Clinical trial NCT03605836
Conditions: Attention Deficit Disorder Attention Deficit Hyperactivity Disorder
Keywords: Centanafadine ADD ADHD
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2019-01-16; Completion date: 2020-05-14
Enrollment: 590 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluated the efficacy, safety, and tolerability of centanafadine sustained-release tablets in adults with ADHD. Participants either received a twice-daily dose of centanafadine sustained-release tablets, or twice-daily placebo.

Detailed description:
Screening \& Washout Period: up to 28 days Investigational Treatment Period: 49 days Follow-up Period : 7 days or 10 days

Arms: arm 1: Placebo-matching tablets BID (twice daily) on Day -7 through Baseline (Day -1). arm 2: Following Single-blind Run-in Period, participants with \<30% improvement on Adult ADHD Self Report Scale (ASRS) scale score were randomized to receive centanafadine 200 mg SR tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. arm 3: Following Single-blind Run-in Period, participants with \<30% improvement on Adult ADHD Self Report Scale (ASRS) scale score were randomized to receive centanafadine 400 mg SR tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. arm 4: Following Single-blind Run-in Period, participants with \<30% improvement on Adult ADHD Self Report Scale (ASRS) scale score were randomized to receive centanafadine SR matching placebo tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period.
Interventions: intervention 1: Centanafadine SR intervention 2: Placebo intervention 3: Centanafadine SR
Intervention descriptions: intervention 1: 100 mg, BID, oral tablets intervention 2: BID, oral tablet intervention 3: 200 mg, BID, oral tablets

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, 
Parallel-group Trial Evaluating the Efficacy, Safety, and Tolerability of 
Centanafadine Sustained-release Tablets in Adults With Attention-
deficit/Hyperactivity Disorder 
NCT Number: 
NCT03605836 
 
Document Date: 
 
Protocol Version 4.0: 15 January 2020 
 
 
 
 
 
 
 
 


Otsuka Pharmaceutical Development & Commercialization, Inc
Investigational Medicinal Product
Centanafadine (EB-1020)
REVISED CLINICAL PROTOCOL
A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel-group 
Trial Evaluating the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release 
Tablets in Adults with Attention-deficit/Hyperactivity Disorder (Trial 405-201-00014)
Protocol No. 405-201-00014
IND No. 119361
CONFIDENTIAL – PROPRIETARY INFORMATION
Clinical Development Phase: 
3
Sponsor:
Otsuka Pharmaceutical Development & 
Commercialization, Inc.
2440 Research Boulevard
Rockville, Maryland 20850, United States
Immediately Reportable Event 
Syneos Health Research Pharmacovigilance 
& Drug Safety
Fax:
E-mail:
Issue Date:
8 Mar 2018
Date of Amendment 1
18 May 2018
Date of Administrative Change 1
30 Aug 2018
Date of Amendment 2
15 Jan 2020
Version No.:
4.0
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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Protocol 405-201-00014
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Protocol Synopsis
Name of Sponsor: Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Investigational Medicinal Product: 
Centanafadine (EB-1020)
Protocol No.: 405-201-00014
IND No.: 119361
Protocol Title:
A Phase 3, Randomized, Double-blind, Multicenter, 
Placebo-controlled, Parallel-group Trial Evaluating the 
Efficacy, Safety, and Tolerability of Centanafadine 
Sustained-release Tablets in Adults with 
Attention-deficit/Hyperactivity Disorder
(Trial 405-201-00014)
Clinical Phase/Trial 
Type:
3
Treatment Indication: 
Adult Attention-deficit/Hyperactivity Disorder (ADHD)
Objective(s):
Primary: To confirm the efficacy of centanafadine 
sustained-release (SR) tablets administered twice-daily (BID; 
200 mg or 400 mg total daily doses [TDDs]) compared to 
placebo in the treatment of adults with ADHD
Secondary: To confirm the safety and tolerability of 
centanafadine SR tablets administered BID (200 mg or 
400 mg TDDs) compared to placebo in the treatment of adults 
with ADHD
Trial Design:
This trial is a phase 3, randomized, double-blind, multicenter, 
placebo-controlled, parallel-group trial to confirm the efficacy, 
safety, and tolerability of centanafadine SR (200 mg TDD or 
400 mg TDD) compared to placebo for the treatment of adults 
with ADHD.
The trial will have 4 periods: (1) screening and washout; 
(2) 1-week single-blind placebo run-in; (3) 6-week 
double-blind treatment; and (4) 7-day follow-up period 
(follow-up telephone calls at 1, 3, and 5 days after the last 
dose of investigational medicinal product (IMP), and in-clinic 
visits 2 and 7 days after the last dose of IMP) for subjects who 
complete the trial, and decide to enroll in 
Trial 405-201-00015. For subjects who terminate early, decide 
to not enroll in Trial 405-201-00015, or who are not eligible to 
enroll in Trial 405-201-00015, they will be required to 
participate in the 7-day follow-up period as well as participate 
in an additional follow-up telephone call 10 days after the last 
dose of IMP. Subjects randomized to receive a TDD of 
200 mg centanafadine SR will start at their target dose at the 
start of the double-blind treatment period.
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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Subjects randomized to receive 400 mg TDD centanafadine 
SR will start the double-blind treatment period at the TDD of 
200 mg centanafadine SR for 7 days, before they are escalated 
to their target TDD of 400 mg for a total of approximately 
42 days of treatment. Subjects will be required to visit the site 
up to 12 times over the trial.
Subjects who complete both the 6-week double-blind 
treatment period and the 7-day follow up (follow-up telephone 
calls at 1, 3, and 5 days after the last dose of IMP, and in-
clinic visits 2 and 7 days after the last dose of IMP), and 
refrain from using prohibited medications after the IMP is 
stopped may be eligible to enroll into Trial 405-201-00015, 
which is a 12-month, observational, open-label trial to 
evaluate the long term safety and tolerability of subjects with 
ADHD who previously participated in Trials 405-201-00013 
or 405-201-00014. Subjects who terminate early, decide to not 
enroll in Trial 405-201-00015, or who are not eligible to enroll 
in Trial 405-201-00015, will be required to participate in the 
7-day follow-up period as well as participate in an additional 
follow-up telephone call 10 days after the last dose of IMP. 
For subjects who early terminate or decline participation in the 
open-label trial, they will be instructed to refrain from utilizing 
prohibited concomitant medications (Section 4.1), including 
ADHD treatments, until after the follow-up telephone call 
10 days after the last dose of IMP.
Subject Population:
A total of up to 1150 male and female subjects with current 
diagnosis ADHD and between the ages of 18 and 55 years, 
inclusive, are planned to be screened in order to randomize 
approximately 450 subjects to yield 292+ completers.
Subjects must meet the Diagnostic and Statistical Manual of 
Mental Disorders Fifth Edition (DSM-5) criteria for ADHD 
(including predominantly inattentive presentation, hyperactive 
presentation, or combined presentation) as confirmed by the 
Adult ADHD Clinical Diagnostic Scale (ACDS) Version 1.2. 
To confirm that ADHD is the primary diagnosis, the Mini 
International Neuropsychiatric Interview (MINI) will be used 
to identify and exclude other psychiatric conditions which 
would preclude enrollment.
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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Subjects who were not receiving any pharmacological 
treatment for ADHD must have an Adult ADHD Investigator 
Symptom Rating Scale (AISRS) score of ≥ 28 at screening and 
baseline. Subjects who were receiving pharmacological 
treatment for ADHD at screening must have a minimum 
AISRS score of ≥ 22 at screening, and a score of ≥ 28 at 
baseline.
All subjects must be willing to discontinue all prohibited 
psychotropic medications (Section 4) starting from the time of 
signing the informed consent through the 7-day follow-up 
period. Subjects that do not rollover into Trial 405-201-00015 
must be willing to discontinue all prohibited psychotropic 
medications starting from the time of signing the informed 
consent until after the follow-up telephone call 10 days after 
the last dose of IMP.
Subjects must have a Clinical Global Impression-Severity of 
Illness Scale (CGI-S) score of ≥ 4 (≥ moderate impairment) at 
baseline.
Inclusion/Exclusion 
Criteria:
Key inclusion criteria are described under Subject Population 
in this synopsis. Key exclusion criteria include the following:
Screening:

Subject has a DSM-5 diagnosis of Other Specified or
Unspecified Attention Deficit/Hyperactivity Disorder.

Subject has a current comorbid psychiatric disorder that 
either could be expected to require treatment with 
medications prohibited in this trial, or to confound efficacy 
or safety assessments. Examples include, but are not 
limited to, psychotic disorder (current or lifetime), bipolar 
disorder (current or lifetime), generalized anxiety disorder, 
obsessive-compulsive disorder, panic disorder, a current 
major depressive episode, or posttraumatic stress disorder, 
as established by the MINI.

In the opinion of the investigator, subject has not derived 
significant therapeutic benefit from 2 or more ADHD 
therapies of 2 different classes (eg, amphetamine and 
methylphenidate, or amphetamine and atomoxetine) given 
with an acceptable dose and duration during adulthood 
(aged 18 or older). NOTE: If subject has not derived 
significant therapeutic benefit due to an inability to tolerate 
side effects, eligibility can be discussed on case-by-case 
basis with the medical monitor.
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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
Subjects that have a positive alcohol test (via breathalyzer 
or blood), a positive drug screen for cocaine, or other illicit 
drugs (excluding marijuana). Subjects with a positive drug 
screen for confirmed prescription or over-the-counter 
(OTC) use of ADHD medications at screening will be 
required to undergo a washout period. NOTE: Subjects 
that test positive for marijuana may be permitted to be 
enrolled if they have no evidence of a substance use 
disorder, and if they agree to refrain from use for the 
duration of the trial. Allowance for subjects testing 
positive for marijuana at screening require explicit 
approval from the medical monitor.
Single-blind placebo run-in:

Subjects who have a positive alcohol test (via breathalyzer 
or blood), a positive drug screen assessed prior to Visit 2 
for cocaine, other illicit drugs (including marijuana), or 
prescription or OTC ADHD medications will be screen 
failed. This includes medications such as opioids or 
benzodiazepines taken without prescription.

Subjects with a ≥ 30% improvement in the (18 item) 
ADHD Symptoms score of the Adult ADHD Self Report 
Scale (ASRS) compared with the score at screening will be 
screen failed, and not eligible for rescreening.
Baseline:

Subjects who have a positive alcohol test (via breathalyzer 
or blood), a positive drug screen assessed prior to the 
baseline visit for cocaine, other illicit drugs (including 
marijuana), or prescription or OTC ADHD medications 
will be early terminated. This includes medications such as 
opioids or benzodiazepines taken without prescription.

Subjects with a ≥ 30% improvement in the (18 item) 
ADHD Symptoms score of the ASRS compared with the 
score at the start of single-blind placebo run-in will be 
early terminated.

In the opinion of the investigator, the subject is unable to 
adhere to the treatment regimen or other requirements 
outlined in the protocol.
Trial Site(s):
The trial is expected to enroll subjects at approximately 
40 sites in the United States.
Clinical Study Report 405-201-00014
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Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration:
The IMP will be supplied as weekly blister cards. All subjects 
will begin oral BID dosing with single-blind matching placebo 
on Visit 2 (Day −7) and continue through Visit 3 (baseline).
Trial assignments for the double-blind treatment period will be 
made once eligibility is confirmed. Eligible subjects will be 
randomized in a 1:1:1 ratio at baseline (Visit 3) to one of the 
following 3 treatment groups:

Centanafadine SR 200 mg

Centanafadine SR 400 mg

Matching placebo
Subjects randomized to receive the target TDD of 200 mg 
centanafadine SR will start at the target dose on Day 1 of the 
double-blind treatment period and remain there for the 
duration of the trial. Subjects randomized to receive a TDD of 
400 mg centanafadine SR will receive a TDD of 200 mg 
centanafadine SR on Day 1 of the double-blind treatment 
period for 7 days before they are escalated to their target TDD 
of 400 mg on Day 8 for the duration of the trial.
Day(s)
Time
Total Daily Dose
200 mg Target
400 mg Target
1 through 
7
2 tablets orally in 
morning
1 × 100 mg +
1 × PBO tablet
1 × 100 mg +
1 × PBO tablet
2 tablets orally 
4-6 hr later
1 × 100 mg +
1 × PBO tablet
1 × 100 mg +
1 × PBO tablet
8 and
thereafter
2 tablets orally in 
morning
1 × 100 mg +
1 × PBO tablet
2 ×100 mg
2 tablets orally 
4-6 hr later
1 × 100 mg +
1 × PBO tablet
2 ×100 mg
PBO = placebo.
Neither the investigator nor the subject will be aware of the 
treatment assignment after randomization. All doses of 
centanafadine SR and matching placebo should be taken orally 
BID and can be administered without regard to meals, and 
should be taken at approximately the same time each day, with 
the first dose taken in the morning. The second dose should be 
taken 4 to 6 hours after the morning dose is administered.
The total duration of the double-blind treatment period will be 
6 weeks for all randomized subjects.
Clinical Study Report 405-201-00014
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Trial Assessments:
Efficacy: AISRS, CGI-S, Clinical Global Impression (CGI)
Change from Baseline
Pharmacokinetic: Sparse pharmacokinetic (PK) samples will 
be taken for determination of concentrations of centanafadine 
and metabolite(s) in plasma on Days 7, 14, 28, 42/end of 
treatment/early termination (ET), and 49/7-day follow-up. 
Samples collected at Day 14 and Day 42/ET should be taken 
concurrently with the serum chemistry sample.
Safety: Adverse event (AE) reporting (including evaluations 
for rash, AEs related to abuse potential, and AEs involving 
medication handling irregularities), clinical laboratory tests, 
physical examinations, vital sign measurements, 
electrocardiograms (ECGs), assessments of withdrawal (Study 
Medication Withdrawal Questionnaire [SMWQ]), and 
suicidality (Columbia-Suicide Severity Rating Scale 
[C-SSRS]).
Screening/Other: ADHD Impact Module - Adult (AIM-A) and 
ASRS. A whole blood sample to extract deoxyribonucleic acid 
(DNA) for genotyping and a future biospecimen research 
sample will be collected at baseline.
Clinical Study Report 405-201-00014
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Criteria for 
Evaluation:
Primary Efficacy Endpoint:
The primary efficacy endpoint is the change from baseline at 
Day 42 in the AISRS total score.
Key Secondary Efficacy Endpoint:
The key secondary efficacy endpoint is change from baseline 
at Day 42 on the CGI-S.
Other Efficacy Endpoints:

Change from baseline in AISRS total score for every 
scheduled visit;

Change from baseline in the Inattentive subscale and 
Hyperactivity-Impulsive subscale scores of the AISRS for 
every scheduled visit;

Change from baseline in CGI-S score for every scheduled 
visit;

CGI Change from Baseline score at each scheduled visit;

