be determined by the Investigator using the 
following explanations: 
 
• 
Not related – The event is clearly not related to the investigational agent/procedure – 
i.e., another cause of the event is most plausible; and/or a clinically plausible temporal 

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sequence is inconsistent with the onset of the event and the study intervention and/or a 
causal relationship is considered biologically implausible. 
 
• 
Possibly related – The event follows a reasonable temporal sequence from the time of 
investigational product administration; and/or follows a known response pattern to the 
study treatment; but could have been produced by other factors such as the subject’s 
clinical state, therapeutic interventions, or concomitant medications administered to the 
subject. 
 
• 
Definitively related – The event follows a reasonable temporal sequence from the time 
of investigational product administration; and follows a known response pattern to the 
investigational product; and cannot be reasonably explained by other factors such as the 
subject’s clinical state, therapeutic interventions, or concomitant medications 
administered to the subject; and either occurs immediately following investigational 
product administration, or improves on stopping the investigational product, or reappears 
on repeat exposure, or there is a positive reaction at the application site. 
 
• 
Non-dosing procedure - The event is not related to the study drug but is related to the 
subject’s participation in the study in another capacity, for example: bruising due to 
venipuncture. 
 
Outcome Assessment 
 
The outcome for each AE should be determined by the Investigator using the following 
explanations: 
 
• 
Fatal 
• 
Not Recovered/Not Resolved 
• 
Recovered/Resolved 
• 
Recovered/Resolved with Sequelae 
• 
Recovering/Resolving 
• 
Unknown 
 
Duration 
 
The date (and time, if available) of the start and end of adverse events will be recorded.  
 
 
 

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Follow-up 
 
Any AEs ongoing at the end of the study, which are considered in any way related to the study 
medication or the study regime, will be followed up until resolved, the condition stabilizes, is 
otherwise explained, or the subject is lost to follow-up.  
 
In addition, any SAEs will be followed up to resolution (or other criteria outlined above). If any 
serious related event is not resolved (or does not meet any other criteria outlined above) prior 
to the completion of the final study report, the report will be issued. If additional information 
becomes available following the completion of the report, an addendum will be generated 
detailing the follow-up information. Any follow-up information on SAEs must be reported to the 
Sponsor within 24 hours of the investigator or study site staff becoming aware of additional 
information. 
 
Reporting serious adverse events 
 
A copy of the SAE form provided in the Investigator Site File should be completed within 24 
hours of the investigator or study staff becoming aware of the event and provide to the 
following contact: 
 
 
 
 
 
It is essential to enter the following information: 
 
• 
Protocol and subject identifiers 
• 
Subject’s demographics 
• 
Description of events, with diagnosis if available 
• 
Investigator opinion of relationship to study treatment 
• 
Criterion for seriousness  
 
The following are desirable and are of relevance for assessment of the adverse event report: 
 
• 
Date of onset of SAE 
• 
Date SAE stopped, if relevant 
• 
Study treatment start date 
• 
Study treatment end date, if relevant 
• 
Action taken on study treatment 

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• 
Outcome, if known 
 
The initial report will be followed up with more information as relevant. This may require the 
Investigator to obtain copies of hospital case reports, autopsy reports, and other documents 
as applicable. If required, any hospital records/reports, admission reports, etc., pertaining to 
the SAE must be redacted prior to sending to the sponsor.  
 
Reporting of SUSARs 
 
Where the adverse reaction is unexpected and serious it may be termed Suspected 
Unexpected Serious Adverse Reaction (SUSAR). Study site personnel should ensure relevant 
information is provided to the Sponsor to allow the Sponsor to meet their obligations to report 
any SUSAR to the relevant competent authority.  
 
SUSARs will be reported, by the site, to the Principal Investigator and Sponsor within 24 hours 
of the site first becoming aware of the event. The Sponsor or designee will then carry out 
reporting as follows: 
 
SUSARs which are fatal or life-threatening: reporting to the Ethics Committee and FDA within 
7 days of becoming aware of the event. A more detailed report will be provided within an 
additional 8 days. 
 
Other SUSARs: reporting to the Ethics Committee and FDA within 15 days of first becoming 
aware of the event. 
 
Serious events reporting by Sponsor will adhere to 21 CFR 312.32 for IND drugs (7-day or 15-
day alerts). Unexpected fatal or life-threatening SAEs considered related to the study drug will 
be reported to the FDA by Sponsor with an IND Safety report within 7 days. The IRB will be 
notified of the alert reports per FDA regulations. 
 
