Conditions: ADHD
Keywords: ADHD bioavailability dexmethylphenidate BA study dMPH d-MPH
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 45
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to compare the bioavailability of CTx-1301 (dexmethylphenidate) to the registered listed drug, Focalin XR and to evaluate dose proportionality of CTx-1301. In addition, this study seeks to characterize the pharmacokinetics of dexmethylphenidate and evaluate the safety and tolerability of CTx-1301.

Detailed description:
The study will comprise of a randomized, single-dose, four-sequence, four-period, in-clinic crossover study in approximately 36 adult ADHD subjects. All subjects considered eligible at Screening will proceed to tolerability test day, dosing 40 mg Focalin XR to evaluate safety and tolerability of the higher dose of d-MPH. If subject is able to safely tolerate the test dose, and meets all inclusion/exclusion criteria, they will be considered eligible for randomization into the study. All subjects will be randomized to receive four treatments throughout the course of the study; one CTx-1301 trimodal d-MPH tablet containing 6.25 mg d-MPH, one Focalin 5 mg XR capsule, one CTx-1301 50 mg tablet, and one 40 mg Focalin XR capsule. Administration of study drug will occur only on Assessment Days; no study drug will be administered during screening or unscheduled days (USVs).

The lowest and highest doses of CTx-1301 (dexmethylphenidate, 6.25 and 50 mg) were selected to bridge to the lowest and highest doses of Focalin XR (dexmethylphenidate, 5 and 40 mg) in this comparative BA study.

Arms:
arm 1: Subjects in sequence ADBC will receive study treatments in the following order: Focalin XR 5 mg capsule, CTx-1301 50 mg tablet, CTx-1301 6.25 mg tablet, Focalin XR 40 mg capsule. arm 2: Subjects in sequence BACD will receive study treatments in the following order: CTx-1301 6.25 mg tablet, Focalin XR 5 mg capsule, Focalin XR 40 mg capsule, CTx-1301 50 mg tablet. arm 3: Subjects in sequence CBDA will receive study treatments in the following order: Focalin XR 40 mg capsule, CTx-1301 6.25 mg tablet, CTx-1301 50 mg tablet, Focalin XR 5 mg capsule. arm 4: Subjects in sequence DCAB will receive study treatments in the following order: CTx-1301 50 mg tablet, Focalin XR 40 mg capsule, Focalin XR 5 mg capsule, CTx-1301 6.25 mg tablet.

Interventions: intervention 1: Dexmethylphenidate 5 Mg Oral Capsule, Extended Release intervention 2: Dexmethylphenidate 6.25 mg Tablet intervention 3: Dexmethylphenidate 40 Mg Oral Capsule, Extended Release intervention 4: Dexmethylphenidate 50 mg Tablet
Intervention descriptions: intervention 1: Reference listed drug (RLD) for comparative BA evaluation intervention 2: Experimental drug for comparative BA evaluation intervention 3: Reference listed drug (RLD) for comparative BA evaluation intervention 4: Experimental drug for comparative BA evaluation

Protocol document:
Prot_000.pdf: 
 
Clinical Protocol Number: CTx-1301-001 
 
A randomized, single-dose, four-sequence, four-period, in-clinic crossover study in adult ADHD subjects 
to establish safety, tolerability, and comparative bioavailability of CTx-1301 (dexmethylphenidate) to the 
listed drug (Focalin XR™) under fasted conditions. 
 
 
NCT04138498 
 
16Jan2020 
 
 


Protocol CTx-1301-001                               Version 4.0, Date: 16 January 2020              
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Cingulate Therapeutics 
                                                                   CONFIDENTIAL 
 
 
CLINICAL STUDY PROTOCOL 
A RANDOMIZED, SINGLE-DOSE, FOUR-SEQUENCE, FOUR-PERIOD, IN-CLINIC 
CROSS-OVER STUDY IN ADULT ADHD SUBJECTS TO ESTABLISH 
SAFETY, TOLERABILITY, AND COMPARATIVE BIOAVAILABLITY OF CTx-
1301 (DEXMETHYLPHENIDATE) TO THE LISTED DRUG  
(FOCALIN XR™) UNDER FASTED CONDITIONS  
Study Number: CTx-1301-001 
Drug Development Phase: 
Phase 1 
Investigational Product: 
Dexmethylphenidate 
Indication: 
Attention-Deficit/Hyperactivity Disorder 
(ADHD) 
Sponsor: 
Cingulate Therapeutics 
1901 W. 47th Place, Suite 310 
Kansas City, KS 66205 
Principal Investigator 
Debra Kelsh, MD 
Date: 
Version 4.0 16 January 2020 
 
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 any and all 
information contained herein has to 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. 
 
 
 


Protocol CTx-1301-001                               
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SUMMARY INFORMATION 
 
Title: 
A randomized, single-dose, four-sequence, four-period, in-
clinic crossover study in adult ADHD subjects to establish 
safety, tolerability, and comparative bioavailability of CTx-
1301 (dexmethylphenidate) to the listed drug  
(Focalin XR™) under fasted conditions.  
 
 
Protocol Number: 
 
CTx-1301-001 
 
 
Sponsor: 
 
Cingulate Therapeutics 
 
Primary Sponsor contact: 
Holly Mitzel 
Cingulate Therapeutics 
1901 W. 47th Place, Suite 310 
Kansas City, KS 66205 
E: Hmitzel@cingulatetherapeutics.com  
P: 913-942-2304 
 
 
Secondary Sponsor contact: 
Matt Brams, MD 
Cingulate Therapeutics 
1901 W. 47th Place, Suite 310 
Kansas City, KS 66205 
E: Mbrams@cingulatetherapeutics.com  
P: 713-557-8374 
 
Principal Medical Investigator: 
Debra Kelsh, MD 
E: DKelsh@altasciences.com 
P: 913-696-1601 
 
Study Site: 
Altasciences Clinical Kansas, Inc. 
10103 Metcalf Avenue 
Overland Park, KS 66212 
P: 913-696-1601 
 
Bioanalytical Site:  
Altasciences  
575 boul. Armand-Frappier 
Laval, Quebec H7V 4B3 
Canada 
P: 450-973-6077 
 
 
 
 


Protocol CTx-1301-001                               
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Cingulate Therapeutics 
                                                                       CONFIDENTIAL 
SPONSOR PROTOCOL APPROVAL 
 
 
Protocol Title: 
A randomized, single-dose, four-sequence, four-period, in-
clinic crossover study in adult ADHD subjects to establish 
safety, tolerability, and comparative bioavailability of CTx-1301 
(dexmethylphenidate) to the listed drug  
(Focalin XR™) under fasted conditions.  
 
 
Protocol Number: 
 
CTx-1301-001 
 
Protocol Version: 
4.0 
 
Date of Version: 
16 January 2020 
Signed for approval by: 
 
 
 
 
Dr. Matt Brams, MD 
Chief Medical Officer 
Cingulate Therapeutics 
 
 
 
 
 
   
 
 
 
 
 
 
 
Dr. Raul Silva, MD 
Chief Science Officer 
Cingulate Therapeutics 
 
 
 
 
  
  


Protocol CTx-1301-001                               
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Cingulate Therapeutics 
                                                                       CONFIDENTIAL 
  
  
 
PROTOCOL SIGNATURE PAGE 
I have read and understand the contents of this clinical protocol for Study No. CTx-
1301-001 date 16 January 2020 and agree to meet all obligations of Cingulate 
Therapeutics as detailed in all applicable regulations and guidelines.  
 
Signed By: 
 
Principal Investigator 
Altasciences Clinical Kansas, Inc.  
 
Date of Signature 
 
____________________________________ ________________________________ 
 
 
 


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TABLE OF CONTENTS  
 
SUMMARY INFORMATION ...................................................................................................................................... 2 
SPONSOR PROTOCOL APPROVAL.......................................................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................................................... 5 
TABLES ......................................................................................................................................................................... 6 
FIGURES ....................................................................................................................................................................... 6 
STUDY SYNOPSIS....................................................................................................................................................... 7 
ABBREVIATIONS........................................................................................................................................................ 9 
INTRODUCTION........................................................................................................................................................ 17 
1 
OBJECTIVES ..................................................................................................................................................... 18 
1.1 
PRIMARY OBJECTIVE(S) ....................................................................................................................... 18 
1.2 
SECONDARY OBJECTIVE(S) ................................................................................................................ 19 
1.3 
EXPLORATORY OBJECTIVE(S)............................................................................................................ 19 
2 
ENDPOINTS ....................................................................................................................................................... 19 
2.1 
PRIMARY ENDPOINT(S) ........................................................................................................................ 19 
2.2 
SECONDARY ENDPOINT(S) .................................................................................................................. 19 
2.3 
EXPLORATORY ENDPOINT(S) ............................................................................................................. 19 
3 
INVESTIGATIONAL PLAN ............................................................................................................................. 19 
3.1 
STUDY DESIGN ....................................................................................................................................... 19 
3.2 
RATIONALE FOR STUDY DESIGN ...................................................................................................... 20 
4 
STUDY POPULATION...................................................................................................................................... 21 
4.1 
SOURCE AND NUMBER OF SUBJECTS .............................................................................................. 21 
4.2 
CRITERIA FOR EVALUATION .............................................................................................................. 21 
4.3 
INCLUSION CRITERIA ........................................................................................................................... 21 
4.4 
EXCLUSION CRITERIA .......................................................................................................................... 22 
4.5 
SUBJECT WITHDRAWAL CRITERIA ................................................................................................... 24 
4.6 
SUBJECT REPLACEMENT ..................................................................................................................... 24 
4.7 
SUBJECT RESTRICTIONS ...................................................................................................................... 25 
5 
STUDY TREATMENTS: ASSIGNMENT & SUPPLY MANAGEMENT ...................................................... 25 
5.1 
STUDY TREATMENTS ........................................................................................................................... 25 
5.2 
STUDY SCREENING PROCEDURE AND TREATMENT ASSIGNMENT ......................................... 29 
5.3 
STUDY TREATMENT SUPPLIES MANAGEMENT ............................................................................. 30 
6 
STUDY SCHEDULE .......................................................................................................................................... 31 
7 
SCREENING AND BASELINE METHODS, MEASUREMENTS AND EVALUATIONS ........................... 31 
7.1 
SCREENING .............................................................................................................................................. 31 
7.2 
SUBJECT CONTINUED ELIGIBILITY ASSESSMENT ........................................................................ 34 
7.3 
MEAL SCHEDULE ................................................................................................................................... 34 
7.4 
EARLY TERMINATION DAY ................................................................................................................ 34 
7.5 
DURATION OF THE STUDY .................................................................................................................. 34 
8 
PHARMACOKINETICS .................................................................................................................................... 34 
8.1 
PHARMACOKINETIC BLOOD SAMPLING ......................................................................................... 34 
8.2 
BIOANALYSIS OF PLASMA SAMPLES ............................................................................................... 35 
9 
SAFETY MEASUREMENTS AND EVALUATIONS ..................................................................................... 35 
9.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .................................................................. 35 
9.2 
PREGNANCY ............................................................................................................................................ 39 
9.3 
LABORATORY EVALUATIONS RELATED TO SAFETY .................................................................. 40 
9.4 
VITAL SIGNS AND OTHER OBSERVATIONS RELATED TO SAFETY........................................... 40 
10 
STATISTICAL/DATA ANALYSIS METHODS .......................................................................................... 40 
10.1 
GENERAL CONSIDERATIONS .............................................................................................................. 40 
10.2 
STATISTICAL AND ANALYTICAL PLAN ........................................................................................... 41 
10.3 
STUDY OBJECTIVES .............................................................................................................................. 41 
10.4 
SAMPLE SIZE DETERMINATION ......................................................................................................... 41 
10.5 
ANALYSIS POPULATIONS .................................................................................................................... 41 
10.6 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................... 41 


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10.7 
PHARMACOKINETIC ANALYSIS ......................................................................................................... 42 
10.8 
SAFETY ANALYSIS ................................................................................................................................ 42 
11 
ETHICAL AND REGULATORY ASPECTS................................................................................................ 43 
11.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI ................................................................... 43 
11.2 
INFORMED CONSENT ............................................................................................................................ 43 
11.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD ................................. 43 
11.4 
FUNDING .................................................................................................................................................. 43 
12 
STUDY REPORT, DOCUMENTATION, CRFS, PUBLICATION, AND RECORD KEEPING ............... 43 
12.1 
INVESTIGATOR’S FILES/RETENTION OF DOCUMENTS ................................................................ 43 
12.2 
SOURCE DOCUMENTS/DATA .............................................................................................................. 44 
12.3 
CASE REPORT FORMS ........................................................................................................................... 44 
12.4 
CLINICAL STUDY REPORT AND PUBLICATION POLICY .............................................................. 44 
13 
PROCESS FOR AMENDING THE PROTOCOL ......................................................................................... 44 
14 
CONDITIONS FOR TERMINATING THE STUDY ................................................................................... 45 
15 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT RECORDS ....................................... 45 
16 
AUDITS/INSPECTIONS ............................................................................................................................... 45 
17 
REFERENCES ............................................................................................................................................... 46 
 
 
TABLES  
TABLE 1: STUDY SYNOPSIS..................................................................................................................................... 7 
TABLE 2: STUDY SCHEDULE................................................................................................................................. 11 
TABLE 3: SCHEDULE FOR CHECK-IN AND TOLERABILITY (DAY -4 TO DAY -3) ..................................... 13 
TABLE 4: SCHEDULE FOR ASSESSMENT DAYS DAY 0, DAY 3, DAY 6, AND DAY 9 DAYS .................... 15 
TABLE 5: STUDY TREATMENTS ........................................................................................................................... 20 
TABLE 6: STUDY DESIGN AND TREATMENT SEQUENCES ............................................................................ 20 
TABLE 7: TREATMENT-EMERGENT ADVERSE EVENTS OCCURRING DURING DOUBLE-BLIND 
TREATMENT (ADULTS) .......................................................................................................................................... 28 
TABLE 8 ...................................................................................................................................................................... 38 
 
 
FIGURES 
FIGURE 1: SCHEMATIC FOR PROPOSED TRIMODAL CTX-1301 TABLET .................................................... 18 
 
 


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Table 1: Study Synopsis  
STUDY SYNOPSIS 
 
Title 
 
A randomized, single-dose, four-sequence, four-period, in-clinic, crossover 
study in adult ADHD subjects to establish safety, tolerability, and comparative 
bioavailability of CTx-1301 (dexmethylphenidate) to the listed drug  
(Focalin XR™) under fasted conditions.  
 
Short Title/Acronym 
CTx-1301 Comparative BA Study 
Protocol Number 
CTx-1301-001 
Objective(s) 
Primary objectives: 
• 
To compare the bioavailability of the marketed product Focalin XR™ 
Extended-Release Capsules to the CTx-1301 trimodal product in a 
fasted state 
• 
To evaluate dose proportionality of CTx-1301 by evaluating the 6.25 
mg dose to the 50 mg dose 
 
Secondary objectives: 
• 
To characterize the pharmacokinetics of dexmethylphenidate  
(d-MPH) blood plasma levels after dosing  
• 
To evaluate safety measurements including ECG, vital signs, lab 
assessments, physical exam, and occurrence of treatment-emergent 
adverse events (TEAEs) 
Study Design and 
Methodology 
A single-center, randomized, four-sequence, four-period, in-clinic, crossover 
study in a fasted state. 
Subjects will be enrolled in approximately 4-5 cohorts (each cohort will enroll 
approximately 6-12 subjects/cohort) to allow for a recruitment total of 
approximately 36 completers and at least 32 evaluable subjects.   
Number of Subjects 
The study will enroll approximately 36 adult ADHD subjects  
Diagnosis and Main 
Inclusion Criteria 
Adult subjects aged 18 to 55 years, inclusive, free from any significant 
diseases/disorders (e.g. psychiatric (excluding ADHD), cardiac, hepatic, renal, 
and gastrointestinal), and can demonstrate tolerability of a single dose of 40 
mg d-MPH will be entered into the study.  
Study Product and 
Planned Use 
The investigational product, CTx-1301, is a (Precision Timed Release™ 
(PTR™) trimodal release d-MPH tablet using an erosion-barrier layer (EBL) 
technology. The investigational doses of CTx-1301 in this study are 6.25 mg 
and 50 mg (d-MPH). 
 
Tablets will be taken orally with 240 mL of room temperature water. 
 
All tablets will be administered under fasted conditions. 


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Reference therapy 
The comparator product (Listed Drug (RLD)) used in this study is Focalin XR™ 
5 mg and Focalin XR™ 40 mg (d-MPH). 
 
Capsules will be taken orally with 240 mL room temperature water. 
 
All capsules will be administered under fasted conditions. 
Treatments 
Four treatments 
a. (1) Focalin XR 5mg  
b. (1) CTx-1301 trimodal dMPH 6.25mg 
c. (1) Focalin XR 40mg 
d. (1) CTx-1301 trimodal dMPH 50mg 
Study Duration 
Each subject’s involvement in the study will be 15 days in-clinic (excluding 
screening). Completion of the clinical study will be defined as last subject, last 
visit (LSLV) at End of Study (EOS) visit.  
Treatment Duration 
Subjects will check in on Day -4, receive a test dose for tolerability (40 mg 
Focalin XR) on Day -3, and if eligible, will be randomized to the study.  The 
study treatment will be administered according to the randomization schedule 
at Day 0, Day 3, Day 6, and Day 9; subjects will remain in clinic throughout the 
study.  End of study/last visit is the EOS visit. 
 
Dosing will be separated by 72 hours (3 days) to allow washout of study drug 
and reference drug (d-MPH).  
PK Sampling Times 
Pre-dose (0) and Hours 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 
16, 20, 24, and 28. 
 
Criteria for Evaluation 
Pharmacokinetics 
The pharmacokinetic parameters to be determined are:  
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, AUC6-9, and AUC9-12, and 
AUC12-16.  Additional measures may be evaluated if deemed necessary. 
Bioanalytical Method 
Analysis of d-MPH in plasma will utilize a validated, high-performance liquid 
chromatography (HPLC) method using tandaem mass spectrometry (MS/MS) 
detection for the determination of methylphenidate in human plasma. 
Safety 
All adverse events (AEs) will be listed for each subject and summarized by the 
body system and preferred term assigned to the event using the latest version 
of the Medical Dictionary for Regulatory Activities (MedDRA) and summarized 
by system organ class and preferred term. Any serious adverse events (SAEs) 
will be listed separately.  
Statistical Methods 
Statistics will be computed and reported for pharmacokinetic and safety 
parameters obtained.  Statistical Analysis Plan (SAP) will be completed a priori 
and before unblinding and analysis of PK samples. 


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ABBREVIATIONS 
 
ADHD 
Attention Deficit and Hyperactivity Disorder 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC0-inf 
Area Under the Curve from time 0 to infinity 
AUClast 
Area Under the Curve from time 0 to 28 hrs 
 
BMI 
Body Mass Index 
Cmax 
Maximum Concentration 
CNS  
Central Nervous System 
eCRF 
Electronic Case Report Form 
CS 
Clinically Significant 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTx 
Cingulate Therapeutics 
d-MPH 
Dexmethylphenidate 
ECG 
Electrocardiogram 
ENT  
Ears, Nose, Throat 
EOS 
End Of Study 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FPFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
GI 
Gastrointestinal 
GRAS 
Generally Regarded As Safe 
Hb  
Hemoglobin 
Hct  
Hematocrit 
HPLC 
High-performance liquid chromatography 
Hr.  
Hour(s) 
ICH  
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
K 
Terminal elimination constant 
kg 
Kilograms 
kg/m2 
kilograms Per Meter Squared 
L 
Liter 
LSLV 
Last Subject Last Visit 
m 
Meter 
MCH 
Mean Cell Hemoglobin 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary For Regulatory Activities 
mg 
Milligram(s) 
min 
Minute 
mL 
Milliliter(s) 
mmHg 
Millimeters Of Mercury 
D-MPH 
Dexmethylphenidate  
MPH 
Racemic Methylphenidate (d, l-MPH) 
ms 
Millisecond 
MS/MS 
Tandem mass spetcrometry 
mSv 
Millisieverts 
NCS  
Not Clinically Significant 
NMS 
Neuroleptic Malignant Syndrome 
PCP 
Primary Care Physician 
PK 
Pharmacokinetic 
RBC 
Red Blood Cell 
RLD 
Reference Listed Drug 
 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 


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TEAE 
Treatment Emergent Adverse Event 
T1/2 
Half Life 
Tlag 
Lag time 
Tmax 
Time of Maximum Concentration 
U 
Unit 
USV 
Unscheduled Visit 
WBC 
White Blood Cell 


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Table 2: Study Schedule 
Procedure 
Screening a 
(Day -28 to 
Day -5) 
Clinic 
Check-In 
(Day -4) 
Tolerability c 
Test 
(Day -3) 
 
(Day -2) 
(Day -1) 
Assessment 
Days 
(Day 0, 3, 6, 
and 9) 
 
Non-
Assessment 
Days 
(Day 1, 2, 4, 5, 
7, & 8) 
 
EOS or 
ETll 
 
Unscheduled 
(USV)m 
Written Informed Consent  
✓ 
 
 
 
 
 
 
 
 
Demographics 
✓ 
 
 
 
 
 
 
 
Medical History  
✓ 
✓ 
 
 
 
 
 
 
Current/Concomitant 
Medications 
✓ 
✓ 
✓ 
 
 
✓ 
✓ 
 
Inclusion & Exclusion 
Criteria 
✓ 
✓ 
✓ 
 
 
✓ d 
 
 
Wash-Out Call 
✓b 
 
 
 
 
 
 
 
Physical Examination 
✓ 
✓ 
 
 
 
✓e 
✓ 
 
MINI 7.0.2 version 
✓ 
 
 
 
 
 
 
 
C-SSRS 
✓ 
✓ 
✓ 
 
 
✓ 
✓ 
 
Electrocardiogram (ECG) 
✓ 
✓ 
✓f 
 
 
✓f 
✓f 
 
Vital Signs  
✓ 
✓ 
✓g 
 
 
✓ g 
✓g 
✓ g 
 
Height 
✓ 
 
 
 
 
 
 
 
 
Weight 
✓ 
✓ 
 
 
 
 
✓ 
 
Serology 
✓ 
 
 
 
 
 
 
 
Clinical Safety Labs:  
 
 
 
 
 
 
 
 
Biochemistry 
✓ 
✓ 
✓ 
 
Hematology 
✓ 
✓ 
✓ 
 
Urinalysis 
✓ 
✓ 
✓ 
 
Serum HCG 
✓h 
✓h 
 
 
 
 
✓h 
 


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Table 2: Study Schedule 
Procedure 
Screening a 
(Day -28 to 
Day -5) 
Clinic 
Check-In 
(Day -4) 
Tolerability c 
Test 
(Day -3) 
 
(Day -2) 
(Day -1) 
Assessment 
Days 
(Day 0, 3, 6, 
and 9) 
 
Non-
Assessment 
Days 
(Day 1, 2, 4, 5, 
7, & 8) 
 
EOS or 
ETll 
 
Unscheduled 
(USV)m 
Urine Screen for Drugs of 
Abuse  
✓ 
✓ 
 
 
 
 
 
 
Breath Alcohol Test 
✓ 
✓ 
 
 
 
 
 
 
AE Assessment 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Ongoing Eligibility  
 
 
 
 
 
✓ 
 
✓ 
 
Test Dose of 40mg Focalin 
XR™  
 
 
✓ c 
 
 
 
 
 
Randomization 
 
 
 
 
 
✓ i 
 
 
Treatment Administration 
 
 
 
 
 
 
✓ j 
 
 
PK Blood Sampling  
 
 
 
 
 
✓ k 
✓ k 
 
 
 
a: Screening day(s) will take place up to 24 days prior to Day -4 (check-in at clinic). 
b. Washout call reminder should be completed 120 hrs (5 days) prior to Day -4.  If subject is screened within the 120 hrs prior to Day -4, the washout call reminder is not required.    
c. Tolerability day with Focalin XR 40 mg must occur on Day -3, allowing 3 days prior to Day 0 /Randomization to ensure washout of d-MPH. Dosing must occur by approximately 8:30 am. If subject 
can’t tolerate test dose, subject must be excluded. 
d. Inclusion/Exclusion assessed at Screening, Day -4, and Day 0 prior to randomization; Eligibility continually assessed throughout study.  
e. PE to occur mid-study on Day 6 
f:  ECG’s administered on tolerability and Assessment days must be done prior to dosing, hr. 6, and hr. 28 (+/-30 min for post-dose ECGs). 
g  Vital signs will be taken prior to dosing and at 1 hr., 2 hr., 6 hr., and 28 hr. post-dose (+/- 10 minutes) at tolerability day (Day -3) and Days 0-9.   
h. Serum HCG tests should be assessed in women of child-bearing potential at Screening, Check-In (Day -4), and EOS/ET. 
i.  Randomization will occur on Day 0 after ensuring subject still meets inclusion/exclusion criteria  
j.  Administration of study treatment must be separated by 3 days (72 hours). Administration of study treatments will occur on Day 0, Day 3, Day 6, and Day 9 by approximately 8:30 am.   
k. Blood samples for PK analysis will be taken pre-dose (0)  -1 to 0 hr.) and post-dose at hrs. 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 24, and 28; if for ET visit, collect one last 
pk draw and record time of collection.  
l.  Early Termination (ET) day assessments should follow the EOS assessment schedule.  If all assessments are not completed, note reason for noncompletion.  
m. USV is at the discretion of an Investigator; USV will have no treatment administration or PK draws/analysis. All other assessments are at the discretion of the investigator. 
 
 


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Table 3: Schedule for Check-In and Tolerability (Day -4 to Day -3)  
Time Relative to 
Dose (hr.)  
Subject Activity 
Fluid/Food 
intake d 
 
ECGc 
Vital 
signse 
Safety and AE Monitoring 
-12 to -10 (check-in, 
Day -4) 
Assessment of 
eligibility. 
Urine analysis for 
drugs and breath 
alcohol test a 
 
 
 
Fasting from at 
least 10 hr. 
prior to dosing. 
 
Water ad 
libitum 
 
 
 
 
Clinical Safety Labs for 
Inclusion/Exclusion 
-1.00 – 0 (pre-dose) 
 
Decaffeinated 
Fluids/Water is 
restricted at 
least 1 hr. prior 
to dosing. 
ECG 
should 
be taken 
within 60-
minute 
window 
prior to 
dosingc 
 
✓ 
 
-.50 - 0 (pre-dose) 
0 
Dosing  
240 mL water 
w/dose 
  
 
Continuous AE monitoring 
↨ 
 
Subject to remain 
seatedb 
 
 
Decaffeinated 
Fluids/Water is 
restricted until 
at least 2 hrs 
after dosing. 
 
✓ 
2 
✓ 
↨ 
 
Fasting from 
dosing to at 
least 4 hrs after 
dosing 
 
Water ad 
libitum.  
 
 
4 
 
Lunchd 
↨ 
 
 
Water ad 
libitum 
 
6 
Snackd 
ECGc     
 
✓ 
↨ 
Water ad 
libitum  
  
 
8 
 
9 
 
Dinnerd 


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Table 3: Schedule for Check-In and Tolerability (Day -4 to Day -3)  
Time Relative to 
Dose (hr.)  
Subject Activity 
Fluid/Food 
intake d 
 
ECGc 
Vital 
signse 
Safety and AE Monitoring 
↨ 
 
Decaffeinated 
fluid ad libitum 
 
 
12 
 
Snackd 
↨ 
 
 
Decaffeinated 
Water / 
decaffeinated 
fluid ad libitum 
 
14 
↨ 
16 
 
 
23 
 
24 
Breakfastd 
↨ 
 
28 
ECGc 
✓ 
 
a  Urine analysis for drugs and breath alcohol test will be conducted and reviewed prior to subject dosing. Tests may be repeated at 
an Investigator's discretion. 
b  Subject must remain seated upright for at least 2 hrs after dosing, unless the subject is required to be supine for a study procedure 
or experiences an AE. Brief periods of standing are okay under supervision (e.g., to use the restroom). Subjects may be ambulatory 
or seated upright from hours 2- 4.  Activity beyond hour 4 is not restricted with the exception that it shouldn’t include any activity that 
may increase the subject’s heart rate. 
c  An ECG should be taken approximately within 60 minutes prior to dosing, hr. 6, and hr. 28 (± 30 min of the target time for post-
dose ECGs) 
d Acceptable water, snack, and lunch/dinner times will be considered ± 30 min of the target time, except for hr 4; hr 4 must occur at 
hr 4 or +30 min.  
e Vital signs will be taken within approximately 60 minutes prior to dosing and at 1 hr., 2 hr., 6 hr., and 28 hr. post-dose (+/- 10 minutes).  
 