Percentage of responders at each post-baseline visit, where 
a responder is defined as a subject with a CGI Change 
from Baseline score of 1 or 2 OR a ≥ 30% improvement in 
ADHD symptoms compared with baseline as measured by 
the AISRS total score.
Exploratory Efficacy Endpoints:
The exploratory endpoints are the change from baseline to 
Day 28 and Day 42 in the AIM-A and the ASRS total score 
and subscale scores.
Safety Endpoints:
Standard safety variables will include AEs (including 
evaluations for rash, AEs related to abuse potential, and AEs 
involving medication handling irregularities), clinical 
laboratory tests (hematology, serum chemistry, and 
urinalysis), physical examinations, vital sign measurements, 
ECGs, assessments of withdrawal (SMWQ), and suicidality 
(C-SSRS).
Abuse-related AEs and AEs involving medication 
irregularities will be recorded verbatim on source 
documentation with detailed narratives.
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Statistical Methods:
A sufficient number of subjects will be enrolled and 
randomized to achieve approximately 405 evaluable subjects 
in the double-blind treatment period (ie, subjects with an 
AISRS total score at baseline and at least 1 subsequent AISRS 
total score in the double-blind treatment period). After 
allowance of 10% nonevaluable subjects in the double-blind 
treatment period, the total number of subjects to be 
randomized is 450 subjects (150 subjects in each treatment 
arm). In order to ensure 405 evaluable subjects, the number of 
nonevaluable subjects will be monitored in a blinded manner 
on an ongoing basis during the trial. The power and sample 
size were obtained using the PASS 14 (2015) statistical 
computing software.
The primary efficacy endpoint is the change from baseline to 
Day 42 in AISRS total score. The estimand for the primary 
efficacy analysis is the difference in outcome improvement if 
all subjects tolerated and adhered to their treatment. This 
approach is Estimand #3, recommended by the 2010 National 
Academy of Sciences’ National Research Council report on 
prevention and treatment of missing data and International 
Council for Harmonisation E9 (R1) “Addendum to Statistical 
Principles for Clinical Trials on Choosing Appropriate 
Estimands and Defining Sensitivity Analyses in Clinical 
Trials”. This estimand focuses on the efficacy of 
centanafadine (SR 200mg TDD or SR 400mg TDD) in change 
from the baseline in AISRS total score. The objective of this 
trial is consistent with the election of an efficacy rather than 
effectiveness estimand.
The primary efficacy analysis will be performed by fitting a 
mixed-effect model repeated measures analysis with an 
unstructured variance covariance structure in which the 
change from baseline in AISRS total score at the scheduled 
double-blind treatment period visits will be the dependent 
variable based on the observed-case data set. The model will 
include fixed class effect terms for treatment, trial center, visit 
day, and an interaction term of treatment by visit day. The 
model will also include baseline values of AISRS total score 
and the interaction term of baseline values of AISRS total 
score by visit day as covariates. The primary comparison 
between the centanafadine (200 mg TDD or 400 mg TDD 
group) and the placebo group at Day 42 in the double-blind 
treatment phase will be estimated as the difference between 
Least Squares means utilizing the computing software SAS 
procedure PROC MIXED.
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The comparison between centanafadine 200 mg TDD or 
400 mg TDD group and placebo group will be tested at a 
significance level of 0.05 (2-sided) in the order of 1) 400 mg 
versus placebo, and 2) 200 mg versus placebo. Additional 
details will be provided in the statistical analysis plan (SAP). 
Based on the results at various dose strengths from phase 2 
centanafadine trials, it is reasonable to expect a treatment 
difference of 5 points with a standard deviation (SD) of 12.5 in 
the mean change from baseline to Day 42 on AISRS total 
score in either the 200 mg TDD or 400 mg TDD arms. The 
planned sample size of 405 evaluable subjects (135 in each 
treatment arm) will yield at least 90% power to detect the 
treatment effects at a 2-tailed significance level of 0.05. The 2-
sided alpha level for the final analysis is 0.05.
Descriptive statistics will be provided for all efficacy and 
safety variables in general. Continuous variables will be 
summarized by tabulations of mean, median, range, and SD. 
Tabulations of frequency distributions will be provided for 
categorical variables.
Trial Duration:
A total of up to 1150 male and female subjects are planned to 
be screened in order to randomize approximately 450 subjects 
to yield approximately 292 completers. Individual 
participation for all subjects in the trial is 12 to 13 weeks, 
consisting of an up to 28-day screening period, a 1-week 
single-blind placebo run-in period, a 6-week double blind 
treatment period, and a 7-day follow-up period (follow-up 
telephone calls at 1, 3, and 5 days after the last dose of IMP, 
and in-clinic visits 2 and 7 days after the last dose of IMP) for 
all subjects. For subjects who early terminate or decline 
participation in the open-label trial, they will be required to 
participate in an additional follow-up telephone call 10 days 
after the last dose of IMP.
Clinical Study Report 405-201-00014
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Table of Contents
Protocol Synopsis...........................................................................................2
Table of Contents.........................................................................................11
List of In-text Tables ...................................................................................16
List of In-text Figures..................................................................................17
List of Appendices........................................................................................18
List of Abbreviations and Definitions of Terms .......................................19
1
Introduction ........................................................................................21
1.1
Nonclinical Data................................................................................................22
1.2
Clinical Data......................................................................................................23
1.3
Known and Potential Risks and Benefits ..........................................................23
2
Trial Rationale and Objectives..........................................................25
2.1
Trial Rationale...................................................................................................25
2.2
Dosing Rationale...............................................................................................25
2.3
Trial Objectives.................................................................................................26
3
Trial Design.........................................................................................26
3.1
Type/Design of Trial .........................................................................................26
3.2
Trial Treatments ................................................................................................29
3.2.1
Single-blind Placebo Run-in Period ...............................................................29
3.2.2
Double-blind Treatment Period......................................................................29
3.3
Trial Population.................................................................................................30
3.3.1
Number of Subjects and Description of Population .......................................30
3.3.2
Subject Selection and Numbering ..................................................................31
3.4
Eligibility Criteria..............................................................................................31
3.4.1
Informed Consent ...........................................................................................31
3.4.2
Inclusion Criteria ............................................................................................32
3.4.3
Exclusion Criteria...........................................................................................33
3.5
Endpoints...........................................................................................................36
3.5.1
Primary Endpoint............................................................................................36
3.5.1.1
Primary Efficacy Endpoint..........................................................................36
3.5.2
Secondary Endpoints ......................................................................................36
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3.5.2.1
Key Secondary Efficacy Endpoint..............................................................36
3.5.2.2
Other Efficacy Endpoints............................................................................36
3.5.3
Exploratory Endpoints....................................................................................36
3.5.4
Safety Endpoints.............................................................................................36
3.6
Measures to Minimize/Avoid Bias....................................................................37
3.6.1
Randomization................................................................................................37
3.7
Trial Procedures ................................................................................................37
3.7.1
Schedule of Assessments................................................................................41
3.7.1.1
Visit 1 (Screening) ......................................................................................41
3.7.1.2
Visit 2 (Single-blind Placebo Run-in).........................................................42
3.7.1.3
Visit 3 (Baseline).........................................................................................42
3.7.1.4
Double-Blind Treatment Period..................................................................43
3.7.1.4.1
Visits 4 through 8 ....................................................................................43
3.7.1.4.2
Visit 9/End of Treatment/Early Termination ..........................................43
3.7.1.5
Visits 10 Through 14 (Follow-up) ..............................................................44
3.7.1.6
Visit 15 (Follow-up)....................................................................................45
3.7.2
Efficacy Assessments .....................................................................................45
3.7.2.1
Adult Attention-deficit/Hyperactivity Disorder Investigator Symptom 
Rating Scale ................................................................................................45
3.7.2.2
Clinical Global Impression-Severity of Illness Scale - Modified for 
Attention-deficit/Hyperactivity Disorder....................................................45
3.7.2.3
Clinical Global Impression Change from Baseline.....................................46
3.7.3
Other Assessments..........................................................................................46
3.7.3.1
Mini International Neuropsychiatric Interview...........................................46
3.7.3.2
Adult ADHD Clinical Diagnostic Scale .....................................................46
3.7.3.3
Attention-deficit/Hyperactivity Disorder Impact Module - Adult..............46
3.7.3.4
Adult Attention-deficit/Hyperactivity Disorder Self-Report Scale, 
Expanded Version.......................................................................................47
3.7.4
Prior and Concomitant Medications...............................................................47
3.7.5
Safety Assessments.........................................................................................47
3.7.5.1
Adverse Events............................................................................................47
3.7.5.2
Clinical Laboratory Assessments................................................................47
3.7.5.3
Physical Examination and Vital Signs........................................................49
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3.7.5.3.1
Physical Examination..............................................................................49
3.7.5.3.2
Vital Signs ...............................................................................................50
3.7.5.4
Electrocardiogram Assessments..................................................................50
3.7.5.5
Other Safety Assessments...........................................................................50
3.7.5.5.1
Study Medication Withdrawal Questionnaire .........................................50
3.7.5.5.2
Columbia-Suicide Severity Rating Scale ................................................50
3.7.6
Pharmacokinetic and Pharmacogenomic Assessments ..................................51
3.7.6.1
Pharmacokinetic Assessments ....................................................................51
3.7.6.1.1
Pharmacokinetic Blood Samples.............................................................51
3.7.6.2
DNA Blood Samples for Pharmacogenomic Testing .................................52
3.7.6.3
Future Biospecimen Research.....................................................................52
3.7.7
End of Trial.....................................................................................................52
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................53
3.8.1
Entire Trial or Treatment Arm(s) ...................................................................53
3.8.2
Individual Site.................................................................................................53
3.8.3
Individual Subject Discontinuation ................................................................53
3.8.3.1
Treatment Discontinuation..........................................................................53
3.8.3.2
Documenting Reasons for Treatment Discontinuation...............................54
3.8.3.3
Withdrawal of Consent ...............................................................................55
3.8.3.4
Procedures to Encourage Continued Trial Participation.............................56
3.9
Screen Failures ..................................................................................................56
3.10
Definition of Completed Subjects.....................................................................57
3.11
Definition of Subjects Lost to Follow-up..........................................................57
3.12
Subject Compliance...........................................................................................57
3.12.1
AiCure Investigational Medicinal Product Adherence and Reminder 
System.............................................................................................................58
3.12.2
AiCure Subject Risk .......................................................................................59
3.12.3
AiCure Subject Confidentiality ......................................................................59
3.13
Protocol Deviations...........................................................................................60
4
Restrictions..........................................................................................60
4.1
Prohibited Medications......................................................................................60
4.2
Other Restrictions..............................................................................................62
4.2.1
Restricted Therapies and Precautions.............................................................62
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4.2.2
Non-therapy Precautions and Restrictions......................................................62
4.2.2.1
Precautions..................................................................................................62
4.2.2.2
Restrictions..................................................................................................62
5
Reporting of Adverse Events.............................................................63
5.1
Definitions.........................................................................................................63
5.2
Eliciting and Reporting Adverse Events ...........................................................65
5.3
Immediately Reportable Events ........................................................................65
5.4
Adverse Events of Special Interest....................................................................65
5.5
Abuse Potential Monitoring Plan, Events Subject to Additional 
Monitoring, and Medication Handling Irregularities ........................................66
5.6
Potential Serious Hepatotoxicity.......................................................................66
5.7
Pregnancy..........................................................................................................67
5.8
Procedure for Breaking the Blind......................................................................68
5.9
Follow-up of Adverse Events............................................................................69
5.9.1
Follow-up of Nonserious Adverse Events......................................................69
5.9.2
Follow-up of Serious Adverse Events and Immediately Reportable 
Events .............................................................................................................69
5.9.3
Follow-up and Reporting of Serious Adverse Events and Immediately 
Reportable Events Occurring after Last Scheduled Contact ..........................70
6
Pharmacokinetic/pharmacogenomic Analysis.................................70
7
Statistical Analysis..............................................................................70
7.1
Sample Size.......................................................................................................70
7.1.1
Datasets for Analysis ......................................................................................71
7.2
Handling of Missing Data .................................................................................71
7.3
Primary, Secondary, and Exploratory Endpoint Analyses................................72
7.3.1
Primary Efficacy Endpoint Analysis ..............................................................72
7.3.1.1
Sensitivity Analyses....................................................................................74
7.3.1.1.1
Sensitivity Analyses for Missing at Random Assumption......................74
7.3.1.1.2
Sensitivity Analyses for Violation of Normality Assumption ................75
7.3.2
Secondary Efficacy Endpoint Analyses..........................................................76
7.3.2.1
Key Secondary Efficacy Endpoint Analysis...............................................76
7.3.2.2
Other Efficacy Endpoint Analyses..............................................................77
7.3.3
Exploratory Efficacy Endpoint Analyses .......................................................77
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7.4
Analysis of Demographic and Baseline Characteristics....................................77
7.5
Safety Analysis..................................................................................................77
7.5.1
Adverse Events ...............................................................................................78
7.5.2
Clinical Laboratory Data ................................................................................78
7.5.3
Physical Examination and Vital Signs Data ...................................................78
7.5.4
Electrocardiogram Data..................................................................................78
7.5.5
Other Safety Data ...........................................................................................79
7.5.6
Abuse Liability Analysis ................................................................................79
8
Management of Investigational Medicinal Product........................79
8.1
Packaging and Labeling ....................................................................................79
8.2
Storage...............................................................................................................79
8.3
Accountability ...................................................................................................80
8.4
Returns and Destruction....................................................................................80
8.5
Reporting of Product Quality Complaints.........................................................80
8.5.1
Eliciting and Reporting Product Quality Complaints.....................................81
8.5.2
Information Required for Reporting Purposes ...............................................81
8.5.3
Return Process ................................................................................................81
8.5.4
Assessment/Evaluation...................................................................................81
9
Records Management.........................................................................82
9.1
Source Documents.............................................................................................82
9.2
Data Collection..................................................................................................82
9.3
File Management at the Trial Site.....................................................................83
9.4
Records Retention at the Trial Site....................................................................84
10
Quality Control and Quality Assurance...........................................84
10.1
Monitoring.........................................................................................................84
10.2
Auditing.............................................................................................................84
11
Ethics and Responsibility...................................................................85
12
Confidentiality ....................................................................................85
13
Amendment Policy..............................................................................85
14
Publication Authorship Requirements.............................................86
15
References............................................................................................88
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List of In-text Tables
Table 3.2.2-1
Dosing Schedule for Centanafadine SR Tablets............................30
Table 3.4.2-1
Inclusion Criteria ...........................................................................32
Table 3.4.3-1
Exclusion Criteria ..........................................................................33
Table 3.7-1
Schedule of Assessments - Screening Through 
End of Treatment ...........................................................................38
Table 3.7-2
Schedule of Assessments - Follow-up...........................................40
Table 3.7.5.2-1
Clinical Laboratory Assessments...................................................48
Table 4.1-1
List of Medications Prohibited Before the Trial............................61
Table 4.1-2
List of Medications Prohibited During the Trial............................61
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List of In-text Figures
Figure 3.1-1
Trial Design Schematic..................................................................28
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List of Appendices
Appendix 1
Collection, Handling, and Shipment of Bioanalytical Samples.....92
Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance .........................................................................94
Appendix 3
Criteria for I13dentifying Vital Signs of Potential 
Clinical Relevance .........................................................................95
Appendix 4
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance..........................................................96
Appendix 5
Protocol Amendment(s)/Administrative Change(s) ......................97
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ACDS
Adult ADHD Clinical Diagnostic Scale
ADHD
Attention-deficit/hyperactivity disorder
ADHD-RS-IV
ADHD Rating Scale Version IV
AE
Adverse event
AESI
Adverse event of special interest
AIM-A
ADHD Impact Module - Adult
AISRS
Adult ADHD Investigator Symptom Rating Scale
ALT
Alanine aminotransferase
Anti-HCV
Hepatitis C antibodies
APMP
Abuse Potential Monitoring Plan
ASRS
Adult ADHD Self Report Scale
AST
Aspartate aminotransferase
BID
Twice daily
BMI
Body mass index
CGI
Clinical Global Impression
CGI-S
Clinical Global Impression-Severity of Illness Scale
CMH
Cochran Mantel Haenszel
CPK
Creatine phosphokinase
CRO
Clinical research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CST
Clinical Surveillance & Training
CTN SR
Centanafadine sustained release
DNA
Deoxyribonucleic acid
DSM
Diagnostic and Statistical Manual of Mental Disorders
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition
ECG
Electrocardiogram
eCRF
Electronic case report form
eICF
Electronic informed consent form
ESAM
Events Subject to Additional Monitoring
ET
Early termination
FAS
Full Analysis Set
FBR
Future biospecimen research
FDA
Food and Drug Administration
FOCBP
Females of childbearing potential
GCP
Good Clinical Practice 
GEE
Generalized estimating equations
HbA1c
Glycosylated hemoglobin
HBsAg
Hepatitis B surface antigen
HDL
High-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
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IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional review board
IRE
Immediately reportable event
ITT
Intent-to-treat
LOCF
Last-observation-carried-forward
LDL
Low-density lipoprotein
LOE
Lack of efficacy
MAR
Missing at random
MCAR
Missing completely at random
MedDRA
Medical Dictionary for Regulatory Activities
MHI
Medication handling irregularities
MI
Multiple Imputation
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed-effect model repeated measures
MNAR
Missing not at random
OC
Observed-case
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc
OTC
Over-the-counter
PBO
Placebo
PK
Pharmacokinetic
PQC
Product Quality Complaint
PT
Prothrombin time
QTcB
QT interval corrected for heart rate by the Bazett formula
QTcF
QT interval corrected for heart rate by the Fridericia formula
QTcN
QT interval corrected for heart rate by the FDA Neuropharm 
Division formula
RBC
Red blood cell
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SMWQ
Study Medication Withdrawal Questionnaire
SR
Sustained release
T4
Thyroxine
TDD
Total daily dose
TEAE
Treatment-emergent adverse event
TSH
Thyroid-stimulating hormone
UDS
Urine drug screen
ULN
Upper limit of normal
US
United States
WBC
White blood cell
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1
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is an increasingly recognized and 
heterogeneous disorder characterized by 3 core symptoms of hyperactivity, 
inattentiveness, and impulsivity.1 Depending on the ADHD subtype, sex, and presence of 
comorbid disorders, individuals with ADHD may display considerably different 
symptomatology, even within a particular age cohort.2
Although ADHD is still considered primarily a childhood disorder, the advent of 
consensus diagnostic criteria for ADHD in conjunction with more rigorous prospective 
research has documented the persistence of this disorder into adolescence in up to 70% 
and into adulthood in up to 66% of childhood cases.3,4 More recently, 2 follow-up trials 
of children with ADHD from child mental health clinics in southeast England and the 
Netherlands showed persistence of ADHD into young adulthood in 79% to 86.5% of 
individuals, respectively.5,6 Long-term follow-up trials report the persistence of this 
disorder into adulthood in as many as 65% of childhood cases.7,8 There is mounting 
evidence that supports adult ADHD is a combination of both childhood ADHD persisting 
into adulthood and adult-onset ADHD without childhood diagnosis.9 Fayyad et al (2007) 
estimated adult (18 to 44 years) ADHD prevalence determined by Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria to be 3.4%.10
Kessler et al (2006) determined adult ADHD prevalence to be 4.4% using the National 
Comorbidity Survey Replication, a lay-administered household survey.11
The exact pathophysiology of ADHD remains uncertain although it is believed that a 
dysregulation of neurotransmitters, specifically dopamine and norepinephrine, in the 
frontostriatal region of the brain are involved.12,13 This hypothesis is based primarily on 
knowledge of the mechanism of action of drugs found to be effective in treating ADHD 
and further supported by molecular genetics and neuroimaging studies.12,14
Environmental and perinatal complications may also be contributing factors.15,16
The pharmacotherapy of ADHD consequently relies on 2 major classes of drugs: 
(1) stimulants, such as methylphenidate and amphetamines, and (2) nonstimulants, such 
as atomoxetine17 and alpha-adrenergic agonists such as guanfacine and clonidine.18
Stimulants have a rapid onset of action in ADHD, are effective in all 3 core deficits of the 
disorder17, and have a response rate of about 70%.19 However, their usefulness is limited 
by adverse reactions, by lack of effect on or exacerbation of comorbidities, and by abuse 
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liability (ie, risks of abuse, dependence, and diversion) with resultant drug prescribing 
restrictions.17
The first nonstimulant drug approved in the United States (US) was atomoxetine. 
Although atomoxetine is an acceptable option for some patients with ADHD, it is 
generally less effective than treatment with stimulant therapy. In an 
atomoxetine/methylphenidate comparison trial, the response rate for atomoxetine was 
superior to placebo, 45% to 24%, respectively. However, the response rate for 
methylphenidate was superior to atomoxetine (56% to 45%).20 In addition, atomoxetine 
is associated with cardiovascular and nervous system adverse events (AEs) and has a 
boxed warning from the Food and Drug Administration (FDA) for increased risk of 
suicidal ideation in children or adolescents.21
Immediate-release clonidine and guanfacine have been evaluated as monotherapy in 
ADHD, however rapid clearance and absorption, negative side effects, and reduced 
efficacy compared with stimulants has limited their usage.22 In addition, patient 
responses to alpha-2 adrenergic agonists have been shown to be not as strong as 
stimulants. An effect size of 0.58 for clonidine was seen compared to 0.82 for stimulants 
in a meta-analysis of ADHD treatment trials. Therefore, as a first line treatment 
immediate release alpha-2 adrenergic agonists are usually not considered for ADHD.23,24
Clinical data available to date suggest that centanafadine sustained release (SR) has the 
potential to be more effective than nonstimulant therapies, with a better side-effect 
profile, and lower abuse potential than currently available stimulant therapies. In the 
current trial a 200 mg and a 400 mg total daily dose (TDD) of centanafadine SR will be 
evaluated against placebo.
Please refer to the Investigator’s Brochure (IB) for more detailed information about the 
investigational medicinal product (IMP).25
1.1
Nonclinical Data
A complete description of the available efficacy and safety pharmacology data from 
nonclinical studies, including pharmacokinetic (PK) and toxicology studies in different 
animal species can be found in the current IB.25
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1.2
Clinical Data
As of the IB data cutoff of 1 Apr 2017, 7 clinical trials in 260 subjects have been 
conducted with centanafadine. A total of 140 healthy subjects or recreational stimulant 
users received centanafadine in five phase 1 trials and 120 subjects with ADHD received 
centanafadine in two phase 2 trials.
Data from the 2 completed phase 2 trials (EB-1020-SR-ADHD-201 and 
NVI-EB-1020-202) demonstrated the efficacy of centanafadine SR in the treatment of 
adult subjects with ADHD. Trial EB-1020-SR-ADHD-201 was an exploratory, 
single-blind pilot trial to evaluate flexible doses (100 to 500 mg) of centanafadine SR. 
Trial NVI-EB-1020-202 was a randomized, double-blind, multicenter, 2-period, 
2-treatment, crossover trial. Due to tolerability issues observed at high doses of 
centanafadine SR (800 and 600 mg), the trial was amended to the maximum TDD of 
400 mg for further evaluation. For both trials, there was a statistically significant 
difference in the primary endpoint using the adult ADHD Rating Scale Version IV 
(ADHD-RS-IV) for subjects that received centanafadine SR compared to placebo 
(p < 0.001). Safety data collected from the complete phase 2 trials indicated that 
centanafadine SR is well tolerated up to 400 mg in subjects with ADHD.
Please refer to the IB for a detailed summary of available clinical data.25
1.3
Known and Potential Risks and Benefits
Based on the IB, data from the completed phase 1 and 2 trials indicate that centanafadine 
is safe and well-tolerated in healthy adult subjects and adult subjects with ADHD. Data 
from the completed phase 2 trials demonstrate that centanafadine is effective in treating 
symptoms of ADHD; based on the positive effect of centanafadine SR on the primary 
efficacy measure, the adult ADHD-RS-IV. Preliminary data suggest centanafadine may 
also confer an improved safety profile and a lower potential for abuse compared to 
currently approved Schedule II stimulant treatments for ADHD. The abuse potential for 
centanafadine is continuing to be evaluated.
Seven clinical trials in 260 healthy adult subjects and adult subjects with ADHD have 
been conducted with centanafadine. A total of 140 healthy adult subjects received 
centanafadine in 5 phase 1 trials and 120 adult subjects with ADHD received 
centanafadine in 2 phase 2 trials. The most common AEs reported in trials with 
centanafadine SR at TDDs ranging from 25 to 800 mg were gastrointestinal (nausea, 
diarrhea, and dry mouth), metabolism/nutrition-related (decreased appetite), and nervous 
system disorders (headache, dizziness, and insomnia). In general, these AEs were mild 
and resolved. To date, 1 serious AE (SAE) (ischemic cardiovascular accident) occurred in 
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a subject with ADHD (initial dosage of centanafadine SR 100 mg, titrated to 500 mg)
6 days after completing treatment, but it was not considered related to centanafadine 
treatment.
Based on the outcome of the phase 2 trials, treatment with centanafadine may be 
associated with increases in blood pressure, heart rate and orthostatic blood pressure 
changes. Increases in blood pressure and heart rate were usually modest and 
asymptomatic; however, hypertension, tachycardia, and orthostasis have occurred. 
During clinical trials, heart rate and blood pressure will be measured prior to initiation of 
therapy, and periodically while on therapy. Subjects will also be monitored for 
tachycardia or hypertension. Centanafadine should be used with caution in subjects with 
hypertension, tachycardia, or cerebrovascular disease or cardiovascular disease (eg,
known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm 
abnormalities, or other serious cardiac problems that may place a subject at increased 
vulnerability to noradrenergic effects).
Rash has been observed in subjects who received centanafadine. One subject experienced 
mild rash that was considered related to treatment after taking 500 mg centanafadine SR 
TDD for 4 days (Trial NVI-EB-1020-201). The rash resolved in 8 days with no change in 
the dose and the subject completed the trial. Eight subjects reported rash after multiple 
doses of centanafadine SR in Trial NVI-EB-1020-202. Rashes resulted in discontinuation 
of dosing for 5 subjects and dose interruption or dose reduction for 3 subjects. The 
severity of the rash in subjects who discontinued IMP ranged from moderate to severe. 
The majority of subjects who experienced rash were exposed to doses greater than 
400 mg/day (2 subjects received 800 mg/day; 4 subjects received 600 mg/day; 2 subjects 
received 400 mg/day). Neither subject who received 400 mg/day discontinued dosing due 
to the rash nor were the rashes in these subjects consistent with the drug eruptions seen in 
subjects who received 600 mg or 800 mg. All of the rashes were nonserious and all but 
one resolved within 12 days of treatment with IMP withdrawal or dose reduction. The 
one exception was a severe rash lasting over 2 months that was considered likely due to 
an existing cutaneous condition and exacerbated by the drug eruption. The dermatologic 
experts who reviewed these AEs concluded that none exhibited a profile consistent with a 
rash that would progress to a serious or otherwise life-threatening AE.
Considering that rash can be a sign of an allergic reaction, subjects will be monitored 
closely for other symptoms of allergic reaction, including shortness of breath, itching and 
swelling of the throat or mouth, or difficulty breathing (see Section 5.4). A 
comprehensive rash monitoring plan will be followed.
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Please refer to the IB for more detailed information about the known and potential risks 
and benefits of centanafadine.25
2
Trial Rationale and Objectives
2.1
Trial Rationale
This phase 3 registrational trial, in conjunction with other registrational trials, is part of 
the centanafadine clinical development program that has been designed to confirm the 
efficacy and safety of centanafadine for the treatment of adults experiencing ADHD 
symptoms. As efficacy is dependent on both treatment duration and dose, a fixed-dose, 
parallel-group approach represents the optimal trial design to evaluate efficacy.
This trial is being conducted to obtain information on the efficacy, safety, and tolerability 
of TDDs of 200 mg and 400 mg centanafadine SR compared to placebo in adults with 
ADHD. A double-blind, randomized design will be used to minimize bias while 
collecting data and when interpreting the results. A single-blind placebo run-in will also 
be used to exclude likely placebo responders before randomization to minimize the 
impact of a placebo-effect on determining the efficacy of centanafadine SR on ADHD 
symptoms during the double-blind treatment period.
2.2
Dosing Rationale
In the current trial, centanafadine will be administered twice daily (BID) as multiple 
100 mg SR tablets to achieve TDDs of 200 mg or 400 mg.
In the phase 2 NVI-EB-1020-202 trial, centanafadine SR was initially administered at a
target dose of 800 mg/day. This dose was revised down to 600 mg/day given the 
incidence of gastrointestinal AEs and 3 reported cases of rash. After an additional 5 cases
of rash were reported at the revised maximal dose of 600 mg/day centanafadine SR, the 
dose was further reduced to 400 mg/day. The primary endpoint, ADHD-RS-IV total 
score, was met in subjects that received 400 mg TDD centanafadine compared to those 
that received placebo (p < 0.001). Given the separation of 400 mg centanafadine from 
placebo, and the positive benefit/risk profile, it was concluded that the maximum 
tolerated dose is 400 mg/day. A TDD of 400 mg centanafadine will be included in this 
trial to further confirm the efficacy, safety, and tolerability of the previously-established 
maximum tolerated dose.
During the NVI-EB-1020-202 trial, subjects that received 100 to 200 mg/day while 
titrating up to the maximum dose of centanafadine exhibited a statistically significant 
separation from placebo at Day 7 (p < 0.001), suggesting a TDD of 200 mg centanafadine 
may also be effective for the treatment of ADHD symptoms. A TDD of 200 mg 
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centanafadine will be included in this trial to further explore the efficacy, safety, and 
tolerability of a minimum effective dose of centanafadine.
Please refer to the IB for additional information about the IMP.25
2.3
Trial Objectives
Primary:
To confirm the efficacy of centanafadine SR tablets administered BID
(200 mg or 400 mg TDDs) compared to placebo in the treatment of adults 
with ADHD
Secondary:
To confirm the safety and tolerability of centanafadine SR tablets 
administered BID (200 mg or 400 mg TDDs) compared to placebo in the 
treatment of adults with ADHD
3
Trial Design
3.1
Type/Design of Trial
This trial is a phase 3, randomized, double-blind, multicenter, placebo-controlled, 
parallel-group trial to confirm the efficacy, safety, and tolerability of centanafadine SR 
(200 mg TDD or 400 mg TDD) compared to placebo for the treatment of adults with 
ADHD. The trial population will include male and female subjects 18 to 55 years of age 
(inclusive) with a current diagnosis of ADHD as confirmed by the Adult ADHD Clinical 
Diagnostic Scale (ACDS) Version 1.2 at screening.
The trial will have 4 periods: (1) screening and washout; (2) 1 week single-blind placebo 
run-in; (3) 6-week double blind treatment; and (4) 7-day follow-up period (follow-up 
telephone calls at 1, 3, and 5 days after the last dose of IMP, and in-clinic visits 2 and 
7 days after the last dose of IMP) for subjects who complete the trial, and decide to enroll
in Trial 405-201-00015. For subjects who terminate early, decide to not enroll in 
Trial 405-201-00015, or who are not eligible to enroll in Trial 405-201-00015, they will 
be required to participate in the 7-day follow-up period as well as participate in an 
additional follow-up telephone call 10 days after the last dose of IMP. Subjects 
randomized to receive a TDD of 200 mg centanafadine SR will start at their target dose at 
the start of the double-blind treatment period. Subjects randomized to receive a TDD of 
400 mg centanafadine SR will start the double-blind treatment period at the TDD of 
200 mg centanafadine SR for 7 days, before they are escalated to their target TDD of 
400 mg for a total of approximately 42 days of treatment. Subjects will be required to 
visit the site up to 12 times over the trial. See Figure 3.1-1 for a schematic of the trial 
design.
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Subjects who complete both the 6-week double-blind treatment period and the 7-day 
safety follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of 
IMP, and in-clinic visits 2 and 7 days after the last dose of IMP), and refrain from using 
prohibited medications (Section 4.1) after the IMP is stopped may be eligible to enroll 
into Trial 405-201-00015, which is a 12-month, observational, open-label trial to evaluate 
the long-term safety and tolerability of subjects with ADHD who previously participated 
in Trials 405-201-00013 or 405-201-00014. Subjects who terminate early, decide to not 
enroll in Trial 405-201-00015, or who are not eligible to enroll in Trial 405-201-00015, 
will be required to participate in the 7-day follow-up period as well as participate in an 
additional follow-up telephone call 10 days after the last dose of IMP. For subjects who 
early terminate or decline participation in the open-label trial, they will be instructed to 
refrain from utilizing prohibited concomitant medications (Section 4.1), including ADHD 
treatments, until after the follow-up telephone call 10 days after the last dose of IMP.
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Figure 3.1-1
Trial Design Schematic
ASRS = Adult ADHD Self Report Scale; CTN SR = centanafadine sustained release; ET = early termination; P = placebo administration; R = randomization.
aAll subjects will be required to participate in the 7-day follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of IMP, and in-clinic 
follow-up visits at 2 and 7 days after the last dose of IMP). Subjects who terminate early, decide to not enroll in Trial 405-201-00015, or who are not 
eligible to enroll in Trial 405-201-00015, will be required to participate in an additional follow-up telephone call 10 days after the last dose of IMP.
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3.2
Trial Treatments
3.2.1
Single-blind Placebo Run-in Period
All subjects will begin BID dosing with single-blind matching placebo on Visit 2 
(Day −7) and continue through Visit 3 (baseline) (Section 3.7.1.2). Two tablets of 
matching placebo should be taken orally in the morning followed by an additional 
2 tablets 4 to 6 hours later. The morning and subsequent dose of matching placebo should 
be taken at approximately the same time each day. All subjects must be unaware of the 
single-blind placebo run-in period so that it is indistinguishable from the double-blind 
treatment period.
3.2.2
Double-blind Treatment Period
Trial assignments for the double-blind treatment period will be made once eligibility is 
confirmed. Eligible subjects will be randomized in a 1:1:1 ratio at baseline (Visit 3) to 
one of the following 3 treatment groups:

Centanafadine SR 200 mg TDD

Centanafadine SR 400 mg TDD

Matching placebo
Neither the investigator nor the subject will be aware of the treatment assignment after 
randomization. All doses of centanafadine SR and matching placebo should be taken 
orally BID and can be administered without regard to meals, and should be taken at 
approximately the same time each day, with the first dose taken in the morning. The 
second dose should be taken 4 to 6 hours after the morning dose is administered.
Subjects randomized to receive the target TDD of 200 mg centanafadine SR will start at 
the target dose on Day 1 of the double-blind treatment period and remain at that dose for 
the duration of the trial (Table 3.2.2-1). Subjects randomized to receive a TDD of 400 mg 
centanafadine SR will receive a TDD of 200 mg centanafadine SR on Day 1 of the 
double-blind treatment period for 7 days before they are escalated to their target TDD of 
400 mg on Day 8 for the duration of the trial (Table 3.2.2-1).
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Table 3.2.2-1
Dosing Schedule for Centanafadine SR Tablets
Total Daily Dose
Day(s)
Time
200 mg Target
400 mg Target
1 
through 
7
2 tablets orally in 
morning
1 × 100 mg + 1 × PBO tablet
1 × 100 mg + 1 × PBO tablet
2 tablets orally 4-6 hr 
later
1 × 100 mg + 1 × PBO tablet
1 × 100 mg + 1 × PBO tablet
8 and
thereafter
2 tablets orally in 
morning
1 × 100 mg + 1 × PBO tablet
2 ×100 mg
2 tablets orally 4-6 hr 
later
1 × 100 mg + 1 × PBO tablet
2 ×100 mg
PBO = placebo.
For subjects randomized to placebo, they will take 2 placebo tablets in the morning and 
2 tablets in the afternoon for the duration of treatment.
Once the subject is at the target dose, further dose modification is not permitted. Dose 
modification is not allowed at any time during the trial.
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
A total of up to 1150 male and female subjects with current diagnosis ADHD and 
between the ages of 18 and 55 years, inclusive, are planned to be screened in order to 
randomize approximately 450 subjects to yield 292+ completers.
Subjects must meet the DSM Fifth Edition (DSM-5) criteria for ADHD (including 
predominantly inattentive presentation, hyperactive presentation, or combined 
presentation) as confirmed by the ACDS Version 1.2. To confirm that ADHD is the 
primary diagnosis, the Mini International Neuropsychiatric Interview (MINI) will be used 
to identify and exclude other psychiatric conditions which would preclude enrollment.
Subjects who are not receiving any pharmacological treatment for ADHD must have an 
Adult ADHD Investigator Symptom Rating Scale (AISRS) score of ≥28 at screening and 
baseline. Subjects who are receiving pharmacological treatment for ADHD at screening 
must have a minimum AISRS score of ≥ 22 at screening, and a score of ≥ 28 at baseline 
(Section 3.4.2). Subjects must washout of their current ADHD therapy, if applicable, and 
any prohibited medications prior to baseline (Table 4.1-1).
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3.3.2
Subject Selection and Numbering
At screening, subjects will be assigned a unique subject identification (ID) number upon 
signing the electronic informed consent form (eICF) based on sequential enrollment in 
the trial. Subjects will be assigned a randomization number upon randomization 
(Section 3.6.1), at the baseline visit (Day −1). The clinical site will maintain a list 
identifying all subjects by their subject ID number and initials.
3.4
Eligibility Criteria
3.4.1
Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The eICF will be approved by the 
same institutional review board (IRB) that approves this protocol.
Each eICF will comply with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline26 and local regulatory requirements. The investigator 
will ensure that the sponsor reviews and authorizes any site-specific eICF used in the trial 
prior to submission to the IRB.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Prospective trial participants will be provided with controlled access to the eICF 
application by trial site staff. When the trial site staff and the participant agree that the 
participant has enough information to make an informed decision to participate, the 
participant will electronically sign in the eICF application and an electronic date and 
timestamp will be applied to the signature. The subject will be given a printed, signed 
copy of the eICF. Any other parties required by the IRB (trial site staff, witnesses, or 
legally authorized representative) are also required to sign electronically and these 
signatures will be stored with the eICF in accordance with the ICH GCP Guideline and 
local regulatory requirements/guidelines. These signatures cannot be altered, removed, or 
copied.
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Subjects may be asked to sign additional eICFs if the protocol is amended and the 
changes to the protocol result in additional information that needs to be provided to the 
subjects, so that they can make a knowledgeable and voluntary decision on continued 
trial participation.
3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1 Inclusion Criteria
Screening
1.
Subjects with a current primary DSM-5 diagnosis of ADHD (including predominantly inattentive 
presentation, hyperactive presentation, or combined presentations) as confirmed by the ACDS
Version 1.2.
2.
Subjects who are not receiving any pharmacological treatment for ADHD must have an AISRS 
score of ≥ 28 at screening. Subjects who are receiving pharmacological treatment for ADHD at 
screening must have a minimum AISRS score of ≥ 22 at screening.
3.
Subject is 18 to 55 years of age, inclusive, at the time of consent.
4.
Subject has a BMI of 18 to 40, inclusive.
5.
Subject is able to swallow multiple tablets.
6.
Subject is willing and able to comply with all testing and requirements as defined in this protocol.
7.
Subject is able to provide electronic informed consent to participate in the trial in accordance with 
the ICH GCP Guidance E6 and applicable regulations before completing any trial-related 
procedures.
8.
Subject is willing to discontinue all prohibited psychotropic medications (Section 4) starting from 
the time of signing the informed consent and up to the 7-day follow-up period. Subjects that do not 
rollover into Trial 405-201-00015 must be willing to discontinue all prohibited psychotropic 
medications starting from the time of signing the informed consent until after the follow-up 
telephone call 10 days after the last dose of IMP.
9.
Subject is able to read English or Spanish well enough to understand the nature of the trial and to 
read and understand the written word in order to complete subject-reported outcome measures and 
be able to communicate effectively to be reliably rated on assessment scales; must be able and 
agree to comply with all protocol requirements, including the prescribed dosage regimens, 
discontinuation of prohibited medications, and report for regularly scheduled office visits.
Inclusion Criteria Assessed at Baseline
10.
Subjects who were not receiving any pharmacological treatment for ADHD at screening must have 
an AISRS score of ≥ 28 at baseline. Subjects who were receiving pharmacological treatment for 
ADHD at screening must also have a minimum AISRS score of ≥ 28 at baseline.
11.
Subject must have a CGI-S score of ≥ 4 (≥ moderate impairment) at baseline.
BMI = body mass index; CGI-S = Clinical Global Impression-Severity of Illness Scale.
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3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1 Exclusion Criteria
Screening
1.
Females who are breast-feeding or who have a positive pregnancy test result prior to receiving 
IMP.
2.
Sexually active males or FOCBP who do not agree to practice 2 different methods of birth 
control or remain abstinent during the course of the trial and for 30 days after the last dose of 
IMP for female subjects, and 90 days after the last dose of IMP for male subjects and their 
partners who are FOCBP. Unless the subject is sterile (ie, women who have had a bilateral 
oophorectomy or hysterectomy or who have been postmenopausal for at least 12 consecutive 
months; or men who have had a bilateral orchidectomy) or remains abstinent, 2 of the following 
precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, 
birth control pills, birth control injection, birth control implant, birth control patch, condom with 
spermicide, or sponge with spermicide. Male subjects who do not agree to refrain from donating 
sperm from screening through 90 days after the last dose of IMP.
3.
Subject has a DSM-5 diagnosis of Other Specified or Unspecified Attention 
Deficit/Hyperactivity Disorder.
4.
Subject has initiated, changed, or discontinued receiving psychological (eg, supportive 
psychotherapy, cognitive behavior therapy, interpersonal therapy) interventions for ADHD 
within the 60 days before the screening visit, or are anticipated to start new treatment during the 
trial. Subjects who are receiving psychotherapy that was initiated > 60 days before the screening 
visit will be allowed to continue to receive their psychotherapy during the trial only if they agree 
to not make any changes in the frequency or nature of their psychotherapy during the course of 
this trial.
5.
Subject has a lifetime history of electroconvulsive therapy, or a lifetime history of vagal nerve 
stimulation or deep brain stimulation for the treatment of depression.
6.
Subject has a current comorbid psychiatric disorder that either could be expected to require 
treatment with medications prohibited in this trial, or to confound efficacy or safety assessments. 
Examples include, but are not limited to, psychotic disorder (current or lifetime), bipolar 
disorder (current or lifetime), generalized anxiety disorder, obsessive-compulsive disorder, panic 
disorder, a current major depressive episode, or posttraumatic stress disorder, as established by 
the MINI.
7.
Subjects with a clinically significant current DSM-5 diagnosis of borderline, antisocial, 
paranoid, schizoid, schizotypal, histrionic, narcissistic, avoidant, or dependent personality 
disorders.
8.
Subjects who meet criteria for C-SSRS Suicidal Ideation Items 4 or 5 within the last 6 months 
prior to screening or subjects who meet criteria for any of the 5 C-SSRS Suicidal Behavior Items 
(actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose 
most recent episode meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items 
occurred within the last 2 years prior to screening,
OR
Subjects who, in the opinion of the investigator, present a serious risk of suicide.
9.
Subject has any medical or psychological condition(s) or state(s) that in the investigator’s 
opinion would prohibit the subject from completing the trial or would go against the subject’s 
best interest with his/her participation in the trial. This would include any significant illness or 
unstable medical condition that could lead to difficulty complying with the protocol. This would 
also include most bariatric surgeries, with the only exception being those where there has been 
no breach of the gastrointestinal wall (ie, uncomplicated lap band surgery) AND no sign of 
malabsorption.
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Table 3.4.3-1 Exclusion Criteria
10.
Subject has a history of epilepsy, seizures (other than infantile febrile seizures), syncope, 
Tourette’s Disorder, serious neurological disease, history of significant head trauma with 
clinically significant loss of consciousness, dementia, cerebrovascular disease, Parkinson’s 
disease, or intracranial lesions.
11.
Subject has a life-time history of a pattern of abuse or diversion of stimulants.
12.
Subject has any current or suspected drug or alcohol use disorder. Subject has met the DSM-5 
criteria for a substance use disorder in the past 6 months. Nicotine use disorder is not 
exclusionary.
13.
Subjects that have a positive alcohol test (via breathalyzer or blood), a positive drug screen for 
cocaine, or other illicit drugs (excluding marijuana). Subjects with a positive drug screen for 
confirmed prescription or OTC use of ADHD medications at screening will be required to 
undergo a washout period (Section 4).
NOTE: Subjects that test positive for marijuana may be permitted to be enrolled if they have no 
evidence of a substance use disorder, and if they agree to refrain from use for the duration of the 
trial. Allowance for subjects testing positive for marijuana at screening require explicit approval 
from the medical monitor.
14.
Subjects with a known intellectual disability or clinical evidence of intellectual disability based 
on the opinion of the investigator.
15.
Subjects with insulin-dependent diabetes mellitus are excluded. Subjects with 
non-insulin-dependent diabetes mellitus may be eligible for the trial if their condition is stable as 
determined by satisfying ALL of the following criteria:

Screening glucose (non-fasting) < 200 mg/dL. (If the non-fasting glucose is ≥200 mg/dL, 
subjects must be retested in the fasting state. Fasting glucose must be ≤125 mg/dL.),

Subject has been maintained on a stable regimen of oral anti-diabetic medication(s) for at 
least 28 days prior to screening or diabetes has been well-controlled by diet for at least 
28 days prior to screening,

Subject has not had any hospitalizations within the 12 months prior to screening due to 
diabetes or complications related to diabetes, AND

Subject’s diabetes is not newly diagnosed during screening for the trial.
16.
Subjects presenting with, or having a history of, uncontrolled hypertension (systolic blood 
pressure > 140 mmHg or diastolic blood pressure > 90 mmHg) or symptomatic hypotension, or 
orthostatic hypotension which is defined as a decrease of ≥30 mmHg in systolic blood pressure
or a decrease of ≥ 20 mmHg in diastolic blood pressure after at least 3 minutes standing 
compared with the previous supine blood pressure, OR development of symptoms.
17.
Subjects with known ischemic heart disease or history of myocardial infarction, congestive heart 
failure (whether controlled or uncontrolled), angioplasty, stenting, coronary artery bypass 
surgery, or other serious cardiac problems that would place him/her at increased vulnerability to 
the sympathomimetic effects of a stimulant medication.
18.
The following laboratory test and ECG results are exclusionary:
1) Platelets ≤ 75,000/mm3
2) Hemoglobin ≤ 9 g/dL
3) Neutrophils, absolute ≤ 1000/mm3
4) AST > 2 × upper limit of normal
5) ALT > 2 × upper limit of normal
6) Creatinine ≥ 2 mg/dL
7) HbA1c ≥ 7%
8) QTcF or QTcB > 450 msec for males or > 470 msec for females
NOTE: In addition, subjects should be excluded if they have any other abnormal laboratory tests, 
vital sign results, or ECG findings which in the investigator’s judgment are medically significant 
and that would impact the safety of the subject or the interpretation of the trial results. Tests with 
abnormal results should be repeated to ensure reproducibility of the abnormality before 
excluding a subject based on the criteria noted above.
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Table 3.4.3-1 Exclusion Criteria
19.
Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with 
medications for at least the past 90 days) or an abnormal result for free T4 at screening (free T4 
is measured only if result for TSH is abnormal).
20.
Subjects receiving any of the prohibited medications within the specified period prior to the start 
of the single-blind placebo run-in period, or who would be likely to require prohibited 
concomitant therapy during the trial (Section 4).
21.
Subject has a history of prior exposure to centanafadine.
22.
Subject has a history of dermatologic adverse reactions secondary to any drug exposure or 
anaphylaxis (or some type of systemic allergic reaction) to any substance.
23.
Subject has participated in a clinical trial involving either an investigational medication or a 
non-medication intervention within the last 60 days prior to screening or has participated in more 
than 2 clinical trials involving either an investigational medication or non-medication 
intervention within the past year.
24.
Subject has previously been randomized in this trial and subsequently withdrawn. 
25.
In the opinion of the investigator, subject has not derived significant therapeutic benefit from 2 
or more ADHD therapies of 2 different classes (eg, amphetamine and methylphenidate, or 
amphetamine and atomoxetine) given with an acceptable dose and duration during adulthood 
(aged 18 or older).
NOTE: If subject has not derived significant therapeutic benefit due to an inability to tolerate 
side effects, eligibility can be discussed on case-by-case basis with the medical monitor.
26.
Any subject who, in the opinion of the investigator, should not participate in the trial.
27.
Subjects with HIV seropositive status/acquired immunodeficiency syndrome, seropositive status 
for hepatitis B (ie, HBsAg positive), or hepatitis C (ie, anti-HCV positive and HCV RNA 
positive).
Exclusion Criteria Assessed Prior to Start of the Single-blind Placebo Run-in
28.
Subjects who have a positive alcohol test (via breathalyzer or blood), a positive drug screen 
assessed prior to Visit 2 for cocaine, other illicit drugs (including marijuana), or prescription or 
OTC ADHD medications will be screen failed. This includes medications such as opioids or 
benzodiazepines taken without prescription.
29.
Subjects with a ≥ 30% improvement in the (18 item) ADHD Symptoms score of the ASRS 
compared to the score at screening will be screen failed, and not eligible for rescreening.
Exclusion Criteria Assessed at Baseline
30.
Subjects who have a positive alcohol test (via breathalyzer or blood), a positive drug screen 
assessed prior to the baseline visit for cocaine, other illicit drugs (including marijuana), or 
prescription or OTC ADHD medications will be early terminated. This includes medications 
such as opioids or benzodiazepines taken without prescription.
31.
Subjects with a ≥ 30% improvement in the (18 item) ADHD Symptoms score of the ASRS 
compared to the score at the start of single-blind placebo run-in will be early terminated.
32.
In the opinion of the investigator, the subject is unable to adhere to the treatment regimen or 
other requirements outlined in the protocol.
ALT = alanine aminotransferase; anti-HCV = hepatitis C antibodies; ASRS = Adult ADHD Self Report 
Scale; AST = aspartate aminotransferase; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; FOCBP = females of childbearing potential; HbA1c = glycosylated 
hemoglobin; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; OTC = over-the-counter; QTcB = QT interval corrected for heart rate by the 
Bazett formula; QTcF = QT interval corrected for heart rate by the Fridericia formula; RNA = 
ribonucleic acid; T4 = thyroxine; TSH = thyroid-stimulating hormone.
Please refer to Section 3.9 for details regarding screen failures.
Subjects must agree to restrictions to medications and lifestyle as described in Section 4.
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3.5
Endpoints
3.5.1
Primary Endpoint
3.5.1.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline at Day 42 in the AISRS total 
score.
3.5.2
Secondary Endpoints
3.5.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is change from baseline at Day 42 on the Clinical 
Global Impression-Severity of Illness Scale (CGI-S).
3.5.2.2
Other Efficacy Endpoints

Change from baseline in AISRS total score for every scheduled visit;

Change from baseline in the Inattentive subscale and Hyperactivity-Impulsive 
subscale scores of the AISRS for every scheduled visit;

Change from baseline in CGI-S score for every scheduled visit;

Clinical Global Impression (CGI) Change from Baseline score at each scheduled 
visit;