8.2 
PREGNANCY 
 
Females with a positive pregnancy test will be excluded from further participation in the study. 
A copy of the Pregnancy Form provided in the Investigator Site File should be completed within 
24 hours of the investigator or study staff becoming aware of the pregnancy and provide to 
the following contact: 
 
 
 
 
 

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Pregnancies will be followed to at least the completion/termination of the pregnancy. The 
investigator will document the subject visits accordingly and record the information in the 
clinical site’s source documents. If the pregnancy continues to delivery, the outcome (health 
of the infant), in addition to the maternal health status, must be included in the report. 
 
Pregnancy will not be considered an AE or SAE. Any pregnancy complication or termination 
of a pregnancy for medical reasons will be recorded as an AE or SAE. 
 
8.3 
LABORATORY EVALUATIONS RELATED TO SAFETY 
 
Clinical safety laboratory assessments (hematology, biochemistry, and urinalysis) will be 
conducted at Screening (Visit 1), and Week 5 (Visit 8) to ensure the subject’s good health and 
to ensure safety. Abnormal results that the Investigator considers to be clinically significant, 
other than those observed at Screening (medical history), will be recorded as an AE. 
 
Clinically significant findings in laboratory tests at Screening (Visit 1) will be considered pre-
existing conditions (medical history), as well as failure to meet eligibility criteria. Subjects will 
be instructed to follow up with their primary physician for any medical event or condition 
discovered at Screening, which, in the opinion of the Investigator, is clinically significant. 
 
8.4 
VITAL SIGNS, PHYSICAL EXAM, ECGS, AND OTHER OBSERVATIONS RELATED TO 
SAFETY 
 
Vital signs, Physical Exams, and ECGs will be assessed at Screening and protocol-specified 
times throughout the study to ensure the subject is, and remains in, good general health. 
Abnormal findings that the Investigator (or central reader/lab for ECGs) considers to be 
clinically significant, other than at screening, will be recorded as an AE. 
 
9 
DATA MANAGEMENT AND STATISTICAL ANALYSIS METHODS 
9.1 
DATA COLLECTION 
 
The investigators authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by appropriate and 
qualified site personnel. Data collection procedures will be discussed at the site initiation visit 
and/or the investigator’s meeting. Once a subject is screened, it is expected that the site 
personnel will complete the eCRF entry as soon as possible after the subject visit to ensure 
accuracy and completeness of the data. 
 
 
 

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9.2 
CLINICAL DATA MANAGEMENT  
 
Data are to be entered per the CRO’s Data Management Plan. Quality control and data 
validation procedures are applied to ensure the validity and accuracy of the clinical database. 
 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using both computerized and manual procedures. 
 
9.3 
SAMPLE SIZE CALCULATION 
 
A pivotal Phase 3 study (2301) for Focalin XR shows a change-from-baseline mean difference 
b/w treatment and placebo of 10.4 with a pooled stdev=14.76, corresponding to an effect size 
of approximately 0.7 in CADS-T total score in the 6-12yr age. Similarities were identified in the 
CADS-T and the ADHD-RS-5 scales in that they both appear to be narrow band and focus on 
ADHD core symptoms, evaluate ADHD using 18 items in the DSM criteria, and evaluate 
functional impairment in terms of learning, behavior, and relationships (insert reference). 
Therefore, an effect size of 0.60 is assumed in this study for the comparison of mean change 
from baseline to week 5 in subjects receiving fixed doses of CTx-1301 and placebo. 
Approximately 77 subjects per treatment group (CTx-1301 18.75 mg: 25 mg: 37.5 mg: 
placebo=1:1:1:1) would provide 90% power at a 2-sided significance level of 0.017 based on 
a two-sample t test with effect size 0.60 after Bonferroni correction (nQuery Version 8.4.1.0), 
which results in a total sample size of 308. Assuming a drop-out rate of 20%, approximately 
385 subjects will be enrolled. 
 
9.4 
ANALYSIS POPULATIONS 
 
Intent-to-Treat (ITT) Population: Subjects who are randomized. 
Safety (SAF) Population: Subjects who have received at least one dose of study drug. 
Modified ITT (mITT) Population: subjects in the ITT population and have at least one post-
baseline  ADHD-RS-5 assessment. 
Per Protocol (PP) Population: Subjects in the ITT population who have no major protocol 
deviations that interfere with the primary efficacy analysis. The PP Population will be 
determined in a blinded manner prior to database lock. 
 