 
 
 


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Table 4: Schedule for Assessment Days Day 0, Day 3, Day 6, and Day 9 Days 
Time Relative 
to Dose (hr.) 
Subject 
Activity 
Blood Sampling b 
Fluid/Food 
intaked 
ECG 
Vital signse 
AE 
Monitoring 
-12 to -10 
(pre-dose) 
Snack is 
available if 
needed 
 
Water ad 
libitum 
 
 
Continuous 
AE 
monitoring 
(subjects 
will not be 
woken to 
answer 
question if 
sleeping) 
-10 
  (pre-dose) 
 
 
Fasting from 
at least 10 hr. 
prior to 
dosing. 
 
 Water ad 
libitum 
 
-1.0 to 0   
(pre-dose) 
 
Venipuncture or 
Insertion of cannula 
and pre-dose 
sample. 
Decaffeinated 
Fluids/Water 
is restricted at 
least    1 hr. 
prior to 
dosing. 
 
ECG should 
be taken 
within 60-
minute 
window prior 
to dosingc 
 
Vital signs 
should be 
taken within 60-
minute window 
prior to dosing 
-.50 to 0 
(pre-dose) 
0 
Dosing  
 
240 mL water 
w/dose 
 
 
↨ 
Subject to 
remain seateda 
Blood sampling 
times: 0.5, 1, 1.5, 2, 
3, 4, 5, 6, 7, 8, 9, 
10, 11, 12, 13, 14, 
15, 16, 20 and 24, 
and 28 hr. post-
dose. b 
 
Decaffeinated 
Fluids/Water 
is restricted 
until at least 2 
hrs after 
dosing. 
 
✓ 
2 
✓ 
↨ 
 
Water ad 
libitum 
 
Fasting from 
dosing to at 
least 4 hrs 
after dosing. 
 
 
4 
 
 
Lunchd 
↨ 
 
Water ad 
libitum 


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Table 4: Schedule for Assessment Days Day 0, Day 3, Day 6, and Day 9 Days 
Time Relative 
to Dose (hr.) 
Subject 
Activity 
Blood Sampling b 
Fluid/Food 
intaked 
ECG 
Vital signse 
AE 
Monitoring 
6 
Snackd 
ECGc 
✓ 
↨ 
Water ad 
libitum 
 
 
8 
 
 
9 
 
Dinnerd 
↨ 
Decaffeinated 
fluid ad libitum 
12 
 
 
 
Snackd 
↨ 
 
Water / 
decaffeinated 
fluid ad libitum 
 
14 
↨ 
16 
 
 
↨ 
 
23 
24 
Breakfastd 
↨ 
 
28b 
ECGc 
✓ 
End of 
Assessment 
Day 
Depart Site f 
 
 
 
 
 
a Subject must remain seated upright for at least 2 hrs. after dosing, unless the subject is required to be supine for a study procedure 
or experiences an AE. Brief periods of standing are okay under supervision (e.g., to use the restroom). Subjects may be ambulatory 
or seated upright from hours 2-4.  Activity beyond hr. 4 is not restricted with the exception that it shouldn’t include any activity that 
may increase the subject’s heart rate. 
b An acceptable pre-dose PK blood sampling time will be considered -1 to 0 hr of target time (0). Post-dose PK blood sampling time 
will be considered ± 5 min of the target time; Exact time of PK draw must be recorded to the hr. and minute.  
c  An ECG should be taken approximately within 60 minutes prior to dosing, hr. 6, and hr. 28 (± 30 min of the target time for post-
dose ECGs) 
d Acceptable water, snack, and lunch/dinner times will be considered ± 30 min of the target time, except for hr 4; hr 4 must occur at 
hr 4 or +30 min.  
e Vital signs will be taken within approximately 60 minutes prior to dosing and at 1 hr., 2 hr., 6 hr., and 28 hr. post-dose (+/- 10 minutes) 
Days 0-9.  Vital signs on non-dosing days should follow the same schedule as dosing days. 
f Subject departs site after hr. 28 on EOS/ET day.  
 


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INTRODUCTION  
 
Attention-deficit and 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 one time considered a childhood illness 
that resolved in adolescence, it is now believed that impulsivity and hyperactivity may morph into executive 
dysfunction and emotional dyscontrol in adults.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 
 
Prior to the introduction of the enantiopure d-MPH (d-threo-(R,R)-MPH, dexmethylphenidate,) in 2002, all 
clinically used MPH formulations contained a racemic (1:1) mixture of d-threo-(R,R)-MPH and l-threo-(R,R)-
MPH isomers. The development of d-MPH product 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 hrs in open label studies.14  
 
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 was developed that could be administered once a day.15  
Using analogue laboratory classroom studies, the onset of action for this formulation was documented at 
30 minutes after medication administration and the duration of affect when compared to placebo 
demonstrated clinically and statistical differences at 12 hrs after initial administration.16,17 Despite this, 
ratings at hour 12 for key symptoms of ADHD yielded results that were worse than baseline symptom levels.  
 
A major drawback to most long acting stimulant products currently on the market is that they do not remain 
effective more than 12 hours after administration. For many adults and college students this duration in 
coverage is not sufficiently long. Furthermore, as blood levels drop precipitously during the latter portions 
of the day, subjects also experience a crash or rebound effect, which often manifests in adverse effects 
such as irritability, mood changes and worsening of clinical presentations. 
 
The current project is a randomized, single-dose, four-sequence, four-period study in adult ADHD subjects 
to establish safety and comparative bioavailability of CTx-1301 to the listed drug, FocalinTM XR Extended-
Release Capsules.  
 
As shown in Figure 1, the release times of the CTx-1301 trimodal tablet is expected to be: 
 
1) 1st dose, immediate release (35% of the total daily dose) 
2) 2nd dose, delayed, sustained release 90 minutes after a 3-4 hour delay (45% of the total daily 
dose) 
3) 3rd dose, delayed, immediate release 7-8 hours post-dose (20% of the total daily dose) 
 
 
 


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Figure 1: Schematic for Proposed Trimodal CTx-1301 Tablet 
 
The study will comprise of a randomized, single-dose, four-sequence, four-period, in-clinic crossover study 
in approximately 36 adult ADHD subjects. All subjects considered eligible at Screening will proceed to 
tolerability test day, dosing 40 mg Focalin XR to evaluate safety and tolerability of the higher dose of d-
MPH. If subject is able to safely tolerate the test dose, and meets all inclusion/exclusion criteria, they will 
be considered eligible for randomization into the study.  All subjects will be randomized to receive four 
treatments throughout the course of the study; one CTx-1301 trimodal d-MPH tablet containing 6.25 mg d-
MPH, one Focalin 5 mg XR capsule, one CTx-1301 50 mg tablet, and one 40 mg Focalin XR capsule. 
Administration of study drug will occur only on Assessment Days; no study drug will be administered during 
screening or unscheduled days (USVs).    
 
The lowest and highest doses of CTx-1301 (dexmethylphenidate, 6.25 and 50 mg) were selected to bridge 
to the lowest and highest doses of Focalin XR (dexmethylphenidate, 5 and 40 mg) in this comparative BA 
study.  
 
 
 
1 
OBJECTIVES  
 
1.1 
PRIMARY OBJECTIVE(S) 
 
• 
To compare the bioavailability of the marketed product FocalinTM XR Extended-Release Capsules 
to the CTx-1301 trimodal product in a fasted state. 
o 
Demonstrate similar and comparative bioavailability of the highest dose of CTx-1301 (50 
mg) to Focalin XR (40 mg) dose 
o 
Demonstrate similar and comparative bioavailability of the lowest dose of CTx-1301 (6.25 
mg) to the lowest dose of Focalin XR (5 mg) 
o 
Demonstrate dose proportionality of CTx-1301 by evaluating the 6.25 mg dose to the 50 
mg dose 
 
 
 
Immediate Release (d-MPH) 
Delayed, Sustained Release (d-MPH)  
Delayed, Immediate Release (d-MPH) 
OralogiK™  
Erosion Barriers  
FIGURE 1 


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1.2 
SECONDARY OBJECTIVE(S) 
 
• 
To provide pharmacokinetic data on blood plasma levels of d-MPH 
• 
To evaluate the safety of CTx-1301 6.25 mg and 50 mg dose 
 
1.3 
EXPLORATORY OBJECTIVE(S) 
 
• 
To further explore the impact of comparative bioavailability of the marketed product FocalinTM XR 
Extended-Release Capsules to the CTx-1301 trimodal product in a fasted state within selected time 
intervals 
 
2 
ENDPOINTS 
 
2.1 
PRIMARY ENDPOINT(S) 
 
• 
 PK parameters including Cmax, AUC0-inf, and AUClast.  
 
2.2 
SECONDARY ENDPOINT(S) 
 
• 
PK plasma concentrations of d-MPH and PK parameters including partial AUCs (e.g. AUC0-3, AUC3-
6, AUC6-9, AUC9-12, and AUC12-16) to examine potential differences between treatments (CTx-1301 
6.25 mg vs. FocalinTM XR 5 mg and CTx-1301 50 mg vs. FocalinTM XR 40 mg) within selected 
time intervals. 
• 
PK plasma concentrations of d-MPH and PK parameters including K, T1/2, tmax, and tlag. 
• 
Safety measurements including ECG, vital signs, lab assessments, physical exam, and the 
incidence of treatment-emergent adverse events (TEAEs) 
 
2.3 
EXPLORATORY ENDPOINT(S) 
 
• 
Additional exploratory analyses may be conducted to examine potential differences between 
treatments (CTx-1301 6.25 mg vs. FocalinTM XR 5 mg and CTx-1301 50 mg vs. FocalinTM XR 40 
mg) within selected time intervals. 
 
3 
INVESTIGATIONAL PLAN 
 
3.1 
STUDY DESIGN 
 
This is a randomized, single-dose, four-sequence, four-period, in-clinic crossover study under fasted 
conditions. The study will involve approximately 36 adult ADHD subjects, male or female.  The Screening 
period will occur from Day -28 to Day -5; subjects that meet eligibility at screening must washout of all 
stimulant medications at least 96 hrs prior to check in on Day -4.  Subjects will remain in clinic from Day -4 
to the EOS visit.  
 
Subjects which complete screening, if eligible, will be brought back for the in-clinic portion of the study.  
Subjects will be reassessed for eligibility at check-in on Day -4 to ensure they still meet study criteria. 
Eligible Subjects will be in-clinic for the entire duration of the 15-day study (Day -4 to EOS).  Study visits 
include: check-in day (Day -4), tolerability assessment (Day -3), Assessment 1 (Day 0), Assessment 2 (Day 
3), Assessment 3 (Day 6), Assessment 4 (Day 9), and EOS.  Subjects that early terminate should follow 
the assessment structure of the EOS day; a final PK draw should be collected and labeled at ET time. 
Additional unscheduled days or assessments may be requested by an Investigator if concerned for subject 
safety.  
 


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Subjects will be dosed with the following treatments according to a pre-defined, balanced, randomized 
crossover schedule: 
 
Table 5: Study Treatments 
 
Treatment A 
FocalinTM XR Extended-Release capsule 5 mg 
Treatment B 
CTx-1301 trimodal 6.25 mg tablet 
Treatment C 
FocalinTM XR Extended-Release capsule 40 mg  
Treatment D 
CTx-1301 trimodal 50 mg tablet 
 
Subjects will be randomized to sequences of treatment according to a 4x4 Williams design. Williams Design 
is a special case of Latin square design and is balanced for carryover effects.  
 
Table 6: Study Design and Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
1 (n = 9) 
A 
D 
B 
C 
2 (n = 9)  
B 
A 
C 
D 
3 (n = 9)  
C 
B 
D 
A 
4 (n = 9)  
D 
C 
A 
B 
 
Subjects must washout of all stimulant medications for a minimum of 96 hrs prior to check in on Day -4. 
Subjects must arrive at the clinic on Day -4 for check in (at least 12 hours prior to hr. 0 on Day -3).  Subjects 
may receive a snack (if needed) from hours -12 to -10 on Day -4; at -10 hrs, all subjects must fast until at 
least hr. 4 post-dose. Water is restricted at least 1 hour prior to dosing and at least 2 hours after dosing. An 
Investigator will assess if a subject has safely tolerated the 40mg dose of Focalin XR and can continue into 
the randomized portion of the study.  
 
Subjects must fast from at least 10 hrs prior to dosing and at least 4 hours post-dose on the test day and 
all Assessment Days (water is restricted at least 1 hr. prior to dosing and at least 2 hrs after dosing).  Blood 
samples for pharmacokinetic analysis will be taken at the protocol-specified time points until 28 hr. post-
dose (see Table 4). Vital signs (blood pressure and pulse) and ECG will be taken at the protocol-specified 
time points until 28 hr. post-dose.   
 
Subjects will be discharged from the study center once they have completed all study assessments. The 
maximum period the subjects will be at the study center is approximately 15 days. 
 
3.2 
RATIONALE FOR STUDY DESIGN 
 
This study will use pharmacokinetic (pk) analysis to investigate the in vivo behavior of CTx-1301 tablets 
compared to Focalin XR™ (RLD) for bridging to the RLD.  
 
The randomized crossover study design allows subjects to act as their own control, thereby optimizing 
model sensitivity by reducing the risk of subject variability between the test formulation and comparator. 
 
The three-day period (72 hrs) between Assessment Days is sufficient for the washout of the drug (the 
plasma elimination half-life of d-MPH is approximately 3 hrs.). Subjects are kept in-clinic to increase 
compliance and reduce drop-out rates.  
 
ADHD subjects meeting all inclusion criteria and no exclusion criteria will be recruited for the study.  
 


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4 
STUDY POPULATION 
 
4.1 
SOURCE AND NUMBER OF SUBJECTS 
 
The study site will recruit potential subjects from its database, referral network, as well as local advertising, 
if required.   
 
Approximately 36 subjects will be randomized in the study to achieve completion of approximately 32 
evaluable subjects for the full study (approximately 8 in each sequence).  
 
 
4.2 
CRITERIA FOR EVALUATION 
 
Eligibility of subjects for study enrollment will be based on the results of a screening medical history, 
physical examination, mental state examination, vital signs (blood pressure and pulse), breath alcohol, 
urine drugs of abuse, tolerance of 40 mg Focalin XR on the test day, and clinical laboratory tests. All 
screening tests will be performed and assessed by qualified study personnel. The nature of any conditions 
present at the time of the physical and mental state examinations and any pre-existing conditions will be 
documented and carefully evaluated by an Investigator. 
 
4.3 
INCLUSION CRITERIA 
 
1. Gender  
a. Male or Female 
 
2. Age 
a. Aged between 18 and 55 years inclusive. 
 
3. Weight and BMI 
a. Body weight ≥ 50 kg 
b. BMI ≥ 18 and ≤ 35  
 
4. Compliance 
a. Understands and is willing, able and likely to comply with all study procedures and restrictions. 
b. If sexually active, male subjects must use the double-barrier method (condom and spermicide) 
for birth control during the study and for 90 days following the last administration of study drug. 
c. If sexually active, female subjects of child-bearing potential must use an acceptable method of 
contraception, including abstinence from heterosexual intercourse, hormonal contraceptives, 
intrauterine device (IUD) with or without hormones, or double-barrier method (e.g. condom and 
spermicide), during the study and for 30 days following the last administration of study drug. 
d. Male subjects must agree not to donate sperm during the study and for 90 days following the 
last administration of study drug. 
e. Female subjects must agree not to donate eggs during the study and for 30 days following the 
last administration of study drug. 
 
5. Consent 
a. Demonstrates understanding of the study and willingness to participate as evidenced by 
voluntary written informed consent (signed and dated) obtained before any study-related 
activities are performed. 
 
6. Indication 
a. Subject must report history of diagnosis of ADHD. 
 


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b. If subject is currently taking stimulant medication, they must be willing and able to safely abstain 
from any other ADHD treatment during 96 hrs. prior to check-in on Day -4 and through the 
complete duration of the study. 
 
7. General Health 
a. Good general health (in the opinion of an investigator) with no clinically significant or relevant 
abnormalities on medical history or physical examination which could affect the safety of the 
subject or study data. 
b. No vomiting or fever within 24-hours of check-in at Day -4  
 
c. Subject has sufficient venous access to allow cannulation and/or venipuncture to obtain the 
required volume of blood for this study. 
 
d. Subject must currently be taking or previously have taken a stimulant medication for ADHD. 
 
8. Smoking/Caffeine/Alcohol 
a. Subject must be able to refrain from smoking cigarettes 1 hour prior to dosing and 7 hours after 
dosing on dosing days.  Subject must agree not to smoke more than one cigarette per hour, 
not to exceed 10 cigarettes per day. 
b. Subject must be able to refrain from caffeine for 10 hours prior to check-in at Day -4 and for 
the duration of the study. 
c. Subject must be able to refrain from using alcohol 48 hrs. prior to Day -4 and for the duration 
of the study. 
 
9. ADHD Medication History 
a. Subject’s medication history suggests they will be able to tolerate a 40 mg dose of 
dexmethylphenidate. 
b. Subject must demonstrate tolerability of dexmethylphenidate assessed by tolerability day/test 
dose of 40 mg Focalin XR as evaluated by the investigator.  
 
4.4 
EXCLUSION CRITERIA 
 
1. Medical History 
 
a. Current and/or recurrent disease or illness that, in the opinion of an investigator, could affect 
the study conduct, study outcome, subject safety, or pharmacokinetic (PK) assessments (e.g., 
hepatic disorders, renal insufficiency, non-self-limiting gastrointestinal disorders, congestive 
heart failure). 
 
b. Current and/or previous history of any other serious, severe or unstable psychiatric illness 
which in the opinion of the investigator, may require treatment (e.g. anxiety, psychosis, mood 
disorder, motor tics or suicidality) or make the subject unlikely to fully complete the study, 
and/or any condition that presents undue risk from the study medication or procedures. 
 
c. Subject cannot have suicidal thoughts within the last 6 months as supported by the Columbia 
Suicide Severity Rating Scale (C-SSRS). 
 
d. Positive test results for Human Immunodeficiency Virus (HIV)-1/HIV-2 antibodies, Hepatitis B 
surface antigen (HBsAg) or Hepatitis C virus antibody (HCVAb). 
 
e. A family history of sudden cardiac or unexplained death. 
 
f. 
Any condition or abnormal laboratory finding that could result in harm to the subject, affect the 
outcome of the study, or suggest unstable medical illness. 
 


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g. As a result of the MINI, medical history, physical examination, and/or screening investigations 
(including ECG results, vital signs and/or laboratory abnormality), an Investigator considers the 
subject disqualified for the study. 
 
h. Subject plans to undergo elective procedures/surgery at any time during the study. 
 
i. 
Subject has had surgery within the past 90 days. 
 
j. 
Subject of child-bearing potential is pregnant or planning to become pregnant during the 
duration of the study or within 30 days of the end of the study. 
 
k. Subject is breast-feeding during the study or within 30 days of the study. 
 
 
2. Medications 
 
a. Subject has taken any medication that, in the opinion of an Investigator, has been shown to alter 
the PK of d-MPH.  
 
b. Use of any prescription medication within 14 days prior to Day -4 (ADHD medications must be 
discontinued at least 96 hours prior to check-in at Day -4), and/or use of any OTC medications 
(such as antacids, vitamins, minerals, dietary/herbal preparations, and nutritional supplements) 
within 7 days prior to Day -3 unless jointly approved by an Investigator and Sponsor.   
i. 
Subjects are permitted to take hormonal contraceptives and hormone replacement 
therapy at acceptable levels if stable at least 30 days prior to Day -4, through the duration 
of the study, and for 30 days after the study ends.  
ii. 
Acetaminophen (up to 2 grams per day) may be used during the study under the direction 
of the Investigator.  
iii. 
On a case-by-case basis, an Investigator is permitted to allow the use of certain 
concomitant medications, for example, to treat an AE, as long as an Investigator 
determines that the medication will not affect the subject’s safety or study integrity (eg, 
topical medications). 
 
 
3. Alcohol/Substance Abuse 
 
a. Recent history (within the last year) of alcohol or other substance abuse.  
 
b. Subject has positive breath alcohol test or urine test for drugs of abuse at screening or check-in 
(except THC). Prescribed ADHD medication is acceptable during screening but must be stopped 
at least 96 hrs prior to check in at Day -4. Note: At the discretion of an Investigator, the tests may 
be repeated.  If THC is positive at screening or check-in, a cannabis intoxication evaluation will be 
done by an investigator at check-in on Day -4;  inclusion will be at the investigator’s discretion, due 
to the slow release of THC from adipose tissue. 
 
4. Smoking 
 
a. Subject regularly smokes more than 10 cigarettes/day (or other nicotine-containing products)  
or Subject has recently discontinued smoking (within the last 3 months)  
 
 
5. Allergy/Intolerance 
 
a. Subject has a history of allergy to d-MPH, to any component of the dosage form, or any other 
allergy, which, in the opinion of an Investigator, contraindicates their participation. 


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6. Clinical Studies 
 
a. Participation in another investigational product study (inclusive of final post-study examination) or 
receipt of an investigational drug within the 30 days before screening day.  
 
b. Previous participation in this study.  
 
 
7. Personnel 
 
a. An employee of the sponsor, study site, or members of their immediate family.  
 
 
8. Blood 
 
a. Subject has donated blood, plasma, or experienced significant blood loss (excess of 500 ml) within 
3 months of screening and for the duration of the study. 
 
4.5 
SUBJECT WITHDRAWAL CRITERIA 
 
Subjects have the right to withdraw from the study at any time for any reason. An 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 reasons, or other 
reasons. It is understood by all 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, all 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 
made at the time of withdrawal following the procedures of EOS, including a final PK draw and an 
explanation of why the subject is withdrawing from the study. All reasons for early withdrawal must be 
recorded. 
 
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 source and electronic case report form 
(eCRF) and AE should be the documented reason for removal. Any AEs ongoing at the final day will be 
followed up until resolved, the condition stabilizes, is otherwise explained, or the subject is lost to follow-
up.   
 
4.6 
SUBJECT REPLACEMENT 
 
Approximately 36 subjects will be randomized in order to achieve the target of 32 evaluable subjects 
completing the entire study.  Subjects that early terminate, or otherwise have insufficient blood 
concentration data as to be evaluable, may be replaced at the discretion of the Sponsor.  All subjects treated 
with at least one dose will be evaluated for the safety population.  All subjects who receive at least one 
study treatment and complete at least one PK blood draw will be included in PK analysis.   
 
Back-up subjects may be recruited to the site on Day -4 in case of screen failures.  The study will be 
conducted in approximately 4-5 cohorts.  It is assumed that each cohort will randomize approximately 6-12 
subjects to allow for a recruitment total of approximately 36 completers and at least 32 evaluable subjects.  
. Subsequent cohorts will accommodate for dropouts should any subjects be identified as not evaluable.  
At the end of the third cohort, enrollment may be evaluated for completeness (e.g. 32 evaluable, 8 per 
sequence, for planned comparisions) by an unblinded biostatistician otherwise not involved in study 
conduct.  If the required number of evaluable subjects is not achieved, the study may proceed with 
additional cohort recruitment.   


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4.7 
SUBJECT RESTRICTIONS 
 
4.7.1 
Lifestyle 
 
• 
Subjects must be able to fast for at least 10 hrs prior to dosing and at least 4 hours post-dose for the 
tolerability test (Day -3) and for each Assessment Day (Day 0, 3, 6, and 9).  
 
• 
Subjects must not consume any fluids for at least 1 hr. prior to dosing and at least 2 hrs following 
dosing, excluding the 240 mL of water administered with the dose. 
 
• 
Subjects must be able to refrain from smoking 1 hour prior to dosing and 7 hours post dose.  Subject 
must not smoke more than 1 cigaratte per hour, not to exceed 10 cigarettes per day. 
 
• 
Subjects must abstain from alcohol consumption for 48 hrs prior to check in at Day -4 and for the 
duration of the study. 
 
• 
Subjects must not consume any caffeine or xanthine-containing beverages or foods (e.g., tea, coffee, 
chocolate, cola) for at least 10 hrs prior to Day -4 and for the duration of the study.   
 
• 
Subject has donated blood, plasma, or experienced significant blood loss (excess of 500 ml) within 3 
months of screening and for the duration of the study. 
 
 
4.7.2 
Medications and treatments 
 
• 
Subjects must discontinue all ADHD medications at least 96 hrs prior to check in at Day -4. 
• 
Subjects must not use prescription medication within 14 days prior to Day -4 (ADHD medications 
must be discontinued at least 96 hours prior to Day -4) and/or use any OTC medications (such as 
antacids, vitamins, minerals, dietary/herbal preparations, and nutritional supplements) within 
7 days prior to Day -3, unless jointly approved by an Investigator and Sponsor.   
 
Subjects will be questioned on compliance with restrictions prior to commencement of each assessment 
day.  An Investigator, with approval from the Medical Monitor, will determine ongoing eligibility and whether 
a deviation from the restrictions warrants the subject’s withdrawal from the study.  All deviations should be 
documented in the source document and eCRF. 
 
 
5 
STUDY TREATMENTS: ASSIGNMENT & SUPPLY MANAGEMENT 
 
5.1 
STUDY TREATMENTS 
 
5.1.1 
Identity of study treatments  
 
An unblinded clinical staff member will dispense the following treatments according to a pre-defined 
randomization schedule provided by the Sponsor. All treatments will be dispensed in a blinded, closed-lid 
cup to blind the subjects and the study staff. The treatments administered during the study are as follows: 
 
Treatment A 
FocalinTM XR Extended-Release capsule 5 mg 
Treatment B 
CTx-1301 trimodal tablet 6.25 mg 
Treatment C 
FocalinTM XR Extended-Release capsule 40 mg 
Treatment D 
CTx-1301 trimodal tablet 50 mg 
 
Trimodal d-MPH tablet  


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Standard pharmaceutical excipients will be used during the manufacturing of the tablets.  The dose of d-
MPH in each tablet will be either 6.25 mg or 50 mg of CTx-1301. 
 
FocalinTM XR Extended-Release Capsule 
This marketed product is a hard gelatin capsule. The dose of d-MPH in each capsule will be either 5 mg or 
40 mg for the Extended Release.  Further pharmaceutical information is available in the Package Insert. 
 
5.1.2 
Selection of doses 
 
Each subject will receive (1) dose of all four treatment arms according to the sequence they are randomized 
to (see Table 6). All sequences include 1 dose of: Focalin XR 5 mg, CTx-1301 6.25 mg, Focalin XR 40 mg, 
and CTx-1301 50 mg.  
 
5.1.3 
Administration 
 
The investigational drug and reference drug will be administered to the subjects by an unblinded clinical 
staff member of the study site and the administration will be witnessed by a second unblinded member of 
clinical staff. 
 
The subjects will be blinded to the dose by way of a blinded dosing cup. Subjects will be dosed sitting down 
and instructed to swallow the dose with 240 ml of room-temperature water; all 240 mls of water must be 
consumed within 60 seconds of swallowing the dose. A mouth check should be done to ensure the subject 
swallowed the dose. The investigational and reference drugs may not be crushed, chewed, or altered in 
anyway.  Subjects must swallow the study drug whole, as provided. After dosing, subjects will remain 
seated upright (no reclining) for at least 2 hours (hrs 0-2) and seated upright and/or ambulatory for hrs 2-4, 
unless position needs to be adjusted for an AE.  Subjects are allowed to move during hrs 0-4 if required for 
study-related procedures, or to use the bathroom.  The subjects will have restricted activity throughout the 
study so as to not increase heart rate by physical exertion. Subject are not allowed to engage in any 
vigorous activity throughout the study. 
 
Study treatment and timing of administration will be documented in the source documents and eCRFs.  Any 
deviation from the protocol-specified dosing regimen and activity restrictions must be recorded. 
 
Trained study site personnel will be onsite for the duration of the Tolerability Test Day and Assessment 
Days.   
 
The unblinded clinical staff will include clinical staff administering and witnessing the dosing, conducting 
the mouth check, and the unblinded pharmacy staff.  The unblinded clinical staff will ensure subjects were 
randomized to the correct sequence and dosed as randomized.   
 
All investigators and other study staff will remain blinded throughout the study.   
 
5.1.4 
Dose schedule 
 
All treatments, including the Tolerability test and Assessment Day treatments, will be dosed in the morning 
(by approximately 8:30 am); all subjects must be dosed within approximately 60 minutes of each other. 
Subjects will have fasted in-clinic for at least 10 hrs prior to each dosing period and at least 4 hours post-
dose. Fluids, including water, are restricted at least 1 hr. prior to dosing and at least 2 hrs after dosing; the 
240 mL of room-temperature water with dosing is allowed and required per protocol. 
 
Subjects will be dosed as per the schedule described in Table 2 in a randomized sequence. 
 
There will be a 72-hour washout (3 days) between each dosing/Assessment day. 
 


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5.1.5 
Dose modification 
 
No dose modification is permitted in this study.  
 