Percentage of responders at each post-baseline visit, where a responder is defined as a 
subject with a CGI Change from Baseline score of 1 or 2 OR a ≥ 30% improvement 
in ADHD symptoms compared with baseline as measured by the AISRS total score;
3.5.3
Exploratory Endpoints
The exploratory endpoints are the change from baseline to Day 28 and Day 42 in the 
ADHD Impact Module - Adult (AIM-A) and the Adult ADHD Self Report Scale (ASRS)
total score and subscale scores.
3.5.4
Safety Endpoints
Standard safety variables will include AEs (including evaluations for rash, an AE of 
special interest [AESI]), clinical laboratory tests (hematology, serum chemistry, and 
urinalysis), physical examinations, vital sign measurements, electrocardiograms (ECGs), 
assessments of withdrawal (Study Medication Withdrawal Questionnaire [SMWQ]), and 
suicidality (Columbia-Suicide Severity Rating Scale [C-SSRS]).
Abuse-related AEs and AEs involving medication irregularities will be recorded verbatim 
on source documentation with detailed narratives (see Section 5.5).
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3.6
Measures to Minimize/Avoid Bias
3.6.1
Randomization
During the trial, administration of the IMP will be double-blind. In other words, neither 
the investigator nor the subject will have knowledge of the treatment assignment 
(eg, centanafadine SR 200 mg, 400 mg, or placebo). Treatment assignments will be based 
on a computer-generated randomization code provided by the Otsuka Pharmaceutical 
Development & Commercialization, Inc (OPDC) Biometrics Department. Sponsor 
personnel, including those involved in monitoring, data management, and data analysis, 
will not have access to the treatment code during the trial. The bioanalytical laboratory 
will also be sent the randomization code. Access to the treatment codes will be restricted 
to personnel charged with generating and maintaining randomization files, packaging 
trial medication, operating electronic case report form (eCRF), and reporting SAEs to 
regulatory agencies. The randomization will be stratified by trial site and designed to 
allocate subjects in a 1:1:1 ratio to centanafadine SR 200 mg/day or 400 mg/day or 
placebo.
3.7
Trial Procedures
The time from enrollment of the first subject to the last subject’s last trial visit will be 
approximately 12 months. Individual participation for subjects who complete the trial 
will be approximately 12 weeks, consisting of a 28-day screening and washout period, a 
1-week single-blind placebo run-in period, a baseline day, a 6-week double-blind 
treatment period, and a 7-day follow-up period (follow-up telephone calls at 1, 3, and 
5 days after the last dose of IMP, and in-clinic visits 2 and 7 days after the last dose of 
IMP). For subjects who terminate early, decide to not enroll in Trial 405-201-00015, or 
who are not eligible to enroll in Trial 405-201-00015, they will be required to participate 
in the 7-day follow-up period as well as participate in an additional follow-up telephone 
call 10 days after the last dose of IMP.
When Trial 405-201-00014 reaches its conclusion, all subjects participating in the trial, 
regardless of trial period, may be eligible to enroll into Trial 405-201-00015, which is a 
12-month, observational, open-label trial (Section 3.1). All subjects will be required to 
comply with the appropriate follow-up procedures described in Section 3.7.1.5 and 
Section 3.7.1.6. 
Trial assessment time points are summarized in Table 3.7-1 and Table 3.7-2.
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Table 3.7-1
Schedule of Assessments - Screening Through End of Treatment
Period
Screeninga
PBO
Run-inb
Double-blind Treatment
NOTES
Days
−35 to −8
Day
−7
Baseline
Day
−1
Day
7
+1
Day
Day
14
±2
Days
Day
21
±2
Days
Day
28
±2
Days
Day
35
±2
Days
Day
42/ET
±2
Days
Visit
1
2
3
4
5
6
7
8
9
ENTRANCE/HISTORY
Informed consent
X
Section 3.4.1
Inclusion/exclusion criteria
X
X
X
Section 3.4
Demography
X
Concomitant medication(s)
X
X
X
X
X
X
X
X
X
Medical history
X
X
X
ACDS
X
Identification of comorbidities using 
MINI
X
Psychiatric evaluation
X
HIV/HBsAg/anti-HCV
X
Section 3.7.5.2
Randomization
X
Section 3.6.1
Urine pregnancy test
X
X
X
X
X
X
X
X
X
Section 3.7.5.2
Section 5.7
EFFICACY
AISRS
X
X
X
X
X
X
X
X
X
Section 3.7.2.1
CGI-S
X
X
X
X
X
X
X
Section 3.7.2.2
CGI Change from Baseline
X
X
X
X
X
X
Section 3.7.2.3
SAFETY
Adverse events
X
X
X
X
X
X
X
X
X
Section 5.2
Physical examination
X
X
X
Section 3.7.5.3.1
Vital signs
X
X
X
X
X
X
X
X
X
Section 3.7.5.3.2
12-lead ECG
X
X
X
X
X
X
X
Section 3.7.5.4
Clinical laboratory tests
X
X
X
X
X
Section 3.7.5.2
SMWQ
X
X
Section 3.7.5.5.1
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Table 3.7-1
Schedule of Assessments - Screening Through End of Treatment
Period
Screeninga
PBO
Run-inb
Double-blind Treatment
NOTES
Days
−35 to −8
Day
−7
Baseline
Day
−1
Day
7
+1
Day
Day
14
±2
Days
Day
21
±2
Days
Day
28
±2
Days
Day
35
±2
Days
Day
42/ET
±2
Days
Visit
1
2
3
4
5
6
7
8
9
UDS/alcohol testing via breathalyzer or 
blood
X
X
X
X
X
X
X
X
X
Section 3.7.5.2
C-SSRS
X
X
X
X
X
X
X
X
X
Section 3.7.5.5.2
PHARMACOKINETIC/PHARMACOGENOMIC
PK blood sample
X
X
X
X
Section 3.7.6.1
Pharmacogenomic and FBR samples
X
Section 3.7.6.2
Section 3.7.6.3
EXPLORATORY
AIM-A
X
X
X
X
Section 3.7.3.1
ASRS
X
X
X
X
X
Section 3.7.3.4
OTHER
IMP/placebo dispensing
X
X
X
X
X
X
X
IMP/placebo return and accountability
X
X
X
X
X
X
X
Section 8.4
Section 3.12
anti-HCV = hepatitis C antibodies; FBR = future biospecimen research; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; 
UDS = urine drug screen.
aScreening will include a washout period that can range from 7 to 28 days
bSee Section 3.7.1.2
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Table 3.7-2
Schedule of Assessments - Follow-up
Period
Follow-upa
NOTES
1 (+1) day
after the last 
dose of IMP
2 (+1) 
days 
after 
the 
last 
dose of 
IMP
3 (+ 1) 
days 
after 
the last 
dose of 
IMP
5 (+ 1) 
days 
after 
the last 
dose of 
IMP
7 (+ 2) 
days after 
the last 
dose of 
IMP
10 (+ 2) 
days 
after the 
last dose 
of IMP
Visit
10
11
12
13
14
15
ENTRANCE/HISTORY
Concomitant medication(s)
X
X
X
X
X
X
EFFICACY
AISRS
X
X
Section 3.7.2.1
SAFETY
Adverse events
X
X
X
X
X
X
Section 5.2
Vital signs
X
X
Section 3.7.5.3.2
SMWQ
X
X
X
X
X
X
Section 3.7.5.5.1
UDS/alcohol testing via breathalyzer or blood
X
X
Section 3.7.5.2
C-SSRS
X
X
Section 3.7.5.5.2
PHARMACOKINETIC/PHARMACOGENOMIC
PK blood sample
X
Section 3.7.6.1
aAll subjects will be required to participate in the 7-day follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of IMP, and in-clinic 
follow-up visits at 2 and 7 days after the last dose of IMP). Subjects who terminate early, decide to not enroll in Trial 405-201-00015, or who are not 
eligible to enroll in Trial 405-201-00015, will be required to participate in an additional follow-up telephone call 10 days after the last dose of IMP.
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3.7.1
Schedule of Assessments
3.7.1.1
Visit 1 (Screening)
The screening period begins after consent is obtained and will take place between 
Day −35 and Day −8 prior to the initiation of the single-blind placebo run-in period. 
Completion of screening activities may require more than 1 visit. All procedures outlined 
for screening in the Schedule of Assessments (Table 3.7-1) will be performed. The 
following should also be noted:

The investigator or his/her designee must obtain informed consent from the subject 
prior to any trial-related procedures being performed.

A urine drug screen will be collected and sent to the central lab for evaluation. If 
subjects are taking disallowed medications and they are able to taper appropriately 
and safely, they will do so during the screening period. If medication taken is for 
ADHD, a minimum of 7 days off stimulants and 21 days off nonstimulants will be 
required before the single-blind placebo run-in period. A complete washout schedule, 
including common excluded medications and herbal preparations, is provided in 
Section 4.1. A subject who tested positive for any prohibited medications at the 
screening visit must have a repeat urine drug screen that is confirmed as negative 
prior to performing Visit 2.

An assessment of all inclusion and exclusion criteria will be made to determine the 
subject’s eligibility for the trial.

Medical and psychiatric history will be recorded, including the DSM-5 diagnosis of 
ADHD using the ACDS Version 1.2.

Subjects will be administered the ASRS.

A urine pregnancy test will be performed for all females of childbearing potential 
(FOCBP). If the urine pregnancy test is positive, the result should be confirmed with 
a serum pregnancy test. Subjects with a positive serum test result will be excluded 
from the trial.
External quality oversight methods will be used by Clinical Surveillance & Training 
(CST) to promote appropriate subject enrollment. Such methods will require sites to 
communicate certain aspects of subject data during the screening period to CST as 
detailed in the Operations Manual. Subjects cannot be randomized until approval from 
CST has been received. The investigator is responsible for ensuring that subjects are 
eligible for enrollment into the trial and for assessing subject safety throughout the trial.
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3.7.1.2
Visit 2 (Single-blind Placebo Run-in)
After the subject has completed the medication washout period (if applicable), the Visit 2 
(Day −7) assessments described in the Schedule of Assessments (Table 3.7-1) will be 
performed. The following should also be noted:

Urine drug screen results from the previous visit will be reviewed. If the subject is 
positive for any prohibited medications at screening (including medications for the 
treatment of ADHD, see Section 4.1), and has not had a negative repeat urine drug 
screen confirmed since, the subject will be screen failed.

Subjects will be administered the ASRS prior to the start of the single-blind placebo 
run-in period, and those with a ≥ 30% improvement in the (18-item) ADHD 
Symptoms score compared to the score at screening will be screen failed, and not 
eligible for rescreening.

All subjects must be unaware of the single-blind placebo run-in period so that it is 
indistinguishable from the double-blind treatment period. All subjects must be under 
the impression that they are starting to receive randomized treatment at the time of 
Visit 2 (Day −7).

Placebo will be dispensed for the single-blind placebo run-in period, and subjects will 
be instructed to take their first dose from the dosing card in the clinic. Subjects will 
be instructed to take their doses at approximately the same time every day.

The subject will download the AiCure Platform (Section 3.12) or receive a 
provisioned device with the AiCure Platform predownloaded, and will be trained on 
IMP compliance using this application.

Subjects who discontinue the trial during the single-blind placebo run-in period 
should be considered early termination subjects, and should proceed with the early 
termination visit (Section 3.7.1.4.2) and follow-up procedures (Section 3.7.1.5 and 
Section 3.7.1.6).
3.7.1.3
Visit 3 (Baseline)
After the subject has completed the single-blind placebo run-in period, the Visit 3 
(Day −1) assessments described in the Schedule of Assessments (Table 3.7-1) will be 
completed.
The following should also be noted:

Urine drug screen results from the previous visit will be reviewed. If the subject is 
positive for any prohibited medications (including medications for the treatment of 
ADHD, see Section 4.1), the subject will be early terminated, and the procedures 
outlined in Section 3.7.1.4.2 will be completed.

Subjects will be administered the ASRS, and those with a ≥ 30% improvement in the 
(18-item) ADHD Symptoms score compared to the score at the start of single-blind 
placebo run-in will be early terminated.
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
Subjects who do not meet eligibility (see Exclusion Criteria #30, #31, and #32) at the 
baseline visit are considered early termination subjects, and should proceed with the 
early termination visit (Section 3.7.1.4.2) and follow-up procedures (Section 3.7.1.5
and Section 3.7.1.6).

Dosing cards from the single-blind run-in period will be returned; accountability and 
compliance will be verified.

Blood samples for genotyping and for future biospecimen research (FBR) will be 
collected.

Subjects entering the double-blind treatment period will be randomized (1:1:1) to 
receive centanafadine SR 200 mg TDD, 400 mg TDD, or placebo.

Subjects will receive a dosing card for dosing on Days 1 to 7, and will be instructed to 
start dosing from the new card on the following day (Day 1), and to take their doses at 
approximately the same time every day.
3.7.1.4
Double-Blind Treatment Period
3.7.1.4.1
Visits 4 through 8
The assessments described for Visits 4 through 8 (Days 7-35) in the Schedule of 
Assessments (Table 3.7-1) will be completed. The following should also be noted:

Urine drug screen results from the previous visit will be reviewed. If the subject is 
positive for any prohibited medications (including medications for the treatment of 
ADHD, see Section 4.1), the subject will be early terminated, and the procedures 
outlined in Section 3.7.1.4.2 will be completed.

At each visit dosing cards from the prior week will be returned; accountability and 
compliance will be verified.

Sparse PK samples will be collected at Visits 4 (Day 7), 5 (Day 14), and 7 (Day 28).

Subjects will receive a dosing card for dosing at each visit for the next week, and will 
be instructed to start dosing from the new card on the following day, and to take their 
doses at approximately the same time every day.
3.7.1.4.2
Visit 9/End of Treatment/Early Termination
The assessments described for Visit 9 (Day 42/early termination [ET]) in the Schedule of 
Assessments (Table 3.7-1) will be completed. If a subject discontinues early before 
Day 42, procedures noted for Day 42 must be completed at the ET visit. Attempts should 
be made to complete ALL evaluations, particularly efficacy assessments (ie, AISRS, CGI 
Change from Baseline, CGI-S, ASRS, and AIM-A), for the Day 42/ET visit prior to the 
administration of any new ADHD medications. However, if the subject receives a new 
ADHD medication or has a urine drug screen positive for any new ADHD medication 
prior to the conduct of ET procedures, no efficacy assessments should be performed.
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The following should also be noted:

Urine drug screen results from the previous visit will be reviewed. If the subject is 
positive for any new ADHD medication, no efficacy assessments should be 
conducted.

Subjects will return their dosing card from the prior week, accountability, and 
compliance will be verified.

Sparse PK sample will be collected.

For all subjects who complete the trial (Section 3.10) and are considering entry into 
the open-label rollover trial, they will be instructed to refrain from utilizing prohibited 
concomitant medications (Section 4.1), including ADHD treatments, during the 7-day 
safety follow-up period. For subjects who early terminate or decline participation in 
the open-label trial, they will be instructed to refrain from utilizing prohibited 
concomitant medications (Section 4.1), including ADHD treatments, until after the 
follow-up telephone call 10 days after the last dose of IMP.

For subjects who early terminate or decline participation in the open-label trial, future 
treatment options will be discussed, and subjects will complete follow-up visits and 
procedures described in Section 3.7.1.5 and Section 3.7.1.6.
3.7.1.5
Visits 10 Through 14 (Follow-up)
All subjects, whether they complete the trial or are withdrawn prematurely for any 
reason, will be followed up for a safety evaluation for 7 days (follow-up telephone calls 
at 1, 3, and 5 days after the last dose of IMP, and in-clinic visits 2 and 7 days after the last 
dose of IMP). The assessments described in the Follow-up Schedule of Assessments 
(Table 3.7-2) will be completed. The following should also be noted:
Subjects who complete both the 6-week double-blind treatment period, the 7-day
follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of IMP, 
and in-clinic visits 2 and 7 days after the last dose of IMP), and who refrain from using 
prohibited medications (Section 4.1) after the IMP is stopped, may be eligible to enroll 
into Trial 405-201-00015, which is a 12-month, observational, open-label trial to evaluate 
the long-term safety and tolerability of subjects with ADHD who previously participated 
in Trials 405-201-00013 or 405-201-00014. For subjects who early terminate or decline 
participation in the open-label trial, they will be instructed to refrain from utilizing 
prohibited concomitant medications (Section 4.1), including ADHD treatments, until 
after the follow-up telephone call 10 days after the last dose of IMP (Section 3.7.1.6).
Subjects who will be rolling over into the open-label trial will need to sign the 
Trial 405-201-00015 informed consent form prior to activities performed at the 7-day 
follow-up visit of Trial 405-201-00014.
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3.7.1.6
Visit 15 (Follow-up)
Subjects who terminate early, decide to not enroll in Trial 405-201-00015, or who are not 
eligible to enroll in Trial 405-201-00015, will be required to participate in an additional 
follow-up via telephone call 10 days after the last dose of IMP. For subjects who early 
terminate or decline participation in the open-label trial, they will be instructed to refrain 
from utilizing prohibited concomitant medications (Section 4.1), including ADHD 
treatments, until after the follow-up telephone call 10 days after the last dose of IMP. The 
assessments described in the Follow-up Schedule of Assessments (Table 3.7-2) will be 
completed.
3.7.2
Efficacy Assessments
It is required that adequately trained and experienced clinicians administer the ACDS, 
MINI, AISRS, CGI-S, and CGI Change from Baseline. All individuals performing these 
assessments must be pre-approved by the sponsor or designee.
3.7.2.1
Adult Attention-deficit/Hyperactivity Disorder Investigator 
Symptom Rating Scale
The AISRS is a modified version of the ADHD Rating Scale that reflects the impact and 
severity of ADHD among adults, and will be administered as described in the Schedule 
of Assessments (Table 3.7-1 and Table 3.7-2). It is a clinician-administered scale that 
measures the 18 symptoms of adult ADHD using a Likert scale: 0 (none); 1 (mild); 
2 (moderate); and 3 (severe), and uses a semi-structured interview methodology with 
suggested prompts for each item to improve interrater reliability. The scale's 18 items 
directly correspond to the 18 DSM-5 symptoms of ADHD where 9 inattentive items 
alternate with 9 hyperactive impulsive items. The maximum total score for the scale is 
54 points, with 27 points for each subscale. The total score is the sum of both the 
Inattentive and Hyperactive Impulsive subscales.27
3.7.2.2
Clinical Global Impression-Severity of Illness Scale - Modified 
for Attention-deficit/Hyperactivity Disorder
The CGI-S modified (Table 3.7-1) is an observer-rated scale that will be used to measure 
symptom severity.28 To perform this assessment, the investigator or rater will respond to 
the following question: “Considering your total clinical experience with adult ADHD, 
how mentally ill is the patient at this time?” Response choices include: 1 = normal, not at 
all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 
6 = severely ill; and 7 = among the most extremely ill patients.29
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3.7.2.3
Clinical Global Impression Change from Baseline
The CGI Change from Baseline (Table 3.7-1) is an observer-rated scale that will be used 
to measure the subject's total improvement compared to before trial drug treatment was 
initiated.28 The rater or investigator will rate the subject’s total improvement relative to 
baseline. Response choices include: 1 = very much improved, 2 = much improved, 
3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 
7 = very much worse.29
3.7.3
Other Assessments
3.7.3.1
Mini International Neuropsychiatric Interview
The MINI30,31,32 will be conducted as outlined in the Schedule of Assessments 
(Table 3.7-1) to rule out exclusionary comorbid psychiatric diagnoses. Detailed 
instructions for administration of this structured interview will be provided.
3.7.3.2
Adult ADHD Clinical Diagnostic Scale
The ACDS Version 1.2 (Table 3.7-1) is a clinician-administered, semistructured 
interview assessment used to establish the presence of current adult symptoms of ADHD, 
with suggested age-specific prompts for rating both childhood and adult symptoms. The 
ACDS includes a retrospective assessment of all childhood ADHD symptoms as well as 
an assessment of recent (last 6 months) adult ADHD symptoms that includes 9 criterion 
symptoms of inattention, 9 criterion symptoms of hyperactivity and impulsivity, and 
14 non-DSM symptoms believed to be relevant to adult ADHD.33
3.7.3.3
Attention-deficit/Hyperactivity Disorder Impact Module - Adult
The AIM-A (Table 3.7-1) is a subject self-report questionnaire which assesses quality of 
life in adults with ADHD. The questionnaire has 4 global quality of life items, 
5 economic impact items, and 5 multi-item scales that assess the following key concepts: 
Living with ADHD, General Well-Being, Work, Home and School Performance and 
Daily Functioning. Additionally, Relationships and Communication, and Impact of 
Symptoms are also included.34
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3.7.3.4
Adult Attention-deficit/Hyperactivity Disorder Self-Report Scale, 
Expanded Version
The ASRS Version 1.1, (Table 3.7-1) is a self-report questionnaire developed by the
WHO. The subject will answer 31 questions. Of those 31, 18 of the questions pertain to 
the 18 DSM-5 ADHD symptoms (ADHD Symptoms). The expanded version includes 
9 additional items that assess Executive Function Deficits, and 4 items that assess 
Emotional Dyscontrol.35
3.7.4
Prior and Concomitant Medications
The investigator will record all medications and therapies taken by the subject from 
30 days prior to signing of informed consent through the end of the evaluation period 
(defined as the time period during which subjects are evaluated for primary and 
secondary objectives) on the eCRF. Details of prohibited and restricted medications are 
provided in Section 4.1. The investigator will record all medications and therapies taken 
by the subject for treatment of an AE or which caused an AE until the end of the trial 
(defined as the last date of contact or date of final contact attempt) on the eCRF.
3.7.5
Safety Assessments
3.7.5.1
Adverse Events
Refer to Section 5.
3.7.5.2
Clinical Laboratory Assessments
A central laboratory designated by the sponsor will be used for all laboratory testing 
required during the trial. The central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow up, if needed). In cases where an 
immediate result is required for a particular laboratory test, the sample should be divided 
and sent to both a local laboratory and the designated central laboratory. Urine will be 
collected and blood will be drawn from each subject during screening prior to treatment 
with the IMP. Subjects should be fasting for a minimum of 8 hours prior to the blood 
draws, if possible. If fasting blood samples are not feasible at screening, nonfasting blood 
samples may be obtained initially for determining eligibility for the trial. If a fasting 
blood sample was obtained at the screening visit and less than 14 days have elapsed since 
the screening visit, clinical laboratory tests (hematology, serum chemistry, and urinalysis) 
do not need to be repeated at the baseline visit. The results of these tests must be 
reviewed by the investigator prior to initiation of the administration of the IMP. Clinical 
laboratory tests at other visits should be drawn fasting, if possible, but must be drawn 
after a minimum 8-hour fast at Day 42/ET. All blood collections must occur after the 
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administration of efficacy assessments and safety assessments (eg, AE monitoring, 
physical examination, vital sign measurements, ECGs, medication withdrawal scales, and 
suicidality) at any given visit. See exclusion criteria (Section 3.4.3) based on screening 
laboratory tests. Additional urine and blood samples may be collected for further 
evaluation of safety as warranted by the investigator’s judgment. Reports from the central 
laboratory will be retained electronically within the laboratory vendor's online portal and 
assessed by the investigator or qualified designee for clinical significance within the 
eCRF.
Table 3.7.5.2-1
Clinical Laboratory Assessments
Hematology:
Hematocrit
Hemoglobin
Mean corpuscular hemoglobin concentration
Mean corpuscular hemoglobin
Mean corpuscular volume
Platelet count
RBC count
WBC count with differential
Urinalysis:
Color
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Microscopic analysis, WBC/RBC counts per high 
powered field
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Urine Drug Screen
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Marijuana
Methadone
Methylphenidate (ritalinic acid)
Opiates
Phencyclidine
Propoxyphene
Other
Alcohol testing via breathalyzer or blood
Serum Chemistry:
Albumin
Alkaline phosphatase
ALT
AST
Bicarbonate
Bilirubin, total 
Blood urea nitrogen
Calcium
Cholesterol (total, HDL, LDL)
Chloride
CPK
Creatinine
Gamma glutamyl transferase 
Glucose
Magnesium
Potassium
Phosphorus
Protein, total 
Sodium
Triglycerides
Uric acid
Additional Tests:
Urine pregnancy (FOCBP), serum test will 
confirm positive urine test results
PT and INR (screening, baseline, and Day 42/ET)
CPK reflex for isoenzymes if CPK > 3 × ULN; 
serum and urine myogloblin collected if 
CPK > 5 × ULN
Additional Tests (Screening Only)
HBsAg
Anti-HCV
HIV
TSH, with reflex to free T4 if TSH is abnormal
HbA1c
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CPK = creatine phosphokinase; HDL = high-density lipoprotein; INR = international normalized ratio; 
LDL = low-density lipoprotein; PT = prothrombin time; RBC = red blood cell; ULN = upper limit of 
normal; WBC = white blood cell.
The total volume of blood to be collected during the trial will be documented in the eICF.
Any value outside the normal range will be flagged for the attention of the investigator 
who must indicate whether or not a flagged value is of clinical significance. If one or 
more values are questionable, the test(s) may be repeated. If the result of any test (or 
repeat test, if done) is indicated as clinically significant in the samples taken during the 
screening period, the subject will NOT be enrolled into the trial without the permission of 
the medical monitor. In addition, unscheduled laboratory tests should be performed if 
clinically significant abnormalities are observed. Unscheduled laboratory tests may be 
repeated at any time at the discretion of the investigator for appropriate medical care. 
Refer to Appendix 2 for criteria for identifying values of potential clinical relevance.
A pregnancy test will be conducted in all FOCBP prior to trial intervention; results must 
be available prior to the administration of the IMP. All positive urine pregnancy test 
results must be confirmed by a serum test. Subjects with a positive serum pregnancy test 
result at screening must not be enrolled. Subjects with a positive serum pregnancy test 
result during the trial must discontinue treatment and be withdrawn from the trial. 
Pregnancy tests will be performed in FOCBP at each visit during the trial. An additional 
pregnancy test will be conducted in FOCBP at the Day 42/ET visit.
3.7.5.3
Physical Examination and Vital Signs
3.7.5.3.1
Physical Examination
A complete physical examination will be performed at screening, and a targeted physical 
examination to address any new concerns will be performed at all other visits indicated in 
the Schedule of Assessments (Table 3.7-1). A complete physical examination will 
include height (screening only), weight, waist circumference, and calculation of body 
mass index (BMI) (screening and Day 42/ET only); and assessment of the head, eyes, 
ears, nose, throat, thorax, abdomen, urogenital, skin and mucosae, neurological, and 
extremities. Examinations with abnormal results that are deemed clinically significant 
should be repeated to ensure reproducibility of the abnormality. Any abnormalities 
considered by the investigator to be clinically significant are to be recorded as AEs on the 
AE eCRF.
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3.7.5.3.2
Vital Signs
Vital signs including systolic blood pressure and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature will be measured at the time points described in 
the Schedule of Assessments (Table 3.7-1 and Table 3.7-2). Blood pressure and heart rate 
measurements will be made in the supine and standing positions after the subject has 
been in each position for at least 3 minutes. The supine measurements will be performed 
first followed by the standing measurements. Temperature and respiratory rate will be 
taken with the subject in the supine position.
Subjects should be monitored for potentially clinically significant vital signs values 
(Appendix 3). Abnormal results that are deemed clinically significant should be repeated 
to ensure reproducibility of the abnormality. Any abnormalities considered by the 
investigator to be clinically significant are to be recorded as AEs on the AE eCRF
(Section 5.2).
3.7.5.4
Electrocardiogram Assessments
The 12-lead ECGs will be performed in the supine position at the time points described in 
the Schedule of Assessments (Table 3.7-1).
Subjects should be monitored for potentially clinically significant ECG results 
(Appendix 4). Tests with abnormal results that are deemed clinically significant should 
be repeated to ensure reproducibility of the abnormality. Any abnormalities considered 
by the investigator to be clinically significant are to be recorded as AEs on the AE eCRF.
3.7.5.5
Other Safety Assessments
3.7.5.5.1
Study Medication Withdrawal Questionnaire
The SMWQ is a questionnaire to assess withdrawal symptoms that will be completed as 
described in the Schedule of Assessments (Table 3.7-1 and Table 3.7-2). The SMWQ is a 
modification of the Amphetamine Withdrawal Questionnaire in which the terms 
“amphetamines and methamphetamine” are replaced with the term “the study 
medication.”36,37,38 At the site, the subject will complete the SMWQ, and on non-site 
days, subjects will complete the SMWQ remotely.
3.7.5.5.2
Columbia-Suicide Severity Rating Scale
Suicidality will be monitored during the trial (Table 3.7-1 and Table 3.7-2) using the 
C-SSRS.39 The C-SSRS is a semi-structured interview that captures the occurrence, 
severity, and frequency of suicide-related thoughts and behaviors during the assessment 
period.39 The interview includes definitions and suggested questions to solicit the type of 
information needed to determine if a suicide-related thought or behavior has occurred. 
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The interview and rating for the C-SSRS must be completed by a licensed clinician who 
has been successfully trained to rate this scale by the sponsor or a designee, and is 
medically responsible for the subject. Documentation of trial training should be 
maintained in the investigational site’s files.
The C-SSRS has a “Screening/Baseline” version, which will be completed at screening 
and a ”Since Last Visit” version that will be completed at all other visits (including the 
ET visit, if applicable). There are a maximum of 19 items to be completed: 7 required, 
10 potential additional items if there is a positive response to a required item, and 2 items 
for suicide/suicide behavior present during the interview. The C-SSRS uses dichotomous 
scales (ie, yes or no), Likert scales, and text or narrative to further describe the thoughts 
or behaviors.
3.7.6
Pharmacokinetic and Pharmacogenomic Assessments
All blood collections must occur after the administration of efficacy assessments and 
safety assessments (eg, AE monitoring, physical examination, vital sign measurements, 
ECGs, medication withdrawal scales, and suicidality) at any given visit.
3.7.6.1
Pharmacokinetic Assessments
3.7.6.1.1
Pharmacokinetic Blood Samples
Five sparse PK samples will be taken for determination of concentrations of 
centanafadine and metabolite(s) in plasma. Blood samples will be collected by trial 
centers that have appropriate facilities. A 2-mL sample will be collected at the time 
points presented in the Schedule of Assessments (Table 3.7-1). Samples collected at 
Day 14 and Day 42/ET should be taken concurrently with the serum chemistry sample. 
The actual date and time of the PK sample collection must be recorded on the eCRF. The 
exact timing of sampling relative to previous dose is not critical and can vary as much as 
is operationally practical. Preferentially, 3 of the 4 PK samples taken during the treatment 
period per subject should be taken as follows:

At least 1 sample should be taken prior to the first morning dose (trough 
concentration) at either Day 7, Day 14, or Day 28

At least 1 sample should be taken at least 1 hour after the morning dose

At least 1 sample should be taken after the afternoon dose
All plasma samples will be shipped to the central laboratory. Detailed handling and 
shipping instructions are in Appendix 1.
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3.7.6.2
DNA Blood Samples for Pharmacogenomic Testing
A blood sample will be collected at the time point presented in the Schedule of 
Assessments (Table 3.7-1) in order to extract deoxyribonucleic acid (DNA) and 
determine the genotypes related to drug metabolizing enzymes and transporters to 
determine the genotypes of genes related to absorption, distribution, metabolism, and 
excretion. Genotypes and estimated phenotypes may be included as part of a population 
PK analysis to be reported separately. All samples will be shipped to the central 
laboratory. Detailed handling and shipping instructions are provided in Appendix 1.
3.7.6.3
Future Biospecimen Research
A blood sample will be collected at the time point presented in the Schedule of 
Assessments (Table 3.7-1) only from those subjects that provided consent for FBR 
sample collection. Research performed on this sample may include genetic analyses 
(DNA), gene expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics or 
the measurement of other analytes. Such research is for biomarker testing to address 
emergent questions not described elsewhere in the protocol (as part of the main trial) and 
will only be conducted on specimens from appropriately consented subjects. The 
objective of collecting specimens for future biomedical research is to explore and identify 
biomarkers that inform the scientific understanding of diseases and their therapeutic 
treatments. Processing, storage, and shipping instructions for FBR samples are provided 
in Appendix 1.
3.7.7
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the post-treatment follow-up eCRF page for the last subject completing or 
withdrawing from the trial.
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3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial or Treatment Arm(s)
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, IRBs, and regulatory authorities in accordance with regulatory 
requirements. Subjects who remain in the trial when the trial reaches its conclusion may 
be eligible to enter an open-label rollover trial (Trial 405-201-00015) if they meet all of 
the inclusion/exclusion criteria for that trial.
3.8.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB if judged to be necessary for medical, safety, regulatory, ethical or other reasons 
consistent with applicable laws, regulations, and GCP. The investigator will notify the 
sponsor promptly if the trial is terminated by the investigator or the IRB at the site.
3.8.3
Individual Subject Discontinuation
3.8.3.1
Treatment Discontinuation
After randomization, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible as described in 
Section 3.8.3.4. Refer to Table 3.7-2 for a description of follow-up procedures.
A urine drug screen will be collected and sent to the central lab at the time points 
described Table 3.7-1 and Table 3.7-2. At the start of the single-blind placebo run-in 
period through the Day 42/ET visit, if the subject is tests positive for any prohibited 
medications (including medications for the treatment of ADHD, see Section 4.1), the 
subject will be early terminated, and the procedures outlined in Section 3.7.1.4.2 will be 
completed.
At the baseline visit only, if subjects have a ≥ 30% improvement in the ASRS (18 item) 
ADHD Symptoms score compared to the score at the start of the single-blind placebo 
run-in, they will be early terminated.
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3.8.3.2
Documenting Reasons for Treatment Discontinuation
A subject may discontinue IMP for a number of reasons including those listed below:

Reasons related to AE:

Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard

Continuing IMP places the subject at undue risk as determined by the investigator 
(eg, a safety concern that is possibly, probably, or likely related to IMP)

SAE

Death

Reasons unrelated to medical condition (provide detail and review AE history with 
subject)

Withdrawal of informed consent (complete written withdrawal of consent form)

Lost to follow-up

Rash (regardless of severity or seriousness) (see Section 5.4)

Pregnancy (see Section 5.7)

Termination of all or part of the trial by the sponsor

Lack of efficacy (LOE)
Subjects withdrawn prior to Day 42 must complete the Day 42/ET evaluations at the time 
of withdrawal. In addition, all subjects who withdraw prematurely from the trial will be 
assessed by telephone 1, 3, and 5 days after the last dose of IMP, in the clinic 2 and 
7 days after the last dose of the IMP, and 10 days via telephone after the last dose of the 
IMP. Three attempts will be made to contact the subject by telephone; in the event the 
site is unable to reach the subject by telephone, the site will attempt to contact the subject 
via certified mail or an alternative similar method where appropriate.
Meeting a screening exclusion criterion post-randomization does not require an automatic 
discontinuation of the subject. The investigator should assess the change for clinical 
significance, determine if an AE should be reported, and make a determination of subject 
continuation based on subject safety. The investigator will consult with the medical 
monitor to determine subject continuation in the trial.
If the subject discontinues IMP due to an AE, the investigator, or other trial personnel, 
will make every effort to follow the event until it has resolved or stabilized. Follow-up 
procedures in Section 5.9 must be followed.
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3.8.3.3
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow up (these methods of follow up will also be noted in the trial eICF):

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources).
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.8.3.1). A subject may, however, indicate that further trial participation is 
creating a burden on their work or social schedule. Therefore, the investigator should 
follow the procedures outlined in Section 3.8.3.4 to determine if the subject can continue 
participation in the trial if modifications to his/her treatment or schedule of assessments 
can be accommodated. Only subjects who withdraw their permission for all of the above 
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degrees of follow-up are considered to have completely withdrawn their consent to 
participate in the trial.
3.8.3.4
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
meet and discuss with the subject their options of continuing in the trial, preferably on 
therapy. The investigator should ensure understanding and documentation of the reasons 
for the subject’s desire to withdraw consent.
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an eICF), but who is not randomized or assigned 
to trial treatment.
For this trial, treatment begins with the first dose of the IMP in the single-blind placebo 
run-in period. Subjects that have a positive alcohol test (via breathalyzer or blood), or 
positive drug screen for cocaine, or other illicit drugs (excluding marijuana) are not 
eligible to be retested or rescreened, and will be considered screen failures. Subjects that 
test positive for marijuana may be permitted to be enrolled if they have no evidence of a 
substance use disorder, and if they agree to refrain from use for the duration of the trial. 
Allowance for subjects testing positive for marijuana at screening require explicit 
approval from the medical monitor. Subjects that test positive for confirmed prescription 
use of ADHD medications at screening will be required to undergo a washout period 
(Section 4.1). If after the allotted washout period, a subject tests positive for ADHD 
medications prior to the start of the single blind placebo run-in period, subjects will be 
screen failed, and not permitted to rescreen. Screen failures previously excluded for a 
positive urine drug screen due to use of prescription or over-the-counter (OTC) 
medications or products not used for the treatment of ADHD, may be retested or 
rescreened for participation in the trial only with the explicit consent of the medical 
monitor. Subjects will be administered the ASRS prior to the start of the single-blind 
placebo run-in period, and those with a ≥ 30% improvement in the (18-item) ADHD 
Symptoms score compared to the score at screening will be screen failed, and not eligible 
for rescreening. Screen failures excluded for any other reasons may be rescreened at any 
time if the exclusion characteristic has changed. In the event that a screen failure is 
rescreened a new eICF must be signed, a new screening number assigned, and all 
screening procedures repeated.
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3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and secondary objectives of the trial irrespective of whether or not the subject 
actually consumed all doses of the IMP. Subjects who are evaluated at the last scheduled 
visit during the treatment period will be defined as trial completers. For purposes of this 
trial, subjects who complete the Day 42/ET visit will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Day 42/ET during the treatment period, 
who do not have a known reason for discontinuation (eg, withdrew consent or AE), and 
for whom a survival status at the end of the trial cannot be determined will be classified 
as “lost to follow-up” as the reason for discontinuation. Survival status can be determined 
from a variety of sources, either by obtaining acceptable documentation for death (ie, 
death certificate, medical records, public records, statement by a family member or 
primary care physician) or acceptable documentation for life (ie, direct contact with the 
subject, medical records, successful telephone contact with the subject, statement by a 
family member or primary care physician, or public records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
3.12
Subject Compliance
Responsible trial personnel will dispense the IMP according to the visits outlined in the 
Schedule of Assessments (Table 3.7-1). Accountability and compliance verification will 
be monitored with a medication adherence monitoring platform, and results should be 
documented in the subject’s trial records. Subjects must be counseled on the importance 
of taking the IMP as directed at all trial visits. If poor compliance continues (eg, multiple 
missed doses resulting in less than 80% overall compliance), discontinuation of the 
subject from the trial should be considered.
Details on the AiCure technology to be used in this trial to assess IMP compliance are 
provided below.
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3.12.1
AiCure Investigational Medicinal Product Adherence and 
Reminder System
This trial will employ an IMP adherence monitoring platform (“AiCure Platform”) for all 
subjects in the trial. The AiCure Platform uses artificial intelligence on smartphones to 
confirm IMP ingestion. In addition, built-in reminders and a communication system 
allow real time intervention in case of IMP interruptions.
Use of this AiCure Platform will in no way supersede or replace the physician or 
prescribed IMP protocol of the subjects. Because the AiCure Platform does not change 
the IMP protocol of the subjects, but rather encourages adherence to the predefined 
protocol, use of this AiCure Platform presents minimal risk to the subjects. Use of the 
AiCure Platform will be required for all subjects in the trial.
The monitoring AiCure Platform requires that all subjects take each dose of the IMP 
while using a smartphone. The AiCure Platform will be provided to subjects preloaded on 
a smartphone, or subjects will download the AiCure Platform onto their own mobile 
device at the start of the single-blind placebo run-in period (Day −7).
When at home, subjects will receive an IMP reminder at a time within a predefined 
window. This notification reminds subjects to take their IMP dose while using the AiCure 
Platform. Subjects will follow a series of prescribed steps in front of the front facing 
webcam to visually confirm their ingestion of the IMP. The application on the 
smartphone will make an automated determination of whether the subject has properly 
taken their IMP at the prescribed time. There is no need for the trial site staff to review 
the administration, nor would the trial site staff need to be available at the time the 
subject takes their IMP. The amount of guidance that the device provides to the subjects 
is automatically reduced as the subject becomes more proficient at using the application.
After the device confirms proper IMP ingestion, video recordings will be encrypted and 
transmitted to a secure centralized location for further analysis, including testing for 
duplicate enrollment. The captured data and video are reviewable through a roles and 
rules restricted system ensuring privacy of the information. The system is compliant with 
the Health Insurance Portability and Accountability Act (HIPAA), which protects the 
privacy and security of healthcare information.
Phone numbers of the subjects may also be collected and stored in an encrypted manner. 
Storing the phone numbers will allow for direct communication with subjects, including 
automated messaging from the AiCure Platform device and contact by the trial site staff 
or other monitoring personnel. At no time is the phone number visible to the trial site 
staff or monitoring personnel on the AiCure Platform. Individuals outside the trial site 
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will not be provided with subject names, nor will they be given access to subject medical 
records.
3.12.2
AiCure Subject Risk
The AiCure Platform provides no more than minimal risk to subjects. This protocol only 
introduces a smartphone-based monitoring application that prompts the user to take their 
IMP, verifies ingestion, and stores encrypted data securely for analysis. When 
functioning properly, use of the AiCure Platform does not affect titration, dosage, route 
of administration, or treatment duration, conforming to any trial requirements as noted by 
trial site staff. 
It is possible, though very unlikely, that the AiCure application can fail to remind 
subjects to take the IMP or tell them to take their IMP when not required. To date, 
AiCure has not encountered such a malfunction.
All trial data, including any identifiable subject information, will be obtained and 
encrypted by the application. Subjects will be coded according to the protocol and their 
identity will not be stored with the trial data obtained. After the subject has taken the IMP 
and confirmation of proper ingestion has been completed, the encrypted data will be 
automatically forwarded to a secure server. The server is compliant with the HIPAA, 
which protects the privacy and security of healthcare information. The data will be 
securely stored and only accessible to the trial site staff and other authorized personnel 
through two-way authentication.
The data may also be retained in a secure manner beyond the term of the trial and utilized 
to improve the operation of the AiCure Platform, categorize adherence activity by disease 
state or other useful categories, or for regulatory filings by the AiCure Platform Provider 
to support future applications for the AiCure Platform Provider’s product. Individuals 
who are not associated with the care and treatment of subjects will not have access to 
subject identity or any medical records.
3.12.3
AiCure Subject Confidentiality
The AiCure Platform Provider will protect subjects’ personal information to the full 
extent required by law. However, information from this trial, including de-identified 
video recording(s) of subject performance of various actions, may be submitted to the 
trial site, and potentially to the FDA. Both information obtained by the application, and 
information in the subject Informed Consent, may be examined by the trial site or the trial 
site’s representatives, and may also be reviewed by the FDA and other regulatory 
agencies, IRBs, or Ethics Committee(s). All of these parties are bound to safeguard the 
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rights, safety, and well-being of all clinical trial subjects, and to maintain all information 
in confidence, with special consideration given to trials that may include vulnerable 
subjects.
The results of this trial may be presented at meetings or in publications; however, specific 
subjects will not be identified by name in these presentations or publications. Information 
from this trial may also be retained by the AiCure Platform Provider for the purpose of 
improving the AiCure Platform, to allow for future analysis of various facial and other 
parameters, the reporting of high level statistical analysis of the AiCure Platform, to 
improve the internal workings of the system running on the smartphone device, or for 
regulatory filings by the AiCure Platform Provider to support future applications for the 
Provider’s product.
3.13
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria), the investigator or designee will contact the sponsor or 
designee at the earliest possible time by telephone. The investigator and sponsor will 
come as quickly as possible to a joint decision regarding the subject’s continuation in the 
trial. This decision will be documented by the investigator and the sponsor, and reviewed 
by the site monitor.
4
Restrictions
4.1
Prohibited Medications
Subjects who are currently taking any therapy for ADHD at screening will washout from 
their current ADHD therapy (see Table 4.1-1) before the start of the single-blind placebo 
run-in period (Day −7). All subjects must agree to discontinue all prohibited medications 
during the screening period. Table 4.1-1 provides the required duration of washout for 
selected prohibited medications. All other prohibited medications must be discontinued at 
least 24 hours before Day −7.
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Table 4.1-1
List of Medications Prohibited Before the Trial
Medication
Required Washout Prior to Start of 
Placebo Run-in Period
1.
Antidepressants
Fluoxetine
All other antidepressants
28 days
14 days
2.
Benzodiazepines
7 days
3.
Hypnotics, including non-benzodiazepine sleep aids
7 days
4.
ADHD medications
Stimulants
Nonstimulants
7 days
21 days
5.
Sedating antihistamines (eg, diphenhydramine, 
hydroxyzine, chlorpheniramine)
7 days
6.
Antihypertensives
Clonidine
Propranolol
Guanfacine
21 days
7.
Anorexics (weight loss supplements)
7 days
8.
Investigational compounds
7 days
Table 4.1-2 lists all medications prohibited during the trial, including exceptions, where 
appropriate.
Table 4.1-2
List of Medications Prohibited During the Trial
1.
All psychotropic agents including, but not limited to, the following:
a) Antipsychotics, including depot formulations
b) Anticonvulsants
c) Antidepressants
d) Mood stabilizers (ie, lithium)
e) Benzodiazepinesa
f)
Hypnotics
g) All medications intended for the treatment or management of ADHD symptoms (on or off 
label use), including but not limited to any form of: amphetamine (mixed salts), atomoxetine, 
clonidine, dexmethylphenidate, guanfacine, lisdexamfetamine, and methylphenidate
h) Opioid analgesics, unless permission is obtained from the medical monitor. Permission for 
opioid use may be considered for a documented and clinically appropriate indication (eg, 
episodic pain condition, tooth extraction) if prescribed at a medically appropriate dose and 
frequency.
i)
Nutritional supplements and non-prescription herbal preparations with central nervous 
system effects (eg, St. John’s Wort, omega-3 fatty acids, melatonin, kava extracts, GABA 
supplements, etc)
j)
Sedating antihistamines (eg, diphenhydramine, hydroxyzine, chlorpheniramine)
2.
Investigational agents
3.
Barbiturates, except for the treatment of migraine headaches, provided that in the opinion of the 
investigator the dosing is medically appropriate.
4.
The following antihypertensive medications: propranolol, clonidine, guanfacine
5.
Varenicline or similar medications, excluding nicotine replacement products
6.
Anorexics (weight loss supplements)
aNon-benzodiazepine sleep aids (ie, zolpidem, zaleplon, zopiclone, and eszopiclone only) are permitted 
for the treatment of insomnia AEs.
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4.2
Other Restrictions
4.2.1
Restricted Therapies and Precautions
St. John’s Wort (Hypericum perforatum) is prohibited for 14 days prior to IMP 
administration and during the trial. Investigators should inform subjects that normal 
consumption of caffeine is permitted.
The subject’s best medical interests should guide the investigator in the management of 
conditions that are pre-existing or that develop during the trial (intercurrent illness or 
AEs). The investigator should examine the acceptability of all concomitant medications 
not explicitly prohibited. In order to ensure that appropriate concomitant therapy is 
administered, it is essential that subjects be instructed not to take any medications (either 
self-administered non-prescription drugs or prescription therapy prescribed by another 
physician) without prior consultation with the investigator. All trial personnel should be 
familiar with the content of the centanafadine IB in order to manage the subject’s 
condition adequately and select appropriate concomitant medications, if needed.
4.2.2
Non-therapy Precautions and Restrictions
4.2.2.1
Precautions
Subjects should not undergo any elective medical procedure without prior consultation 
with the investigator. An elective procedure (minor surgery, dental surgery, orthopedic 
surgery, etc) that might require hospitalization or general anesthesia should be deferred 
until after the trial whenever clinically appropriate.
4.2.2.2
Restrictions
Subjects may only receive psychotherapy for ADHD (eg, supportive psychotherapy, 
cognitive behavior therapy, interpersonal therapy) if they have been participating in the 
therapy regularly (ie, at consistent intervals) for at least 60 days prior to screening and 
commit to maintain their participation during the course of the trial with no changes 
unless permission is obtained from the medical monitor.
Subjects will be instructed to refrain from drinking alcoholic beverages or using illicit 
drugs (including marijuana) during participation in the trial. The investigator may request 
a blood or urine drug screen at any time during the trial if there is a suspicion of illicit 
drug use.
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5
Reporting of Adverse Events
5.1
Definitions
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. Adverse events would not include information recorded 
as medical history at screening for preplanned procedures for which the underlying 
condition was known and no worsening occurred. An adverse reaction is any untoward 
and unintended response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of Investigational New Drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the IMP and the AE. Suspected adverse reaction implies a lesser degree of certainty about 
causality.
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred. It does not include an event that, had it 
occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions.