9.5 
DATA ANALYSIS 
9.5.1 SUBJECT DISPOSITION 
 
Subject disposition will be summarized for randomized subjects. Subjects who complete the 
study and early withdraw from the study, including reason for early withdrawal will be 
summarized by treatment group.  
 

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9.5.2 DRUG EXPOSURE AND COMPLIANCE 
 
Study drug exposure and drug compliance will be summarized descriptively in the safety 
population. 
 
9.5.3 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
 
Demographic and baseline characteristics will be summarized by age group (6-12 and 13-17) 
and overall, in the ITT and safety populations.  
 
9.5.4 MEDICAL HISTORY 
 
Medical history will be coded by system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary Activities (MedDRA) in the safety population. A diagnosis of ADHD is an 
inclusion criterion and should be recorded as part of the Subject’s Medical History. 
 
9.5.5 PSYCHIATRIC HISTORY 
 
Psychiatric history will be summarized by DSM-5. The frequency and percentage of subjects 
under each DSM-5 code will be summarized in the safety population. 
 
9.6 
STATISTICAL CONSIDERATIONS 
9.6.1 STATISTICAL APPROACH 
 
Analysis Populations: Baseline analysis will be performed using the ITT and safety 
Populations. Efficacy analysis will be performed using the ITT, mITT, and PP populations. 
Safety analysis will be performed in the safety population.  
 
Efficacy analysis: The primary efficacy analysis will be conducted in the ITT population, with 
supportive analyses conducted in the mITT and per protocol (PP) populations. Missing data 
will be imputed with multiple imputation. The CGI-S will be analyzed similarly using MMRM in 
the ITT population. 
 
Descriptive Statistics: For descriptive statistics, the following will be reported: 
 
• 
Continuous data: n, mean, standard deviation, median, minimum, and maximum 
• 
Categorical data: n/N and percent per arm (Placebo and each fixed dose CTx-1301) 
 
Missing Data: The following applies to the primary endpoint and is applicable to analysis of 
efficacy data collected in the randomized double-blind portion of the study. A sensitivity 

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analysis using tipping point methods will be performed. Details of the sensitivity analysis will 
be included in the SAP.  
 
9.6.2 
PRIMARY EFFICACY ENDPOINT ANALYSIS 
 
The primary efficacy endpoint is defined as the change in the ADHD-RS-5 Total Score from 
baseline to week 5. 
 
The estimand for the primary efficacy endpoint of this study is defined here in accordance with 
the ICH E9 Addendum: 
1. 
Population: The population targeted for the scientific questions is defined via the inclusion 
and exclusion criteria in children aged 6 to 17 years diagnosed with Attention-
Deficit/Hyperactivity Disorder (ADHD) confirmed by an ADHD-Rating Scale (RS)-5 score 
of at least 28 and Clinical Global Impressions Scale (CGI-S) score of 4 or higher at 
baseline. 
2. 
Variable (or endpoint): Change from baseline to week 5 of the treatment period in ADHD-
RS-5 total score. Each of the 18 items on the scale are rated from 0 (rarely) to 3 (very 
often). The sum of the scores for the 18 items provides the total score ranging from 0 to 
54. 
3. 
Intercurrent Events: A treatment policy strategy has been adopted for handling all known 
or unknown intercurrent events in this study. To this end, the ITT principle will serve as 
the analytical basis for interpreting the estimand. See SAP for more details on analysis 
visit mapping for early termination subjects. 
4. 
Population level summary: The change of ADHD-RS-5 total score from baseline to week 
5 will be analyzed using a mixed model for repeated measures (MMRM). MMRM 
assumes the data are missing at random (MAR). Missing data will be accounted for by 
the model.  
 
The observed and change from Baseline ADHD-RS-5 will be summarized at each applicable 
visit using the number of subjects, mean, standard deviation, median, minimum, and maximum 
values. Results will be presented by age group (6-12, 13-17) and overall.  
 