5.1.6 
Treatment compliance 
 
A record of the administration of study products will be kept using the Investigational Product(s) Dispensing 
and Accountability Record and the source documents; any comments on the performance of this procedure 
should be recorded on the source document and eCRF.  
 
Any violation of compliance will require evaluation by an Investigator and Sponsor to determine if the subject 
will continue in the study.  
 
5.1.7 
Precautions 
 
No special precautions are necessary provided that the study is conducted according to this protocol. The 
Principal Investigator is responsible to oversee the medical well-being of the subjects during the course of 
the study. Ongoing monitoring days will be conducted by the sponsor-appointed CRO to ensure compliance 
to the protocol. 
 
5.1.8 
Over-dosage 
 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than specified in 
the protocol.   
 
Overdose per se is not an AE; it should be recorded as a protocol deviation and the CRO/Sponsor should 
be notified immediately. However, any clinical sequelae of an overdose should be reported as an AE (and 
an SAE, if appropriate). See Section 9.1.2 for reporting instructions.  
 
It is unlikely that over-dosage will occur in this study as treatments are prepared on an individual basis 
according to an approved manufacturing protocol and administered by clinical staff, not by the subjects 
themselves. 
 
5.1.9 
Rescue therapy 
 
No rescue therapy is applicable for this study. 
 
5.1.10 Risks 
 
The perceived risks involved in this study relate to: 
 
Drug 
 
The study population may not benefit from the single-dose treatment at each day. Inclusion and exclusion 
criteria have been chosen in order to enable a uniform study population and to minimize possible risks in 
relation to the administration of CTx-1301 tablet and FocalinTM XR Extended-Release capsule. 
 
The most common adverse reactions after taking FocalinTM XR Extended Release capsules (at least 5% 
and twice the incidence among placebo-treated subjects) are dry mouth, dyspepsia, headache, and anxiety 
for adult subjects. Adverse reactions are expected to be similar for both CTx-1301 and Focalin™ XR based 
on a pilot study for CTx-1301. 
 
Table 7 shows the treatment-emergent adverse events resulting from a placebo-controlled, parallel-group 
study in adults with ADHD at fixed Focalin XR doses of 20, 30 and 40 mg per day.  Only events that occurred 
in 5% or more of the subjects and for which the incidences appear to increase with dose are reported. 


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Table 7: Treatment-Emergent Adverse Events Occurring during Double-Blind Treatment (Adults) 
 
 
Focalin XR 
20 mg 
N=57 
Focalin XR 
30 mg 
N=54 
Focalin XR 
40 mg 
N=54 
Placebo 
 
N=53 
No. of Subjects with AEs 
       Total 
 
84% 
 
94% 
 
85% 
 
68% 
Primary system Organ Class 
/ Adverse Event Preferred 
Term 
 
Gastrointestinal Disorders 
28% 
32% 
44% 
19% 
       Dry Mouth 
7% 
20% 
20% 
4% 
       Dyspepsia 
5% 
9% 
9% 
2% 
Nervous System Disorders 
37% 
39% 
50% 
28% 
       Headache 
26% 
30% 
39% 
19% 
Psychiatric Disorders 
40% 
43% 
46% 
30% 
       Anxiety 
5% 
11% 
11% 
2% 
Respiratory, Thoracic and 
Mediastinal Disorders 
16% 
9% 
15% 
8% 
       Pharyngolaryngeal Pain 
4% 
4% 
7% 
2% 
 
Two other adverse reactions occurring in clinical studies with Focalin XR at a frequency greater than 
placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness 
(6% and 2%, respectively). 
 
Nervousness and insomnia are the most common adverse reactions reported with other Methylphenidate 
HCl Dosage Forms. 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 
subjects 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, 
subjects were concurrently receiving therapies associated with NMS. 
 
Further information can be found in the FocalinTM XR Extended-Release Package Insert. 
 
Blood Sampling 
 
Blood samples will be taken for safety and/or pharmacokinetic assessments during screening and follow-
up medical examinations as well as on Assessment Days. There is a risk of bruising and fainting during 
blood sampling.   
 
Direct venipuncture or cannula (small plastic tube) may be used to obtain PK samples.  This may be a little 
uncomfortable and may leave a bruise. A cannula may be used because it allows several blood samples 
to be drawn without the need to insert a needle in the subject's arm each time. The cannula may remain in 
place for the duration of the Assessment Day but may need to be re-sited during this time. There is a very 
small risk of inflammation of the vein and changes in the sensation in the subject's arm following blood 
sampling.  
 
If blood sampling via venipuncture is not possible, and/or not preferred, a cannula will be inserted by study 
staff.  Use of venipunctures and/or cannulas should be recorded in the CRFs.   
 
5.2 
STUDY SCREENING PROCEDURE AND TREATMENT ASSIGNMENT 
 
5.2.1 
Screening procedure 
 
A unique screening number will identify all subjects screened for study participation. Screening numbers 
will be noted with an “S” followed by three digits, assigned in ascending numerical and sequential order, 
according to appearance at the study site, e.g. S-001, S-002, etc. All subjects that consent must be 
assigned a screening number. A subject who screen fails prior to, or on Day -4 , but may still be a suitable 
candidate for the study, may be rescreened.  Subjects who are rescreened will be assigned a new screening 
number. 
 
Screening numbers must be maintained by the study staff in the source documents and eCRF. 
 
5.2.2 
Randomization procedure 
 
This is a randomized study. Subjects should only be enrolled and randomized if they meet 
inclusion/exclusion both at screening and again at Day -4, Day -3, and Day -1.   
 
Subjects who meet all of the inclusion and none of the exclusion criteria will be enrolled/randomized to the 
study. The subject enrollment/randomization numbers correspond to a pre-defined randomization schedule 
prepared by the Sponsor.  Subject enrollment numbers will be assigned in ascending numerical order per 
cohort as enrolled.  Randomization numbers will be assigned in sequence across cohorts; replacement 
randomization numbers will be formatted in a manner similar to those initially assigned, but unique to the 
replacement patient.   
 
There should be no sequence gaps in subject enrollment and initial randomization numbers.  If a subject 
early terminates that enrollment/randomization number must still remain attached to the early termination 
subject. If an initial randomization sequence is skipped, the unblinded pharmacist (or unblinded qualified 
pharmacy staff) must immediately consult with the unblinded statistician at the CRO for next steps. 
 
Following the completion of the planned cohorts and replacement assignments, an unblinded statistician 
may review the allocations as described in Section 4.6.  


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Any subject randomized that does not complete the study will be an early termination and reason for 
termination must be noted in the source document and eCRF.   
 
5.2.3 
Blinding procedure  
 
The unblinded pharmacy staff will prepare the study medications and maintain documentation of study drug 
administration for each subject according to the randomization schedule provided by the sponsor or sponsor 
representative/CRO.  A second verification by an unblinded study member will be conducted to ensure the 
enrolled subjects are randomized to the correct randomization sequence per the subject 
enrollment/randomization number and ensure that the correct treatment was provided on each treatment 
day. The pharmacy staff must follow the Site’s pharmacy dispensing SOP. All doses will be administered 
from a blinded cup with a closed lid to prevent subjects from inspecting the tablets or capsules as well as 
to keep the subjects and study staff blinded. 
 
Note: The tolerability dose on Day -3 is unblinded and may be administered by a member of the protocol- 
trained clinical staff. 
 
As described in Section 4.6, an unblinded statistician not involved in study conduct may review subject 
randomization allocations following the completion of initial and replacement assignments. 
 
5.3 
STUDY TREATMENT SUPPLIES MANAGEMENT 
 
5.3.1 
Manufacture, Packaging and Labeling 
 
Manufacture, packaging and labeling of all study treatments will be carried out by a qualified vendor.  
 
All CTx-1301 Investigational drug will be provided in 100-ct, white plastic bottles, and will be labeled as 
specified with the following information: study number, investigational drug name, batch number, count, 
storage requirements, manufacturing information, and "Caution: New Drug--Limited by Federal (or United 
States) Law to Investigational Use." 
  
FocalinTM XR Extended Release Capsules are a commercially marketed product and will be provided by 
and sourced by the Phase I unit. The clinical site will place a label on the bottle stating: Protocol Number 
CTx-1301-001,  For Clinical Trial Use Only. 
 
5.3.2 
Accountability of study supplies 
 
The unblinded study pharmacist, or designee, will maintain a full record of study treatment accountability. 
A second unblinded clinical staff member must double check correct randomization sequence and correct 
accountability. An Investigational Product Dispensing and Accountability Record should be kept up to date 
with the following information: 
 
• 
The identification of the subject to whom the study treatment was dispensed.  
• 
The time, date, and assigned treatment and sequence of the study treatment dispensed to the 
subject.  
 
In order to comply with FDA rules and regulations, the clinical research unit will retain an adequate 
quantity of reserve samples for the test and reference formulations that shall permit, if required, to 
perform 5 times all of the release tests required in the application or supplemental application (New Drug 
Application [NDA's] or Abbreviated New Drug Application [ANDA's]). The labeling, storage conditions and 
retention period of the reserve samples shall comply with the current version of FDA regulation 21 Code 
of Federal Regulations (CFR) section 320.38 and/or 320.63 and the May 2004 FDA guidance Handling 
and Retention of BA and BE Testing Samples. 
 


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At the end of the study, all study supplies should be reconciled with this record. Any unused materials that 
are not retained as reserve samples must be maintained at the study site and returned or destroyed as 
directed by the sponsor.  
 
5.3.3 
Storage of study treatment supplies 
 
Study drug must be held at USP controlled-room temperature of 20-25°C.   
 
Throughout the duration of the study, all study medication will be securely stored within the pharmacy.  The 
pharmacy is monitored by the REEs system, which provides continuous temperature monitoring and alerts 
the pharmacy staff prior to a temperature deviation.   
 
If a temperature or storage deviation occurs, the CRO and Sponsor should be alerted immediately.  Sponsor 
will determine if excursion falls within acceptable stability limits or if drug should be quarantined.  
 
6 
STUDY SCHEDULE 
  
 
The summary of the Study Schedule (Table 2) includes a detailed schedule for the tolerability test day 
(Table 3) and assessment days (Table 4). 
 
7 
SCREENING AND BASELINE METHODS, MEASUREMENTS AND EVALUATIONS 
 
7.1 
SCREENING 
 
7.1.1 
Informed consent 
 
An Investigator, or medically qualified designee, must obtain written (signed and dated by the subject) 
informed consent from each subject, participating in this study after adequate explanation of the aims, 
methods, objectives, and potential hazards of the study.   
 
An Investigator, or medically qualified designee, must also explain to the subjects 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 will be provided by the Sponsor or designated CRO. An Investigator, or designee, should 
sign and date the consent form to confirm that the consent process was completed correctly.   
 
The subject will be provided with a copy of their signed and dated consent form, along with any other written 
information, which they should be instructed to retain. The original informed consent must be stored in the 
regulatory file for the study. All subjects that complete an ICF must have an assigned screening number. 
 
If, during a subject’s participation in the study, any new information becomes available that may affect a 
subject’s 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 should be provided with a copy of the signed and 
dated amended consent form.   Any new consent forms must be stored in the regulatory file along with all 
previous signed consent forms. 
 
7.1.2 
Demographics 
 
An Investigator, or designee, will record each subject's date of birth, gender, and race in the source 
documents and eCRF. 
 
7.1.3 
Medical history 
 
An Investigator, or medically qualified designee, will take a medical history from each subject. Details of 
any relevant medical or surgical history, including allergies, drug sensitivity, and previous ADHD treatments 
will be recorded. All concomitant medications will also be recorded. 


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7.1.4 
Physical examination 
 
An Investigator, or medically qualified designee, will perform the physical examination at specified time-
points according to the Study Schedule, which will include assessment of the following body systems: 
central nervous system (CNS); eyes; ears, nose and throat (ENT); respiratory; cardiovascular; 
gastrointestinal; musculoskeletal; neurological; endocrine/metabolic; hematopoietic/lymphatic; and 
dermatological. 
 
The outcome of these assessments will be documented in the source document and eCRF and any 
abnormalities will be described.  If any abnormalities are observed, they will be recorded as medical history 
or AEs, pending timing of observation.   
 
7.1.5 
ECG 
 
An Investigator will read all ECGs and evaluate for clinical significance.  If investigator deems the ECG 
abnormal, a cardiologist will conduct an overread and the Investigator will discuss with the Medical 
Monitor. 
 
7.1.6 
MINI Version 7.0.2 and C-SSRS 
 
An Investigator, or medically qualified designee, will perform a mental state examination and suicide 
assessment at specified time-points according to the Study Schedule, which will include assessment of 
potential psychosis, mania and suicidal thinking. The C-SSRS Baseline version will be administered at 
screening and the C-SSRS Since Last Visit will be administered at subsequence time-points. 
 
The outcome of these assessments will be documented in the source document and eCRF. Any potential 
subject deemed to be at risk will be excluded from the study. 
 
7.1.7 
Body mass index (BMI) 
 
Height (cm) and weight (kg) will be measured and recorded in the CRF. BMI will then be calculated as 
follows: 
 
BMI = (Weight (kg) / (Height (cm)2) x 10,000. 
 
BMI must be between 18.0 – 35.0 inclusive to be eligible for study participation. 
 
7.1.8 
Vital signs 
 
Arterial blood pressure and heart rate will be recorded at screening and at specified time-points according 
to the Study Schedule when subjects are resting in a sitting position for a minimum of 5 minutes; vital signs 
and time must be recorded in the source document and eCRF.   
 
Data must be collected in the source and eCRFs.  If Blood Pressure window overlaps with PK window, BP 
should be taken prior to PK draw. 
 
Vital signs should be taken at the protocol-specified time (± 10 minutes) for the tolerability day, 
assessment/treatment days, and non-treatment days. 
 
An Investigator can interpret individual findings based on the subject’s age, physical state and level of 
fitness. Subjects with vital signs outside the normal range which, in the investigator’s opinion, are not 
clinically significant and would not affect the subject’s safety during the study may be included; this 
decision will be documented in the source document and eCRF. 
 


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7.1.9 
Clinical laboratory tests 
 
An Investigator, or appropriately qualified designee, will collect blood samples for hematology,   
biochemistry analysis, and TSH at screening and check-in (Day -4). Blood samples for serology (HIV, 
HBsAg, and HCV antibody) will be taken at screening only. Urine samples for urinalysis will be collected at 
screening, check-in at Day -4, and EOS/ET.  A woman will be considered to have no child-bearing potential 
if they are surgically sterile (hysterectomy, tubal ligation, or endometrial ligation) or post-menopausal (12 
months since last menses). For women of child-bearing potential, serum HCG will be collected/analyzed at 
screening, check-in (Day -4), and EOS/ET.  Values for the laboratory safety tests must be within normal 
ranges (as defined by an accredited laboratory facility) or considered not clinically significant (NCS) by a 
medically qualified designee for the subject to be eligible for the study.  The results of all tests conducted 
at Day -4 must be available and reviewed before the tolerability day on Day -3.   
 
Blood samples for hematology, biochemistry, TSH, and urine samples for urinalysis will be repeated at the 
EOS visit and should be reviewed for clinically significant changes from screening; if clinically significant 
changes are observed, they should be recorded as AEs.  
 
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) and platelets. 
 
Biochemistry 
Sodium, potassium, chloride, BUN, creatinine, alkaline phosphatase, bilirubin, albumin, adjusted 
calcium, phosphate, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-
glutamyl transpeptidase (GGT), glucose and urate. 
 
Thyroid 
Thyroid Stimulating Hormone (TSH) 
 
Serology 
HIV-1, HIV-2, Hep-B, and Hep-C 
 
Urinalysis 
Bilirubin, urobilinogen, ketones, glucose, proteins, blood, nitrite, pH, specific gravity, and leukocytes. 
 
All subjects with any clinically significant laboratory finding or other significance will not be eligible for the 
study and will be advised to follow up with their own PCP or walk-in clinic.  
 
7.1.10 Breath alcohol test and serum screen for pregnancy and drugs of abuse  
 
Urine samples will be tested at screening and check-in at Day -4 for levels of the following drugs of abuse: 
amphetamines, methylphenidate, benzodiazepines, cocaine, methamphetamine and morphine/opiates. 
THC will also be assessed for abuse but will be considered exclusionary at the discretion of the investigator. 
A breath alcohol test will also be performed at screening and check-in at Day -4.  
 
Subjects testing positive for any exclusionary substances (other than ADHD prescribed medication) at 
screening or at check in on Day -4 must not be enrolled in the study.  Subjects that test positive for 
amphetamine or methylphenidate at screening must agree to washout of the ADHD medication 96 hrs. prior 
to check in at Day -4 and for the duration of the study. ADHD subjects must test negative for all ADHD 
medications at check-in on Day -4 to be eligible for the study. If THC is positive at screening or check-in, a 
cannabis intoxication evaluation will be done by an investigator at check-in on Day -4; inclusion will be at 
the investigator’s discretion, due to the slow release of THC from adipose tissue. 
 


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All women of child-bearing potential will have a serum HCG test at screening, check in on Day -4, and 
EOS/ET; HCG must be negative to be eligible for the study.   
 
Repeat urine analysis may be conducted at the discretion of an Investigator.  Investigator may also opt to 
conduct a urine screen at an unscheduled day to ensure compliance with the protocol. 
 
7.2 
SUBJECT CONTINUED ELIGIBILITY ASSESSMENT 
 
Prior to participation in each Assessment Day, an Investigator, or designee, will assess the subject’s 
continued eligibility for the study by confirming the subject still meets the entry criteria on the Assessment 
Day, as outlined in Sections 4.3 and 4.4, and has adhered to the restrictions outlined in  Section 4.7. 
 
7.3 
MEAL SCHEDULE 
 
During the Assessment Days, subjects will not be allowed any food or drinks other than those provided by 
the study site staff. 
 
Subjects will be given lunch at approximately 4 hr., a snack at approximately 6 hr., dinner at approximately 
9 hr., another snack at approximately 12 hr., and breakfast at approximately 24 hr. post-dose, respectively. 
Meal times are approximate and should be evaluated in regard to other protocol-specified evaluations.   
 
Water will be available ad libitum from at least 2 hr. post-dose and decaffeinated fluids will be available ad 
libitum from approximately 9 hr. post-dose on assessment days.  
 
7.4 
EARLY TERMINATION DAY 
 
The early termination visit should follow the same study schedule as EOS day, and include a final PK draw 
if possible.  Every effort should be made to obtain as much information as possible if a subject early 
terminates. An Investigator should contact the medical monitor if subject is discontinued for any reason.  
 
7.5 
DURATION OF THE STUDY 
 
The study will be conducted over the course of approximately 4-6 weeks from screening to completion for 
each subject. Subjects will remain in-clinic from Day -4 through EOS for a total of 15 days in-clinic. 
 
The end of the clinical phase of the study will be defined as last subject, last day in clinic (EOS). 
 
 
8 
PHARMACOKINETICS 
 
8.1 
PHARMACOKINETIC BLOOD SAMPLING 
 
At each Assessment Day blood samples will be drawn by suitably trained site staff using an indwelling 
cannula or by venipuncture at appropriate time-points to allow an assessment of methylphenidate 
concentrations in the plasma. PK draws should be in the same arm throughout the study, if possible. The 
arm used for PK draws should be recorded for each PK timepoint. 
 
The total blood volume taken at each time-point will be approximately 5 mL (4 mL sample volume and 1 
mL waste volume).  There is a risk of bruising and fainting during the blood sampling procedure.  See AE 
section for reporting procedure-related AEs. 
 
A pre-dose (0) blood sample will be taken no more than 60 minutes prior to dosing.  Blood samples will 
then be withdrawn at specified intervals: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 24, 
and 28 hr. post-dose.  
 


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Blood samples will be collected in vacutainers containing K2-EDTA as the anticoagulant.  Each blood tube 
will be labelled with the Subject number, Assessment Day, and time-point as a minimum.  Blood samples 
should be kept in ice/water bath until centrifugation. Blood samples will be centrifuged at 1,500 g for 10 
minutes at 4°C 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 actual sample times (times samples actually taken) should be recorded on the Blood Sampling Source 
Document and should be entered at the time of sampling. Time collected should be reported as the start of 
the sampling collection, defined as the actual drawing of blood volume. The actual times must be recorded 
in the 24-hr format. Any blood sample taken more than ±5 min outside of the set sampling times will be 
recorded as a protocol deviation. 
 
8.2 
BIOANALYSIS OF PLASMA SAMPLES 
 
The analysis of these samples will be undertaken by a Sponsor-approved 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 (see 
Bioanalytical Plan for further information on collection, methods, and validation).   
  
Pharmacokinetic metrics to be evaluated are:  AUC0-inf, AUClast, K, T1/2, Cmax, tmax, and tlag, including partial 
AUCs (AUC0-3, AUC3-6, AUC6-9, AUC9-12, and AUC12-16).  Graphical analysis will use protocol-stated times.  
PK analysis will use exact blood draw time, defined above. 
 
Additional parameters may also be calculated if considered appropriate. 
 
 
9 
SAFETY MEASUREMENTS AND EVALUATIONS 
 
9.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
An Investigator and site staff are responsible for detecting, documenting, and reporting events that meet 
the definition of an Adverse Event (AE), Serious Adverse Event (SAE) or Suspected Unexpected Serious 
Adverse Reaction (SUSAR). 
 
9.1.1 
Definitions 
 
Adverse event 
 
An adverse event is any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of an investigational product whether or not considered related to the 
investigational product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of an investigational product.  
Events meeting the definition of an AE include, but are not limited to:  
• 
Exacerbation (worsening) 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. 


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• 
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 
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. 
• 
Pregnancy (of a study subject or partner of a study subject), although any medical 
conditions arising from pregnancy may be classed as an AE. 
Clinical AEs should be described by diagnosis and not by symptoms when possible (e.g., upper respiratory 
tract infection (URI), 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 physician’s office or out-subject setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfils any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
If hospitalization occurs due to an elective treatment of a pre-existing condition which did not worsen from 
baseline, it is not considered an AE. 
d) 
Results in disability/incapacity, or 


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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. 
9.1.2 
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 consents.  AEs collected between consent and prior to 
randomization should be evaluated to determine if attributed to study procedure, tolerability dose, or prior 
medical condition since test drug has not yet been administered.  Assessments obtained at Screening 
should be recorded as medical history unless related to study procedure. AEs collected after randomization 
should be evaluated for relatedness to study drug, study procedures, or both. AEs will be assessed until 
the end of the study (EOS), early termination (if applicable), or until resolved or stabilized.  
 
SAEs will be collected over the same time period and same process as stated for AEs. SAEs should be 
evaluated by the PI as related to study drug or study procedures. Scientific rationale for attribution to drug 
or procedures should be recorded in the source document and eCRF. SAEs must be reported to the 
Sponsor within 24 hrs of an 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.  
Medical conditions that are exacerbated while on study should be evaluated as to normal fluctuation of 
disease state or relation to study drug or procedure. 
 
Reporting adverse events 
 
Adverse events can be reported at any time while on study and site should record in the AE source 
document as well as the AE section of the eCRF. 
 
Any new medical conditions not present prior to participation in the study reported by the subject which 
meet the definition of an AE (described above) should be recorded as stated above. AEs must be recorded 
in detail on both the AE source document and in the eCRF.  If the same AE occurs multiple times, the AE 
is to be recorded for each occurrence. AEs should also be recorded as reported.   
 
After randomization on Day 0, AEs will be evaluated for relation to study drug or study procedure.   
 
9.1.3 
Adverse event grading and assessments 
 
Intensity grading 
 
All AEs will be graded on a three-point scale and reported in detail as indicated on the CRF: 
 


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• 
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 
 
Relationship assessment 
 
Study drug or study procedure relationship for each AE should be determined by an Investigator using the 
following rationale and explanations: 
 
• 
Not related to Study Drug 
o 
The AE does not follow a reasonable temporal sequence from investigational product 
administration or can be reasonably explained by the subject’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, and concomitant medications). 
 
• 
Related to Study Drug 
o 
The AE follows a reasonable temporal sequence from the investigational product 
administration and cannot be reasonably explained by the subject’s clinical state or other 
factors (eg, disease under study, concurrent diseases, or concomitant medications).  
o 
The AE follows a reasonable temporal sequence from the investigational product 
administration and represents a known reaction to the investigational product under study or 
other drugs in its class or is predicted by the known pharmacological properties of the drug.  
o 
The AE resolves with discontinuation of the investigational product and/or recurs with 
rechallenge, if applicable. 
 
• 
Procedure related  
o 
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 or intolerability of Focalin XR 40 
mg at tolerability day.  
 
Duration 
 
Start and end-dates of the adverse event will be recorded.  
 
Follow-up 
 
Any AEs ongoing at the follow-up day, 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 the other criteria as 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 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 hrs. 
 
Reporting serious adverse events 
 
A copy of the SAE report form provided in the regulatory site file should be completed as fully as possible 
and must be reported within 24 hours of first learning of the SAE to CRO via the following 
SAE fax/e-mail address.  Additionally, the SAE should be recorded into the EDC. 
 
Table 8 


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Premier Research Pharmacovigilance 
Email 
GlobalPV-US@premier-research.com 
 
Fax number 
+1 215-972-8765 
 
 
It is essential to enter the following information: 
• 
Protocol and subject identifiers 
• 
Subject’s demography 
• 
Description of events, with diagnosis if available 
• 
Investigator opinion of relationship to study treatment or study procedure 
• 
Criterion for seriousness  
 
The following are desirable and are of particular 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 
• 
Outcome if known 
 
The initial report will be followed up with more information as relevant.  This may require an Investigator to 
obtain copies of hospital case reports, autopsy reports and other documents as applicable.  If CRO or 
Sponsor request copies of any subject-identifying information such as hospital forms, the forms should be 
redacted, and the subject number should be written on the forms for study identification.   
 
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 all 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 Sponsor or CRO within 24 hrs. 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. 
 
All other SUSARs: reporting to the Ethics Committee and FDA within 15 days of first becoming aware 
of the event. 
 
 
9.2 
PREGNANCY 
 
9.2.1 
Time period for collecting pregnancy information 
 
All women of child-bearing potential will require a serum HCG test at screening, check-in at Day -4, and 
EOS/ET. All subjects of child-bearing potential must use a double-barrier method form of birth control or 
meet other birth control methods as defined per protocol, while on study.  Females that are confirmed 
pregnant during screening and/or before randomization are excluded from the study. Females that are 
breastfeeding during screening and/or before randomization, and/or for 30 days following the study, are 
excluded from the study. 


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9.2.2 
Action to be taken if pregnancy occurs 
 
The Investigator, or designee, will record pregnancy information on the appropriate pregnancy data 
collection form and submit it to the CRO within 24 hours of learning of the pregnancy.  
 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective termination 
for medical reasons will be recorded as an AE or SAE as defined in Section 9.1.2. Note that termination 
itself is not an AE, only any medical reasons for a termination should be recorded as an AE. 
 
A spontaneous abortion is always considered to be an SAE and will be reported as such. An SAE occurring 
in association with a pregnancy, brought to the Investigator’s attention after the subject completed the study 
and considered by the Investigator as possibly related to the investigational product, must be promptly 
recorded.  
 
The Investigator, or designees, should report pregnancy only, or pregnancy with an associated SAE, 
immediately to the CRO via the following fax/e-mail address.   
 
Premier Research Pharmacovigilance 
Email 
GlobalPV-US@premier-research.com 
 
Fax number 
+1 215-972-8765 
 
 
9.3 
LABORATORY EVALUATIONS RELATED TO SAFETY 
 
Clinical safety laboratory assessments (hematology, biochemistry and urinalysis) will be conducted during 
the screening day and at check-in (Day -4) to ensure the subject’s good health.  Subjects with clinically 
significant labs at screening and/or at check-in (Day -4), as assessed by an Investigator, should not be 
enrolled in the study. Clinical safety laboratory assessments will be repeated at EOS (or ET day, if 
applicable) to ensure the subject’s health has not been adversely affected by their participation in this study. 
Abnormal results detected at EOS (or ET day, if applicable) which differ from check-in labs (Day -4) and 
the Investigator considers to be clinically significant, will be recorded as an AE. 
 
Clinically significant findings in laboratory tests at screening and/or at check-in on Day -4, will be considered 
pre-existing conditions (medical history), as well as failure to meet eligibility criteria; they will not be 
considered AEs. However, for any medical event or condition discovered at screening, which, in the opinion 
of an investigator, is significant enough to be followed up externally, subject will be asked to follow up with 
their primary care physician. 
 
9.4 
VITAL SIGNS AND OTHER OBSERVATIONS RELATED TO SAFETY 
 
Vital signs will be assessed at screening, the tolerability day for Focalin XR 40 mg, at each Assessment 
Day, and non-assessment days to ensure the subject is, and remains in, good general health. Abnormal 
findings that the Investigator considers to be clinically significant, other than at screening, will be recorded 
as an AE. 
 