Requires in-patient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.

Congenital anomaly/birth defect.

Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse.
Nonserious adverse events are all AEs that do not meet the criteria for a "serious" AE.
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Immediately Reportable Event (IRE):

Any SAE.

Any AESI (see Section 5.4).

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 5.6).

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be documented on the AE eCRF if there is an 
abnormality or complication.
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available. This review will be 
documented by the investigator’s dated signature on the laboratory report. For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject. This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed. The investigator may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests. If this laboratory value is 
considered medically relevant by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, or fulfills a seriousness criterion, this is considered an AE.
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF. The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE.
Not Related: 
There is no temporal or causal relationship between the IMP and 
the AE.
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5.2
Eliciting and Reporting Adverse Events
The investigator will periodically assess subjects for the occurrence of AEs. To avoid 
bias in eliciting AEs, subjects should be asked the non-leading question: “How have you 
felt since your last visit?” All AEs (serious and nonserious) reported by the subject must 
be recorded on the source documents and eCRF provided by the sponsor. Serious AE
collection is to begin after a subject has signed the eICF.
Use medical terminology in AE reporting. Adverse events should be reported as a single 
unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, as 
individual signs or symptoms. Exacerbation or disease progression should be reported as 
an AE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined below, in Section 5.3. Special attention should 
be paid to recording hospitalization and concomitant medications.
5.3
Immediately Reportable Events
The investigator must immediately report after either the investigator or site personnel 
become aware of any SAE, AE related to occupational exposure, AESI, potential serious 
hepatotoxicity, or confirmed pregnancy, by telephone, fax, or e-mail to the sponsor or 
designee using the contact information on the cover page of this protocol. An IRE form 
must be completed and sent by e-mail, fax, or overnight courier to the sponsor or 
designee. (Please note that the IRE form is NOT the AE eCRF.)
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal or have otherwise been 
explained. It is expected that the investigator will provide or arrange appropriate 
supportive care for the subject and will provide prompt updates on the subject’s status to 
the sponsor or designee.
5.4
Adverse Events of Special Interest
Newly acquired skin eruptions that are non-traumatic will be considered AESIs. These 
may include, but are not limited to eruptions such as skin rashes, skin irritations, skin 
reactions, or acneiform lesions. This does not include localized contact irritation at ECG 
lead sites due to application or removal of lead adhesive.
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Refer to the separate rash workup plan for complete details, including reporting forms, 
and extra measures that must be performed to characterize any skin AESI of a newly 
acquired skin eruption that is non-traumatic. The trial site will have a local designated 
dermatologist available for immediate consultation during the trial for these AESIs.
All AESIs should be reported as IREs (Section 5.3).
5.5
Abuse Potential Monitoring Plan, Events Subject to Additional 
Monitoring, and Medication Handling Irregularities
A key objective of the Abuse Potential Monitoring Plan (APMP) is to monitor for 
instances of abuse or diversion of the trial medication and other psychoactive substances. 
In addition to monitoring for irregularities in medication handling, AEs that may be 
suggestive of a developing abuse issue will also receive special attention. As part of the 
APMP, medication handling irregularities (MHIs) must be reported, and AEs related to 
abuse potential and AEs involving MHIs must be reported as Events Subject to 
Additional Monitoring (ESAMs) with detailed narratives. 
Investigators and site staff at each trial site will be trained on reporting potentially abuse-
related AEs (eg, recording a description of the event in the subject’s own words in the 
source documents as well as the eCRF, in addition to the clinical term, and to be aware 
that a subject’s report may encompass more than one event and that these should be 
recorded separately). The investigators will be provided with examples of potentially 
abuse-related AEs, and trained on how to handle such events (eg, additional monitoring). 
While the investigators will be provided with examples of AE terms as a guide during 
trial conduct, the analysis of potentially abuse-related AEs will be based on a search of all 
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, all verbatim 
terms, and any open text fields within the AE data to identify text strings suggestive of 
abuse potential, in line with the 2017 FDA guidance (Assessment of Abuse Potential of 
Drugs).40 Refer to the separate APMP documentation for complete details on MHIs and 
ESAMs, including documenting and reporting procedures, examples of potentially abuse-
related AE terms that meet the criteria for ESAM reporting, and guidance for the training 
of investigators and trial site staff.
5.6
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) that is 3 times the upper limit of normal (ULN), a total 
bilirubin level should also be evaluated. If the total bilirubin is 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the eCRF.
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5.7
Pregnancy
Females of childbearing potential are defined as female subjects for whom menstruation 
has started and who are not documented as sterile (ie, have had a bilateral oophorectomy 
or hysterectomy or who have been postmenopausal for at least 12 consecutive months).
For FOCBP and for males who are sexually active, there must be a documented 
agreement that the subject and their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
30 days after the last dose of IMP for female subjects, and 90 days after the last dose of 
IMP for male subjects and their partners who are FOCBP. Unless the subject is sterile (ie, 
women who have had a bilateral oophorectomy or hysterectomy or who have been 
postmenopausal for at least 12 consecutive months; or men who have had a bilateral 
orchidectomy) or remains abstinent, 2 of the following precautions must be used: 
vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pills, birth 
control injection, birth control implant, birth control patch, condom with spermicide, or 
sponge with spermicide. Any single method of birth control, including vasectomy and 
tubal ligation, may fail, leading to pregnancy. The contraceptive method will be 
documented at each trial visit. Male subjects must also agree not to donate sperm from 
screening through 90 days after the last dose of IMP.
Before enrolling FOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all FOCBP. The topics should generally include:

General information

Informed consent form

Pregnancy prevention information

Drug interactions with hormonal contraceptives

Contraceptives in current use

Guidelines for the follow-up of a reported pregnancy
Before trial enrollment, FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form stating that the 
abovementioned risk factors and the consequences were discussed with her.
A urine or serum pregnancy test for human chorionic gonadotropin will be performed at 
screening on all subjects that are FOCBP. If a urine test is performed and is positive, the 
investigator will follow up with a confirmatory serum test.
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During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial.
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure during the trial and for 30 days after the last dose of IMP for female 
subjects, and for 90 days after the last dose of IMP for partners of male subjects, and 
record the event on the IRE form and forward it to the sponsor. The sponsor will forward 
Pregnancy Surveillance Form(s) for monitoring the outcome of the pregnancy.
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the 
investigator must report to the sponsor, on appropriate Pregnancy Surveillance Form(s), 
follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants will be followed for a minimum of 6 months from the date of 
birth.
5.8
Procedure for Breaking the Blind
The investigator is encouraged to contact the sponsor/clinical research organization 
(CRO) medical monitor to discuss their rationale for unblinding. However, to prevent 
delays to the investigator or medical personnel responding to a potentially emergent 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical advisor (ie, the investigator will be able to 
obtain the code break information independent of the sponsor/CRO medical advisor). The 
investigator must contact the sponsor/CRO medical advisor by telephone or e-mail with 
an explanation of the need for opening the treatment assignment code within 24 hours of 
opening the code. If the blind is broken, the Clinical Safety and Pharmacovigilance 
department must be notified immediately (see the cover page of this protocol for contact 
information). Documentation of breaking the blind should be recorded in the subject’s 
medical record with the date and time the blind was broken and the names of the 
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personnel involved. Once the blind is broken for a subject, that subject may not reinitiate 
treatment with the IMP.
5.9
Follow-up of Adverse Events
5.9.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing on the eCRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as 
risk-related behavior, family history and occupation).
5.9.2
Follow-up of Serious Adverse Events and Immediately 
Reportable Events
This trial requires that subjects that complete the trial be actively monitored for SAEs and 
IREs up to 7 days after the last dose of IMP is administered. Subjects that decide to not 
enroll in Trial 405-201-00015, or for subjects that do not complete Trial 405-201-00014, 
will be actively monitored for SAEs and IREs up to 10 days after the last dose of IMP is 
administered.
Serious AEs and nonserious IREs that are identified or ongoing at the last scheduled 
contact must be recorded as such on the AE eCRF page. If updated information (eg, 
resolved status) on SAE or IRE status becomes available after a subject’s last scheduled 
contact (up to last in-clinic visit for the entire trial), this must be reported to the sponsor 
according to the appropriate reporting procedures. The investigator will follow SAEs 
until the events are resolved, stabilized, or the subject is lost to follow-up or has died. 
Resolution means that the subject has returned to the baseline state of health and 
stabilized means that the investigator does not expect any further improvement or 
worsening of the subject’s condition. The investigator will continue to report any 
significant follow-up information to the sponsor up to the point the event has resolved or 
stabilized, or the subject is lost to follow-up, or has died.
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5.9.3
Follow-up and Reporting of Serious Adverse Events and 
Immediately Reportable Events Occurring after Last Scheduled 
Contact
Any new SAEs or IREs reported to the investigator which occur after the last scheduled 
contact and are determined by the investigator to be reasonably associated with the use 
of the IMP, should be reported to the sponsor. This may include SAEs or IREs that are 
captured on follow-up telephone contact or at any other time point after the defined trial 
period. The investigator should follow SAEs or IREs identified after the defined trial 
period and continue to report any significant follow-up information to the sponsor until 
the events are resolved or stabilized, or the subject is lost to follow-up or has died.
6
Pharmacokinetic/pharmacogenomic Analysis
The PK samples will be analyzed for centanafadine (EB-1020) and its metabolite(s)
concentrations. Times postdose will be determined from the date and time of first pill 
captured by AiCure for the dose prior to the PK sample and the sampling date and time 
captured in the eCRF; for the sample taken 7 days after the last dose of IMP (Day 49 for 
completers), the date and time of the first pill from last dose taken (on Day 42 for 
completers) will be used as the date and time of the dose prior to the sample. No formal 
statistical comparisons are planned. A separate population or PK/pharmacogenomic 
modeling may be performed using the data from this trial and other trials.
7
Statistical Analysis
7.1
Sample Size
The primary efficacy endpoint is the change from baseline at Day 42 in AISRS total 
score. The trial will compare the placebo arm to the centanafadine dose arms, randomized 
at a ratio of 1:1:1, with an overall alpha of 0.05 for the primary endpoint.
Based on the results at various dose strengths from phase 2 centanafadine trials, it is 
reasonable to expect a treatment difference of 5 points with a standard deviation (SD) of 
12.5 in the mean change from baseline to Day 42 on AISRS total score in either the 
200 mg TDD or 400 mg TDD arms. The planned sample size of 405 evaluable subjects 
(135 in each treatment arm) will yield at least 90% power to detect the treatment effects 
at a 2-tailed significance level of 0.05. The 2-sided alpha level for the final analysis is 
0.05.
A sufficient number of subjects will be enrolled and randomized to achieve 
approximately 405 evaluable subjects in the double-blind treatment period (ie, subjects 
with an AISRS total score at baseline and at least 1 subsequent AISRS total score in the 
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double-blind treatment period). After allowance of 10% nonevaluable subjects in the 
double-blind treatment period, the total number of subjects to be randomized is 
450 subjects (150 subjects in each treatment arm). In order to ensure 405 evaluable 
subjects, the number of nonevaluable subjects will be monitored in a blinded manner on 
an ongoing basis during the trial. The power and sample size were obtained using the 
PASS 14 (2015) statistical computing software.
7.1.1
Datasets for Analysis
The following samples are defined for this trial:

Enrolled Sample: comprises all subjects who signed an eICF for the trial and enrolled 
into the single-blind placebo run-in period

Randomized Sample: comprises of all subjects who were randomized in the 
double-blind treatment period. Subjects are considered randomized when they are 
assigned a treatment group by eCRF at the end of the single-blind placebo run-in 
period. A subject receiving IMP outside of the eCRF will not be considered 
randomized, but safety will be reported.

Safety Sample: comprises those randomized subjects in the double-blind treatment 
period who receive at least 1 dose of double-blind IMP as indicated on the dosing 
record. Subjects will only be excluded from this population if there is documented 
evidence (ie, drug dispensed = drug returned or no IMP dispensed) that the subject 
did not take IMP. If a subject is dispensed IMP and is lost to follow-up, he/she will be 
considered exposed.

Efficacy Sample: the Full Analysis Set (FAS) comprises all subjects in the Safety 
Sample who have a baseline value and at least 1 valid post-randomization efficacy 
evaluation for AISRS total score in the double-blind treatment period.
The core dataset for all efficacy analyses is the FAS, which is created based on the 
intent-to-treat (ITT) principle. However, as will be described below, in order to handle 
missing data and restrictions imposed by different types of analyses (eg, change from 
baseline analysis), datasets derived from the FAS dataset will be used for the efficacy 
analysis.
7.2
Handling of Missing Data
The AISRS is utilized as the primary efficacy assessment of a subject’s level of ADHD 
symptoms. This 18-item scale directly corresponds to the 18 DSM-5 symptoms of ADHD 
where 9 Inattentiveness items alternate with 9 Hyperactivity/Impulsivity items. Each item 
is scored as follows: 0 (none), 1 (mild), 2 (moderate), 3 (severe). For all items, 0 is the 
“best” rating and 3 is the “worst” rating. The maximum total score for the scale is 
54 points, with 27 points for each subscale. The AISRS total score is the sum of the 
Inattentiveness and Hyperactivity/Impulsivity subscale scores. The range of the AISRS 
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total score is from 0 to 54. The AISRS Inattentive subscale score and 
Hyperactivity/Impulsivity subscale score, as well as the AISRS total score is set to be 
missing if more than one item of a subscale is missing for Inattentiveness subscale or 
Hyperactivity/Impulsivity subscale, separately. If one item is missing for a given subscale 
(Inattentiveness or Hyperactivity/Impulsivity), then the subscale score will be derived as 
the mean of scores for non-missing items multiplied by 9. All imputed scores are rounded 
to the first decimal place.
The mixed-effect model repeated measures (MMRM) assumes data are missing at 
random (MAR), which is a reasonable assumption in longitudinal clinical trials in 
ADHD. However, the possibility of “missing not at random” (MNAR) data can never be 
ruled out. As sensitivity analyses, either selection model41 pattern-mixture 
model42,43,44,45 or shared parameter model46 will be used to explore data missing 
mechanisms of MNAR and investigate the response profile of dropout reason. Pattern 
Mixture Models based on Multiple Imputation (MI) with mixed missing data mechanisms 
will be used to investigate the response profile of dropout subjects by last dropout reason 
under MNAR mechanism for the following 3 scenarios: 1) Dropout reasons due to either 
AE or lack of efficacy as MNAR, 2) Dropout reasons due to either AE or lack of efficacy 
or subject withdrew consent as MNAR, 3) All dropouts as MNAR using both 1) Delta 
adjustment imputation method which is to departure from MAR assumption by 
progressively increasing the delta until conclusion from the primary analysis is 
overturned, and 2) Placebo based imputation methods in which missing data for both 
placebo and drug group are imputed based on the imputation model derived from placebo 
data. If drug improved outcomes prior to dropout, this benefit is carried into subsequent 
imputed values, but will diminish over time in accordance with the correlation structure. 
Details of these exploratory analyses will be provided in the statistical analysis plan 
(SAP).
7.3
Primary, Secondary, and Exploratory Endpoint Analyses
7.3.1
Primary Efficacy Endpoint Analysis
The objective of the primary efficacy analysis is to compare the efficacy between 
centanafadine (SR 200 mg TDD or SR 400 mg TDD) and placebo. The primary efficacy 
endpoint is the change from baseline to Day 42 in AISRS total score. For analysis of the 
double-blind treatment period data, baseline is defined as the last available measurement 
prior to the first dose of double-blind IMP in the double-blind treatment period.
The estimand for the primary efficacy analysis is the difference in outcome improvement 
if all subjects tolerated and adhered to their treatment. This approach is Estimand #3,
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recommended by the 2010 National Academy of Sciences’ National Research Council 
report on prevention and treatment of missing data and ICH E9 (R1) “Addendum to 
Statistical Principles for Clinical Trials on Choosing Appropriate Estimands and Defining 
Sensitivity Analyses in Clinical Trials”.
This estimand focuses on the efficacy of centanafadine (SR 200 mg TDD or SR 400 mg 
TDD) in change from the baseline in AISRS total score. The objective of this trial is 
consistent with the election of an efficacy rather than effectiveness estimand.
The primary analysis will be performed on the Efficacy Sample which includes all 
randomized subjects who took at least 1 dose of IMP in the double-blind treatment period 
and who have both baseline and at least 1 post-randomization AISRS total score during 
the double-blind treatment period. The primary efficacy analysis will be performed by 
fitting a MMRM analysis with an unstructured variance covariance structure in which the 
change from baseline in AISRS total score at the scheduled double-blind treatment period 
visits will be the dependent variable based on the observed cases (OC) data set. The 
model will include fixed class effect terms for treatment, trial center, visit day, and an 
interaction term of treatment by visit day. The model will also include baseline values for 
the double-blind treatment period of AISRS total score and the interaction term of 
baseline values of AISRS total score by visit day as covariates. The primary comparison 
between the centanafadine (400 mg TDD group or 200 mg TDD group) and the placebo 
group at Day 42 in the double-blind treatment phase will be estimated as the difference 
between Least Squares means utilizing the computing software SAS procedure PROC 
MIXED. The comparison between the centanafadine (400 mg TDD group or the 200 mg 
TDD group) and the placebo group will be tested at a significance level of 0.05 (2-sided)
in the order of 1) 400 mg versus placebo, and 2) 200 mg versus placebo. If there is a 
convergence problem with the unstructured variance covariance matrix of the MMRM 
model, the following structures other than unstructured will be used in order of 
1) heterogeneous toeplitz, 2) heterogeneous autoregressive of order 1, and 
3) heterogeneous compound symmetry and the first (co)variance structure converging to 
the best fit will be used as the primary analysis. If a structured covariance has to be used, 
the “sandwich” estimator of the standard error of the fixed effects parameters will be used 
in order to deal with possible model misspecification of the covariance matrix. Details of 
this analysis will be provided in the SAP.
Small centers will be defined as centers that do not have at least 1 evaluable subject 
(evaluable with regard to the primary efficacy variable) in each treatment arm in the 
double-blind treatment period. All small centers will be pooled to form “pseudo centers” 
for the purpose of analysis according to the following algorithm. Small centers will be 
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ordered from the largest to the smallest based on the number of evaluable subjects (ie, 
subjects who have baseline and at least 1 post-baseline value for the primary endpoint in 
the double-blind treatment period). The process will start by pooling the largest of the 
small centers with the smallest of the small centers until a non-small center is formed. 
This process will be repeated using the centers left out of the previous pass. In case of ties 
in center size, the center with the smallest center code will be selected. If any centers are 
left out at the end of this process, they will be pooled with the smallest pseudo centers, or 
if no pseudo centers exist, they will be pooled with the smallest non-small center.
In the case of gross violations of the linear model assumptions, nonparametric van 
Elteren test will be performed to compare the treatment effect at Day 42 in the 
double-blind treatment period on both last-observation-carried-forward (LOCF) and MI 
data. Details will be provided in the SAP.
7.3.1.1
Sensitivity Analyses
7.3.1.1.1
Sensitivity Analyses for Missing at Random Assumption
Traditionally the dropout mechanisms are divided into 3 types43: (1) missing completely 
at random (MCAR), in which the probability of dropout doesn’t depend on the observed 
data and the missing data; (2) MAR, in which the probability of dropout depends on the 
observed data, and (3) MNAR, where the probability of dropout depends on the missing 
data and possibly the observed data.
Most of MNAR methods41 have treated all observations with dropout as if they fall 
within the same dropout type. In practice, we would find that different dropout reasons 
may be related to the outcomes in different ways, for example, detailed dropout reasons 
for this trial are: AE, lack of efficacy, death, reasons unrelated to medical condition, 
withdrawal of informed consent, lost to follow-up, rash, pregnancy, and termination of all 
or part of the trial by sponsor. Dropout due to an AE, rash, and LOE may lead to MNAR 
dropout. Subjects that withdrew consent may also lead to MNAR dropout. However, it is 
debatable whether a dropout caused by subjects that withdrew consent are MAR or 
MNAR. Except AE, rash, LOE, and subjects that withdrew consent, all the other dropout 
reasons may be assumed as either MCAR or MAR dropout.
As sensitivity analyses for MAR assumptions, analyses for MNAR will be carried out. 
Pattern Mixture Models based on MI with mixed missing data mechanisms will be used 
to investigate the response profile of dropout subjects by last dropout reason under the 
MNAR mechanism for the following 3 scenarios:
1) Dropout reasons due to either AE, rash, or LOE as MNAR
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2) Dropout reasons due to either AE, rash, or LOE or subject withdrew consent as 
MNAR
3) All dropouts as MNAR
Delta Adjustment Imputation Methods
This MNAR sensitivity analysis will be performed to address a departure from the MAR 
assumptions by progressively increasing the delta until the conclusion from the primary 
analysis is overturned. The delta is 0%, 10%, 20%, 30%, .., 100% of the expected 
treatment difference of 5 points and/or the observed treatment difference between 
centanafadine and placebo from the primary analysis of MMRM model until the 
conclusion of the primary analysis is overturned. When delta=0 it is MAR. When delta 
> 0 it is MNAR.
1) Using Monte Carlo Markov Chain methodology from PROC MI to impute the 
intermittent missing data to a monotone missing pattern;
2) Using a standard MAR-based multiple imputation approach from PROC MI to 
impute the monotone missingness data
3) For subjects in the treated group and with a dropout reason of AE or LOE or 
subject withdrew consent, a delta will be added for all the values after the dropout 
time. 
4) Using MMRM model in the primary analysis to analyzed the completed data 
using PROC MIXED on the multiple imputed data
5) Obtaining the overall results using PROC MIANALYZE
Placebo Based Imputation Methods
The placebo-based imputation methods will be similar to the “Standard” multiple 
imputations method, except the parameters for the imputation model will only be 
obtained from the placebo (control) group. Missing data for both the placebo and drug
groups are imputed based on the imputation model derived from placebo data. If drug 
improved the outcomes prior to dropout, this benefit is carried into subsequent imputed 
values, but will diminish over time in accordance with the correlation structure.
In addition, model based MNAR methods such as the shared parameter model46 and 
random coefficient pattern mixture model44 will be also performed.
7.3.1.1.2
Sensitivity Analyses for Violation of Normality Assumption
The primary endpoint MMRM analysis is a maximum likelihood method that relies on 
the normality assumption. Residual analyses will be carried out to examine model 
assumption.
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In the case of gross violations of the normality assumptions, nonparametric van Elteren 
test47 will be performed to compare treatment effect at Day 42 on both LOCF dataset and 
MI data. The van Elteren test is a generalized Cochran Mantel Haenszel (CMH)
procedure useful for stratified continuous data in non-normal setting. It belongs to a 
general family of Mantel-Haenszel mean score tests. The test is performed via SAS 
procedure PROC FREQ, by including CMH2 and SCORES=MODRIDIT options in the 
TABLE statement. The stratification factor is trial center.
In addition, other methods that are robust to distributional assumption will also be 
performed to provide different views on the primary efficacy result, these include 
generalized estimating equations (GEE), weighted GEE, and MI-robust regression.48
For MI-van Elteren test and MI-robust regression, imputation datasets will be generated 
with SAS MI procedure, each dataset will be analyzed, and then an overall estimate is 
derived with SAS MIANALYZE procedure.
7.3.2
Secondary Efficacy Endpoint Analyses
7.3.2.1
Key Secondary Efficacy Endpoint Analysis
The key secondary efficacy endpoint is the change from baseline to Day 42 between 
treatment groups using the CGI-S. The estimand for the key secondary efficacy analysis 
is also the difference in outcome improvement if all subjects tolerated and adhered to 
their treatment. This approach is Estimand #3 recommended by the 2010 National 
Academy of Sciences’ National Research Council report on prevention and treatment of 
missing data and ICH E9 (R1) Addendum. This key secondary efficacy endpoint will be 
analyzed by fitting the same MMRM model described in the primary analysis.
To control the overall experiment-wise type I error at 0.05 level, a fixed-sequence testing 
approach will be applied. 
The statistical test will be performed in the following order:
1) Change from baseline to Day 42 in the double-blind treatment period in AISRS total 
score between centanafadine 400 mg TDD and placebo;
2) Change from baseline to Day 42 in CGI-S score between centanafadine 400 mg TDD
and placebo;
3) Change from baseline to Day 42 in the double-blind treatment period in AISRS total 
score between centanafadine 200 mg TDD and placebo;
4) Change from baseline to Day 42 in CGI-S score between centanafadine 200 mg TDD
and placebo.
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7.3.2.2
Other Efficacy Endpoint Analyses
Other efficacy analyses are listed below. All other efficacy variables will be evaluated at 
a nominal 0.05 level (2-sided) without adjusting for multiplicity.
1) Change from baseline in AISRS total score for every scheduled visit during the 
double-blind treatment period other than the Day 42 visit;
2) Change from baseline for the Inattentive subscale and Hyperactive-Impulsive 
subscale of the AISRS for scheduled visits during the double-blind treatment period, 
separately at every visit
3) Change from baseline in CGI-S for every scheduled visit during the double-blind 
treatment period other than the Day 42 visit
4) CGI Change from Baseline at each scheduled visit
5) Percentage of responders at each post-baseline visit, where a responder is defined as a 
subject with a CGI Change from Baseline score of 1 or 2 OR a ≥ 30% improvement 
in ADHD symptoms compared with baseline as measured by the AISRS total score
Variable (1) through variable (3) will be evaluated using the same MMRM model 
described in the primary analysis. Variable (4) will be evaluated by the CMH Row Mean 
Score Differ Test controlling, in LOCF analysis, for trial center. Variable (5) will be 
evaluated by the CMH General Association Test controlling, in LOCF analysis, for trial
center. An OC analysis will also be conducted for variables (4) and (5), but will not 
control for trial center. Statistical significance for analysis of all other efficacy variables 
will be evaluated at a nominal 0.05 level (2-sided).
7.3.3
Exploratory Efficacy Endpoint Analyses
Statistical analysis of the exploratory endpoints will be further described in the SAP.
7.4
Analysis of Demographic and Baseline Characteristics
Baseline demographic characteristics including age, race, ethnicity, gender, weight, 
height, and BMI for the randomized subjects will be summarized by descriptive statistics 
(frequency, mean, median, SD, maximum, minimum, and percentage when applicable).
Baseline disease severity and medical history will be also be summarized by descriptive 
statistics for the Safety Sample to identify any potential lack of balance between the 
treatment groups.
7.5
Safety Analysis
Safety analysis regarding safety and tolerability in the double-blind treatment period will 
be conducted based on the Safety Sample defined in Section 7.1.1. In general, baseline of 
a safety variable is defined as the last observation of the variable before taking the first 
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dose of IMP, unless specified otherwise. Prospectively defined criteria will be used to 
identify potentially clinically relevant abnormal values for clinical laboratory tests, vital 
signs, ECGs, and body weight. Details of safety analysis will be provided in the SAP.
7.5.1
Adverse Events
All AEs will be coded by system organ class and MedDRA preferred term. The incidence 
of the following events will be summarized by treatment group:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs potentially causally related to the IMP