The null hypotheses for the primary efficacy endpoint of the equality of CTx-1301 and placebo 
is: 
• 
H01,1: mean change in ADHD-RS-5 total score between baseline and Visit 8week 5 
between the 18.75 mg CTx-1301 and placebo groups are equal 
• 
H01,2: mean change in ADHD-RS-5 total score between baseline and week 5Visit 8 
between the 25 mg CTx-1301 and placebo groups are equal 
• 
H01,3: mean change in ADHD-RS-5 total score between baseline and week 5Visit 8 
between the 37.5 mg CTx-1301 and placebo groups are equal 
The alternative hypothesis for the primary efficacy endpoint of the equality of CTx-1301 and 
placebo is: 

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• 
Ha: mean change in ADHD-RS-5 total score between baseline and week 5 
between any CTx-1301 fixed dose (18.75, 25, 37.5) and placebo groups are 
not equal 
 
The study will be considered successful if any one (or more) of the above null hypotheses 
are rejected.  
The estimate of the difference between CTx-1301 (active) and placebo will be analyzed  using 
a mixed-effects model for repeated measures (MMRM) with change from baseline as the 
dependent variable, visit, treatment group, age group, and the interaction of visit and treatment 
group as fixed effects with baseline ADHD-RS-5 as a covariate. To protect the study-wide 
Type I error rate at the 2-sided 0.05 level for testing across multiple dosage groups on the 
primary endpoint, Bonferroni correction is applied so that the hypothesis in each dose group 
is tested at alpha = 0.017 level.  More details in the primary efficacy analysis  will be described 
in the Statistical Analysis Plan (SAP).  
 
9.6.3 KEY SECONDARY EFFICACY ENDPOINT ANALYSIS 
 
The key secondary endpoint is defined as the change in the CGI-S score from baseline to 
week 5. CGI-S will be analyzed using the same MMRM model, as described above. The 
baseline CGI-S score will be used as the covariate.  
 
The null hypothesis for the key secondary efficacy endpoint of the equality of CTx-1301 and 
placebo is: 
H02: mean change in CGI-S score between baseline and week 5 in the  treatment groups are 
equal. 
 
The key secondary endpoint (CGI-S) in each dose group will be analyzed following the fixed-
sequential (hierarchical) testing procedure. If the hypothesis is significant for the primary 
endpoint at the 2-sided 0.017 significance level, the key secondary endpoint will be analyzed. 
 
9.7 
PK ANALYSIS 
 
Pharmacokinetic parameters for individual subjects will be evaluated at Day 1 (Visit 3) for 
single dose pk and Week 5 (Visit 8) steady state. The pharmacokinetic samples collected will 
be used to model and simulate the following pharmacokinetic parameters using population 
PK: Maximum Concentration (Cmax), Time of Maximum Concentration (Tmax), terminal 
elimination constant (K), lag time (Tlag), Half Life (T1/2), Area Under the Curve from time 0 to 
28 hrs (AUClast), Area Under the Curve from time 0 to infinity (AUC0-¥), and partial areas AUC0-
3, AUC3-6, AUC3-7, AUC6-9, AUC7-12, AUC9-12, and AUC12-16. Additional measures may be 
evaluated if deemed necessary. PK parameters will be evaluated by study visit, time post-
dose, and by age group. 
 
Additional details of pharmacokinetic analysis will be included in a separate PK analysis plan. 
 

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9.8 
SAFETY 
 
The safety data will be analyzed on the safety set. Safety endpoints include the occurrence of 
TEAEs, vital signs, blood labs, physical exams, BMI, and weight, C-SSRS, and ECG results.  
 
Exposure to investigational product will be summarized.  
 
Adverse events will be coded using the agreed upon version of the Medical Dictionary for 
Regulatory Activities.  
 
The number of events, incidence, and percentage of TEAEs will be calculated overall, by 
System Organ Class (SOC), by preferred term, and by treatment group. TEAEs (including 
severity/relationship) will be summarized by treatment and phase of study. TEAEs related to 
investigational products, AEs leading to withdrawal, SAEs, and deaths will be summarized. 
 
Vital signs, ECG, weight, height, physical exams, and BMI will be summarized by treatment 
and visit using the appropriate descriptive statistics. 
 
9.9 
OTHER SECONDARY ENDPOINT ANALYSIS 
CGI-I collected at Visit 8 or early termination will be summarized by treatment group and age 
group. 
 