 
10 
STATISTICAL/DATA ANALYSIS METHODS 
 
10.1 
GENERAL CONSIDERATIONS 
This section describes the rules and conventions to be used in the presentation and analysis of the data. 
A comprehensive presentation of the data management plan and statistical analysis plan will be approved 
by the Sponsor prior to PK analysis and unblinding of the study data. 


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10.2 
STATISTICAL AND ANALYTICAL PLAN 
This is a randomized, single-dose, four-sequence, four-period, in-clinic crossover PK study to evaluate 
PK concentrations of d-MPH in the investigational drug compared to the registered listed drug (RLD) 
under fasted conditions.   
 
The following variables will be assessed over the course of the study, by day and time: AUC0-inf, AUClast, 
and Cmax, including partial AUCs (AUC0-3, AUC3-6, AUC6-9, AUC9-12, and AUC12-16).  Additional parameters 
may also be evaluated. 
 
Safety will be assessed by recording any AEs, concomitant medications, physical exams, vital signs, and 
ECGs. 
 
10.3 
STUDY OBJECTIVES 
The primary trial objective is to compare the bioavailability of the marketed product (Focalin XR) to CTx-
1301 trimodal investigational product under fasted conditions and demonstrate dose proportionality of 
CTx-1301. 
 
The secondary trial objectives include evaluation of data on blood plasma levels of d-MPH and to 
evaluated safety measurements including ECG, vital signs, lab assessments, physical exam, C-SSRS, 
and occurrence of treatment-emergent adverse events.  
 
10.4 
SAMPLE SIZE DETERMINATION 
 
The study design is a randomized, single-dose, four-sequence, four-period, in-clinic crossover study. 
Cmax, AUC0-inf, and AUClast are the key PK endpoints which will be used to evaluate the relative 
bioavailability of CTx-1301 6.25 mg vs. FocalinTM XR 5 mg (treatment B vs. treatment A) and CTx-1301 
50 mg vs. FocalinTM XR 40 mg (treatment D vs. treatment C). The basis of evaluation for these endpoints 
will be 90% confidence intervals for the ratios of adjusted geometric means as described in Section 10.7. 
In the context of a bioavailability analysis, similarity will be concluded if the 90% confidence interval (CI) 
of the geometric mean ratios for Cmax, AUCinf, AUClast fall near or within the 90% CI of [0.80—1.25]. 
This is the same as performing two one-sided hypothesis tests (TOST procedure), each conducted at a 
5% siginicant level. The TOST procedure will identify two treatments as equivalent when the lower bound 
of a 90% confidence interval falls near or below 1.25 or the upper bound of a confidence interval falls 
near or above 0.80 (or both).   
 
Based on the conservative TOST methodology assumptions, that the bioavailability analysis falls within 
the 90% CI of [0.80—1.25], a sample size of at least 32 completers will provide at least 88% power with 
the assumption of within-subject CV (coefficient of variation) of 17-21% and true bioavailability ratio (B/A 
and D/C) of 93-107%. With assumption of the drop-out rate of 11%, 36 subjects total (6-12 subjects per 
cohort) will be randomized. No adjustment for multiple comparisons will be made. 
 
 
10.5 
ANALYSIS POPULATIONS 
 
• 
Safety Population (SAF): The SAF Population includes all subjects who receive at least 1 dose 
of study drug. 
• 
PK Population: The PK Population includes all subjects who receive at least 1 dose of study 
drug and provide at least one evaluable PK plasma concentration. 
 
 
10.6 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
 


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Baseline data, relevant screening data and demographic characteristics will be summarized for the safety 
population. 
 
 
10.7 
PHARMACOKINETIC ANALYSIS 
 
Pharmacokinetic sample analysis will be performed by a central laboratory. The results will be shared with 
the CRO for the PK parameter calculations and the final PK analysis report. 
 
Pharmacokinetic analysis will be based on PK population. Plasma CTx-1301 and FocalinTM XR 
concentrations will be summarized descriptively by treatment and nominal sampling time point. 
 
Pharmacokinetic parameters (including AUC0-inf, AUClast, K, T1/2, Cmax, tmax, and tlag) will be summarized 
descriptively by treatment group as appropriate.  Partial AUCs and dose-normalized PK parameters 
(including dose normalized AUC0-, AUClast, Cmax) will also be calculated (by dividing the nominal dose) and 
summarized similarly. 
 
Natural log-transformed pharmacokinetic parameters (including AUC0-inf, AUClast, and Cmax) will be analyzed 
using a mixed-effect model with sequence, period, and treatment as fixed effects and subject within 
sequence as a random effect.  A sensitivity analysis may be conducted to analyze any unexpected 
differences among cohorts.  Estimates of the adjusted mean differences (CTx-1301 6.25 mg vs. FocalinTM 
XR 5 mg and CTx-1301 50 mg vs. FocalinTM XR 40 mg) and corresponding 90% confidence intervals will 
be obtained from the model.  The adjusted mean differences and 90% confidence intervals for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric means (Treatment 
B/A and Treatment D/C) and 90% confidence intervals for the ratios. 
 
Natural log-transformed, dose-normalized, pharmacokinetic parameters (including AUC0-inf, AUClast, and 
Cmax) will also be analyzed using a mixed-effect model with sequence, period, and treatment as fixed effects 
and subject within sequence as a random effect.  A sensitivity analysis may be conducted to analyze any 
unexpected differences among cohorts.  Estimates of the adjusted mean differences (CTx-1301 6.25 mg 
vs. FocalinTM XR 5 mg and CTx-1301 50 mg vs. FocalinTM XR 40 mg) and corresponding 90% confidence 
intervals will be obtained from the model.  The adjusted mean differences and 90% confidence intervals for 
the differences will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Treatment B/A and Treatment D/C) and 90% confidence intervals for the ratios. Dose proportionality will 
also be evaluated based on the model for dose-normalized parameters, using a ratio of adjusted gometric 
means (Treatment C/B) for comparison of the CTx-1301 50 mg and CTx-1301 6.25 mg groups, along with 
corresponding 90% confidence intervals. 
 
Natural log-transformed, dose-normalized, pharmacokinetic parameters (including AUC0-inf, AUClast, and 
Cmax) will also be analyzed to evaluate dose proportionality of CTx-1301 using the 6.25 mg and 50 mg 
doses.    
 
Exploratory analyses may be conducted  to examine potential differences between treatments (CTx-1301 
6.25 mg vs. FocalinTM XR 5 mg and CTx-1301 50 mg vs. FocalinTM XR 40 mg)  within selected time intervals.   
 
Additional details of pharmacokinetic analysis will be included in the statistical analysis plan. 
 
PK plasma concentrations of d-MPH will be summarized by treatment and time point. 
 
10.8 
SAFETY ANALYSIS 
 
Safety analysis will be performed for the Safety Population. 
 


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Safety will be assessed by clinical review of all relevant safety data including treatment-emergent adverse 
events (TEAEs), laboratory tests, ECGs, physical exams, C-SSRS, and vital signs. No inferential testing 
for statistical significance will be performed. 
 
Adverse events will be classified using Medical Dictionary for Regulatory Activities (MedDRA) classification 
system.  Adverse events will be summarized by treatment Summary for TEAEs will be classified by system 
organ class, preferred term, severity, and relationship to treatment. 
 
Data for laboratory tests, vital signs, ECG, physical exams and C-SSRS will be summarized descriptively.  
More details will be provided in the statistical analysis plan (SAP). 
 
11 
ETHICAL AND REGULATORY ASPECTS 
 
11.1 
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, as well as the Declaration of Helsinki, ICH, 
GCP, and GLP Guidelines. 
 
11.2 
INFORMED CONSENT 
 
It is the responsibility of the Investigator, or medically qualified designee, to obtain written (signed and dated 
by the subject) informed consent from each individual participating in this study. 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 form and active subjects 
will be re-consented.  Refer to Section 7.1.1. 
 
 
11.3 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD 
 
This protocol (and any modifications) as well as appropriate consent procedures, will be reviewed and 
approved by an IEC/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 also 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 IEC/IRB 
responsible for the study.  
 
The outcome of the study (e.g. completed) will be reported to the IEC/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 IEC/IRB responsible for the study within 15 days.  
 
11.4 
FUNDING 
 
The study is funded by the Sponsor, Cingulate Therapeutics. 
 
 
12 
STUDY REPORT, DOCUMENTATION, CRFS, PUBLICATION, 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 


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two categories: (1) Study Regulatory file, and (2) 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/IEC approvals for the study protocol and all amendments 
• 
All 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 enrollment) should be specified in a source document designation form.  
 
12.3 
CASE REPORT FORMS 
 
For each subject who has given informed consent, an eCRF must be completed and signed by the Principal 
Investigator to certify that all collected data are complete and correct. This also applies to those subjects 
who are screened but not entered into the study. If a subject is withdrawn from the study because of a 
treatment-limiting AE, thorough efforts should be clearly made to document the outcome and provide the 
reason for withdrawal from the study as an AE in the eCRF. 
 
All source documents should be completed during (or immediately after) a subject assessment. Source 
documents should be completed in a GCP-compliant manner. The text should be written with a black or 
blue ballpoint pen and must be legible. If a source document entry needs correction, the error should be 
crossed out with a single line (not obliterated or covered with correction fluid) and the correct information 
should be written next to the original entry. The change must be initialed and dated by the Investigator or 
designee. 
 
The study monitor(s) will review all source documents and 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 
CLINICAL STUDY REPORT AND PUBLICATION POLICY 
 
An ICH-compliant clinical and statistical study report will be written after completion of the study and data 
analysis.  The results of the study may be published in a relevant peer-reviewed journal by the Sponsor, 
without regard for status and ranking of contributors. Contributions of the participating investigators, 
institutions, CRO, and Sponsor will be listed, unless otherwise requested. 
 
13 
PROCESS FOR AMENDING THE PROTOCOL 
 
All major/substantial protocol modifications must be reviewed and approved by an appropriate IEC/IRB. 
Approval from the IEC/IRB must be received before the revised edition can be implemented. 
 


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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. 
 
 
14 
CONDITIONS FOR TERMINATING THE STUDY 
 
It is agreed that for reasonable cause, the Sponsor may terminate this study, provided a written notice is 
submitted at a reasonable time in advance of intended termination and  provided to each investigator. If 
the study is terminated prematurely or suspended, the IEC/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 requirement. 
If a drug-related SUSAR occurs at any time during the study, the Medical Monitor and Sponsor will review 
the case immediately. 
The study will not be restarted until all parties have agreed to the course of action to be taken and the 
IRB/EC has been notified. 
If terminating the study, the Sponsor will assure that adequate consideration is given to the protection of 
the Subject’s interests.  
 
 
15 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT RECORDS 
 
The Investigator must ensure that subjects’ anonymity is maintained.  Subjects should not be identified by 
their names or initials on eCRFs, but by a subject identification code (screening number or subject 
enrollment/randomization number). 
 
The Investigator should keep a separate log of subjects’ codes and names. Documents which may identify 
the subject, e.g., subjects’ written consent forms, hospital records, etc. will be maintained in strict 
confidence. Any electronic files that contain subjects’ personal data will be appropriately encrypted. 
 
 
16 
AUDITS/INSPECTIONS 
 
The Investigator and study subjects should understand that source documents for this study should be 
made available to appropriately qualified personnel or designee(s) from health authority inspectors after 
appropriate notification. The verification of the eCRF data may be by direct inspection of source documents 
(where permitted by law) or through an interview exchange. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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17 
REFERENCES 
 
1. Cantwell DP. 1996. Attention deficit disorder: A review of the past 10 years. J Am Acad Child Adolesc 
Psychiatry, 35:978-987. 
2. Dulcan M. 1997. Work group on quality issues. Practice parameters for the assessment and treatment 
of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child 
Adolesc Psychiatry, 36:85S-121S. 
3. Swanson JM, Seargent JA, Taylor E, et al. 1998. Attention deficit disorder and hyperkinetic disorder. 
Lancet, 351:429-433. 
4. Kessler, R.C. (2016, February 04). How ADHD Grew Up as Kids Grew into ADHD Adults. Retrieved 
from https://apsard.org/how-adhd-grew-up-as-kids-grew-into-adhd-adults/ . 
5. Mannuzza S, Klein RG, Bessler A, et al. 1998. Adult psychiatric status of hyperactive boys grown up. 
Am J Psychiatry, 155:493-498. 
6. Bradley C. 1937. The behavior of children receiving benzedrine. Am J Psychiatry, 94:577-585. 
7. Greenhill LL, Pliszka S, Dulcan MK, et al. 2002. American Academy of Child and Adolescent 
Psychiatry. Practice parameter for use of stimulant medications in the treatment of children, 
adolescents, and adults. J Am Acad Child Adolesc Psychiatry, 41(2 Suppl):26S-49S. 
8. Kimko HC, Cross JT, Abernethy DR, et al. 1999. Pharmacokinetics and clinical effectiveness of 
methylphenidate. Clin Pharmacokinet, 37(6):457-70. 
9. Srinivas NR, Hubbard JW, Quinn D, et al. 1992 Enantioselective pharmacokinetics and 
pharmacodynamics of dl-threo-methylphenidate in children with attention deficit hyperactivity disorder. 
Clin Pharmacol Ther. 52(5):561-8. 
10. Quinn D, Wigal S, Swanson J, et al. 2004. Comparative pharmacodynamics and plasma 
concentrations 
of 
d-threo-methylphenidate 
hydrochloride 
after 
single 
doses 
of 
d-threo-
methylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in a double-blind, 
placebo-controlled, crossover laboratory school study in children with attention-deficit/hyperactivity 
disorder. J Am Acad Child Adolesc Psychiatry, 43(11):1422-9. 
11. Patrick KS, Caldwell RW, Ferris RM, et al. 1987. Pharmacology of the enantiomers of threo-
methylphenidate. J Pharmacol Exp Ther, B: 152-158. 
12. Lim HK, Hubbard JW, Midha KK. 1986. Development of enantioselective gas chromatographic 
quantitation assay for d.l-threo-methylphenidate in biological fluids. J Chromatography, A 378(1):109-
23. 
13. Srinivas NR, Quinn D, Hubbard JW, et al. 1987. Stereoselective disposition of methylphenidate in 
children with attention-deficit disorder. J Pharmacol Exp Ther, 241(1):300-6. 
14. PDR Focalin, Insert package, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, 2005 
15. Silva R, Tilker HA, Cecil JT, et al. 2004. Open-label study of dexmethylphenidate hydrochloride in 
children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc 
Psychopharmacol, 14(4):555-63.  


Protocol CTx-1301-001                               
Version 4.0 16 January 2020 
               
   Page 47 of 47 
Cingulate Therapeutics 
                                                                       CONFIDENTIAL 
16. PDR Focalin XR, Insert package, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, 
May 2005 
17. Brams, M., Muniz, R., Childress, A. Giblin, J., Mao, A., Turnbow, J,  Borrello, M.,   McCague, K., Lopez, 
F., Silva, R. 2008. A randomized, double-blind, crossover study of once daily dexmethylphenidate: 
Rapid onset of effect. CNS Drugs 22(8):693-704.  
18. Silva, R, Muniz, R, McCague, K, Childress, A, Brams, M, Mao, A 2008: Treatment of Children With 
Attention-Deficit/Hyperactivity Disorder (ADHD): Results of a Randomized, Multicenter, Double-Blind, 
Crossover Study of Extended-Release Dexmethylphenidate and d,l-Methylphenidate and Placebo in 
a Laboratory Classroom Setting. Psychopharmacology Bulletin 41(1)19-33. 
19. Novartis. Focalin (dexmethylphenidate hydrochloride) tablets prescribing information. East Hanover, 
NJ; 2015, Apr 
 
20. Novartis. Focalin XR (dexmethylphenidate hydrochloride) extended-release capsules prescribing 
information. East Hanover, NJ; 2015 – Jun 
 
21. Aurora SK, Kori AH, Barrodale P, et al. (2006) Gastric stasis in migraine: More than just a paroxysmal 
abnormality during a migraine attack. Headache.46:57-63. 
22. Horowitz MHP, Maddox A, Maddern GJ et al. (1986) Gastric and oesophageal emptying in insulin 
dependent diabetes mellitus. J Gastroenterol Hepatol. 1: 97-113. 
23. Prescott LF, Yoovathaworn K, Makarananda K et al. (1993) Impaired absorption of paracetamol in 
vegetarians. Br. J. Clin. Pharmacol. 36:237-240. 
24. Wald A, Thiel DHV, Hoechstetter L et al. (1981) Gastrointestinal transit: the effect of the menstrual 
cycle. Gastroenterology 80:1497-1500. 
25. Hart D and Wall BF. (2002) Radiation exposure of the UK population from medical and dental x-ray 
examinations. Oxon, UK: National Radiological Protection Board.  

SAP_001.pdf: 
 
Statistical Analysis Plan: CTx-1301-001 
 
A randomized, single-dose, four-sequence, four-period, in-clinic crossover study in adult ADHD subjects 
to establish safety, tolerability, and comparative bioavailability of CTx-1301 (dexmethylphenidate) to the 
listed drug (Focalin XR™) under fasted conditions. 
 
 
NCT04138498 
 
12Feb2020 
 
 


 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 05FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 1 of 96 
 
   Statistical Analysis Plan 
Sponsor 
Cingulate Therapeutics 
Protocol Title: 
A randomized, single-dose, four-sequence, four-period, in-clinic 
crossover study in adult ADHD subjects to establish safety, 
tolerability, and comparative bioavailability of CTx-1301 
(dexmethylphenidate) to the listed drug (Focalin XR™) under 
fasted conditions. 
Protocol Number: 
CTx-1301-001 
Premier Research PCN: 
CING8178 
Document Version: 
Final Version 1.0  
Document Date:  
12-FEB-2020 
Approvals 
Role 
Signatures 
Date (dd-Mmm-yyyy) 
Premier Research 
Biostatistician 
Print Name: Vanessa Beddo 
 
Sign Name: 
 
 
 
 
 
Cingulate 
Therapeutics 
Representative 
Print Name: Holly Mitzel 
 
Sign Name: 
 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 2 of 96 
 
Document History 
Version 
Date 
Author 
Description 
1.0 
12FEB2020 
Vanessa Beddo 
Final Draft 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 3 of 96 
 
Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
1. 
Overview ............................................................................................................................. 8 
2. 
Study Objectives and Endpoints ......................................................................................... 8 
2.1. 
Study Objectives ........................................................................................................... 8 
2.1.1. Primary Objectives........................................................................................................ 8 
2.1.2. Secondary Objectives.................................................................................................... 8 
2.1.3. Exploratory Objectives ................................................................................................. 9 
2.2. 
Study Endpoints ............................................................................................................ 9 
2.2.1. Primary Endpoints ........................................................................................................ 9 
2.2.2. Secondary Endpoints .................................................................................................... 9 
2.2.3. Exploratory Endpoints .................................................................................................. 9 
3. 
Overall Study Design and Plan ........................................................................................... 9 
3.1. 
Overall Design .............................................................................................................. 9 
3.2. 
Sample Size and Power ............................................................................................... 11 
3.3. 
Study Population ......................................................................................................... 11 
3.4. 
Treatments Administered ............................................................................................ 11 
3.5. 
Method of Assigning Subjects to Treatment Sequences/Arms................................... 11 
3.6. 
Blinding and Unblinding............................................................................................. 12 
3.7. 
Schedule of Events ...................................................................................................... 12 
4. 
Statistical Analysis and Reporting .................................................................................... 15 
4.1. 
Introduction ................................................................................................................. 15 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 15 
5. 
Analysis Populations ......................................................................................................... 15 
6. 
Statistical Definitions and Algorithms .............................................................................. 16 
6.1. 
Baseline ....................................................................................................................... 16 
6.2. 
Adjustments for Covariates......................................................................................... 16 
6.3. 
Multiple Comparisons ................................................................................................. 16 
6.4. 
Handling of Dropouts or Missing Data ....................................................................... 16 
6.5. 
Analysis Visit Windows ............................................................................................. 17 
6.6. 
Pooling of Sites ........................................................................................................... 17 
6.7. 
Derived Variables ....................................................................................................... 17 
6.8. 
Data Adjustments/Handling/Conventions .................................................................. 17 
7. 
Study Subjects and Demographics.................................................................................... 18 
7.1. 
Disposition of Subjects and Withdrawals ................................................................... 18 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 4 of 96 
 
7.2. 
Protocol Violations and Deviations ............................................................................ 18 
7.3. 
Demographics and Baseline Characteristics ............................................................... 18 
7.4. 
Medical History .......................................................................................................... 18 
7.5. 
Prior and Concomitant Medication ............................................................................. 19 
7.6. 
Exposure and Compliance .......................................................................................... 20 
8. 
Pharmacokinetic Analysis ................................................................................................. 20 
8.1. 
Analysis on Primary PK Endpoints ............................................................................ 20 
8.1.1. Primary PK Analysis................................................................................................... 20 
8.1.2. Sensitivity Analysis on Primary PK Endpoints .......................................................... 21 
8.2. 
Analysis on Secondary PK Endpoints ........................................................................ 21 
8.2.1. Secondary PK Analysis............................................................................................... 21 
8.2.2. Sensitivity Analysis on Secondary PK Endpoints ...................................................... 22 
9. 
Safety and Tolerability Analysis ....................................................................................... 22 
9.1. 
Adverse Events ........................................................................................................... 22 
9.1.1. Adverse Events Leading to Study or Drug Withdrawal ............................................. 23 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 23 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 23 
9.3. 
Physical Examination.................................................................................................. 24 
9.4. 
Vital Signs ................................................................................................................... 24 
9.5. 
Electrocardiograms (ECG).......................................................................................... 24 
9.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................... 24 
9.7. 
MINI International Neuropsychiatric Interview (M.I.N.I.) ........................................ 25 
10. 
References ......................................................................................................................... 25 
11. 
Tables, Listings, and Figures ............................................................................................ 25 
11.1. Planned Table Descriptions ........................................................................................ 27 
11.2. Planned Figure Descriptions ....................................................................................... 29 
11.3. Planned Listing Descriptions ...................................................................................... 30 
12. 
Tables, Listings, and Listing Shells .................................................................................. 31 
12.1. Standard Layout for all Tables, Listings, and Figures ................................................ 31 
12.2. Planned Table Shells ................................................................................................... 32 
Table 14.1.1     Study Populations and Subject Disposition  All Enrolled Subjects (ITT) ........... 33 
Table 14.1.2.1  Demographics and Baseline Characteristics  All Enrolled Subjects (ITT) ......... 35 
Table 14.1.2.2  Demographics and Baseline Characteristics  Safety Population ......................... 37 
Table 14.1.2.3  Demographics and Baseline Characteristics  PK Population .............................. 37 
Table 14.1.3.1  Medical History Safety Population ...................................................................... 38 
Table 14.1.3.2  Prior Medication Safety Population ..................................................................... 39 
Table 14.1.3.3  Concomitant Medication Safety Population ........................................................ 40 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 5 of 96 
 
Table 14.1.4     Summary of Drug Exposure  Safety Population .................................................. 41 
Table 14.2.1.1  Primary PK Analysis of Natural log-transformed PK Parameters (Cmax, AUC0-∞, 
and AUClast)  Summary of Estimates of Mean Differences between Treatments from 
Mixed Effect Model PK Population ................................................................................. 42 
Table 14.2.1.1.1  Sensitivity Analysis on Primary PK Endpoints: Natural log-transformed PK 
Parameters (Cmax, AUC0-∞, and AUClast)  Summary of Estimates of Mean Differences 
between Treatments from Mixed Effect Model PK Population ....................................... 43 
Table 14.2.1.1.2  Primary PK Analysis of Natural log-transformed PK Parameters (Cmax, AUC0-∞, 
and AUClast)  Summary of Descriptive Statistics PK Population ..................................... 44 
Table 14.2.1.2  Primary PK Analysis of Natural log-transformed, Dose-normalized PK 
Parameters (Cmax, AUC0-∞, and AUClast)  Summary of Estimates of Mean Differences 
between Treatments from Mixed Effect Model PK Population ....................................... 45 
Table 14.2.1.2.1  Sensitivity Analysis on Primary PK Endpoints: Natural log-transformed, Dose-
normalized PK Parameters (Cmax, AUC0-∞, and AUClast)  Summary of Estimates of Mean 
Differences between Treatments from Mixed Effect Model PK Population .................... 45 
Table 14.2.1.2.2  Primary PK Analysis of Natural log-transformed, Dose-normalized PK 
Parameters (Cmax, AUC0-∞, and AUClast)  Summary of Descriptive Statistics PK 
Population ......................................................................................................................... 45 
Table 14.2.2.1  Secondary PK Analysis of Natural log-transformed PK Parameters (Partial 
AUCs)  Summary of Estimates of Mean Differences between Treatments from Mixed 
Effect Model PK Population ............................................................................................. 46 
Table 14.2.2.1.1  Sensitivity Analysis on Secondary PK Endpoints: Natural log-transformed PK 
Parameters (Partial AUCs)  Summary of Estimates of Mean Differences between 
Treatments from Mixed Effect Model PK Population ...................................................... 46 
Table 14.2.2.1.2  Secondary PK Analysis of Natural log-transformed PK Parameters (Partial 
AUCs)  Summary of Descriptive Statistics PK Population .............................................. 46 
Table 14.2.2.2  Secondary PK Analysis of Natural log-transformed, Dose-normalized PK 
Parameters (Partial AUCs)  Summary of Estimates of Mean Differences between 
Treatments and Dose Levels from Mixed Effect Model PK Population .......................... 46 
Table 14.2.2.2.1  Sensitivity Analysis on Secondary PK Endpoints: Natural log-transformed, 
Dose-normalized PK Parameters (Partial AUCs)  Summary of Estimates of Mean 
Differences between Treatments from Mixed Effect Model PK Population .................... 46 
Table 14.2.2.2.2  Secondary PK Analysis of Natural log-transformed, Dose-normalized PK 
Parameters (Partial AUCs)  Summary of Descriptive Statistics PK Population .............. 46 
Table 14.2.2.3  Secondary PK Analysis of Natural log-transformed PK Parameters (K and T1/2)  
Summary of Descriptive Statistics PK Population ........................................................... 47 
Table 14.2.2.4  Secondary PK Analysis of PK Parameters (tmax and tlag)  Summary of Descriptive 
Statistics PK Population .................................................................................................... 48 
Table 14.2.2.5  Secondary PK Analysis: Summary of Plasma Concentration of d-MPH (unit)  PK 
Population ......................................................................................................................... 49 
Table 14.3.1.1.1  Summary of all TEAEs  Safety Population ...................................................... 50 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 6 of 96 
 
Table 14.3.1.1.2  Summary of all TEAEs, Non-Current Cigarette Smokers Safety Population .. 51 
Table 14.3.1.1.3  Summary of all TEAEs, Current Cigarette Smokers Safety Population .......... 51 
Table 14.3.1.2.1  TEAEs by SOC and Preferred Term  Safety Population .................................. 52 
Table 14.3.1.2.2  TEAEs by SOC and Preferred Term, Non-Current Cigarette Smokers Safety 
Population ......................................................................................................................... 53 
Table 14.3.1.2.3  TEAEs by SOC and Preferred Term, Current Cigarette Smokers Safety 
Population ......................................................................................................................... 53 
Table 14.3.1.3  TEAEs by SOC, Preferred Term and Severity Safety Population ....................... 54 
Table 14.3.1.4  TEAEs by SOC, Preferred Term and Relationship to Treatment Safety 
Population ......................................................................................................................... 56 
Table 14.3.1.5  TEAEs leading to Death by SOC and Preferred Term  Safety Population .......... 57 
Table 14.3.1.6  TESAEs by SOC and Preferred Term  Safety Population ................................... 57 
Table 14.3.1.7  AEs leading to Study or Drug Withdrawal by SOC and PT  Safety Population . 57 
Table 14.3.2.1  Summary of Biochemistry by Treatment  Safety Population .............................. 58 
Table 14.3.2.2  Summary of Hematology by Treatment  Safety Population ................................ 59 
Table 14.3.2.3  Summary of Urinalysis by Treatment Safety Population .................................... 59 
Table 14.3.2.4  Biochemistry Shift from Baseline to EOS/ET Visit Safety Population .............. 60 
Table 14.3.2.5  Hematology Shifts from Baseline to EOS/ET Visit Safety Population ............... 61 
Table 14.3.2.6  Urinalysis Shifts from Baseline to EOS/ET Visit Safety Population .................. 61 
Table 14.3.3.1  Summary of Physical Examination by Treatment Safety Population.................. 62 
Table 14.3.4.1  Summary of Vital Signs by Treatment Safety Population ................................... 63 
Table 14.3.5.1  Summary of ECG Parameters by Treatment Safety Population .......................... 65 
Table 14.3.5.2.1  Incidence of Investigator ECG Interpretation by Treatment Safety Population66 
Table 14.3.5.2.2  Incidence of Investigator ECG Interpretation by Treatment, Non-Current 
Cigarette Smokers Safety Population ............................................................................... 67 
Table 14.3.5.2.3  Incidence of Investigator ECG Interpretation by Treatment, Current Cigarette 
Smokers Safety Population ............................................................................................... 67 
Table 14.3.6.1  C-SSRS, Incidence of Ideation/Behaviour by Treatment Safety Population ...... 68 
12.3. Planned Figure Shells ................................................................................................. 69 
Figure 14.2.2.6.1 Plasma Concentration of d-MPH Scatterplot (linear)  PK Population ............. 69 
Figure 14.2.2.6.2 Plasma Concentration of d-MPH Scatterplot (semi-logarithmic) PK Population
........................................................................................................................................... 69 
Figure 14.2.2.6.3 Mean Plasma Concentration of d-MPH vs. Time by Treatment (linear)  PK 
Population ......................................................................................................................... 69 
Figure 14.2.2.6.4 Mean Plasma Concentration of d-MPH vs. Time by Treatment (semi-
logarithmic) PK Population .............................................................................................. 69 
12.4. Planned Listing Shells................................................................................................. 70 
Listing 16.2.1.1 Study Populations and Disposition  All Enrolled Subjects (ITT) ...................... 70 
Listing 16.2.1.2 Randomization and Treatment Completion  All Enrolled Subjects (ITT) ......... 71 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 7 of 96 
 