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP

Abuse-related AEs and AEs involving MHIs
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP.
7.5.2
Clinical Laboratory Data
Summary statistics for changes from baseline in the routine clinical laboratory 
measurements will be provided. In addition, potentially clinically significant laboratory 
results will be identified using criteria prospectively defined in the SAP, and will be 
summarized.
7.5.3
Physical Examination and Vital Signs Data
By-subject listings will be provided for physical examination findings. Summary 
statistics for changes from baseline in vital signs and body weight will be provided. 
Potentially clinically significant results in vital signs and body weight will also be 
summarized. The SAP will define other information to be analyzed for physical 
examination data.
7.5.4
Electrocardiogram Data
Mean change from baseline and incidence of clinically significant changes will be 
calculated for ECG parameters.
For the analysis of QT and QTc, data from 3 consecutive complexes (representing 
3 consecutive heart beats) will be measured to determine average values. The following 
QT corrections will be used for reporting purposes in the clinical trial report:
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1) QTcB is the length of the QT interval corrected for heart rate by the Bazett formula:
QTcB = QT / (RR)0.5
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia 
formula: QTcF = QT / (RR)0.33
3) QTcN is the length of the QT interval corrected for heart rate by the FDA 
Neuropharm Division formula: QTcN = QT / (RR)0.37
7.5.5
Other Safety Data
Medication withdrawal symptoms assessed by SMWQ total scores at the scheduled 
visit(s) will be summarized by treatment group by descriptive statistics. Details will be 
described in the SAP.
Suicidality monitored during the trial using the C-SSRS will be summarized by treatment 
group by descriptive statistics. Details will be described in the SAP.
7.5.6
Abuse Liability Analysis
Abuse potential will be assessed through the active monitoring of ESAMs (eg, AEs 
related to abuse potential and AEs involving MHI).
8
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the centanafadine IB.25
8.1
Packaging and Labeling
Trial medication will be provided to the investigators and the persons designated by the 
investigator(s) or institution(s) by the sponsor or designated agent. The IMP will be 
supplied as weekly blister cards. Each blister card used in the dosing period will be 
labeled to clearly disclose the subject ID, compound ID, trial number, sponsor’s name 
and address, instructions for use, route of administration, and appropriate precautionary 
statements.
8.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to investigators and their designees. Neither investigators nor any designees may provide 
IMP to any subject not participating in this protocol.
The IMP will be stored at controlled room temperature conditions as per the clinical label 
on the IMP. The clinical site staff will ensure that the temperature log is maintained in the 
drug storage area and that the temperature is recorded at least once each working day. 
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The clinical site staff will maintain a temperature log in the IMP storage area recording 
the temperature at least once each working day.
8.3
Accountability
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned.
8.4
Returns and Destruction
Upon completion or termination of the trial, all used IMP containers, unused IMP, and 
partially used IMP must be returned to the sponsor or a designated agent, or destroyed at 
the trial site. The IMP may only be destroyed by the trial site, if approved by the sponsor 
and if the IMP destruction meets all local regulations.
All IMP returned to the sponsor must be accompanied by the appropriate documentation 
and be clearly identified by protocol number and trial site number on the outermost 
shipping container. Returned supplies should be in the original containers (eg, subject 
kits). The assigned trial monitor will facilitate the return or destruction of used IMP 
containers, unused IMP, and partially-used IMP.
8.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving:

Failure/malfunction of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Blister defects (eg, missing, empty blisters)

Bottle defects (eg, under/over-fill, no safety seal)

Vial defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
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8.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor, or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
designee must notify the sponsor (or sponsor’s designee) by e-mail or telephone within 
24 hours of becoming aware of the PQC according to the procedure outlined below.

Online: Send information required for reporting purposes (listed below) to 

Phone:
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
8.5.2
Information Required for Reporting Purposes

Description of compliant

Reporter identification (eg, subject, investigator, site, etc)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, coding)

Clinical protocol reference (number or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return
8.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return. If 
complaint sample is available for return, return it in the product retrieval package, which 
will be provided by the sponsor.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
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9
Records Management
9.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments. All 
source documents pertaining to this trial will be maintained by the investigators and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the eICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
9.2
Data Collection
During each subject’s visit to the clinic, a clinician participating in the trial will record 
progress notes to document all significant observations. At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed;

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.
Source documents and source data will be captured electronically in this trial, and will 
meet the same fundamental elements of data quality (eg, attributable, legible, 
contemporaneous, original, and accurate) as paper records. These data will be collected 
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into a system that is fully validated. Changes to the data will be captured by an automatic 
audit trail.
The trial site will be given a tablet to directly record subject data and clinical 
observations on electronic forms. Designated trial site staff will not be given access to the 
system until they have been appropriately trained. Information to be originally captured 
and reviewed electronically shall include details of the subject visit and the protocol 
required assessments performed as a part of these visits, medical history, AEs, and 
concomitant medications. Because this trial is using an electronic source record as the 
original point of data capture, there is no additional data entry step for the trial site for 
data collected directly into the application – rather, the electronic source record directly 
populates the trial database.
Some data may be captured via paper and then entered into the eSource system. These 
and any other data treated in this manner will be source data verified by the trial clinical 
research associate, and the location of the source data (ie, eSource, paper, or a local 
electronic system) will be documented before the trial start. Any changes to information 
in paper source documents will be initialed and dated on the day the change is made by a 
trial site staff member authorized to make the change. Changes will be made by striking a 
single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation 
by the clinician.
Another exception will be safety laboratory or central ECG data, where the official 
source documentation will be considered the report issued by the analyzing laboratory.
Remote monitoring of the original electronic source records will take place, however 
on-site monitoring inspections will continue to take place in order to review data entry of 
source documentation directly captured on paper and transcribed into the system, to 
ensure protocol adherence, to assess trial site operational capabilities and to perform 
other monitoring activities that cannot be performed remotely.
At the end of the trial, the investigator must certify that the data entered into the eSource 
application are complete and accurate. After database lock, the investigator will receive 
an electronic copy of the subject data.
9.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP Guideline E626 and as required by applicable local regulations. 
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The investigator/institution will take measures to prevent accidental or premature 
destruction of these documents.
9.4
Records Retention at the Trial Site
Food and Drug Administration (FDA) regulations require all investigators participating in 
clinical drug trials to maintain detailed clinical data for one of the following periods:

A period of at least 2 years after the date on which a New Drug Application is 
approved by the FDA;

A period of 2 years after the sponsor has notified the FDA that investigation with this 
drug is discontinued.
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for the sponsor 
to collect such records. The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
If the investigator withdraws from the trial (eg, due to relocation or retirement), all trial-
related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe. Notice of such transfer will be given to the sponsor in 
writing.
10
Quality Control and Quality Assurance 
10.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators and 
clinical site personnel will undergo initial and ongoing training for this particular trial, 
and this training will be clearly documented.
10.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
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the informed consent process, and comparison of the eCRF with source documents. The 
investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
11
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations, ICH GCP 
Guideline (E6), international ethical principles derived from the Declaration of Helsinki 
and Council for International Organizations of Medical Science (CIOMS) guidelines, and 
applicable local laws and regulations. Each trial site will seek approval/favorable opinion 
by an IRB according to regional requirements, and the investigator will provide that 
documentation to the sponsor. The IRB will evaluate the ethical, scientific and medical 
appropriateness of the trial. Further, in preparing and handling the eCRF, the investigator, 
sub-investigator and their staff will take measures to ensure adequate care in protecting 
subject privacy. To this end, a subject number and subject ID code will be used to 
identify each subject.
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
12
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject numbers in eCRF. If further subject ID
is required, subjects’ full names may be made known to a regulatory agency or other 
authorized officials if necessary, subject to local regulations.
13
Amendment Policy
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB. Any permanent 
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change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “non-substantial” amendments, investigators will wait for 
IRB approval/favorable opinion of the amended protocol before implementing the 
change(s). Administrative amendments are defined as having no effect on the safety of 
subjects, conduct or management of the trial, trial design, or the quality or safety of 
IMP(s) used in the trial. A protocol change intended to eliminate an apparent immediate 
hazard to subjects should be implemented immediately after agreement by the sponsor 
and investigator, followed by IRB notification within local applicable timelines. The 
sponsor will submit protocol amendments to the applicable regulatory agencies within 
local applicable timelines.
When the IRB, investigators, or the sponsor conclude that the protocol amendment 
substantially alters the trial design or increases the potential risk to the subject, the 
currently approved eICF will require similar modification. In such cases, after 
approval/favorable opinion of the new eICF by the IRB, repeat written informed consent 
will be obtained from subjects enrolled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented.
14
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial participants who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
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trial, investigators or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
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15
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41 Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis. Applied 
Statistics. 1994;43:49-93.
42 Little RJA. Pattern-mixture models for multivariate incomplete data. J Am Stat 
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missing data in longitudinal studies. Psychological Methods. 1997;2:64-78.
45 Ali MW, Siddiqui O. Multiple imputation compared with some information dropout 
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46 Wu MC, Bailey KR. Estimation and comparison of changes in the presence of 
informative right censoring: conditional linear model. Biometrics. 1989;45(3):939-
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47 van Elteren PH. On the combination of independent two sample tests of Wilcoxon. 
Bull Int Stat Inst. 1960;37:351-361.
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Data Using Multiple Imputation in Conjunction with Robust Regression. Biometrics. 
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Appendix 1
Collection, Handling, and Shipment of Bioanalytical Samples
Pharmacokinetic Sample Collection
Blood (2 mL) will be collected for the determination of plasma concentrations of 
centanafadine (EB-1020) and its metabolite(s).
The PK samples will be collected into 2-mL Vacutainer® tubes containing potassium 
ethylenediaminetetraacetic acid (K2EDTA). Each tube must be gently inverted at least 
8 times. Within 60 minutes of collection, the blood tubes must be centrifuged at 2000 to 
3000 rpm for 10 to 15 minutes at 4°C (± 3°C). The rpm, time and temperature should 
remain the same throughout the trial. Within 90 minutes of collection, the separated 
plasma from the tube should then be transferred to the bar-code labeled transfer or plasma
tube.
All tubes must be labeled using the labels provided by the sponsor or sponsor designee. If 
information needs to be written on the tube label, then the pen will need to use 
waterproof ink and the label must be covered with transparent tape, or other means, in 
order to prevent damage to the label during freeze/thaw cycles. An electronic manifest 
must be provided with all sample shipments and must be approved by the sponsor prior to 
sample shipment.
The sample must be stored at −70°C (± 10°C). If a −70°C freezer is not available, the PK
samples must be shipped on dry ice to the central laboratory on the day of collection, 
otherwise samples should be shipped on dry ice within 1 month of collection.
Pharmacogenomic Sample Collection
A 4-mL whole blood sample for the pharmacogenomic determination of drug 
metabolizing enzymes and transporters will be collected by venipuncture into one 4-mL 
K2EDTA Vacutainer tube. Each tube should be gently inverted 10 times to ensure proper 
mixing with the anticoagulant. Refrigerate the whole blood samples at 4C (± 3°C) for at 
least 1 day (but no longer than 4 days). Then, the samples should be stored upright at 
−20C (± 10°C) or below. If refrigerating is not possible, samples can be frozen directly 
from ambient. The tube will be shipped on dry ice to the central laboratory.
Blood Samples for Future Biospecimen Research
Blood (approximately 10 mL) will be collected into an evacuated collection tube(s). The 
trial site is expected to follow the instructions for collection, processing, storage, and 
shipment of blood samples. The FBR samples will be shipped to the central laboratory.
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The FBR samples will be stored for potential analysis for up to 20 years from acquisition. 
The specimens will be stored under strict supervision in a limited access facility which 
operates to ensure the integrity of the specimens.
Sample Shipment
Plasma samples must be neatly packed in a Styrofoam container which should be 
completely filled with dry ice to avoid air spaces that allow evaporation of the dry ice. 
The Styrofoam container should be sealed with tape and placed in a cardboard box. The 
recipient of the samples must be alerted of sample shipment. Packages will be shipped 
via an overnight carrier and must not be shipped on Thursdays, Fridays, Saturdays, or any 
day prior to a holiday without the expressed consent of the sponsor. The names and 
addresses of the laboratories for shipping purposes will be provided in the Operations 
Manual.
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Appendix 2
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance
Laboratory Tests
Criteria
Chemistry
AST
3 × ULN
ALT
3 × ULN
Alkaline phosphatase
3 × ULN
Blood urea nitrogen
30 mg/dL
Creatinine
2.0 mg/dL
Uric acid
Men
10.5 mg/dL
Women
8.5 mg/dL
Bilirubin (total)
2.0 mg/dL
Creatine phosphokinase
> 3 × ULN
Hematology
Hematocrit
Men
37% and decrease of 3 percentage points from baseline
Women
32% and decrease of 3 percentage points from baseline
Hemoglobin
Men
11.5 g/dL
Women
9.5 g/dL
WBC count
2,800 mm3 or 16,000 mm3
Eosinophils
10%
Neutrophils
15%
Absolute neutrophil count
1,500/mm3
Platelet count
75,000/mm3 or 700,000/mm3
Urinalysis
Protein
Increase of 2 units
Glucose
Increase of 2 units
Additional Criteria
Chloride
90 mEq/L or 118 mEq/L
Potassium
2.5 mEq/L or 6.5 mEq/L
Sodium
126 mEq/L or 156 mEq/L
Calcium
8.2 mg/dL or 12 mg/dL
Glucose
Fasting
100 mg/dL
Nonfasting
200 mg/dL
Total cholesterol, fasting
240 mg/dL
LDL cholesterol, fasting
160 mg/dL
HDL cholesterol, fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, fasting
150 mg/dL
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Appendix 3
Criteria for Identifying Vital Signs of Potential 
Clinical Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Heart rateb
> 100 bpm
< 50 bpm
10 bpm increase
10 bpm decrease
Systolic blood pressureb
≥ 140 mmHg Supine
< 90 mmHg
20 mmHg increase
20 mmHg decrease
Diastolic blood pressureb
≥ 90 mmHg Supine
< 60 mmHg
10 mmHg increase
10 mmHg decrease
Orthostatic hypotension
30 mmHg decrease in systolic blood 
pressure or a decrease of ≥ 20 mmHg in 
diastolic blood pressure after at least 
3 minutes of standing compared to the 
previous supine blood pressure.
Not applicable
(baseline status not 
considered)
Orthostatic tachycardia
25 bpm increase in heart rate from 
supine to standing
Not applicable
(baseline status not 
considered)
Weight
−
7% increase
7% decrease
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bAs defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information 
in an Original New Drug Application Submission and for Organizing Information in Periodic Safety 
Updates,” FDA Division of Neuropharmacological Drug Products draft (2/27/87).
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Appendix 4
Criteria for Identifying Electrocardiogram Measurements of 
Potential Clinical Relevance
Variable
Criterion Valuea
Change Relative to 
Baselinea
Rate
Tachycardia
120 bpm
increase of 15 bpm
Bradycardia
50 bpm
decrease of 15 bpm
Rhythm
Sinus tachycardiab
120 bpm
increase of 15 bpm
Sinus bradycardiac
50 bpm
decrease of 15 bpm
Supraventricular premature beat
all
not present present
Ventricular premature beat
all
not present present
Supraventricular tachycardia
all
not present present
Ventricular tachycardia
all
not present present
Atrial fibrillation
all
not present present
Atrial flutter
all
not present present
Conduction
1atrioventricular block
PR 200 msec
increase of 50 msec
2atrioventricular block
all
not present present
3atrioventricular block
all
not present present
Left bundle-branch block
all
not present present
Right bundle-branch block
all
not present present
Pre-excitation syndrome
all
not present present
Other intraventricular conduction blockd
QRS 120 msec
increase of 20 msec
Infarction
Acute or subacute
all
not present present
Old
all
not present present
12 weeks post trial entry
ST/T Morphological
Myocardial ischemia
all
not present present
Symmetrical T-wave inversion
all
not present present
Increase in QTc
QTcF > 450 msec
(men)
QTcF > 470 msec
(women)
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column.
bNo current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality.
cNo current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
dNo current diagnosis of left bundle branch block or right bundle branch block.
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Appendix 5
Protocol Amendment(s)/Administrative Change(s)
Amendment Number:
1
Issue Date:
18 May 2018
PURPOSE:
This amendment serves to provide clarifications, additions, and subtractions to trial 
procedures intended to gather additional safety data during the follow-up period. In 
addition, administrative clarifications were made, including corrections to typographical, 
punctuation, and formatting errors. These changes were minor and do not change the 
design or content of the protocol, and therefore, are not summarized in this appendix.
BACKGROUND:
These changes to clinical trial protocol 405-201-00014, issued 08 Mar 2018, were made
to address preliminary FDA comments received on 27 Apr 2018 in regards to the Type C 
briefing package, and to address other minor administrative changes.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Added additional follow-up contacts to be conducted via telephone on 1, 3, and 
5 days after the last dose of IMP for all subjects enrolled in Trial 405-201-00014.

Revised the last day of subject contact from Day +14 to Day +10 for subjects that 
do not complete Trial 405-201-00014, are not eligible for, or do not rollover to 
Trial 405-201-00015.

Added criteria excluding subjects with HIV seropositive status/acquired 
immunodeficiency syndrome, seropositive status for hepatitis B (ie, HBsAg 
positive), or hepatitis C (ie, anti-HCV positive and HCV RNA positive).

Clarified that pregnancy testing at screening should only be performed on 
FOCBP.

Added wording in the clinical laboratory table indicating that a CPK reflex for 
isoenzymes if CPK > 3 × ULN; serum and urine myogloblin collected if 
CPK > 5 × ULN, and that the UDS should include ritalinic acid.

Revised exclusion language regarding participating in other prior clinical trials.

Added statistical language to address new requirements set forth by the 
ICH E9(R1) Addendum.

Removed Appendices 5-8 from the protocol and replaced in-text references to 
these appendices with reference to external documentation.

Revised postmenopausal criteria to be aligned with template text.