10 
ETHICAL AND REGULATORY ASPECTS 
 
10.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI 
 
The Principal Investigator will ensure that this study is conducted in full conformance with the 
laws and regulations of the country in which the research is conducted (FDA), as well as the 
Declaration of Helsinki 1964 and ICH GCP Guidelines  
 
10.2 
INFORMED CONSENT 
 
The Investigator, or designated study staff, must obtain written (signed and dated) IRB-
approved parental permission and informed consent from the parent/legal guardian, and/or 
caregiver (if applicable) prior to their participation in this study. Informed consent will be 
obtained after full explanation of the aims, methods, objectives, and potential hazards of the 
study and prior to conducting any study specific procedures (i.e., any procedures described in 
the protocol). There must also be written (signed and dated) assent indication that the subject 
is aware of the investigational nature of the study, and the required procedures and 
restrictions, prior to the performance of any study-related procedures. The process of 
obtaining informed consent and assent should be documented in the subject source 
documents. 

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The Investigator, or designated study staff, must also explain to the subjects, parent/legal 
guardian, and/or caregiver (if applicable) that they are completely free to refuse to enter the 
study or to withdraw from it at any time. Appropriate forms for documenting a written consent 
and assent must be obtained prior to any study procedures being conducted. The Investigator, 
or designated study staff, should sign and date the consent and assent form to confirm that 
the consent process was completed correctly and the subject, parent/legal guardian, and/or 
caregiver (if applicable) has fully understood the objectives of the study as well as the risks.  
 
The subject, legal guardian, and/or caregiver (if applicable) will be provided with a copy of their 
signed and dated consent and assent form, along with any other written information, which 
they should be instructed to retain. The original will be stored with the subject’s source 
documents. 
 
Major/substantial amendments to the protocol that affect the scope of the study at the subject 
level and/or updates to the safety profile of an investigational product will be reflected in the 
updated consent and assent form and active subjects will be re-consented. 
 
10.3 
FDA 
 
This clinical study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), and applicable US regulatory requirements.  
  
10.4 
INSTITUTIONAL REVIEW BOARD (IRB) 
 
This protocol (and any modifications) as well as appropriate consent procedures, will be 
reviewed and approved by an Institutional Review Board (IRB). This body must operate in 
accordance with the current local requirements. A letter or certificate of approval must be 
received prior to initiation of the study, and when subsequent, substantial modifications to the 
protocol are made. 
 
If the study is stopped due to adverse events, it will not be recommenced without reference to 
the IRB responsible for the study.  
 
The outcome of the study (e.g., completed) will be reported to the IRB responsible for the 
study within 90 days of completion of the last subject’s final study procedures. In the event of 
the study being prematurely terminated, a report will be submitted to the IRB responsible for 
the study within 15 days.  
 
10.5 
FUNDING 
 
The study is funded by Cingulate Therapeutics, the Sponsor of the investigational study. 
 

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11 
MONITORING OF THE STUDY 
 
The extent and nature of monitoring will be described in a written monitoring plan held in the 
Trial Master File (TMF). 
 
12 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
12.1 
INVESTIGATOR’S FILES/RETENTION OF DOCUMENTS 
 
The Investigator will maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 
will be classified into three categories: (1) Trial Master File (2) Regulatory file, and (3) 
study/subject clinical source documents (including CRF). The site’s regulatory file must be 
held at the study site for as long as needed to comply with national and international 
regulations. The Sponsor will notify the Investigator(s)/institution(s) when the study-related 
records are no longer required. The Investigator agrees to adhere to the document retention 
procedures by signing the protocol. Essential documents include: 
 
•  
IRB approvals for the study protocol and amendments, 
•  
Source documents and laboratory records, 
•  
CRF copies (electronic copies on a CDROM or USB/thumb drive), 
• 
Subjects' informed consent forms (with study number and title of study), 
•  
FDA form 1572, 
•  
Any other pertinent study document. 
 
12.2 
SOURCE DOCUMENTS/DATA 
 
The source documents (e.g., clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
subject files and records kept at the pharmacy, at the laboratory and at the medico-technical 
departments involved in the clinical study) which contain the source of data recorded in the 
eCRF, and source data recorded directly into the eCRF (e.g., inclusion/exclusion criteria, 
subject enrolment) should be specified in a source document designation form.  
 
12.3 
ELECTRONIC CASE REPORT FORMS 
 
For each subject with documented informed consent, an eCRF must be completed and signed 
by the Principal Investigator to certify that the data are complete and correct. This also applies 
to those subjects who are screened but not entered the study; data should be entered up to 
the point of screen failure. If a subject is withdrawn from the study because of a treatment-
limiting AE, thorough efforts should be clearly made to document the outcome. An early 
termination eCRF must be completed for early terminations; if early termination is due to an 

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AE, it must be clearly noted that subject was terminated for an AE, specifying which AE 
required termination (if multiple AEs occur). 
 