Listing 16.2.2.1 Inclusion and Exclusion Criteria  All Subjects ................................................... 72 
Listing 16.2.2.2 Protocol Deviations  All Enrolled Subjects (ITT) .............................................. 73 
Listing 16.2.4.1 Demographics  All Enrolled Subjects (ITT)....................................................... 74 
Listing 16.2.4.2 Medical History  Safety Population.................................................................... 75 
Listing 16.2.4.3 Prior and Concomitant Medication  Safety Population ...................................... 76 
Listing 16.2.4.4 Cigarettes Smoking Log Safety Population ....................................................... 77 
Listing 16.2.5.1 Study Drug Administration  Safety Population .................................................. 78 
Listing 16.2.5.2 Tolerability Drug Administration  Safety Population ........................................ 79 
Listing 16.2.6.1 Plasma Concentration of d-MPH PK Population ............................................... 80 
Listing 16.2.6.2 PK Parameters PK Population ............................................................................ 81 
Listing 16.2.7.1 All Adverse Events ............................................................................................. 82 
Listing 16.2.7.2 Serious Adverse Events  Safety Population ....................................................... 83 
Listing 16.2.7.3 Adverse Events leading to Discontinuation  Safety Population ......................... 83 
Listing 16.2.7.4 Listing of Deaths  Safety Population .................................................................. 83 
Listing 16.2.8.1 Biochemistry Safety Population ......................................................................... 84 
Listing 16.2.8.2 Hematology Safety Population ........................................................................... 85 
Listing 16.2.8.3 Urinalysis Safety Population .............................................................................. 85 
Listing 16.2.8.4 Thyroid Safety Population .................................................................................. 85 
Listing 16.2.8.5 Urine Drug Screen Safety Population ................................................................ 86 
Listing 16.2.8.6 Serology Safety Population ................................................................................ 86 
Listing 16.2.8.7 Pregnancy  Safety Population ............................................................................. 87 
Listing 16.2.8.8 Breath Alcohol Test  Safety Population ............................................................. 88 
Listing 16.2.9.1 Physical Examination  Safety Population ........................................................... 89 
Listing 16.2.9.2 Vital Signs  Safety Population ............................................................................ 90 
Listing 16.2.9.3 Electrocardiogram (ECG)  Safety Population .................................................... 91 
Listing 16.2.9.4 C-SSRS  Safety Population ................................................................................ 92 
Listing 16.2.9.5 M.I.N.I.  Safety Population................................................................................. 93 
Appendix 1: List of Abbreviations ............................................................................................... 94 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 8 of 96 
 
1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Cingulate 
Therapeutics protocol number CTx-1301-001 (A randomized, single-dose, four-sequence, four-
period, in-clinic crossover study in adult subjects with attention deficit and hyperactivity disorder 
(ADHD) to establish safety, tolerability, and comparative bioavailability of CTx-1301 
(dexmethylphenidate) to the listed drug (Focalin XR™) under fasted conditions.), version 4.0, 
dated 16JAN2019. Reference materials for this SAP include the protocol and the accompanying 
sample data collection documents. Operational aspects related to collection and timing of planned 
clinical assessments are not repeated in this SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements identified 
by the Food and Drug Administration (FDA), European Medicines Agency (EMA), and 
International Conference on Harmonization (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical Trials1. All work 
planned and reported for this SAP will follow internationally accepted guidelines, published by 
the American Statistical Association2 and the Royal Statistical Society3, for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not necessarily 
identified in this SAP may be performed to further examine study data. Any post-hoc or unplanned, 
exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to the Cingulate Therapeutics study 
CTx-1301-001. 
2. 
Study Objectives and Endpoints 
2.1. 
Study Objectives 
2.1.1. Primary Objectives 
• To compare the bioavailability of the marketed product Focalin XRTM Extended-Release 
Capsules to the CTx-1301 trimodal product in a fasted state.  
 Demonstrate similar and comparative bioavailability of the highest dose of CTx-
1301 (50 mg) to Focalin XR™ (40 mg) dose 
 Demonstrate similar and comparative bioavailability of the lowest dose of CTx-
1301 (6.25 mg) to the lowest dose of Focalin XR™ (5 mg) 
 Demonstrate dose proportionality of CTx-1301 by evaluating the 6.25 mg dose to 
the 50 mg dose 
 
2.1.2. Secondary Objectives 
• To provide pharmacokinetic data on blood plasma levels of dexmethylphenidate (d-MPH) 
• To evaluate the safety of CTx-1301 6.25 mg and 50 mg dose 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 9 of 96 
 
2.1.3. Exploratory Objectives  
• To further explore the impact of comparative bioavailability of the marketed product 
Focalin XR™ Extended-Release Capsules to the CTx-1301 trimodal product in a fasted 
state within selected time intervals 
2.2. 
Study Endpoints 
2.2.1. Primary Endpoints 
• PK parameters including Cmax, AUC0-∞, and AUClast. 
2.2.2. Secondary Endpoints 
• PK plasma concentrations of d-MPH  
• PK parameters including partial AUCs (e.g. AUC0-3, AUC3-6, AUC6-9, AUC9-12, and 
AUC12-16) to examine potential differences between treatments (CTx-1301 6.25 mg vs. 
Focalin XR™ 5 mg and CTx-1301 50 mg vs. Focalin XR™ 40 mg) within selected time 
intervals. 
• PK parameters including K, T1/2, tmax, and tlag. 
• Safety measurements including ECG, vital signs, lab assessments, physical exam, and the 
incidence of treatment-emergent adverse events (TEAEs) 
2.2.3. Exploratory Endpoints 
• Additional exploratory analyses may be conducted to examine potential differences 
between treatments (CTx-1301 6.25 mg vs. Focalin XR™ 5 mg and CTx-1301 50 mg vs. 
Focalin XR™ 40 mg) within selected time intervals as needed 
The exploratory endpoints will be evaluated post-hoc and described in the CSR. 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is a randomized, single-dose, four-sequence, four-period, in-clinic crossover study under 
fasted conditions. The study will involve approximately 36 adult ADHD study completers, male 
or female. The Screening period will occur from Day -28 to Day -5; subjects that meet eligibility 
at screening must washout of all stimulant medications at least 96 hours (hrs) prior to check in on 
Day -4. Subjects will remain in clinic from Day -4 to the end of study (EOS) visit at Day 10.  
Subjects who complete screening, if eligible, will be brought back for the in-clinic portion of the 
study. Subjects will be reassessed for eligibility at check-in on Day -4 to ensure they still meet 
study criteria. Eligible Subjects will be in-clinic for the entire duration of the 15-day study (Day -
4 to EOS at Day 10). Study visits include check-in day (Day -4), tolerability assessment (Day -3), 
Assessment 1 (Day 0), Assessment 2 (Day 3), Assessment 3 (Day 6), Assessment 4 (Day 9), and 
EOS (Day 10). Subjects that early terminate should follow the assessment structure of the EOS 
day; a final PK draw should be collected and labeled at early termination (ET) time. Additional 
unscheduled visits or assessments may be requested by an Investigator if concerned for subject 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 10 of 96 
 
safety.  
Subjects will be dosed with the following treatments according to a pre-defined, balanced, 
randomized crossover schedule: 
 
Table 1: Study Treatments 
Treatment A 
Focalin XR™ Extended-Release capsule 5 mg 
Treatment B 
CTx-1301 trimodal 6.25 mg tablet 
Treatment C 
Focalin XR™ Extended-Release capsule 40 mg  
Treatment D 
CTx-1301 trimodal 50 mg tablet 
 
Subjects will be randomized to sequences of treatment according to a 4×4 Williams design. 
Williams Design is a special case of Latin square design and is balanced for carryover effects.  
 
Table 2: Study Design and Treatment Sequences 
Sequence 
Period 1 
Period 2 
Period 3 
Period 4 
1 (n = 9) 
A 
D 
B 
C 
2 (n = 9)  
B 
A 
C 
D 
3 (n = 9)  
C 
B 
D 
A 
4 (n = 9)  
D 
C 
A 
B 
 
Subjects must washout of all stimulant medications for a minimum of 96 hrs prior to check in on 
Day -4. Subjects must arrive at the clinic on Day -4 for check in (at least 12 hrs prior to receiving 
the test dose of 40mg Focalin XR™ at hr 0 on Day -3). Subjects may receive a snack (if needed) 
from hrs -12 to -10 on Day -4; at -10 hrs, all subjects must fast until at least hr 4 post-dose on Day 
-3. Water is restricted at least 1 hour (hr) prior to dosing and at least 2 hrs after dosing. An 
Investigator will assess if a subject has safely tolerated the 40mg dose of Focalin XR™ and can 
continue into the randomized portion of the study.  
Subjects must fast from at least 10 hrs prior to dosing and at least 4 hrs post-dose on the test day 
and all Assessment Days (water is restricted at least 1 hr. prior to dosing and at least 2 hrs after 
dosing). Blood samples for pharmacokinetic analysis will be taken at the protocol-specified time 
points until 28 hrs post-dose (see Table 3). Vital signs (blood pressure and pulse) and ECG will be 
taken at the protocol-specified time points until 28 hrs post-dose.  
Subjects will be discharged from the study center once they have completed all study assessments. 
The maximum period the subjects will be at the study center is approximately 15 days. 


 
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3.2. 
Sample Size and Power 
The study design is a randomized, single-dose, four-sequence, four-period, in-clinic crossover 
study. Cmax, AUC0-∞, and AUClast are the key PK endpoints which will be used to evaluate the 
relative bioavailability of CTx-1301 6.25 mg vs. Focalin XR™ 5 mg (treatment B vs. treatment 
A) and CTx-1301 50 mg vs. Focalin XR™ 40 mg (treatment D vs. treatment C). The basis of 
evaluation for these endpoints will be 90% confidence intervals for the ratios of adjusted geometric 
means as described in Section 10.7 in protocol. In the context of a bioavailability analysis, 
similarity will be concluded if the 90% confidence interval (CI) of the geometric mean ratios for 
Cmax, AUC0-∞, AUClast fall near or within the 90% CI of [0.80–1.25]. This is the same as performing 
two one-sided hypothesis tests (TOST procedure), each conducted at a 5% significance level. The 
TOST procedure can identify two treatments as similar when the lower bound of a 90% confidence 
interval falls near or below 1.25 or the upper bound of a confidence interval falls near or above 
0.80 (or both).  
Based on the conservative TOST methodology assumption, that the bioavailability analysis falls 
within the 90% CI of [0.80, 1.25], a sample size of at least 32 evaluable subjects included in the 
PK Population, as described in Section 5, will provide at least 88% power with the assumption of 
within-subject coefficient of variation (CV) of 17-21% and true bioavailability ratio (B/A and D/C) 
of 93-107%. With assumption of the drop-out rate of 11%, approximately 36 completers will be 
randomized. No adjustment for multiple comparisons will be made. 
3.3. 
Study Population 
Approximately 36 study completers will be randomized in the study to achieve 32 evaluable 
subjects for the full study (at least 8 in each treatment sequence).  
3.4. 
Treatments Administered 
Subjects will be randomized to the 4 treatment sequences in Table 2 at the ratio of 1:1:1:1.  
3.5. 
Method of Assigning Subjects to Treatment Sequences/Arms 
This is a randomized study. Subjects should only be enrolled/randomized if they meet eligibility 
criteria both at screening and again at Day -4, Day -3, and Day -1.  
Subjects who meet all of the inclusion and none of the exclusion criteria will be 
enrolled/randomized to the study. Subject enrollment numbers will be assigned in ascending 
numerical order as enrolled. Subject randomization numbers will correspond to a pre-defined 
randomization schedule prepared by the Sponsor. Randomization numbers will be assigned in 
sequence across cohorts; replacement randomization numbers will be formatted in a manner 
similar to those initially assigned, but unique to the replacement patient.  
There should be no sequence gaps in subject enrollment or initial randomization numbers. If a 
subject early terminates, then the assigned enrollment and randomization numbers must still 
remain attached to the early termination subject. If an initial randomization sequence is skipped, 
then the unblinded pharmacist must immediately consult with the unblinded statistician at the CRO 
for next steps.  
An unblinded statistician may review the allocations to ensure the required number of completers 
(or evaluable PK Population patients) per treatment sequence was achieved as described in Section 
3.2. This may be done after completion of a cohort and/or at the end of the study, depending on 
the number of dropouts and when they occur.  Subjects which are not evaluable members of the 


 
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PK Population (Section 5) may be replaced if the required number of completers is not achieved 
for a sequence. 
Any randomized subject that does not complete the study will be an early termination and reason 
for termination must be noted in the source document and eCRF. 
3.6. 
Blinding and Unblinding 
The unblinded pharmacy staff will prepare the study medications and maintain documentation of 
study drug administration for each subject according to the randomization schedule provided by 
the sponsor or sponsor representative/CRO. Verification by a second unblinded pharmacy member 
will be conducted to ensure the unblinded pharmacist has randomized the subject to the correct 
randomization sequence per the randomization schedule and instructions. The unblinded pharmacy 
staff must follow the site’s pharmacy dispensing SOP. All doses will be administered from a 
blinded cup with a closed lid to prevent subjects from inspecting the tablets or capsules as well as 
to keep the subjects and study site staff blinded. 
An unblinded statistician not involved in study conduct may review subject randomization 
allocations as described in Section 3.5. 
3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 3. 
 


 
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Table 3: Schedule of Events 
Procedure 
Screening a 
(Day -28 to 
Day -5) 
Clinic 
Check-In 
(Day -4) 
Tolerability c 
Test 
(Day -3) 
 
(Day -2) 
(Day -1) 
Assessment 
Days 
(Day 0, 3, 6, and 
9) 
 
Non-
Assessment 
Days 
(Day 1, 2, 4, 5, 
7, & 8) 
 
EOS/ETl
l 
 
Unscheduled 
(USV)m 
Written Informed Consent  
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
Medical History  
 
 
 
 
 
 
 
 
Current/Concomitant 
Medications 
 
 
 
 
 
 
 
 
Inclusion & Exclusion Criteria 
 
 
 
 
 
 d 
 
 
Wash-Out Call 
b 
 
 
 
 
 
 
 
Physical Examination 
 
 
 
 
 
e 
 
 
MINI 7.0.2 version 
 
 
 
 
 
 
 
 
C-SSRS 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
 
 
f 
 
 
f 
f 
 
Vital Signs  
 
 
g 
 
 
 g 
g 
 g 
 
Height 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
Serology 
 
 
 
 
 
 
 
 
Clinical Safety Labs:  
 
 
 
 
 
 
 
 
Biochemistry 
 
 
 
 
 
Hematology 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
Serum HCG 
h 
h 
 
 
 
 
h 
 
Urine Screen for Drugs of 
Abuse  
 
 
 
 
 
 
 
 
Breath Alcohol Test 
 
 
 
 
 
 
 
 
AE Assessment 
 
 
 
 
 
 
 
 
 


 
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Procedure 
Screening a 
(Day -28 to 
Day -5) 
Clinic 
Check-In 
(Day -4) 
Tolerability c 
Test 
(Day -3) 
 
(Day -2) 
(Day -1) 
Assessment 
Days 
(Day 0, 3, 6, and 
9) 
 
Non-
Assessment 
Days 
(Day 1, 2, 4, 5, 
7, & 8) 
 
EOS/ETl
l 
 
Unscheduled 
(USV)m 
Ongoing Eligibility  
 
 
 
 
 
 
 
 
 
Test Dose of 40mg Focalin 
XR™  
 
 
 c 
 
 
 
 
 
Randomization 
 
 
 
 
 
 i 
 
 
Treatment Administration 
 
 
 
 
 
 
 j 
 
 
PK Blood Sampling  
 
 
 
 
 
 k 
 k 
 
 
a: Screening day(s) will take place up to 24 days prior to Day -4 (check-in at clinic). 
b. Washout call reminder should be completed 120 hrs (5 days) prior to Day -4. If subject is screened within the 120 hrs prior to Day -4, the washout call reminder is not required.   
c. Tolerability day with Focalin XR 40 mg must occur on Day -3, allowing 3 days prior to Day 0 /Randomization to ensure washout of d-MPH. Dosing must occur before 8:30 am. If subject 
can’t tolerate test dose, subject must be excluded. 
d. Inclusion/Exclusion assessed at Screening, Day -4, and Day 0 prior to randomization; Eligibility continually assessed throughout study.  
e. PE to occur mid-study on Day 6 
f:  ECG’s administered on tolerability and Assessment days must be done prior to dosing, hr. 6, and hr. 28 (+/-30 min for post-dose ECGs). 
g  Vital signs will be taken prior to dosing and at 1 hr., 2 hr., 6 hr., and 28 hr. post-dose (+/- 10 minutes) at tolerability day (Day -3) and Days 0-9.  
h. Serum HCG tests should be assessed in all women of child-bearing potential; Serum HCG should be assessed at Screening, check in on Day -4, and EOS. 
i. Randomization will occur on Day 0 after ensuring subject still meets inclusion/exclusion criteria  
j. Administration of study treatment must be separated by 3 days (72 hours). Administration of study treatments will occur on Day 0, Day 3, Day 6, and Day 9 before 8:30 am.  
k. Blood samples for PK analysis will be taken pre-dose (0)  -1 to 0 hr.) and post-dose at hrs. 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 24, and 28; if for ET visit, 
collect one last PK draw and record time of collection.  
l. Early Termination (ET) day assessments should follow the EOS assessment schedule. If all assessments are not completed, note reason for noncompletion.  
m. USV is at the discretion of an Investigator; USV will have no treatment administration or PK draws/analysis. All other assessments are at the discretion of the investigator. 
 


 
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4. 
Statistical Analysis and Reporting 
All final, planned analyses identified in this SAP will be performed after the study database has 
been locked.  
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS® (release 9.4 or higher). All PK 
parameter estimations will be performed using Phoenix WinNonlin® version 8.0 or later. If the use 
of other software is warranted, the final statistical methodology report will detail what software 
was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum. The 
minimum and maximum will be reported with the same degree of precision (ie, the same number 
of decimal places) as the observed data. Measures of location (mean and median) will be reported 
to 1 degree of precision more than the observed data and measures of spread (SD) will be reported 
to 2 degrees of precision more than the observed data.  
Categorical (qualitative) variable summaries will include the frequency and percentage of subjects 
who are in a particular category or each possible value. Percentages will be presented to 1 decimal 
place, unless otherwise specified. 
Unless stated otherwise, disposition and demographic characteristics data at baseline will be 
summarized overall, and by treatment sequence, while safety and PK data will be presented by 
treatment group and period/visit (e.g. reported within the treatment group associated with the 
scheduled visit), unless otherwise specified. The EOS/ET visit will be displayed based on the last 
treatment group received by a subject.  
A subject must have been dosed with drug in a specified period in order to be included in the 
reporting for that period; data will be analyzed based on the treatment received for a specified 
period.  
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses or Data Monitoring Committee are planned. 
An unblinded analysis of the randomization and disposition data will be performed as described 
in Section 3.5. Since the review will be performed by an unblinded statistician with no involvement 
in study activities for purposes of ensuring the planned enrollment requirements have been 
satisfied, there will be no statistical penalty for this review. 
5. 
Analysis Populations 
The following analysis populations are planned for this study:  
• All Enrolled Subjects (ITT): Includes all intent-to-treat (ITT) subjects who have signed 
the informed consent form (ICF), meet the eligibility criteria, and are randomized to a 


 
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treatment sequence. This population will be used for subject disposition and protocol 
deviation summaries and listings.  
• Safety Population (SAF): The Safety Population includes all enrolled subjects who 
receive at least 1 dose of study drug. The SAF will be used for demographics and other 
baseline characteristic summaries and listings, for analyses of all safety endpoints, and for 
the exposure listing.  
• Pharmacokinetic (PK) Population: The PK Population includes all subjects who receive 
at least 1 dose of study drug and provide at least 1 evaluable PK plasma concentration. The 
PK Population will be used for all PK analyses.  
6. 
Statistical Definitions and Algorithms 
6.1. 
Baseline 
The last observation recorded prior to the first dose will be used as the baseline, or to derive the 
baseline in summaries of demographic and baseline characteristics. Baseline of clinical 
laboratory evaluations, physical examinations, and the Columbia Suicide Severity Rating Scale 
(C-SSRS) is the last observation prior to the first dose of study medication.  
The last observation prior to dose of treatment at each treatment period (pre-dose time point) will 
be used as the baseline observation of that treatment period in calculating changes from baseline 
of vital signs, ECGs and PK concentrations.  
6.2. 
Adjustments for Covariates 
Additional variables may be explored in post hoc analyses if deemed appropriate; additional 
covariate analyses will be described in CSR.   Adverse event and ECGs will report selected 
summaries by cigarette smoking status (non-current smokers, current smokers); additional 
analyses may be performed as appropriate. 
6.3. 
Multiple Comparisons 
No adjustments will be made for multiple comparisons. 
6.4. 
Handling of Dropouts or Missing Data 
Approximately 36 subjects will be randomized in order to achieve the target of 32 evaluable 
subjects (at least 8 in each treatment sequence) completing the entire study. Subjects that early 
terminate may be replaced at the discretion of the Sponsor. All subjects treated with at least one 
dose will be in the SAF. All subjects who receive at least one study treatment and complete at least 
one PK blood draw will be included in PK analyses.  
Back-up subjects may be recruited to the site on Day -4 in case of screen failures. The study will 
be conducted in approximately 4-5 cohorts. After completion of each cohort, randomization data 
may be reviewed by an unblinded statistician as described in Section 3.5.  
There will be no data imputation for PK or safety endpoints.  


 
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6.5. 
Analysis Visit Windows 
In general, summary tables of all variables for this study will use the nominal time point as 
collected in the eCRF/database. An exception to this is the derivation of baseline as defined in 
Section 6.7. Baseline values will be based on all assessments, whether scheduled or unscheduled. 
Unscheduled visits will be presented in data listings.  
6.6. 
Pooling of Sites 
No pooling of sites will be conducted; there is only one site in the study.  
6.7. 
Derived Variables 
• Age (years) at Baseline = Integer of (Day 0 visit date – Date of Birth) / 365.25 
• Study Day = Assessment Day – Date of First Dose (Day 0) 
• Body Mass Index (BMI) = (Weight (kg) / (Height (cm)2) x 10,000 
• Change from baseline = value at current time point – value at baseline 
• TEAE = any adverse event (AE) with an onset date on or after the first dose of study 
medication on Day 0 after randomization 
• Medications which continue or start after the first administration of study medication on 
Day 0 will be considered concomitant. 
6.8. 
Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
Adverse events will be coded using the MedDRA version 22.0 dictionary. 
A treatment-related AE is any AE identified as “Related to study drug” in the eCRF; procedure 
related AEs are those which are identified as “Procedure related” in the eCRF. 
If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date prior to the first dose in 
which case the month after the first dose is used; and if both month and day are missing then the 
month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 


 
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Prior to any imputation, given the multiple treatments administered in this study, dates will be 
queried to make all attempts at completeness in order to ensure reporting coincides with the 
appropriate treatment period for the subject.  
7. 
Study Subjects and Demographics 
All demographic and baseline summaries including disposition, demographic and baseline 
characteristics, medical history, and prior medication will be presented overall (all treatment 
sequences), and by treatment sequence for All Enrolled Subjects, SAF, and PK Populations, as 
needed.    
Concomitant medication and study drug exposure will be summarized by treatment group and 
period for the SAF. Concomitant medications will additionally be summarized by treatment group 
over all periods, as described in Section 7.5.  
7.1. 
Disposition of Subjects and Withdrawals 
The number and percentage of subjects included in each analysis population, who complete the 
study, who complete each period, who receive each treatment, and who early terminate from 
treatment at any time during the study will be tabulated  by treatment sequence and overall for All 
Enrolled Subjects (ITT).  
A by-subject enrollment and disposition listing will be presented for All Enrolled Subjects.  
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be listed for All Enrolled Subjects.  
7.3. 
Demographics and Baseline Characteristics 
Summary statistics for age, gender, race, ethnicity, cohort, height, weight, BMI, and cigarette 
smoking status at baseline will be presented overall, and by treatment sequence based on All 
Enrolled Subjects (ITT), SAF, as well as for the PK Populations.  
For the continuous variables, the number of non-missing values and the mean, standard deviation, 
minimum, median, and maximum will be tabulated. For the categorical variables, counts and 
proportions of each value will be presented.   
Demographic and other baseline characteristics will be presented in subject listings for All 
Enrolled Subjects.  
7.4. 
Medical History 
The number and percent of subjects reporting various medical histories, grouped by MedDRA 
system organ class and preferred term (coded using MedDRA v. 22.0), will be tabulated overall 
and by treatment sequence. If a subject has multiple records under the same System Organ Class 
(SOC) and preferred term, only one will be counted. This analysis will be conducted for the SAF.  
By-subject listings of all medical history will be presented for the SAF.  


 
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7.5. 
Prior and Concomitant Medication 
Prior medications will be presented separately from concomitant medications. Medications will be 
coded using WHO-DD v. March 1, 2019 and reported in Anatomical Therapeutic Chemical (ATC) 
Level 4.  
Medications that started prior to the first administration of study drug on Day 0 will be considered 
prior medications whether or not they were stopped prior to first administration of study 
medication. Prior medications will be summarized descriptively with counts and percentages 
overall, and by treatment sequence for the SAF.  
Any medications continuing or starting post the first administration of study medication on Day 0 
will be considered to be concomitant. Concomitant medications will be summarized by treatment 
group (including All CTx-1301 and All Focalin XR™ groups) and period, based on the time that 
concomitant medication continues or starts. Concomitant medication will be assigned to a 
treatment period if the start date and time is on or after the drug administration date and time of 
that treatment period, and before the drug administration date and time of the next treatment period. 
In the case that a single medication belongs to more than one treatment period, the medication will 
be counted in all treatment groups (including All CTx-1301 and All Focalin XR™ groups)/periods 
it falls into. Concomitant medications will additionally be summarized by treatment group 
(including All CTx-1301 and All Focalin XR™ groups) over all periods. 
If a medication starts prior to the first administration of study medication on Day 0 and continues 
after that, it will be considered both prior and concomitant. Subjects will be counted only once for 
each Anatomical Therapeutic Chemical (ATC) and Preferred Term in each treatment sequence or 
group column. A by-subject listing of all prior and concomitant medications will be presented for 
the SAF.  
 