ECRF pages should be completed during (or immediately after) a subject assessment.  
 
The study monitor(s) will review eCRFs and any queries will be highlighted to the Investigator, 
or designee(s), enabling the errors to be addressed prior to data lock of the eCRF pages.  
 
12.4 
CONTROLLED SUBSTANCE REGULATIONS AND LEGISLATION 
 
When using controlled substances, the Investigator must comply with local, state, and national 
laws pertaining to registration/reporting with the appropriate regulatory body and 
control/handling of such substances. 
 
13 
PROCESS FOR AMENDING THE PROTOCOL 
 
Protocol modifications to the study, which could potentially adversely affect the safety of 
subjects, or which alter the scope of the investigation, the scientific quality of the study, the 
experimental design, dosages, duration of therapy, assessment variables, the number of 
subjects treated, or subject selection criteria must be made only after appropriate assessment 
of the issues involved. 
 
Major/substantial protocol modifications/amendments must be reviewed and approved by the 
IRB. Approvals from the IRB must be received before the amended protocol can be 
implemented. 
 
Modifications which eliminate an apparent immediate hazard to subjects do not require pre-
approval by the IEC/IRB, but the IEC/IRB will be notified of these amendments. 
 
Approval of amendments will be made by the original Investigator signatories to the protocol. 
 
14 
CONDITIONS FOR TERMINATING THE STUDY 
 
The Sponsor reserves the right to terminate the study at any time. 
 
In terminating the study, the Sponsor will assure that adequate consideration is given to the 
protection of the subject’s interests. If the study is terminated prematurely or suspended, the 
IRB will be informed and provided with the reason(s) for termination or suspension by the 
Sponsor or by the Investigator/institution, as specified by the applicable regulatory 
requirements. 
 

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15 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT RECORDS 
 
The Investigator must ensure that the anonymity of the subject, parent/legal guardian, and/or 
caregiver (if applicable) is maintained. On eCRFs or other documents, subjects should not be 
identified by their names or initials, but by an identification code. 
 
Data on subjects collected on eCRFs during the trial will be documented in an anonymous 
fashion and the subject will only be identified by the subject number, and by his/her initials If, 
as an exception, it is necessary for safety or regulatory reasons to identify the subject, parties 
are bound to keep this information confidential. 
 
The investigator will guarantee that persons involved will respect the confidentiality of any 
information concerning the trial subjects. Parties involved in the study will maintain strict 
confidentiality to assure that neither the person nor the family privacy of a subject participating 
in the trial is violated. Likewise, the appropriate measures shall be taken to prevent access of 
non-authorized persons to the trial data. 
 
The Investigator should keep a separate log of subjects’ codes and names. Documents which 
may identify the subject, e.g., subjects’ written consent forms, will be maintained in strict 
confidence. Any electronic files that contain subjects’ personal data will be appropriately 
encrypted. Any data sent to the sponsor must be redacted of personal identifying information 
prior to sending. 
 
16 
AUDITS/INSPECTIONS 
 
In addition to the routine monitoring procedures, the Sponsor or the regulatory authority can 
conduct an audit or an inspection (during the study or after its completion) to evaluate 
compliance with the protocol and the principles of Good Clinical Practice. 
 
The Investigator agrees that representatives of the Sponsor and Regulatory Authorities will 
have direct access, both during and after the course of this study, to audit and review study-
relevant medical records. 
 
The Investigator and study subjects should understand that source documents for this study 
may be made available to appropriately qualified personnel for the study or designee(s) from 
FDA. The verification of the eCRF data may be by direct inspection of source documents (CRO 
and FDA) or through an interview exchange (FDA). 
 
17 
DISCLOSURE OF INFORMATION 
 
Information provided to the Investigator by Cingulate Therapeutics or their designee, will be 
kept strictly confidential. No disclosure shall be made except in accordance with a written right 
of publication if granted to the Investigator. 
 

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No information about this study or its progress will be provided to anyone not involved in the 
study other than to Cingulate Therapeutics or its authorized representatives, or in confidence 
to the IEC/IRB, or similar committee, except if required by law. 
 
 

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