 


 
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7.6. 
Exposure and Compliance 
Exposure to each of the four treatments on Day 0, 3, 6, and 9 will be summarized by treatment 
group (including All CTx-1301 and All Focalin XR™ groups) and overall for the SAF. Individual 
data listings will be provided for the SAF. A separate listing will be provided for the tolerability 
test on Day -3.  
8. 
Pharmacokinetic Analysis 
Unless otherwise stated, all PK analyses will be created using the PK Population.   
Plasma Concentrations 
Individual plasma concentration vs actual time data will be used to estimate the PK parameters by 
standard non-compartmental methods for each subject in the PK population, as data permit. 
For plasma concentration data, all values below the limit of quantification (BLQ) will be set to 0 
for summary statistics and graphs. Individual plasma concentrations of d-MPH will be summarized 
by treatment group at each time point using descriptive statistics. Individual concentration plots 
and mean data graphs will be produced. All graphs will be presented using both linear and semi-
logarithmic scales. 
Pharmacokinetic Parameters 
Pharmacokinetic parameter estimation will be performed using the individual plasma 
concentration-time data. The actual elapsed times will be used for all calculations. For the PK 
parameter calculation, BLQ plasma concentrations occurring before Tmax will be set to 0, with the 
exception of a BLQ value occurring between two measurable concentrations, in which case it will 
be set to missing. BLQ plasma concentrations occurring after Tmax will be set to missing. 
Pharmacokinetic parameter estimates and summaries will be completed for subjects in the PK 
population having sufficient measurable concentrations to define the PK profile. AUC0-∞ values 
for which the extrapolated part exceeds 20% of the total AUC will be excluded from the calculation 
of the descriptive statistics. No value for AUC0-∞, kel, and t½ will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration-time data. 
Pharmacokinetic parameter estimates will be summarized by treatment group using descriptive 
statistics, including arithmetic and geometric means, SD, % CV, median, minimum, and 
maximum. For Tmax and Tlag, only the median and the range will be reported. 
8.1. 
Analysis on Primary PK Endpoints 
8.1.1. Primary PK Analysis 
The primary PK analysis will be based on PK parameters including Cmax, AUC0-∞, and AUClast.  
The three natural log-transformed PK parameters (including Cmax, AUC0-∞, and AUClast) will be 
summarized descriptively by treatment group and compared between treatment groups (CTx-1301 
6.25 mg vs. Focalin XR™ 5 mg and CTx-1301 50 mg vs. Focalin XR™ 40 mg) using a mixed-
effect model with sequence, period, and treatment as fixed effects and subject within sequence as 
a random effect. Estimates of the adjusted mean differences (CTx-1301 6.25 mg vs. Focalin XR™ 


 
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5 mg and CTx-1301 50 mg vs. Focalin XR™ 40 mg) and corresponding 90% confidence intervals 
(CIs) will be obtained from the model. The adjusted mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Treatment B/A and Treatment D/C) and 90% CIs for the ratios. The resulting CIs will be 
compared to an acceptability region of [0.80, 1.25], which is equivalent to performing two one-
sided hypothesis tests (TOST procedure), each conducted at a 5% significant level. The two 
treatments will be identified as similar with comparative bioavailability when the 90% CI falls 
near or inside [0.80, 1.25].  
Natural log-transformed, dose-normalized PK parameters (including Cmax, AUC0-∞, and AUClast) 
will also be calculated (by dividing the nominal dose) and summarized similarly. Dose 
proportionality will also be evaluated based on the model for dose-normalized parameters, using 
a ratio of adjusted geometric means (Treatment C/B) for comparison of the CTx-1301 50 mg and 
CTx-1301 6.25 mg groups, along with corresponding 90% confidence intervals. 
8.1.2. Sensitivity Analysis on Primary PK Endpoints 
A sensitivity analysis may be conducted to evaluate any cohort effect on the primary PK endpoints 
(including Cmax, AUC0-∞, and AUClast). Sensitivity analysis will be done on both natural log-
transformed and natural log-transformed, dose-normalized PK parameters. 
Cohort at enrollment will be added as a random effect into the mixed-effect model for primary PK 
analysis as described in Section 8.1.1. Estimates of adjusted mean differences and corresponding 
90% CIs will be obtained from the model and will be exponentiated to provide estimates of the 
ratios of adjusted geometric means and 90% CIs for the ratios.  
All plasma concentration parameters will be presented in a data listing. 
8.2. 
Analysis on Secondary PK Endpoints 
8.2.1. Secondary PK Analysis 
PK plasma concentrations of d-MPH  
Plasma concentration data of d-MPH will be analyzed as described in Section 8. All plasma 
concentration data will be presented in a data listing.  
PK parameters (partial AUCs)  
PK parameters including partial AUCs (e.g. AUC0-3, AUC3-6, AUC6-9, AUC9-12, and AUC12-16) to 
examine potential differences between treatments (CTx-1301 6.25 mg vs. Focalin XR™ 5 mg and 
CTx-1301 50 mg vs. Focalin XR™ 40 mg) within selected time intervals will be summarized 
similarly as primary analysis described in Section 8.1. 
PK parameters (K, T1/2, tmax, and tlag) 
PK parameters including K and T1/2 will be summarized descriptively by treatment group. For tmax 
and tlag, the median and the range (minimum, maximum) will be reported.  
All PK parameter data will be presented in a data listing. 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 22 of 96 
 
8.2.2. Sensitivity Analysis on Secondary PK Endpoints  
A sensitivity analysis may be conducted to evaluate any cohort effect on the secondary PK 
endpoints (partial AUCs). Sensitivity analysis may also be conducted on the log-transformed and 
natural log-transformed dose-normalized PK parameters. 
Cohort at enrollment will be added as a random effect into the mixed-effect model for secondary 
PK analysis as described in Section 8.2.1. Estimates of adjusted mean differences and 
corresponding 90% CIs will be obtained from the model and will be exponentiated to provide 
estimates of the ratios of adjusted geometric means and 90% CIs for the ratios.  
 
9. 
Safety and Tolerability Analysis 
Safety analyses will be based on the SAF. Safety will be assessed by clinical review of all relevant 
safety data including treatment-emergent adverse events (TEAEs), clinical laboratory tests, 
physical exams, vital signs, ECGs, and C-SSRS. No inferential testing for statistical significance 
will be performed.  
All safety presentations will be based on the SAF. 
9.1. 
Adverse Events 
All AEs, TEAEs, and serious adverse events (SAEs) will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) classification system. TEAE is defined as any adverse event 
with an onset date on or after the first dose of study medication on Day 0 after randomization.  
Adverse events are considered treatment emergent for a period if the event begins at the time of or 
after drug administration for a specified period; events are reported based on the treatment received 
during a specified period. Subjects are counted only once within a specified period for each 
category of reporting (e.g. system organ class [SOC] and preferred term [PT]). TEAE incidences 
will be reported by period and treatment group (including All CTx-1301 and All Focalin XR™ 
groups), as well as over all periods by treatment group. 
An overall summary of treatment emergent adverse event will be provided, which includes the 
number and percentage of subjects who experience at least one: TEAE (and by maximum severity); 
treatment related TEAE; procedure related TEAE; TEAE related to study or drug withdrawal; 
treatment-emergent serious adverse event (TESAE); TESAE related to study drug; TESAE related 
to procedure; and a TEAE leading to death. This summary will be reproduced by cigarette smoking 
status. 
The number and percent of subjects reporting TEAEs, grouped by MedDRA system organ class 
(SOC) and preferred term (PT) will be tabulated by severity, and relationship to treatment. Subjects 
will be counted only once for each SOC and PT in each treatment period. Such summaries will be 
displayed for the following: 
• TEAEs by SOC and PT (also produced by cigarette smoking status) 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 23 of 96 
 
• TEAEs by SOC, PT, and severity 
• TEAEs by SOC, PT, and relationship to treatment 
• TEAEs leading to death by SOC and PT 
• Treatment-emergent SAEs (TESAEs) by SOC and PT 
• AEs leading to study or drug withdrawal by SOC and PT 
In the summaries showing severity and relationship to treatment the event with the maximum 
severity or strongest relationship will be reported. For example, if a particular event is missing the 
severity, then the strongest possible severity will be assumed for analysis (severity = severe). 
In the AE data listings, all AEs will be displayed and TEAEs will be flagged.  
9.1.1. Adverse Events Leading to Study or Drug Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug by treatment group, period, SOC, and PT will be prepared. As described in Section 9.1, 
these events will also be summarized by period and treatment group (including All CTx-1301 and 
All Focalin XR™ groups), as well as over all periods by treatment group.  
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying details 
of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
All TESAEs will be listed and also tabulated by SOC and PT and presented by treatment group 
(including All CTx-1301 and All Focalin XR™ groups) and period. As described in Section 9.1, 
these events will also be summarized by period and treatment group, as well as over all periods by 
treatment group. 
9.2. 
Clinical Laboratory Evaluations 
Descriptive summaries of actual (absolute) values and changes from baseline to EOS/ET visit will 
be presented for each clinical laboratory analyte (including biochemistry, hematology and 
urinalysis) by treatment group (including All CTx-1301 and All Focalin XR™ groups) based on 
the last treatment received prior to the EOS/ET visit and overall for the SAF.   Baseline values will 
be presented in aggregate over all participants. 
The number and percentage of subjects with clinical laboratory values below, within, or above the 
normal range and the shift from baseline to EOS/ET visit will be tabulated for each clinical 
laboratory analyte by treatment group as defined above and overall for the SAF.  
By-subject listings of laboratory analytes will be presented for the SAF. Any out-of-range values 
that are identified by the investigator as being clinically significant will be flagged as high, low, 
or out-of-range on this listing. Pregnancy, urine drug screens, and breath alcohol test results will 
also be listed. Pregnancy test includes serum pregnancy tests, which are collected and will be 
analyzed in women of child-potential only.  


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 24 of 96 
 
9.3. 
Physical Examination 
Physical exam results will be summarized descriptively by treatment group (including All CTx-
1301 and All Focalin XR™ groups) and overall by visit for the SAF, where the number and 
percentages of subjects with abnormal findings will be tabulated for each test. Visits will be 
displayed based on the last treatment received prior to evaluation. Baseline values will be presented 
in aggregate over all participants. 
A by-subject listing of abnormal findings will be provided with clinical significance being 
indicated.  
9.4. 
Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for systolic 
blood pressure, diastolic blood pressure and heart rate measured pre- and post-dose on Days 0, 3, 
6 and 9, and presented by treatment group (including All CTx-1301 and All Focalin XR™ groups) 
and overall by nominal sampling time point during each treatment period and over all periods for 
the SAF. The EOS/ET visit will be presented based on the last treatment received prior to study 
completion/discontinuation.  
By-subject listing of all vital sign measurements including height, weight and BMI will be 
presented.  
9.5. 
Electrocardiograms (ECG) 
Descriptive summaries of actual values and changes from baseline will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTcF, and ventricular rate measured pre- and 
post-dose on Days 0, 3, 6 and 9, and presented by treatment group (including All CTx-1301 and 
All Focalin XR™ groups) and overall by nominal sampling time point during each treatment 
period and over all periods for SAF. The EOS/ET visit will be presented based on the last treatment 
received prior to study completion/discontinuation.  
The number and percentage of subjects with normal and abnormal ECG results will be summarized 
by visit for the SAF as described above. This summary will also be reported by cigarette smoking 
status. 
A by-subject listing of all ECG measures and incidences of abnormalities will be presented. 
9.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
A summary of incidence (counts and percentages) of suicidal ideation and behavior will be 
presented by treatment group (including All CTx-1301 and All Focalin XR™ groups) and overall 
by visit for the SAF. Visit data, including the EOS/ET visit, will be displayed based on the last 
treatment received prior to evaluation. Baseline values will be presented in aggregate over all 
participants. All incidences of suicidal ideation and behavior collected on the C-SSRS will be 
listed by subject.  


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 25 of 96 
 
9.7. 
MINI International Neuropsychiatric Interview (M.I.N.I.) 
The M.I.N.I. summary responses at screening visit will be listed by subject. M.I.N.I. version 7.0.2 
will be used.  
10. 
References 
1. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm 
2. RSS. 
(2014) 
The 
Royal 
Statistical 
Society: 
Code 
of 
Conduct, 
2014. 
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf. 
3. US Federal Register. (1998) International Conference on Harmonization; Guidance on 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and 
Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, 
pages 49583-49598. September 16, 1998. 
11. 
Tables, Listings, and Figures 
All tables, listings, and figures will have a header showing the sponsor company name and protocol 
and a footer showing the version of SAS, the file name and path, and the source of the data (listing 
number) with a run date and time stamp. 
 
 Labels for Treatment Sequences and Treatment Groups:  
All the TLF will be using “Sequence 1, 2, 3, 4” and “Treatment A, B, C, D” with reference to the 
treatment sequences and treatment groups as described in Section 3.1, Table 1 and Table 2.  In 
draft and final TLF outputs, the following general footnote will be added appropriately to specify 
complete treatment sequences information and treatment names.  General footnote for every 
output:  
Note: This is a randomized, single-dose, four-sequence, four-period crossover study. Sequence 1 
= ADBC, Sequence 2 = BACD, Sequence 3 = CBDA, Sequence 4 = DCAB where A = Focalin 
XR™ Extended-Release capsule 5 mg; B = CTx-1301 trimodal 6.25 mg tablet; C = Focalin XR™ 
Extended-Release capsule 40 mg; D = CTx-1301 trimodal 50 mg tablet. 
Additional information:  If a note already exists on an output as “Note,” include this information 
first and ensure “Note” is relabeled “Notes.” 
For selected Section 14.1 (noted when needed) and 14.3 (assumed all) tables, additional 
columns will be included to accommodate All CTx-1301, All Focalin XR™ (and some of these 
also include Overall)reporting in addition to the Treatment A, B, C, or D.  Please see 
programming notes as to when these additional columns are needed. They will be added in 
the order specified on the right side of the reporting table. 
 
General Reporting Conventions: 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 26 of 96 
 
• All tables and data listings will be developed in landscape orientation using Times New 
Roman font. 
• Specialized text styles, such as bolding, italics, borders, shading, superscripted and 
subscripted text will not be used in tables and data listings unless they add significant value 
to the table, figure, or data listing.  
• Only standard keyboard characters should be used in tables and data listings. Special 
characters, such as nonprintable control characters, printer-specific characters, or font 
specific characters, will not be used on a table, figure, or data listing. Hexadecimal 
character representations are allowed (e.g. µ, α, β). 
• In the header, the sponsor’s company name and protocol will be left justified at the top of 
the page. Page x of y (total number of pages), indicating page number, will be right justified 
at the top of the page. 
• All titles will be centered on a page. The ICH numbering convention is to be used for all 
outputs. 
• All footnotes will be left justified and at the bottom of a page.  
• Missing values for both numeric and character variables will be presented as blanks in a 
table or data listing. A value of zero may be used if appropriate to identify when the 
frequency of a variable is not observed. 
• All date values will be presented as ddmmmyyyy (e.g., 29AUG2011) format. A 4-digit 
year is preferred for all dates. 
• If applicable, all observed time values will be presented by using a 24-hour clock 
HH:MM:SS format (e.g., 01:35:45 or 11:26). Seconds should only be reported if they were 
measured as part of the study.  
Population Summary Conventions 
• Population sizes may be presented for each classification factor as totals in the column 
header as (N=xxxx), where appropriate.  
• Population sizes shown with summary statistics are the sample size (n) of subjects with 
non-missing values.  
• All population summaries for categorical variables will include all categories that were 
planned and for which the subjects may have had a response. Percentages corresponding 
to null categories (cells) will be suppressed, however counts and percentages of missing 
values may be needed. 
• All population summaries for continuous variables will include: N, mean, median, standard 
deviation (SD), minimum, and maximum. Other summaries (e.g., number missing or 
CV%) may be used as appropriate.  
• All percentages are rounded and reported to a single decimal point (xx.x %). A percentage 
of 100% will be reported as 100%. No value of 0% will be reported. Any computation of 
percent that results in 0% is to be presented as a 0.  


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 27 of 96 
 
 
11.1. Planned Table Descriptions 
The following are planned summary tables for protocol number CTx-1301-001. The table numbers 
and page numbers are place holders only and will be determined when the tables are produced. 
Table Number 
Population 
Table Title 
14.1 Demographics and Baseline Tables 
14.1.1 
All Enrolled 
Study Populations and Subject Disposition 
14.1.2.1 
All Enrolled 
Demographics and Baseline Characteristics 
14.1.2.2 
SAF 
Demographics and Baseline Characteristics 
14.1.2.3 
PK Population 
Demographics and Baseline Characteristics 
14.1.3.1 
SAF 
Medical History 
14.1.3.2 
SAF 
Prior Medication 
14.1.3.3 
SAF 
Concomitant Medication 
14.1.4 
SAF 
Summary of Drug Exposure 
14.2 PK Tables 
14.2.1.1 
PK Population 
Primary PK Analysis of Natural log-transformed PK Parameters (Cmax, 
AUC0-∞, and AUClast) 
Summary of Estimates of Mean Differences between Treatments from 
Mixed Effect Model 
14.2.1.1.1 
PK Population 
Sensitivity Analysis on Primary PK Endpoints: Natural log-transformed PK 
Parameters (Cmax, AUC0-∞, and AUClast) 
Summary of Estimates of Mean Differences between Treatments from 
Mixed Effect Model 
14.2.1.1.2 
PK Population 
Primary PK Analysis of Natural log-transformed PK Parameters (Cmax, 
AUC0-∞, and AUClast) 
Summary of Descriptive Statistics 
14.2.1.2 
PK Population 
Primary PK Analysis of Natural log-transformed, Dose-normalized PK 
Parameters (Cmax, AUC0-∞, and AUClast) 
Summary of Estimates of Mean Differences between Treatments and Dose 
Levels from Mixed Effect Model 
14.2.1.2.1 
PK Population 
Sensitivity Analysis on Primary PK Endpoints: Natural log-transformed, 
Dose-normalized PK Parameters (Cmax, AUC0-∞, and AUClast) 
Summary of Estimates of Mean Differences between Treatments from 
Mixed Effect Model 
14.2.1.2.2 
PK Population 
Primary PK Analysis of Natural log-transformed, Dose-normalized PK 
Parameters (Cmax, AUC0-∞, and AUClast) 
Summary of Descriptive Statistics 
14.2.2.1 
PK Population 
Secondary PK Analysis of Natural log-transformed PK Parameters (Partial 
AUCs) 
Summary of Estimates of Mean Differences between Treatments from 
Mixed Effect Model 
14.2.2.1.1 
PK Population 
Sensitivity Analysis on Secondary PK Endpoints: Natural log-transformed 
PK Parameters (Partial AUCs) 
Summary of Estimates of Mean Differences between Treatments from 
Mixed Effect Model 
14.2.2.1.2 
PK Population 
Secondary PK Analysis of Natural log-transformed PK Parameters (Partial 
AUCs) 
Summary of Descriptive Statistics 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 28 of 96 
 
14.2.2.2 
PK Population 
Secondary PK Analysis of Natural log-transformed, Dose-normalized PK 
Parameters (Partial AUCs) 
Summary of Estimates of Mean Differences between Treatments from 
Mixed Effect Model 
14.2.2.2.1 
PK Population 
Sensitivity Analysis on Secondary PK Endpoints: Natural log-transformed, 
Dose-normalized PK Parameters (Partial AUCs) 
Summary of Estimates of Mean Differences between Treatments from 
Mixed Effect Model 
14.2.2.2.2 
PK Population 
Secondary PK Analysis of Natural log-transformed, Dose-normalized PK 
Parameters (Partial AUCs) 
Summary of Descriptive Statistics 
14.2.2.3 
PK Population 
Secondary PK Analysis of Natural log-transformed PK Parameters (K and 
T1/2) 
Summary of Descriptive Statistics 
14.2.2.4 
PK Population 
Secondary PK Analysis of PK Parameters (tmax and tlag) 
Summary of Descriptive Statistics 
14.2.2.5 
PK Population 
Secondary PK Analysis: Summary of Plasma Concentration of d-MPH 
14.3 Safety and Tolerability Tables 
14.3.1 Displays of Adverse Events 
14.3.1.1.1 
SAF 
Summary of all TEAEs 
14.3.1.1.2 
SAF 
Summary of all TEAEs, Non-Current Cigarette Smokers 
14.3.1.1.3 
SAF 
Summary of all TEAEs, Current Cigarette Smokers 
14.3.1.2.1 
SAF 
TEAEs by SOC and Preferred Term 
14.3.1.2.2 
SAF 
TEAEs by SOC and Preferred Term, Non-Current Cigarette Smokers 
14.3.1.2.3 
SAF 
TEAEs by SOC and Preferred Term, Current Cigarette Smokers 
14.3.1.3 
SAF 
TEAEs by SOC, Preferred Term and Severity 
14.3.1.4 
SAF 
TEAEs by SOC, Preferred Term and Relationship to Treatment 
14.3.1.5 
SAF 
TEAEs leading to Death by SOC and Preferred Term 
14.3.1.6 
SAF 
TESAEs other than Death by SOC and Preferred Term 
14.3.1.7 
SAF 
AEs leading to Premature Discontinuation by SOC and PT 
14.3.2 Laboratory Safety Data 
14.3.2.1 
SAF 
Summary of Biochemistry by Treatment 
14.3.2.2 
SAF 
Summary of Hematology by Treatment 
14.3.2.3 
SAF 
Summary of Urinalysis by Treatment 
14.3.2.4 
SAF 
Biochemistry Shift from Baseline to EOS/ET Visit 
14.3.2.5 
SAF 
Hematology Shift from Baseline to EOS/ET Visit 
14.3.2.6 
SAF 
Urinalysis Shift from Baseline to EOS/ET Visit  
14.3.3 Physical Examination Data 
14.3.3.1 
SAF 
Summary of Physical Examination by Treatment 
14.3.4 Vital Signs and ECG Data 
14.3.4.1 
SAF 
Summary of Vital Signs by Treatment 
14.3.5.1 
SAF 
Summary of ECG Parameters by Treatment 
14.3.5.2.1 
SAF 
Incidence of Investigator ECG Interpretation by Treatment 
14.3.5.2.2 
SAF 
Incidence of Investigator ECG Interpretation by Treatment, Non-Current 
Cigarette Smokers 
14.3.5.2.3 
SAF 
Incidence of Investigator ECG Interpretation by Treatment, Current 
Cigarette Smokers 
14.3.6.1  
SAF 
C-SSRS, Incidence of Ideation/Behavior by Treatment 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 29 of 96 
 
11.2. Planned Figure Descriptions 
The following are planned figures for protocol number CTx-1301-001. The table numbers are 
place holders only and will be determined when the tables are produced. 
Figure Number 
Population 
Figure Title 
14.2 PK Figures 
14.2.4.1 
PK Population 
Individual Plasma Concentration of d-MPH Scatterplot (linear) 
14.2.4.2 
PK Population 
Individual Plasma Concentration of d-MPH Scatterplot (semi-logarithmic) 
14.2.4.3 
PK Population 
Mean Plasma Concentration of d-MPH vs. Time by Treatment (linear) 
14.2.4.4 
PK Population 
Mean Plasma Concentration of d-MPH vs. Time by Treatment (semi-
logarithmic) 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 30 of 96 
 
11.3. Planned Listing Descriptions 
The following are planned data and subject data listings for protocol number CTx-1301-001.  
In general, one listing will be produced per CRF domain. All listings will be sorted by planned 
treatment sequence and subject number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (eg, repetition of subject number), then only the first occurrence will be 
displayed. 
In data listings, the information for one subject will be kept on one page if at all possible, rather 
than splitting a subject’s information across pages. 
Listing Number 
Population 
Listing Title 
16.2.1 Subject Disposition 
16.2.1.1 
All Enrolled  
Study Populations and Disposition 
16.2.1.2 
All Enrolled 
Randomization and Treatment Completion 
16.2.2 Protocol Deviations 
16.2.2.1 
All Subjects 
Inclusion and Exclusion Criteria 
16.2.2.2 
All Enrolled  
Protocol Deviations 
16.2.4 Demographics and Other Baseline Characteristics 
16.2.4.1 
All Enrolled 
Demographics 
16.2.4.2 
SAF 
Medical History 
16.2.4.3 
SAF 
Prior and Concomitant Medication 
16.2.4.4 
SAF 
Cigarettes Smoking Log 
16.2.5 Drug Exposure  
16.2.5.1 
SAF 
Study Drug Administration 
16.2.5.2 
SAF 
Tolerability Drug Administration 
16.2.6 Efficacy and PK Listings (PK Concentration) 
16.2.6.1 
PK 
Plasma concentration of d-MPH 
16.2.6.2 
PK 
PK Parameters 
16.2.7 Adverse Event Listings 
16.2.7.1 
SAF 
All Adverse Events 
16.2.7.2 
SAF 
Serious Adverse Events 
16.2.7.3 
SAF 
Adverse Events leading to Discontinuation 
16.2.7.4 
SAF 
Listing of Deaths 
16.2.8 Laboratory Data Listings 
16.2.8.1 
SAF 
Biochemistry  
16.2.8.2 
SAF 
Hematology  
16.2.8.3 
SAF 
Urinalysis  
16.2.8.4 
SAF 
Thyroid 
16.2.8.5 
SAF 
Urine Drug Screen  
16.2.8.6 
SAF 
Serology  
16.2.8.7 
SAF 
Pregnancy  
16.2.8.8 
SAF 
Breath Alcohol Test  
16.2.9 Other Clinical Observations and Measurements 
16.2.9.1 
SAF 
Physical Examination  
16.2.9.2 
SAF 
Vital Signs  
16.2.9.3 
SAF 
Electrocardiogram (ECG)  
16.2.9.4 
SAF 
C-SSRS 
16.2.9.5 
SAF 
M.I.N.I. 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 31 of 96 
 
12. 
Tables, Listings, and Listing Shells 
12.1. 
Standard Layout for all Tables, Listings, and Figures 
The following standard layout will be applied to all Tables, Listings, and Figures in support of this study. Note that programming notes 
may be added if appropriate after each TLF shell.  
Standardized Layout 
Cingulate Therapeutics, Inc 
Page xx of xx 
Protocol: CTx-1301-001 
<Version>  
 
<Table, Listing, Figure> xx.x.x 
<Title of Table Listing or Figure> 
<Study Population and if applicable subgroup Description> 
________________________________________________________________________________________________________________________________________________ 
 
 
Body of Table, Listing or Figure 
 
 
________________________________________________________________________________________________________________________________________________ 
<Note: If directly Applicable> 
Footnote 1 <if applicable>  
Footnote 2 <if applicable> 
Footnote n <if applicable> 
Source: Listing xx.x.x, xx.x.x <if applicable> 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 32 of 96 
 
12.2. 
Planned Table Shells 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 33 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Table 14.1.1     
Study Populations and Subject Disposition  
All Enrolled Subjects (ITT) 
 
 
 
 
 
 
 
Status or 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Overall 
   Variable/Statistic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
All Enrolled Subjects [1] 
xx 
xx 
xx 
xx 
xx 
Safety Population (SAF) [2] 
xx 
xx 
xx 
xx 
xx 
Pharmacokinetic (PK) Population [3] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Completed Study  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Early Termination 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Reason for Early Termination [4] 
 
 
 
 
 
    Withdrawal by subject 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Adverse event 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Abnormal lab test result 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Protocol deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Non-compliance with study restrictions 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Administrative reasons 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Note: Unless otherwise stated, percentages are based on the number of subjects in the SAF Population. Planned treatment sequences are presented.  
[1] All Enrolled Subjects includes all subjects who have signed the informed consent form, meet eligibility criteria, and are randomized to a treatment sequence.  
[2] The Safety Population (SAF) includes all subjects who receive at least 1 dose of study drug. 
[3] The Pharmacokinetic (PK) Population includes all subjects who receive at least 1 dose of study drug and provide at least one evaluable PK plasma concentration.  
[4] Percentages are based off of number of early terminations per applicable treatment column. 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 34 of 96 
 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Table 14.1.1 (Continued)  
Study Populations and Subject Disposition  
All Enrolled Subjects (ITT) 
 
 
 
 
 
 
 
Status or 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Overall 
   Variable/Statistic 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
Period Completion 
 
 
 
 
xx 
    Period 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Period 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Period 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Period 4  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Treatment Completion 
 
 
 
 
 
    Treatment A 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Treatment B 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Treatment C 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Treatment D 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Note: Unless otherwise stated, percentages are based on the number of subjects in the SAF Population. Planned treatment sequences are presented.  
[1] All Enrolled Subjects includes all subjects who have signed the informed consent form, meet eligibility criteria, and are randomized to a treatment sequence  
[2] The Safety Population (SAF) includes all subjects who receive at least 1 dose of study drug. 
[3] The Pharmacokinetic (PK) Population includes all subjects who receive at least 1 dose of study drug and provide at least one evaluable PK plasma concentration.  
[4] Percentages are based off of number of early terminations per applicable treatment column. 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 35 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Table 14.1.2.1  
Demographics and Baseline Characteristics  
All Enrolled Subjects (ITT) 
 
 
 
 
 
 
 
Variable 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Overall 
     Statistics or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
Age (years) 
 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Gender 
 
 
 
 
 
    Male 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Female 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     
 
 
 
 
 
Ethnicity 
 
 
 
 
 
    Hispanic or Latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Not Hispanic or Latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    
 
 
 
 
 
Race  
 
 
 
 
 
    American Indian/Alaska Native 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Asian 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Black or African American 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Native Hawaiian or Other Pacific Islander 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    White 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. Planned treatment sequences are presented.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 36 of 96 
 
Table 14.1.2.1 (Continued)  
Demographics and Baseline Characteristics  
All Enrolled Subjects (ITT) 
 
 
 
 
 
 
 
Variable 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Overall 
     Statistics or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. Planned treatment sequences are presented.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 37 of 96 
 
Table 14.1.2.1 (Continued)  
Demographics and Baseline Characteristics  
All Enrolled Subjects (ITT) 
 
 
 
 
 
 
 
Variable 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Overall 
     Statistics or Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
Cohort  
 
 
 
 
 
    1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
.. 
 
 
 
 
 
Cigarette Smoking Status 
 
 
 
 
 
    Current Cigarette Smoker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Former Cigarette Smoker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Never Smoked Cigarettes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. Planned treatment sequences are presented.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
Programming Note:  Check with the biostatistician as to the number of cohorts required; only report up to the number of cohorts actually used in the study. 
 
Table 14.1.2.2  
Demographics and Baseline Characteristics  
Safety Population 
{Programming note: Repeat 14.1.2.1 with Safety Population} 
 
Table 14.1.2.3  
Demographics and Baseline Characteristics  
PK Population 
{Programming note: Repeat 14.1.2.1 with PK Population} 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 38 of 96 
 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.1.3.1  
Medical History 
Safety Population 
 
 
 
 
 
 
 
System Organ Class [1] 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Overall 
     Preferred Term 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
Number of subjects with at least one 
medical history event 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     
 
 
 
 
 
SOC 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PT 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PT 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PT 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
SOC 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PT 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PT 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    … 
 
 
 
 
 
    
 
 
 
 
 
    
 
 
 
 
 
    
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. Planned treatment sequences are presented. Subjects are counted only once for each System Organ Class and Preferred Term. Coded terms 
have been displayed alphabetically by System Organ Class and similarly by Preferred Term within System Organ Class. 
[1] Medical History is coded using MedDRA version 22.0.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 39 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.1.3.2  
Prior Medication 
Safety Population 
 
 
 
 
 
 
 
ATC [1] 
Sequence 1 
Sequence 2 
Sequence 3 
Sequence 4 
Overall 
     Preferred Term 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
Number of subjects with at least one prior 
medication 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     
 
 
 
 
 
ATC 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
ATC 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    … 
 
 
 
 
 
    
 
 
 
 
 
    
 
 
 
 
 
    
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are 100*n/N. Planned treatment sequences are presented. Subjects are counted only once for each Anatomical Therapeutic Chemical (ATC) and 
Preferred Term. A prior medication is any medication that started prior to the first administration of study drug on Day 0 whether or not they were stopped prior to first 
administration of study medication.  Medications are displayed alphabetically by ATC and similarly by Preferred Term within ATC. 
[1] Prior Medication is coded using WHO-DD v. March 1, 2019. 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 40 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.1.3.3  
Concomitant Medication 
Safety Population 
 
 
 
 
 
 
ATC [1] 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
     Preferred Term 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
All Periods 
xx 
xx 
xx 
xx 
Number of subjects with at least one concomitant 
medication 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     
 
 
 
 
ATC 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
ATC 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Medication 2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    … 
 
 
 
 
{Programming notes: Repeat for Period 1, 2, 3, 4 respectively} 
 
 
 
 
 
 
 
 
 
Note: Percentages are based on the number of subjects treated within the specified period. A concomitant medication is any medications continuing or starting after drug 
administration within the specified period. In the case that a single medication belongs to more than one treatment period, the medication will be counted in all treatment 
groups/periods it falls into. Subjects are counted only once for each Anatomical Therapeutic Chemical (ATC) and Preferred Term.  Medications are displayed alphabetically by 
ATC and similarly by Preferred Term within ATC. 
[1] Concomitant Medication is coded using WHO-DD v. March 1, 2019. 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
Programming note: Each period must display a denominator.  This denominator will represent the number of patients treated in each period. This table is 
one selected in this section (14.1) which needs to have the All CTx-1301 and All FocalinTM columns added. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 41 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.1.4     
Summary of Drug Exposure  
Safety Population 
 
 
 
 
 
 
 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
 Period (Treatment Day) 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
Period 1 (Day 0) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Period 2 (Day 3) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Period 3 (Day 6) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Period 4 (Day 9) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     
 
 
 
 
 
Note: Percentages are 100*n/N. 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
Programming note: This table is one selected in this section (14.1) which needs to have the All CTx-1301, All FocalinTM, and Overall columns added. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 42 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.2.1.1  
Primary PK Analysis of Natural log-transformed PK Parameters (Cmax, AUC0-∞, and AUClast)  
Summary of Estimates of Mean Differences between Treatments from Mixed Effect Model 
PK Population 
 
 
 
 
 
 
 
 
 
Treatment 
Adjusted Geometric 
Mean (90% CI)/ 
Treatment 
Adjusted Geometric 
Mean (90% CI)/ 
Dose Proportionality 
Adjusted Geometric 
Mean (90% CI)/ 
Parameter 
Effect 
Ratio (90% CI)  
Effect 
Ratio (90% CI) 
 
Ratio (90% CI) 
 
 
 
 
 
 
 
Cmax  
Treatment A 
xx.x (xx.xx, xx.xx) 
Treatment C 
xx.x (xx.xx, xx.xx) 
 
 
 
Treatment B 
xx.x (xx.xx, xx.xx) 
Treatment D 
xx.x (xx.xx, xx.xx) 
 
 
 
Treatment B/A 
xx.x (xx.xx, xx.xx) 
Treatment D/C 
xx.x (xx.xx, xx.xx) 
Treatment C/B 
xx.x (xx.xx, xx.xx) 
 
 
 
 
 
 
 
AUC0-∞ 
Treatment A 
xx.x (xx.xx, xx.xx) 
Treatment C 
xx.x (xx.xx, xx.xx) 
 
 
 
Treatment B 
xx.x (xx.xx, xx.xx) 
Treatment D 
xx.x (xx.xx, xx.xx) 
 
 
 
Treatment B/A 
xx.x (xx.xx, xx.xx) 
Treatment D/C 
xx.x (xx.xx, xx.xx) 
Treatment C/B 
xx.x (xx.xx, xx.xx) 
 
 
 
 
 
 
 
AUClast 
Treatment A 
xx.x (xx.xx, xx.xx) 
Treatment C 
xx.x (xx.xx, xx.xx) 
 
 
 
Treatment B 
xx.x (xx.xx, xx.xx) 
Treatment D 
xx.x (xx.xx, xx.xx) 
 
 
 
Treatment B/A 
xx.x (xx.xx, xx.xx) 
Treatment D/C 
xx.x (xx.xx, xx.xx) 
Treatment C/B 
xx.x (xx.xx, xx.xx) 
     
 
 
 
 
 
 
 
Note: Estimates of adjusted mean differences and corresponding 90% confidence intervals are estimated from a mixed-effect model with sequence, period, and treatment as fixed 
effects and subject within sequence as a random effect and natural log-transformed PK parameter as responding variable. The estimated adjusted mean differences and 90% 
confidence intervals are exponentiated to provide estimates of the ratio of adjusted geometric means and 90% confidence intervals for the ratios.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
Programming note:  Dose proportionality will only appear in Table 14.2.1.2 only (this is why it is italicized).  It is not planned to be presented in all tables of 
this type. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 43 of 96 
 
Table 14.2.1.1.1  
Sensitivity Analysis on Primary PK Endpoints: Natural log-transformed PK Parameters (Cmax, AUC0-∞, and AUClast)  
Summary of Estimates of Mean Differences between Treatments from Mixed Effect Model 
PK Population 
{Programming Note: Repeat Table 14.2.1.1 by changing the model and footnote.} 
 
Note: Estimates of adjusted mean differences and corresponding 90% confidence intervals are estimated from a mixed-effect model with sequence, period, and treatment as 
fixed effects and subject within sequence and cohort as random effects and natural log-transformed PK parameter as responding variable. The estimated adjusted mean 
differences and 90% confidence intervals are exponentiated to provide estimates of the ratio of adjusted geometric means and 90% confidence intervals for the ratios.  
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 44 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Table 14.2.1.1.2  
Primary PK Analysis of Natural log-transformed PK Parameters (Cmax, AUC0-∞, and AUClast)  
Summary of Descriptive Statistics 
PK Population 
 
 
 
 
 
 
Parameter 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
     Statistics  
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
Cmax 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
    Arithmetic  Mean 
xx.x 
xx.x 
xx.x 
xx.x 
    Geometric Mean 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    CV% 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
     
 
 
 
 
AUC0-∞ 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
    Arithmetic Mean 
xx.x 
xx.x 
xx.x 
xx.x 
    Geometric Mean 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    CV% 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
AUClast 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
    Arithmetic Mean 
xx.x 
xx.x 
xx.x 
xx.x 
    Geometric Mean 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    CV% 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
     
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 45 of 96 
 
Note: Descriptive statistics are based on natural log-transformed PK parameters. 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
Table 14.2.1.2  
Primary PK Analysis of Natural log-transformed, Dose-normalized PK Parameters (Cmax, AUC0-∞, and AUClast)  
Summary of Estimates of Mean Differences between Treatments from Mixed Effect Model 
PK Population 
{Programming Note: Repeat Table 14.2.1.1 by using dose-normalized PK Parameters; change footnote accordingly. Add another two columns to the right of the table for 
Treatment C/B reporting to evaluate dose proportionality.  This is the only table in which this calculation is reviewed.} 
 
Table 14.2.1.2.1  
Sensitivity Analysis on Primary PK Endpoints: Natural log-transformed, Dose-normalized PK Parameters (Cmax, AUC0-∞, and AUClast)  
Summary of Estimates of Mean Differences between Treatments from Mixed Effect Model 
PK Population 
{Programming Note: Repeat Table 14.1.1.1 by using dose-normalized PK Parameters; change footnote accordingly.} 
 
 
Table 14.2.1.2.2  
Primary PK Analysis of Natural log-transformed, Dose-normalized PK Parameters (Cmax, AUC0-∞, and AUClast)  
Summary of Descriptive Statistics 
PK Population 
{Programming Note: Repeat Table 14.2.1.2 by using dose-normalized PK Parameters; change footnote accordingly.} 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 46 of 96 
 
 
Table 14.2.2.1  
Secondary PK Analysis of Natural log-transformed PK Parameters (Partial AUCs)  
Summary of Estimates of Mean Differences between Treatments from Mixed Effect Model 
PK Population 
{Programming Note: Repeat Table 14.2.1.1 by partial AUC Parameters (e.g. AUC0-3, AUC3-6, AUC6-9, AUC9-12, AUC12-16; change footnote accordingly.} 
 
Table 14.2.2.1.1  
Sensitivity Analysis on Secondary PK Endpoints: Natural log-transformed PK Parameters (Partial AUCs)  
Summary of Estimates of Mean Differences between Treatments from Mixed Effect Model 
PK Population 
{Programming Note: Repeat Table 14.2.1.1.1 by partial AUC Parameters (e.g. AUC0-3, AUC3-6, AUC6-9, AUC9-12, AUC12-16; change footnote accordingly.} 
 
Table 14.2.2.1.2  
Secondary PK Analysis of Natural log-transformed PK Parameters (Partial AUCs)  
Summary of Descriptive Statistics 
PK Population 
{Programming Note: Repeat Table 14.2.1.2 by partial AUC Parameters (e.g. AUC0-3, AUC3-6, AUC6-9, AUC9-12, AUC12-16; change footnote accordingly.} 
 
 
Table 14.2.2.2  
Secondary PK Analysis of Natural log-transformed, Dose-normalized PK Parameters (Partial AUCs)  
Summary of Estimates of Mean Differences between Treatments and Dose Levels from Mixed Effect Model 
PK Population 
{Programming Note: Repeat Table 14.2.1.1 by dose-normalized partial AUC Parameters (e.g. AUC0-3, AUC3-6, AUC6-9, AUC9-12, AUC12-16; change footnote accordingly.} 
 
Table 14.2.2.2.1  
Sensitivity Analysis on Secondary PK Endpoints: Natural log-transformed, Dose-normalized PK Parameters (Partial AUCs)  
Summary of Estimates of Mean Differences between Treatments from Mixed Effect Model 
PK Population 
{Programming Note: Repeat Table 14.2.1.1.1 by dose-normalized partial AUC Parameters (e.g. AUC0-3, AUC3-6, AUC6-9, AUC9-12, AUC12-16; change footnote accordingly.} 
 
Table 14.2.2.2.2  
Secondary PK Analysis of Natural log-transformed, Dose-normalized PK Parameters (Partial AUCs)  
Summary of Descriptive Statistics 
PK Population 
{Programming Note: Repeat Table 14.2.1.2 by dose-normalized partial AUC Parameters (e.g. AUC0-3, AUC3-6, AUC6-9, AUC9-12, AUC12-16; change footnote accordingly.} 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 47 of 96 
 
 
Table 14.2.2.3  
Secondary PK Analysis of Natural log-transformed PK Parameters (K and T1/2)  
Summary of Descriptive Statistics 
PK Population 
{Programming Note: Repeat Table 14.2.1.2 by PK Parameters K, T1/2; change footnote accordingly.} 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 48 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.2.2.4  
Secondary PK Analysis of PK Parameters (tmax and tlag)  
Summary of Descriptive Statistics 
PK Population 
 
 
 
 
 
 
Parameter 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
     Statistics  
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
tmax 
 
 
 
 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
     
 
 
 
 
tlag 
 
 
 
 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
     
 
 
 
 
 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 49 of 96 
 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.2.2.5  
Secondary PK Analysis: Summary of Plasma Concentration of d-MPH (unit)  
PK Population 
 
 
 
 
 
 
Timepoint 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
     Statistics  
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
Pre-dose 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    CV% 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
     
 
 
 
 
0.5 hr Post-dose 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
    Mean 
xx.x 
xx.x 
xx.x 
xx.x 
    Standard Deviation 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    CV% 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
    Median 
xx.x 
xx.x 
xx.x 
xx.x 
    Minimum, Maximum 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
1 hr Post-dose 
 
 
 
 
    … 
 
 
 
 
 
 
 
 
 
(Programming Notes: Continue for all post-dose timepoints for PK collection} 
 
 
 
 
 
 
 
     
 
 
 
 
 
Note: Treatment groups are based on treatment received.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 50 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.3.1.1.1  
Summary of all TEAEs  
Safety Population 
 
 
 
 
 
 
 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
All Periods 
xx 
xx 
xx 
xx 
Subjects with at least one  
 
 
 
 
    Treatment Emergent Adverse Event (TEAE)  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Mild 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Moderate 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Severe 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    TEAE Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    TEAE Related to Procedure 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
    Serious Adverse Event (SAE) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    SAE Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    SAE Related to Procedure 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
    Adverse Event Leading to Study or Drug 
Withdrawal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Adverse Event Leading to Death 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
{Programming notes: Repeat for Period 1, 2, 3, 4 respectively} 
 
 
 
     
 
 
 
 
Note: Percentages are based on the number of subjects treated within the specified period. Adverse events are considered treatment emergent for a period if the event 
begins at the time of or after drug administration for a specified period; events are reported based on the treatment received during a specified period. Subjects are counted 
only once within a specified period for each category of reporting. If a particular event is missing severity or relationship, then the maximum severity or strongest relationship 
will be assumed. Subjects are counted only once for each adverse event category.  Medications are displayed alphabetically by ATC and similarly by Preferred Term within 
ATC. 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 51 of 96 
 
Programming note: Each period must display a denominator.  This denominator will represent the number of patients treated in each period. 
 
 
Table 14.3.1.1.2  
Summary of all TEAEs, Non-Current Cigarette Smokers 
Safety Population 
{Programming Note: Repeat Table 14.3.1.1.1 on subset of non-current cigarette smokers.}  
 
 
Table 14.3.1.1.3  
Summary of all TEAEs, Current Cigarette Smokers 
Safety Population 
{Programming Note: Repeat Table 14.3.1.1.1 on subset of current cigarette smokers.}  
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 52 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.3.1.2.1  
TEAEs by SOC and Preferred Term  
Safety Population 
 
 
 
 
 
 
System Organ Class  
Treatment A 
Treatment B 
Treatment C 
Treatment D 
    Preferred Term 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
All Periods 
xx 
xx 
xx 
xx 
Number of subjects with at least one TEAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
    SOC1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        PT1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        PT2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        PT3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
    SOC1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        PT1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        PT2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        … 
 
 
 
 
 
 
 
 
 
{Programming notes: Repeat for Period 1, 2, 3, 4 respectively} 
 
 
 
     
 
 
 
 
 
Note: Percentages are based on the number of subjects treated within the specified period. Adverse events are considered treatment emergent for a period if the event 
begins at the time of or after the drug administration for a specified period; events are reported based on the treatment received during a specified period. Subjects are 
counted only once within a specified period for each category of reporting (e.g. system organ class [SOC] and preferred term [PT]). If a particular event is missing severity or 
relationship, then the maximum severity or strongest relationship will be assumed. Events are displayed alphabetically by System Organ Class and similarly by Preferred Term 
within System Organ Class.   
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
Programming note: Each period must display a denominator.  This denominator will represent the number of patients treated in each period. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 53 of 96 
 
Table 14.3.1.2.2  
TEAEs by SOC and Preferred Term, Non-Current Cigarette Smokers 
Safety Population 
{Programming Note: Repeat Table 14.3.1.2.1 on subset of non-current cigarette smokers.}  
 
 
Table 14.3.1.2.3  
TEAEs by SOC and Preferred Term, Current Cigarette Smokers 
Safety Population 
{Programming Note: Repeat Table 14.3.1.2.1 on subset of current cigarette smokers.}  
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 54 of 96 
 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.3.1.3  
TEAEs by SOC, Preferred Term and Severity 
Safety Population 
 
System Organ Class  
 
 
 
 
    Preferred Term 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
          Severity 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
All Periods 
xx 
xx 
xx 
xx 
Number of subjects with at least one TEAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
SOC1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Mild 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Moderate 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Severe 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PT1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Mild 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Moderate 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Severe 
 
 
 
 
        … 
 
 
 
 
 
 
 
 
 
{Programming notes: Repeat for Period 1, 2, 3, 4 respectively} 
 
 
 
 
 
 
 
     
 
 
 
 
 
Note: Percentages are based on the number of subjects treated within the specified period. Adverse events are considered treatment emergent for a period if the event 
begins at the time of or after the drug administration for a specified period; events are reported based on the treatment received during a specified period. Subjects are 
counted only once within a specified period for each category of reporting (e.g. system organ class [SOC] and preferred term [PT]). If a particular event is missing severity, 
then the maximum severity has been assumed. Events are displayed alphabetically by System Organ Class and similarly by Preferred Term within System Organ Class.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
Programming note: Each period must display a denominator.  This denominator will represent the number of patients treated in each period. 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 55 of 96 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 56 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Table 14.3.1.4  
TEAEs by SOC, Preferred Term and Relationship to Treatment 
Safety Population 
 
System Organ Class  
 
 
 
 
    Preferred Term 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
          Relationship to Treatment 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
All Periods 
xx 
xx 
xx 
 
Number of subjects with at least one TEAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
SOC1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Not related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Procedure Related 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Not Known 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    PT1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Not related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Related to Study Drug 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Procedure Related 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Not Known 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    … 
 
 
 
 
 
 
 
 
 
{Programming notes: Repeat for Period 1, 2, 3, 4 respectively} 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
Note: Percentages are based on the number of subjects treated within the specified period. Adverse events are considered treatment emergent for a period if the event 
begins at the time of or after the drug administration for a specified period; events are reported based on the treatment received during a specified period. Subjects are 
counted only once within a specified period for each category of reporting (e.g. system organ class [SOC] and preferred term [PT]). If a particular event is missing relationship, 
then strongest relationship will be assumed. Events are displayed alphabetically by System Organ Class and similarly by Preferred Term within System Organ Class.   
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
Programming note: Each period must display a denominator.  This denominator will represent the number of patients treated in each period. Also note that 
this table is the only one in this section (14.1) which needs to add the All CTx-1301 and All FocalinTM columns for reporting. 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 57 of 96 
 
 
 
Table 14.3.1.5  
TEAEs leading to Death by SOC and Preferred Term  
Safety Population 
{Programming Note: Repeat 14.3.1.2 subset to TEAEs leading to death} 
 
Table 14.3.1.6  
TESAEs by SOC and Preferred Term  
Safety Population 
{Programming Note: Repeat 14.3.1.2 subset to TESAEs } 
 
Table 14.3.1.7  
AEs leading to Study or Drug Withdrawal by SOC and PT  
Safety Population 
{Programming Note: Repeat 14.3.1.2 subset to AEs leading to study or drug withdrawal} 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 58 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.3.2.1  
Summary of Biochemistry by Treatment  
Safety Population 
 
Parameter 
 
 
 
 
 
 
 
 
 
 
 
    Visit 
Treatment A 
(N=xx) 
 
Treatment B 
(N=xx) 
 
Treatment C 
(N=xx) 
 
Treatment D 
(N=xx) 
        Statistics  
 
 
 
 
Absolute 
Values 
Change from 
Baseline 
 
Absolute 
Values 
Change from 
Baseline 
 
Absolute 
Values 
Change from 
Baseline 
 
Absolute 
Values 
Change from 
Baseline 
Analyte 1 (unit) 
 
 
 
 
 
 
 
 
 
 
 
    Baseline  
 
 
 
 
 
 
 
 
 
 
 
        n 
 
 
 
 
 
 
 
 
 
 
 
        Mean 
 
 
 
 
 
 
 
 
 
 
 
        Standard Deviation 
 
 
 
 
 
 
 
 
 
 
 
        Median 
 
 
 
 
 
 
 
 
 
 
 
        Minimum, Maximum 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
    EOS/ET Visit  
 
 
 
 
 
 
 
 
 
 
 
        n 
 
 
 
 
 
 
 
 
 
 
 
        Mean 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
        Standard Deviation 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
        Median 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
        Minimum, Maximum 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
{Programming Notes: Repeat for all other parameters} 
     
 
 
 
 
 
 
 
 
 
 
 
 
Note: Baseline is the last observation prior to the first dose of study medication. Data is presented based on the last treatment received prior to the EOS/ET visit.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM columns added 
(all 14.3) but also needs an Overall column for reporting.  Baseline values will only be reported in the Overall column only.  
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 59 of 96 
 
Table 14.3.2.2  
Summary of Hematology by Treatment  
Safety Population 
{Programming Note: Repeat 14.3.2.1 with hematology analytes} 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM columns added 
(all 14.3) but also needs an Overall column for reporting. 
 
Table 14.3.2.3  
Summary of Urinalysis by Treatment 
Safety Population 
{Programming Note: Repeat 14.3.2.1 with urinalysis analytes} 
 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM columns added 
(all 14.3) but also needs an Overall column for reporting. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 60 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Table 14.3.2.4  
Biochemistry Shift from Baseline to EOS/ET Visit 
Safety Population 
 
Treatment prior to EOS/ET Visit 
 
    Parameter 
Baseline Category  
        Category 
 
 
Low 
Normal  
High 
Missing 
 
 
 
 
 
Treatment A (N=xx) 
 
 
 
 
    Analyte 1 (unit) 
 
 
 
 
        Low 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        High 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
        Missing 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
{Programming Note: Continue for all applicable parameters and treatment groups} 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
Note: Percentages are 100*n/N. Baseline is the last observation prior to the first dose of study medication. Data is presented based on the last treatment received prior to the 
EOS/ET visit. 
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM groups added (all 
14.3) but also needs Overall reporting. 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 61 of 96 
 
Table 14.3.2.5  
Hematology Shifts from Baseline to EOS/ET Visit 
Safety Population 
{Programming Note: Repeat 14.3.2.4 with hematology analytes} 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM groups added (all 
14.3) but also needs Overall reporting. 
 
 
Table 14.3.2.6  
Urinalysis Shifts from Baseline to EOS/ET Visit 
Safety Population 
{Programming Note: Repeat 14.3.2.4 with urinalysis analytes} 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM groups added (all 
14.3) but also needs Overall reporting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 62 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Table 14.3.3.1  
Summary of Physical Examination by Treatment 
Safety Population 
 
 
 
 
 
 
Body System  
 
 
 
 
    Visit 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
       Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
Body System 1 
 
 
 
 
      Baseline 
 
 
 
 
       Normal 
 
 
 
 
       Abnormal, not clinically significant 
 
 
 
 
       Abnormal, clinically significant 
 
 
 
 
 
 
 
 
 
    Day 6 Visit 
xx 
xx 
xx 
xx 
       Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       Abnormal, not clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       Abnormal, clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
   EOS/ET Visit 
xx 
xx 
xx 
xx 
       Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       Abnormal, not clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       Abnormal, clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are based on non-missing assessments at scheduled visit. The baseline value is the last assessment prior to first dose of study medication. Treatment groups 
are based on the last treatment received prior to assessment. Early termination data will be reported based on the last treatment received prior to discontinuation.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM columns added 
(all 14.3) but also needs an Overall column for reporting.  Baseline values will only be reported in the Overall column only. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 63 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.3.4.1  
Summary of Vital Signs by Treatment 
Safety Population 
 
Parameter 
 
 
 
 
 
 
 
 
 
 
 
    Timepoint 
Treatment A 
(N=xx) 
 
Treatment B 
(N=xx) 
 
Treatment C 
(N=xx) 
 
Treatment D 
(N=xx) 
        Statistics  
 
 
 
 
Absolute 
Values 
Change from 
Baseline 
 
Absolute 
Values 
Change from 
Baseline 
 
Absolute 
Values 
Change from 
Baseline 
 
Absolute 
Values 
Change from 
Baseline 
  
 
 
 
 
 
 
 
 
 
 
 
Parameter (unit) 
 
 
 
 
 
 
 
 
 
 
 
    Period 1, Pre-dose 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
 
 
xx 
 
 
xx 
 
 
xx 
 
        Mean 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
        Standard Deviation 
xx.xx 
 
 
xx.xx 
 
 
xx.xx 
 
 
xx.xx 
 
        Median 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
        Minimum, Maximum 
xx, xx 
 
 
xx, xx 
 
 
xx, xx 
 
 
xx, xx 
 
     
 
 
 
 
 
 
 
 
 
 
 
    Period 1, 1 hr Post-dose 
 
 
 
 
 
 
 
 
 
 
 
        n 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
xx 
xx 
        Mean 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
        Standard Deviation 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
        Median 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
        Minimum, Maximum 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
    Period 1, 2 hr Post-dose 
 
 
 
 
 
 
 
 
 
 
 
    … 
 
 
 
 
 
 
 
 
 
 
 
    EOS/ET Visit 
 
 
 
 
 
 
 
 
 
 
 
{Programming Notes: Continue for all post-dose timepoints for vital signs and all parameters, and repeat for Period 1, 2, 3, 4 respectively} 
     
 
 
 
 
 
 
 
 
 
 
 
 
Note: Treatment groups are based on treatment received. Early termination data will be reported based on the last treatment received prior to discontinuation.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 64 of 96 
 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM columns added 
(all 14.3) but also needs an Overall column for reporting. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 65 of 96 
 
Table 14.3.5.1  
Summary of ECG Parameters by Treatment 
Safety Population 
{Programming Notes: Repeat 14.3.4.1 with ECG parameters and timepoints} 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM columns added 
(all 14.3) but also needs an Overall column for reporting. 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 66 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
 
Table 14.3.5.2.1  
Incidence of Investigator ECG Interpretation by Treatment 
Safety Population 
 
 
 
 
 
 
Timepoint 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
    Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
Period 1, Pre-dose 
 
 
 
 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Abnormal, not clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Abnormal, clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     
 
 
 
 
Period 1, 6 hr Post-dose 
 
 
 
 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Abnormal, not clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Abnormal, clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Period 1, 28 hr Post-dose 
 
 
 
 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Abnormal, not clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Abnormal, clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
…. 
 
 
 
 
EOS/ET Visit 
 
 
 
 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Abnormal, not clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Abnormal, clinically significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
{Programming notes: Repeat for Period 1, 2, 3, 4 respectively} 
 
 
 
     
 
 
 
 
 
Note: Treatment groups are based on treatment received. Early termination data will be reported based on the last treatment received prior to discontinuation.  
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 67 of 96 
 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM columns added 
(all 14.3) but also needs an Overall column for reporting. 
 
Table 14.3.5.2.2  
Incidence of Investigator ECG Interpretation by Treatment, Non-Current Cigarette Smokers 
Safety Population 
{Programming Note: Repeat Table 14.3.5.2.1 on subset of non-current cigarette smokers.}  
 
 
Table 14.3.5.2.3  
Incidence of Investigator ECG Interpretation by Treatment, Current Cigarette Smokers 
Safety Population 
{Programming Note: Repeat Table 14.3.5.2.1 on subset of current cigarette smokers.}  
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 68 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
               Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Table 14.3.6.1  
C-SSRS, Incidence of Ideation/Behaviour by Treatment 
Safety Population 
 
 
 
 
 
 
Visit 
Treatment A 
Treatment B 
Treatment C 
Treatment D 
   Category 
(N=xx) 
(N=xx) 
(N=xx) 
(N=xx) 
 
 
 
 
 
Baseline 
 
 
 
 
    Any Suicidal Ideation 
 
 
 
 
    Any Suicidal Behaviour 
 
 
 
 
 
 
 
 
 
Day 3 Visit 
xx 
xx 
xx 
xx 
    Any Suicidal Ideation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Any Suicidal Behaviour 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Day 6 Visit 
xx 
xx 
xx 
xx 
    Any Suicidal Ideation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Any Suicidal Behaviour 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Day 9 Visit 
xx 
xx 
xx 
xx 
    Any Suicidal Ideation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Any Suicidal Behaviour 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
{Programming Notes: Repeat for EOS/ET visit} 
 
 
 
 
 
 
 
 
Note: Percentages are based on non-missing assessments at scheduled visit. The baseline value is the last assessment prior to first dose of study medication.  Treatment groups 
are based on the last treatment received prior to assessment. Early termination data will be reported based on the last treatment received prior to discontinuation.   
SOURCE:  Listings xx.x.x, xx.x.x 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
Programming note: This table is one of the selected in this section (14.3) which not only needs to have the All CTx-1301 and All FocalinTM columns added 
(all 14.3) but also needs an Overall column for reporting. Baseline value will only be reported in the Overall column only. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 69 of 96 
 
12.3. 
Planned Figure Shells 
Figure 14.2.2.6.1 
Plasma Concentration of d-MPH Scatterplot (linear)  
PK Population 
{Programming Note: Scatter plot of plasma concentration by subject. Y = plasma concentration (linear scale), X = Time}  
 
Figure 14.2.2.6.2 
Plasma Concentration of d-MPH Scatterplot (semi-logarithmic) 
PK Population  
{Programming Note: Scatter plot of plasma concentration by subject. Y = plasma concentration (semi-logarithmic scale), X = Time} 
 
Figure 14.2.2.6.3 
Mean Plasma Concentration of d-MPH vs. Time by Treatment (linear)  
PK Population 
{Programming Note: Scatter plot of mean plasma concentration by treatment. Y = plasma concentration (linear scale), X = Time}  
 
Figure 14.2.2.6.4 
Mean Plasma Concentration of d-MPH vs. Time by Treatment (semi-logarithmic) 
PK Population  
{Programming Note: Scatter plot of mean plasma concentration by treatment. Y = plasma concentration (semi-logarithmic scale), X = Time} 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 70 of 96 
 
12.4. 
Planned Listing Shells 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.1.1 
Study Populations and Disposition  
All Enrolled Subjects (ITT) 
 
Planned Treatment: Sequence x 
 
Subject ID 
Enrolled 
 
Cohort 
Actual Treatment 
Sequence 
SAF 
PK 
Completed 
Study? 
Date of 
Completion/ 
Discontinuation 
Reason for Discontinuation 
 
 
 
 
 
 
 
 
 
XXXXX 
Yes 
1 
Sequence x 
Yes 
Yes 
Yes 
DDMMMYYYY 
 
 
 
 
 
 
 
 
 
 
XXXXX 
Yes 
1 
Sequence x 
Yes 
Yes 
No 
DDMMMYYYY 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
XXXXX 
Yes 
2 
Sequence x 
Yes 
Yes 
Yes 
DDMMMYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: PK = Pharmacokinetic Population, SAF = Safety Population. 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 71 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.1.2 
Randomization and Treatment Completion  
All Enrolled Subjects (ITT) 
Planned Treatment: Sequence x 
 
Subject ID 
 
Cohort 
Randomization 
Number 
Period 
(Planned Treatment Day) 
Treatment Date  
(Study Day) [1] 
Planned Treatment 
Actual Treatment 
 
 
 
 
 
 
 
XXXXX 
1 
xxxx 
1 (Day 0) 
DDMMMYYYY (xx) 
Treatment A 
Treatment A 
 
 
 
2 (Day 3)  
DDMMMYYYY (xx) 
Treatment D 
Treatment D 
 
 
 
3 (Day 6)  
DDMMMYYYY (xx) 
Treatment B 
Treatment B 
 
 
 
4 (Day 9)  
DDMMMYYYY (xx) 
Treatment C 
Treatment C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose  
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY  
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 72 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.2.1 
Inclusion and Exclusion Criteria  
All Subjects 
Not Randomized 
 
Screening ID/Subject ID 
Did subject meet all eligibility criteria? 
 
Criteria Not Met 
Reason Not Met 
 
 
 
 
XXXXX 
No 
Inclusion #1 
xxxxxxxxxxxxxx 
 
 
Exclusion #2 
xxxxxxxxxxxxxxxxxxx 
 
 
 
 
{Programming notes: Repeat for Treatment Sequence 1, 2, 3, 4, where 
“Subject ID” will take place of “Screening ID” in 1st column header.} 
 
 
 
 
 
XXXXX 
Yes 
 
 
 
 
 
 
XXXXX 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Randomized patients will have both a screening and subject identification number; patients who have not been randomized will be displayed by their screening number 
only. 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 73 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.2.2 
Protocol Deviations  
All Enrolled Subjects (ITT) 
Planned Treatment: Sequence x 
 
Subject ID 
Event Date 
 
Event Report Date 
Event Type 
Event Category 
Description 
 
 
 
 
 
 
XXXXX 
DDMMMYYYY 
DDMMMYYYY 
Major 
xxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
XXXXX 
DDMMMYYYY 
DDMMMYYYY 
Major 
xxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
XXXXX 
DDMMMYYYY 
DDMMMYYYY 
Minor 
xxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 74 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.4.1 
Demographics  
All Enrolled Subjects (ITT) 
Planned Treatment: Sequence x 
 
Subject 
ID 
Cohort 
Informed Consent 
Date: Protocol 
Version 
 
Date of Birth 
Age 
(years) 
Gender 
If female, 
childbearing 
potential? 
Ethnicity 
Race 
Baseline 
Height 
(cm) 
Baseline 
Weight 
(kg) 
Baseline 
BMI 
(kg/m2) 
Cigarettes 
Smoking 
Status 
Number of 
Cigarettes 
Smoked/day 
Cigarettes 
Smoking Start 
Date/End Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
1 
DDMMMYYYY: v1.0 
DDMMMYYYY 
xx 
Female 
Yes 
xxxxxxxx 
xxxxx 
xx 
xx 
xx 
Never 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
1 
DDMMMYYYY: v1.0 
DDMMMYYYY 
xx 
Female 
No 
xxxxxxx 
xxxxx 
xx 
xx 
xx 
Former 
xx 
DDMMMYYYY/
DDMMMYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
2 
DDMMMYYYY: v3.0 
DDMMMYYYY 
xx 
Male 
 
xxxxxx 
xxxx 
xx 
xx 
xx 
Current 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 75 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.4.2 
Medical History  
Safety Population 
Planned Treatment: Sequence x 
 
Subject ID 
Any Medical 
History? 
System Organ Class [1]/ 
    Preferred Term/ 
        Verbatim Term 
Start Date 
End Date/Ongoing 
 
 
 
 
 
XXXXX 
Yes 
XXXXXXXXXXXXXXXXXXXXXXX/ 
    XXXXXXXXXXXX/ 
        XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DDMMMYYYY 
DDMMMYYYY 
 
 
 
 
 
XXXXX 
Yes 
XXXXXXXXXXXXXXXXXXXXXXX/ 
    XXXXXXXXXXXX/ 
        XXXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DDMMMYYYY 
Ongoing 
 
 
 
 
 
XXXXX 
No  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Medical history was coded using MedDRA version 22.0. 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 76 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.4.3 
Prior and Concomitant Medication  
Safety Population 
Planned Treatment: Sequence x 
 
Subject ID 
Any Meds? 
Type [1] 
Anatomic Therapeutic Class (level 4) [2]/ 
  Preferred Term/ 
    Verbatim Term 
Start Date (Study Day)/ 
End Date (Study Day) [3] 
Indication 
Dose (unit)/ 
    Route/ 
      Frequency 
 
 
 
 
 
 
 
XXXXX 
Yes 
C1, C2, C3 
XXXXXXXXXXXXXXXXXXX/ 
  XXXXXXX/ 
    XXXXXXXXXXXXXXXXXXXXXXXXXXXXX 
DDMMMYYYY (xx)/ 
DDMMMYYYY (xx) 
xxxxxxxxxx 
XXXXXXXXXXXXXXXXXXX <units> / 
     XXXXXXX/ 
       XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
C1, C2, P 
XXXXXXXXXXXXXXXXXX/ 
  XXXXXXX/ 
    XXXXXXXXXXXXXXXXXXXXXXXX 
DDMMMYYYY (xx)/ 
ONGOING 
xxxxxxx 
XXXXXXXXXXXXXXXXXXX <units> / 
     XXXXXXX/ 
       XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
XXXXX 
No 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
Yes 
C1, P 
XXXXXXXXXXXXXXXXXX/ 
  XXXXXXX/ 
    XXXXXXXXXXXXXXXXXXXXXXXX 
DDMMMYYYY (xx)/ 
ONGOING 
xxxxxxx 
XXXXXXXXXXXXXXXXXXX <units> / 
     XXXXXXX/ 
       XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] C1-C4 = Concomitant medication, any medications continuing or starting during Period 1-4; P = Prior medication, any medications that started prior to the first administration 
of study medication on Day 0 whether or not they were stopped prior to first administration of study medication; ATC = Anatomic Therapeutic Chemical. 
[2] Medications were coded using WHO-DD v. March 1, 2019 and reported in ATC Level 4. 
[3] Study Day = Assessment Date – Date of First Dose  
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 77 of 96 
 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.4.4 
Cigarettes Smoking Log 
Safety Population 
Planned Treatment: Sequence x 
 
Subject ID 
Current Cigarette 
Smoker? 
Visit  
(Study Day [1]) 
Any Cigarettes Smoked This 
Day? 
Smoking Start Date 
Smoking Start Time 
 
 
 
 
 
 
XXXXX 
No 
 
 
 
 
 
 
 
 
 
 
XXXXX 
Yes 
Clinic Check-in (xx) 
Yes 
DDMMMYYYY 
HH:MM 
 
 
Tolerability Test (xx) 
Yes 
DDMMMYYYY 
HH:MM 
 
 
Day 0 Assessment (xx) 
  No 
 
 
 
 
Day 1 Non-Assessment (xx) 
  No 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose  
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 78 of 96 
 
 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.5.1 
Study Drug Administration  
Safety Population 
Planned Treatment: Sequence x 
 
Subject 
ID 
Visit 
Drug 
Administered
? 
Reason not 
administere
d 
Date of 
administration (Study 
Day) [2] 
Time of 
administratio
n 
Restriction 
from fluids 
[1] 
completed? 
Reason not 
completed 
Were 240 mL 
of water 
administered
? 
Mouth check 
performed? 
Reason not 
checked 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
Day 0 
Yes 
 
DDMMMYYYY (xx) 
HH:MM 
Yes 
 
Yes 
Yes 
 
 
Day 3 
Yes 
 
DDMMMYYYY (xx) 
HH:MM 
Yes 
 
Yes 
Yes 
 
 
Day 6 
Yes 
 
DDMMMYYYY (xx) 
HH:MM 
Yes 
 
Yes 
Yes 
 
 
Day 9 
Yes 
 
DDMMMYYYY (xx) 
HH:MM 
No 
xxxxxxxxxxxxxx 
No 
No 
xxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Restriction from fluids is completed is the subject complete the 10-hour overnight fast pre-dose and 4-hour post-dose fast as well as the 1-hour pre-dose and 2-hour post 
dose restriction from fluids. 
[2] Study Day = Assessment Date – Date of First Dose 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 79 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.5.2 
Tolerability Drug Administration  
Safety Population 
Planned Treatment: Sequence x 
 
Subject ID 
Test drug Administered? 
Reason not administered 
Date of administration 
(Study Day) [1] 
Time of administration 
Test drug safety Tolerated? 
 
 
 
 
 
 
XXXXX 
Yes 
 
DDMMMYYYY (xx) 
HH:MM 
Yes 
 
 
 
 
 
 
XXXXX 
No 
xxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 80 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.6.1 
Plasma Concentration of d-MPH 
PK Population 
Planned Treatment: Sequence x 
 
Subject ID 
Visit 
PK samples 
collected? 
Reason not 
collected 
Timepoint 
Sample 
collected? 
Reason not 
collected 
Date 
collected 
Time collected  
Arm used 
Plasma 
concentration (unit) 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
Day 0 
Yes 
 
Pre-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
Right 
xx 
 
 
 
 
0.5 hr Post-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
Right 
xx 
 
 
 
 
1 hr Post-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
Right 
xx 
 
 
 
 
1.5 hr Post-dose 
 
 Yes 
 
DDMMMYYYY  
HH:MM 
Right 
xx 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
28 hr Post-dose 
Yes 
 
DDMMMYYYY 
HH:MM 
Right 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
Day 3 
Yes 
 
Pre-dose 
No 
xxxxxxxx 
 
 
 
 
 
 
 
 
0.5 hr Post-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
Right 
xx 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
No 
xxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 9 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS/ET 
Yes 
 
N/A 
N/A 
N/A 
DDMMMYYYY  
HH:MM 
Right 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 81 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.6.2 
PK Parameters 
PK Population 
Planned Treatment: Sequence x 
 
Subject ID 
Period (Treatment Day) 
 
Planned Treatment 
Actual Treatment 
Parameter (Unit) 
Value   
 
 
 
 
 
 
XXXXX 
1 (Day 0) 
Treatment A 
Treatment A 
XXX 
xx 
 
 
 
 
XXXX 
xx 
 
 
 
 
XXXXX 
xx 
 
 
 
 
XXX  
xx 
 
 
 
 
XXXX  
xx 
 
 
 
 
XXX 
xx 
 
 
 
 
 
 
 
2 (Day 3) 
Treatment B 
Treatment B 
XXX 
xx 
 
 
 
 
XXXXX 
xxx 
 
 
 
 
… 
 
 
 
 
 
 
 
 
3 (Day 6) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 (Day 9)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 82 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.7.1 
All Adverse Events 
 
Planned Treatment: Sequence x 
 
Subject ID 
[1] 
System Organ Class [2]/ 
  Preferred Term/ 
       Verbatim Term 
Start Datetime (Study Day) [3]/ 
End Datetime (Study Day)  
Serious 
Severity/ 
Relationship 
to  Study 
Drug(s) 
Outcome/ 
Med treatment received/ 
Action taken with Study 
Drug 
CA/DIS/HO/ 
DE/LT/OTH [4] 
TEAE  
(Period) 
[5] 
 
 
 
 
 
 
 
 
XXXXX 
xxxxxxxxxx xxxxx xxxxx/ 
  xxxxxxxxxxxxxxxxx/ 
    xxxxxxxxxxxxxxxxxx 
DDMMMYYYY:HH:MM (xx)/ 
DDMMMYYYY:HH:MM (xx) 
No 
xxxxxxx/ 
xxxxxxxxxxxx 
xxxxxxxxxxxxx/ 
xxxxxxxxxxx xxxxxx/ 
xxxxxxxxxxxxxxx 
No/No/No/ 
No/No/No 
Yes (1) 
 
 
 
 
 
 
 
 
XXXXX 
xxxxxxxxxx xxxxx xxxxx/ 
  xxxxxxxxxxxxxxxxxxxxxx/ 
    xxxxxxxxxxx xxxxxxxxxxxx 
DDMMMYYYY:HH:MM (xx)/ 
DDMMMYYYY:HH:MM (xx) 
Yes 
xxxxxxx/ 
xxxxxxxxxxxx 
 
xxxxxxxxxxxxx/ 
xxxxxxxxxxx/  
xxxxxxxxx  
No/No/Yes/ 
No/No/Yes 
Yes (4) 
 
 
 
 
 
 
 
 
XXXXX 
xxxxxxxxxx xxxxx xxxxx/ 
  xxxxxxxxxxxxxxxxx/ 
    xxxxxxxxxxxxxxxxxx 
DDMMMYYYY:HH:MM (xx)/ 
ONGOING 
No 
xxxxxxx/ 
xxxxxxxxxxxx 
 
xxxxxxxxxxxxx/ 
xxxxxxxxxxx /  
xxxxxx 
No/No/No/ 
No/No/No 
No (2) 
 
 
 
 
 
 
 
 
 
[1] For patients not randomized or treated, (Planned Treatment: Not Treated) this column will list Screening ID. 
[2] Adverse Events were coded using MedDRA version 22.0. 
[3] Study Day = Assessment Date – Date of First Dose  
[4] DE = Death (fatal), LT = Life-threatening event, HO = Hospitalization or prolongation of hospitalization, DIS = Persistent or significant disability/incapacity, CA = Congenital 
abnormality or birth defect, OTH = Other important medical event.  
[5] TEAE is defined as any adverse event with an onset date on or after first dose of first treatment period after randomization.  TEAE are identified as treatment emergent based 
period in which the start of the event occurred; an event is only considered treatment emergent for a period if the dose assigned for the period was administered. 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
Programming note:  This is the only listing of AEs which will include patients who screen fail if applicable.  At the end of the listings, include Planned Treatment: Not Treated 
section for reporting patients by Screening ID.  If no AEs are identified for patients not treated or randomized, renumber the footnotes and eliminate references to Not Treated. 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 83 of 96 
 
Listing 16.2.7.2 
Serious Adverse Events  
Safety Population 
{Programming Note: Repeat 16.2.7.1 with only SAEs. Remove references to Screening ID (renumber footnotes and remove Not Treated from reporting if applicable).} 
 
Listing 16.2.7.3 
Adverse Events leading to Discontinuation  
Safety Population 
{Programming Note: Repeat 16.2.7.1 with only AEs leading to discontinuation. Remove references to Screening ID (renumber footnotes and remove Not Treated from 
reporting if applicable).} 
 
Listing 16.2.7.4 
Listing of Deaths  
Safety Population 
{Programming Note: Repeat 16.2.7.1 with only fatal AEs. Remove references to Screening ID (renumber footnotes and remove Not Treated from reporting if applicable).} 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 84 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.8.1 
Biochemistry 
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
 
 
Standard 
Reference Range 
 
Subject ID 
/Age/Gender 
Analyte 
(unit) 
Visit  
(Study Day [1]) 
Sample 
collected? 
Reason 
not 
collected 
Date collected 
Time collected 
Test Result 
[2] 
Units 
Low 
High 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX/xx/M 
xxxx (xx) Screening (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xxxx 
xx 
xx 
xx 
 
 
Clinic Check-in (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xxxx 
xx 
xx 
xx 
 
 
Unscheduled (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xxxx 
xx 
xx 
xx 
 
 
… 
 
  
 
 
 
 
 
 
 
 
 
 
EOS/ET (xx) 
Yes 
 
DDMMMYYYY 
HH:MM 
xx 
xxxx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX/xx/F 
xxxx (xx)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose  
[2] L = low result, H = high result, ^ = abnormal result. 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 85 of 96 
 
Listing 16.2.8.2 
Hematology 
Safety Population 
{Programming Note: Repeat 16.2.8.1 with hematology analytes} 
 
Listing 16.2.8.3 
Urinalysis 
Safety Population 
{Programming Note: Repeat 16.2.8.1 with urinalysis analytes} 
 
Listing 16.2.8.4 
Thyroid 
Safety Population 
{Programming Note: Repeat 16.2.8.1 with TSH} 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 86 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.8.5 
Urine Drug Screen 
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
 
 
Subject ID 
Analyte 
Visit  
(Study Day [1]) 
Drug screen 
performed? 
Reason not 
performed 
Date collected 
Time collected 
Test Result 
Comments 
 
 
 
 
 
 
 
 
 
XXXXX 
xxxxxxx 
Screening (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
Negative 
 
 
 
Clinic Check-in (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
Negative 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose  
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
Listing 16.2.8.6 
Serology 
Safety Population 
{Programming Note: Repeat 16.2.8.5 with Serology analytes} 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 87 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.8.7 
Pregnancy  
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
Subject ID 
Visit  
(Study Day [1]) 
Sample 
collected? 
Reason not 
collected 
Date collected 
Time collected 
Test Result 
 
 
 
 
 
 
 
XXXXX 
Screening (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
Negative 
 
 
No 
xxxxxxxxxxxx 
 
 
 
 
Clinic Check-in (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
Negative 
 
 
Yes 
 
DDMMMYYYY  
HH:MM 
Negative 
 
EOS/ET (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
Negative 
 
 
 
 
 
 
 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Serum and Urine pregnancy tests are analyzed in women of child-bearing potential only.  
[1] Study Day = Assessment Date – Date of First Dose 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 88 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.8.8 
Breath Alcohol Test  
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
Subject ID 
Visit  
(Study Day [1]) 
Test 
performed? 
Reason not 
performed 
Date performed 
Time performed 
Test Result 
 
 
 
 
 
 
 
XXXXX 
Screening (xx) 
Yes 
 
DDMMMYYYY  
HH:MM 
Negative 
 
Clinic Check-in (xx) 
No 
xxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose 
[2] L = low result, H = high result, ^ = abnormal result. 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 89 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.9.1 
Physical Examination  
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
 
 
Subject ID 
Visit  
(Study Day [1]) 
Exam 
performed? 
Reason not 
performed 
Exam Date 
Body System 
Result 
Abnormal 
Findings 
Clinically 
Significant 
[2] 
 
 
 
 
 
 
 
 
 
XXXXX 
Screening (xx) 
Yes 
 
DDMMMYYYY  
xxxxxxxxxxxxx 
xxxxx 
 
 
 
 
 
 
 
xxxxxxxxxxxxx 
xxxxx 
 
 
 
 
 
 
 
xxxxxxxxxxxxx 
xxxxx 
xxxxxxxxxx 
NCS 
 
 
 
 
 
xxxxxxxxxxxxx 
xxxxx 
 
 
 
 
 
 
 
xxxxxxxxxxxxx 
xxxxx 
 
 
 
 
 
 
 
xxxxxxxxxxxxx 
xxxxx 
xxxxxxxxxx 
CS 
 
 
 
 
 
 
 
 
 
 
Clinic Check-in (xx) 
No 
xxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 (xx) 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS/ET (xx) 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose  
[2] CS = clinically significant, NCS = not clinically significant 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 90 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.9.2 
Vital Signs  
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject ID 
Visit  
(Study Day [1]) 
Timepoint 
Vital signs 
assessed? 
Reason 
not 
assessed 
Date 
Collected 
Time 
Collected 
Heart 
Rate 
(bpm) 
SBP/DBP [2] 
(mmHg) 
Arm used for 
SBP/DBP 
Weight 
(kg) 
Height 
(cm) 
BMI 
(kg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
Screening (xx) 
 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx/xx 
Right 
xx 
xx 
xx 
 
Clinic Check-in (xx) 
 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx/xx 
Right 
xx 
 
 
 
Tolerability Test (xx) 
 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx/xx 
Right 
 
 
 
 
Day 0 (xx) 
Pre-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx/xx 
Right 
 
 
 
 
 
1 hr Post-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx/xx 
Right 
 
 
 
 
 
2 hr Post-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx/xx 
Right 
 
 
 
 
 
6 hr Post-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx/xx 
Right 
 
 
 
 
 
28 hr Post-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx/xx 
Right 
 
 
 
 
Day 3 (xx) 
… 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS/ET (xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose  
 [2] SBP = Systolic blood pressure; DBP = Diastolic blood pressure 
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 91 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.9.3 
Electrocardiogram (ECG)  
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID 
Visit  
(Study Day[1]) 
Timepoint 
ECG 
assessed? 
Reason 
not 
assessed 
ECG Date 
ECG 
Time 
Heart 
Rate 
(bpm) 
PR 
(msec) 
QRS 
(msec) 
QT 
(msec) 
QTcF 
(msec) 
VR [2] 
(msec) 
Rhythm 
Investigator 
Interpretation 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX 
Screening (xx) 
 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx 
xx 
xx 
xx 
xx 
Normal 
xx 
xxxxxxxx 
 
Clinic Check-in (xx) 
 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx 
xx 
xx 
xx 
xx 
Normal 
xxxxxxxxxxx 
xxxxxxx 
 
Tolerability Test (xx) 
 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx 
xx 
xx 
xx 
xx 
Normal 
 
 
 
Day 0 (xx) 
Pre-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx 
xx 
xx 
xx 
xx 
Normal 
 
 
 
 
6 hr Post-dose 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx 
xx 
xx 
xx 
xx 
Normal 
 
 
 
 
28 hr Post-
dose 
Yes 
 
DDMMMYYYY  
HH:MM 
xx 
xx 
xx 
xx 
xx 
xx 
Normal 
 
 
 
Day 3 (xx) 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS/ET (xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
XXXXX  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = Assessment Date – Date of First Dose  
 [2] VR = Ventricular Rate.  
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 92 of 96 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.9.4 
C-SSRS  
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
 
Subject ID 
Visit  
(Study Day [1]) 
Completed? 
Reason not 
completed 
Assessment Date 
Category   
Question Text 
Result 
 
 
 
 
 
 
 
 
XXXXX 
Screening (xx) 
Yes 
 
DDMMMYYYY  
Suicidal Ideation 
xxxxxxxxxxxx xxxxx xxxxxxxxx 
xxxxxxx 
 
 
 
 
 
 
xxxxxxxxx xxxxx xxxxxx 
xxxxx 
 
 
 
 
 
 
xxxxxxxxxx xxxxx xxxxxxxxx 
xxxxxx 
 
 
 
 
 
Intensity of Ideation 
xxxxxxxxxxxx xxxxx xxxxxxxxx 
xxxxxxx 
 
 
 
 
 
 
xxxxxxxxx 
xxxxx 
 
 
 
 
 
 
xxxxxxxxxx xxxxxxxxx 
xxxxxxx 
 
 
 
 
 
Suicidal Behaviour 
xxxxxxxxxx 
xxx 
 
xxxx (xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: C-SSRS = Columbia Suicide Severity Rating Scale  
[1] Study Day = Assessment Date – Date of First Dose  
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 93 of 96 
 
 
Cingulate Therapeutics, Inc.  
 
 
 
 
 
 
 
 
 
 
 
                                 Page 1 of 1 
Protocol CTx-1301-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       FINAL 
Listing 16.2.9.5 
M.I.N.I.  
Safety Population 
Planned Treatment: Sequence x 
 
 
 
 
 
 
 
 
Subject ID 
Visit 
Completed? 
Reason not 
completed 
Interview Date 
Start/Stop Time 
Module  
Question Text 
Result 
 
 
 
 
 
 
 
 
XXXXX 
Screening 
Yes 
 
DDMMMYYYY  
HH:MM/HH:MM 
A 
xxxxxxxxxxxx xxxxx xxxxxxxxx 
xxxxxxx 
 
 
 
 
 
 
xxxxxxxxx xxxxx xxxxxx 
xxxxx 
 
 
 
 
 
 
xxxxxxxxxx xxxxx xxxxxxxxx 
xxxxxx 
 
 
 
 
 
B 
xxxxxxxxxxxx xxxxx xxxxxxxxx 
xxxxxxx 
 
 
 
 
 
 
xxxxxxxxx 
xxxxx 
 
 
 
 
 
 
xxxxxxxxxx xxxxxxxxx 
xxxxxxx 
 
 
 
 
 
 
 
 
XXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: M.I.N.I. = MINI International Neuropsychiatric Interview  
T:\Cingulate\CTx-1301\...\xxxxxx.sas run on DDMMMYYYY at HH:MM on data extracted on DDMMMYYYY 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 94 of 96 
 
Appendix 1: List of Abbreviations 
 
Abbreviation 
Definition 
ADHD 
attention deficit and hyperactivity disorder 
AE 
adverse event 
BLQ 
beneath limit of quantification 
BMI 
body mass index 
CI 
confidence intervals 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
d-MPH 
dexmethylphenidate 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European medicines agency 
EOS 
end of Study 
ET 
early termination 
EU 
European Union 
FDA 
food and drug administration 
HR 
heart rate 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 95 of 96 
 
Abbreviation 
Definition 
ICF 
informed consent or informed consent form 
ICH 
international council for harmonization  
ID 
identification 
ITT 
intent-to-treat 
MedDRA 
medical dictionary for regulatory activities 
N 
number 
NA 
not applicable 
NCS 
non-clinically significant 
PD 
protocol deviation 
PE 
physical examination 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TOST 
two one-sided hypothesis tests 
WHO-DD 
world health organization drug dictionary 


 
Statistical Analysis Plan,  
 
Sponsor Cingulate Therapeutics  
 
Protocol Number CTx-1301-001  
 
PCN Number CING8178 
AD-ST-33.05  Effective date: 22-Jan-2018 
Final Version 1.0    |    Date 12FEB2020    |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 96 of 96