Clarified that SMWQ will be completed by the subject at the site and completed 
remotely for non-site visits.
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
Removed CYP2D6 inhibitors and substrates from the List of Medications 
Prohibited Before the Trial table and the List of Medications Prohibited During 
the Trial table.

Corrected various typographical errors and provided clarifications to text.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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Protocol 405-201-00014
Confidential - Proprietary Information
99
Version 4.0, 15 Jan 2020
Administrative Change Number:
1
Issue Date:
30 Aug 2018
PURPOSE:
The purpose of this administrative change is to provide clarifications to trial procedures.
This administrative change will not affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the trial.
BACKGROUND:
These changes to clinical trial protocol 405-201-00014, originally issued on 08 Mar 2018 
and amended on 18 May 2018, were made to address administrative changes and correct 
minor errors.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Updated the email address for reporting IREs.

Changed the FBR blood volume collection from “up to 10 mL” to “approximately 
10 mL”.

Changed “birth control depot injection” to “birth control injection”.

Clarified which clinical laboratory assessments are performed at screening only.

Added clarification that subjects who will be rolling over into the open-label trial 
will need to sign the Trial 405-201-00015 informed consent form prior to 
activities performed at the 7-day follow-up visit of Trial 405-201-00014.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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Protocol 405-201-00014
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Version 4.0, 15 Jan 2020
Amendment Number:
2
Issue Date:
15 Jan 2020
PURPOSE:
The purpose of this protocol amendment is to remove the mention of the interim analysis
and provide revisions and clarifications to exclusion criteria. In addition, there are 
revisions to a number of planned screen subjects and clarifications around the drug 
screening. 
BACKGROUND:
These changes to clinical trial protocol 405-201-00014, originally issued on 08 Mar 2018,
amended on 18 May 2018, and an administrative change on 30 Aug 2018, were made to 
remove the interim analysis based on FDA comments received, and to address other 
administrative changes.
MODIFICATIONS TO PROTOCOL:
General Revisions:

Number of planned screened subjects revised from 900 to 1150 in Section 3.3.1. 

The statement added to exclusion criteria 9 “this would also include most bariatric 
surgeries, with the only exception being those where there has been no breach of 
the gastrointestinal wall (ie, uncomplicated lap band surgery) AND no sign of 
malabsorption”.

Exclusion criteria 22 revised to provide clarity to the text.

Exclusion criteria 28 and 30 revised to clarify that a drug screen will be assessed 
prior to Visit 2 and baseline visit, respectively, and clarification added that the 
criteria include medications such as opioids or benzodiazepines taken without 
prescription.

Interim analysis was removed from the following:

Section 3.7 Trial Procedures

Section 3.7.8 Interim Analysis Review Committee

Section 3.8.1 Entire Trial or Treatment Arm(s)

Section 7.1 Sample Size

Section 7.3.2.1 Key Secondary Efficacy Endpoint Analysis

Section 7.3.4 Interim Analysis

Clarification around positive drug screenings and negative repeat screens added to 
Section 3.7.1.1, Visit 1 (Screening) and Section 3.7.1.2, Visit 2 (Single-blind 
Placebo Run-in).

Statement added in Section 3.7.1.1, Visit 1 (Screening) “a urine drug screen will 
be collected and sent to the central lab for evaluation” for clarity. 
Clinical Study Report 405-201-00014
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Protocol 405-201-00014
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Version 4.0, 15 Jan 2020

Removed language that urine drug screen should be performed prior to the start of 
any other screening procedures added to Section 3.7.1.1.1, Visit 1 (Screening).

Removed language that urine drug screen should be performed prior to the start of 
any other screening procedures and added a clarifier that urine drug screen results 
from the previous visit will be reviewed. Revisions were made in the following 
sections:

Section 3.7.1.2, Visit 2 (Single-blind Placebo Run-in)

Section 3.7.1.3, Visit 3 (Baseline)

Section 3.7.1.4.1, Visits 4 through 8

Section 3.7.1.4.2, Visit 9/End of Treatment/Early Termination

Revisions for clarification around blood samples for genotyping made to 
Section 3.7.6.2, DNA Blood Samples for Pharmacogenomic Testing and 
Section 3.7.1.3, Visit 3 (Baseline).

Corrected various typographical errors.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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Protocol 405-201-00014
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Version 4.0, 15 Jan 2020
Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, centanafadine (EB-1020), the 
concurrent medications, the efficacy and safety parameters and the conduct of the trial in general. 
I am aware that this protocol must be approved by the Institutional Review Board (IRB) or receive 
a favorable opinion by the Independent Ethics Committee (IEC) responsible for such matters in 
the clinical trial facility where centanafadine (EB-1020) will be tested prior to commencement of 
this trial. I agree to adhere strictly to the attached protocol (unless amended in the manner set 
forth in the sponsor's Clinical Trial Agreement, at which time I agree to adhere strictly to the 
protocol as amended).
I understand that this IRB- or IEC-approved protocol will be submitted to the appropriate 
regulatory authority/ies by the sponsor. I agree that clinical data entered on case report forms by 
me and my staff will be utilized by the sponsor in various ways, such as for submission to 
governmental regulatory authorities and/or in combination with clinical data gathered from other 
research sites, whenever applicable. I agree to allow sponsor and designee monitors and 
auditors full access to all medical records at the research facility for subjects screened or enrolled 
in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for 
informational purposes only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 405-201-00014 Protocol Amendment 2
Document Number: 0001304465
Document Version: 5.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Biostatistics Approval
15-Jan-2020
20:19:19
Clinical Approval
15-Jan-2020
19:44:51
Clinical Pharmacology
Approval
15-Jan-2020
21:00:18
Clinical Study Report 405-201-00014
16.1.1 Protocol and Protocol Amendments
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SAP_001.pdf: 
 
Official Title: 
A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, 
Parallel-group Trial Evaluating the Efficacy, Safety, and Tolerability of 
Centanafadine Sustained-release Tablets in Adults With Attention-
deficit/Hyperactivity Disorder 
NCT Number: 
NCT03605836 
 
Document Date: 
 
SAP Final Version : 26 May 2020 
 
 
 
 
 
 
 
 


Table of Contents
Table of Contents..................................................................................................................... 1
Statistical Analysis Plan; Final: 26 May 2020......................................................................... 3
STAT-1.1   Adjusted Mean Change from Baseline in AISRS Line Items at Day 42 -
MMRM (Efficacy Sample)...................................................................................................... 47
STAT-1.2   Adjusted Mean Change from Baseline in ASRS Line Items at Day 42 -
MMRM (Efficacy Sample)...................................................................................................... 52
STAT-3.1   MMRM Output for Test on Treatment by Sex Interaction at Day 42 (Efficacy
Sample).................................................................................................................................... 57
STAT-3.2   MMRM Output for Test on Treatment by Race Interaction at Day 42
(Efficacy Sample).....................................................................................................................85
STAT-4.1.1   Proc Mixed Output for Change from Baseline in AISRS Total Score,
MMRM (UN), DDFM=KENWARDROGER (Efficacy Sample)........................................... 113
STAT-4.1.2   Proc Mixed Output for Change from Baseline in AISRS Total Score,
MMRM (UN), DDFM=SATTERTHWAITE (Efficacy Sample)............................................131
STAT-4.2   Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score,
LOCF (Efficacy Sample)......................................................................................................... 145
STAT-4.3   Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score,
OC (Efficacy Sample).............................................................................................................. 151
STAT-4.4   Proc GLM Output for Treatment by Center Interaction at Day 42 in AISRS
Total Score, LOCF (Efficacy Sample).....................................................................................157
STAT-4.5.1   Summary of Mean Change at Day 42 from Baseline in AISRS Total Score
By Center - LOCF (Efficacy Sample)......................................................................................159
STAT-4.5.2   Differences in Unadjusted Mean Changes of AISRS Total Score at Day 42
Among Treatment Groups By Center - LOCF (Efficacy Sample).......................................... 163
STAT-4.6   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by
Study Day in AISRS Total Score, LOCF (Efficacy Sample).................................................. 165
STAT-4.7   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by
Study Day in AISRS Total Score, OC (Efficacy Sample)....................................................... 189
STAT-4.8   Non-Parametric Stratified by Center Analysis of Mean Change from Baseline
to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF (Efficacy
Sample).................................................................................................................................... 213
STAT-4.9   Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS
Total Score, Primary Efficacy Analysis Model (Efficacy Sample)......................................... 219
STAT-4.10   Proc Mixed Output Using Heterogeneous Variance Structure for Treatment
Groups (Efficacy Sample)........................................................................................................230
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
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STAT-5.1   Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)
(Efficacy Sample).....................................................................................................................256
STAT-5.2   Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale,
LOCF (Efficacy Sample)......................................................................................................... 270
STAT-5.3   Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, OC
(Efficacy Sample).....................................................................................................................276
STAT-6.1.1   Shapiro-Wilk Test for Residual by Week from Proc Mixed for Change from
Baseline in AISRS Total Score, Primary Efficacy Analysis Model (Efficacy Sample).......... 282
STAT-6.1.2   Residual by Week from Proc Mixed for Change from Baseline in AISRS
Total Score, Primary Efficacy Analysis Model (Efficacy Sample)......................................... 283
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
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SAP 405-201-00014 
Confidential - Proprietary Information  
1
26 May 2020
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Centanafadine (EB-1020)
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Evaluation the 
Efficacy, Safety and Tolerability of Centanafadine Sustained-release in Adults with 
Attention-deficit/Hyperactivity Disorder
Protocol No. 405-201-00014
IND No. 119,361
Statistical Analysis Plan
Version: Final
Date: May 26, 2020
CONFIDENTIAL – PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
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26 May 2020
Table of Contents
Table of Contents ..........................................................................................2
1
Introduction..........................................................................................5
2
Study Objectives...................................................................................5
3
Study Design .........................................................................................5
4
Sample Size and Power Justification..................................................7
5
Data Sets for Analysis and Missing Data ...........................................7
5.1
Data Sets for Analysis.........................................................................................7
5.2
Handling of Missing Data ...................................................................................8
6
Study Conduct ......................................................................................9
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation...........9
6.2
Treatment Compliance ........................................................................................9
6.3
Protocol Deviation.............................................................................................10
7
Baseline Characteristics.....................................................................10
7.1
Baseline Definition............................................................................................10
7.2
Demographic Characteristics ............................................................................10
7.3
Medical and Psychiatric History .......................................................................10
7.4
Neuropsychiatric Diagnosis ..............................................................................11
7.5
Baseline Psychiatric Evaluation........................................................................11
8
Efficacy Analysis ................................................................................11
8.1
Primary Efficacy Endpoint................................................................................11
8.1.1
Primary Efficacy Analysis..............................................................................11
8.1.2
Technical Computation Details for Primary Efficacy Analysis .....................13
8.1.3
Sensitivity Analyses........................................................................................14
8.1.3.1
Sensitivity Analyses for Missing at Random (MAR) Assumption.............14
8.1.3.2
Per Protocol Analyses .................................................................................15
8.1.3.3
Other Sensitivity Analyses..........................................................................15
8.1.3.4
Sensitivity Analyses for Violation of Normality Assumption....................16
8.1.4
Subgroup Analyses.........................................................................................17
8.2
Key Secondary Efficacy Endpoint ....................................................................17
8.3
Other Efficacy Endpoints..................................................................................18
Clinical Study Report 405-201-00014
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8.4
Exploratory Efficacy Endpoints........................................................................18
8.5
Exploratory Analysis.........................................................................................19
9
Safety Analysis....................................................................................20
9.1
Adverse Events..................................................................................................20
9.1.1
Adverse Events in the Double-Blind Treatment Period .................................21
9.1.2
Adverse Events in the Single-blind Placebo Run-in Period...........................21
9.2
Clinical Laboratory Tests..................................................................................21
9.2.1
Clinical Laboratory Tests in Double-Blind Treatment Period .......................22
9.2.2
Drug Induced Liver Injury (DILI)..................................................................22
9.2.3
Clinical Laboratory Tests in the Single-blind Placebo Run-in Period ...........22
9.3
Vital Signs.........................................................................................................22
9.3.1
Vital Signs in the Double-Blind Treatment Period.........................................22
9.3.2
Vital Signs in the Single-blind Placebo Run-in Period ..................................23
9.4
Electrocardiogram (ECG) Data.........................................................................23
9.4.1
ECG Data in the Double-Blind Treatment Period..........................................23
9.4.2
ECG Data in the Single-blind Placebo Run-in Period....................................24
9.5
Physical Examinations ......................................................................................24
9.5.1
Body Weight, Waist Circumference and Body Mass Index (BMI)................24
9.6
Suicidality Data.................................................................................................24
9.7
SMWQ ..............................................................................................................25
9.8
Medication Handling Irregularities (MHIs) and Events Subject to Additional 
Monitoring (ESAMs) ........................................................................................25
9.9
Concomitant Medications .................................................................................25
9.10
Extent of Exposure............................................................................................26
10
Conventions.........................................................................................26
10.1
Study Visit Windows ........................................................................................26
10.2
Pooling of small centers ....................................................................................27
10.3
Scales: Rules for Scoring and Handling of Missing Data.................................27
10.3.1
Adult ADHD Investigator Symptom Rating Scale (AISRS)..........................27
10.3.2
Clinical Global Impression Severity of Illness Scale – Modified for 
Attention-Deficit Hyperactivity Disorder.......................................................28
10.3.3
Clinical Global Impression Change from Baseline ........................................28
10.3.4
Attention-Deficit Hyperactivity Disorder Impact Module – Adult (AIM-A) 28
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10.3.5
Adult ADHD Self Report Scale (ASRS)........................................................29
10.3.6
Study Medication Withdrawal Questionnaire (SMWQ) ................................29
10.3.7
Columbia-Suicide Severity Rating Scale (C-SSRS).......................................29
11
References ...........................................................................................31
12
Potential Clinical Relevance Criteria from Protocol ......................32
13
Proposed List of Summary Tables....................................................35
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1
Introduction
This statistical analysis plan (SAP) documents the statistical methodology and data analysis 
algorithms and conventions to be applied for statistical analysis and reporting of efficacy and 
safety data of study 405-201-00014. All amendments to the protocol are taken into 
consideration in developing this SAP. 
2
Study Objectives
Primary:  To confirm the efficacy of centanafadine SR tablets administered BID (200 mg or 
400 mg TDDs) compared to placebo in the treatment of adults with ADHD
Secondary:  To confirm the safety and tolerability of centanafadine SR tablets administered 
BID (200 mg or 400 mg TDDs) compared to placebo in the treatment of adults with ADHD 
3
  Study Design
This trial is a phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-
group trial to confirm the efficacy, safety, and tolerability of centanafadine SR (200 mg TDD 
or 400 mg TDD) compared to placebo for the treatment of adults with ADHD. The trial 
population will include male and female subjects 18 to 55 years of age (inclusive) with a 
current diagnosis of ADHD as confirmed by the Adult ADHD Clinical Diagnostic Scale 
(ACDS) Version 1.2 at screening.
The trial will have 4 periods: (1) screening and washout; (2) 1 week single-blind placebo run-
in; (3) 6-week double blind treatment; and (4) 7-day follow-up period (follow-up telephone 
calls at 1, 3, and 5 days after the last dose of IMP, and in-clinic visits 2 and 7 days after the 
last dose of IMP) for subjects who complete the trial, and decide to enroll in Trial 405-201-
00015. For subjects who terminate early, decide to not enroll in Trial 405-201-00015, or who 
are not eligible to enroll in Trial 405-201-00015, they will be required to participate in the 7-
day follow-up period as well as participate in an additional follow-up telephone call 10 days 
after the last dose of IMP. Subjects randomized to receive a TDD of 200 mg centanafadine SR 
will start at their target dose at the start of the double-blind treatment period. Subjects 
randomized to receive a TDD of 400 mg centanafadine SR will start the double-blind 
treatment period at the TDD of 200 mg centanafadine SR for 7 days, before they are escalated 
to their target TDD of 400 mg for a total of approximately 42 days of treatment. Subjects will 
be required to visit the site up to 12 times over the trial. See Figure 3-1 for a schematic of the 
trial design.
Subjects who complete both the 6-week double-blind treatment period and the 7-day safety 
follow-up period (follow-up telephone calls at 1, 3, and 5 days after the last dose of IMP, and 
in-clinic visits 2 and 7 days after the last dose of IMP), and refrain from using prohibited 
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medications after the IMP is stopped may be eligible to enroll into Trial 405-201-00015, 
which is a 12-month, observational, open-label trial to evaluate the long-term safety and 
tolerability of subjects with ADHD who previously participated in Trials 405-201-00013 or 
405-201-00014. Subjects who terminate early, decide to not enroll in Trial 405-201-00015, or 
who are not eligible to enroll in Trial 405-201-00015, will be required to participate in the 7-
day follow-up period as well as participate in an additional follow-up telephone call 10 days 
after the last dose of IMP. For subjects who early terminate or decline participation in the 
open-label trial, they will be instructed to refrain from utilizing prohibited concomitant 
medications, including ADHD treatments, until after the follow-up telephone call 10 days 
after the last dose of IMP.
Figure 3-1    Trial Design Schematic
ASRS = Adult ADHD Self Report Scale; CTN SR = centanafadine sustained release; ET = early termination; 
P = placebo administration; R = randomization.
aAll subjects will be required to participate in the 7-day follow-up period (follow-up telephone calls at 1, 3, 
and 5 days after the last dose of IMP, and in-clinic follow-up visits at 2 and 7 days after the last dose of 
IMP). Subjects who terminate early, decide to not enroll in Trial 405-201-00015, or who are not eligible to 
enroll in Trial 405-201-00015, will be required to participate in an additional follow-up telephone call 10 
days after the last dose of IMP.
During the trial, administration of the investigational medicinal product (IMP) will be double-
blinded. In other words, neither the investigator nor the subject will have knowledge of the 
treatment assignment (e.g., centanafadine SR 200 mg, 400 mg, or placebo). Treatment 
assignments will be based on a computer-generated randomization code provided by the 
Otsuka Pharmaceutical Development & Commercialization, Inc (OPDC) Biometrics 
Department. Sponsor personnel, including those involved in monitoring, data management, 
and data analysis, will not have access to the treatment code during the trial. The bioanalytical 
Screening 
Period
Double-blind Treatment Period
Safety
Follow-up Perioda
Adults aged 18 to 
55 years with 
ADHD confirmed 
by ACDS
Up to 28 days 
prior to Day −7
Visit 3
Day −1
(Baseline)
Visit 9
Day 42/ET
Subjects will be randomly assigned (1:1:1) to one of the 
following treatments:
Visit 4
Day 7
Visit 5
Day 14
Visit 6
Day 21
Visit 7
Day 28
Visit 8
Day 35
Visit 14
+7 days
Visit 12
+3 days
Visit 2
Day −7
Single-blind 
Placebo Run-in 
Period
P
CTN SR 200 mg total daily dose
CTN SR 400 mg total daily dose
Placebo
N = 450
N = 900
Subjects with ≥ 30% 
improvement in ASRS at 
Baseline will be early 
terminated
Visit 1
Visit 15
+10 days
R
Day 1
1st dose
Visit 10
+1 day
Visit 11
+2 days
Visit 13
+5 days
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laboratory will also be sent the randomization code. The randomization will be stratified by 
trial site and designed to allocate subjects in a 1:1:1 ratio to centanafadine SR 200 mg/day or 
400 mg/day or placebo.
4
Sample Size and Power Justification
The primary efficacy endpoint is the change from baseline at Day 42 in Adult ADHD 
Investigator Symptom Rating Scale (AISRS) total score.  The trial will compare the placebo 
arm to the centanafadine dose arms, randomized at a ratio of 1:1:1, with an overall alpha of 
0.05 for the primary endpoint.
Based on the results from Phase 2 centanafadine trials, it is reasonable to expect a treatment 
effect of 5 points with a standard deviation (SD) of 12.5 in the mean change from baseline to 
Day 42 on AISRS total score. The planned sample size of 405 evaluable subjects (135 in each 
treatment arm) will yield at least 90% power to detect the treatment effects at a 2-tailed 
significance level of 0.05.
A sufficient number of subjects will be enrolled and randomized to achieve approximately 
405 evaluable subjects in the Double-blind Treatment Phase (i.e., subjects with an AISRS 
total score at baseline and at least 1 subsequent AISRS total score in the Double-blind 
Treatment Phase).  After allowance of 10% non-evaluable subjects in the Double-blind 
Treatment Phase, the total number of subjects to be randomized is 450 (150 in each treatment 
arm).  In order to ensure 405 evaluable subjects, the number of non-evaluable subjects will be 
monitored in a blinded manner on an ongoing basis During the trial.  The power and sample 
size were obtained using the PASS 14 (2015) statistical computing software.
5
Data Sets for Analysis and Missing Data 
5.1
Data Sets for Analysis
The following analysis samples are defined for this trial:
Enrolled Sample:  comprises all subjects who signed an informed consent form (ICF) for the 
trial and enrolled into the single-blind placebo run-in period.
Randomized Sample:  comprises all subjects who were randomized in the double-blind 
treatment period.  Subjects are considered randomized when they are assigned a treatment 
group by eSource at the end of single-blind placebo run-in period. A subject receiving IMP 
outside of the eSource will not be considered randomized, but safety will be reported.
Safety Sample:  comprises those randomized subjects in the double-blind treatment period 
who received at least one dose of double-blind IMP as indicated on the dosing record.  
Subjects will only be excluded from this population if there is documented evidence (i.e., drug 
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dispensed = drug returned or no IMP dispensed) that the subject did not take IMP. If a subject 
is dispensed IMP and is lost to follow up, he/she will be considered exposed.
Efficacy Sample:  the Full Analysis Set (FAS) comprises all subjects in the Safety Sample 
who have a baseline value and at least one valid post-randomization efficacy evaluation for 
AISRS total score in the double-blind treatment period.
Per Protocol (PP) Sample: comprises those subjects in the Efficacy Sample who complete at 
least the first 2 weeks of double-blind medication ((last day of IMP - first day of IMP + 1) ≥ 
14 days) and have at least one post baseline AISRS measurement on or after Day 14 visit 
during the double-blind treatment period without major protocol violations deemed to 
compromise the assessment of efficacy. These major protocol violations will be any of the 
followings: 
1. Subjects who were not at least 80% or were more than 120% compliant with double-
blind IMP or missed 7 or more consecutive days of dosing immediately prior to the 
Day 42/ET AISRS measurement date during the double-blind treatment period based 
on subject-reported (eCRF) compliance data 
2. Subjects who reported concomitant medication use that will impact the primary 
efficacy endpoint  
3. Subjects who had major protocol deviation as represented on the protocol deviation 
eCRF page that will impact the primary efficacy endpoint 
4. Subjects who took the wrong study treatment 
The core dataset for all efficacy analyses is the FAS, which is created based on the 
intent-to-treat (ITT) principle.  However, as will be described below, in order to handle 
missing data and restrictions imposed by different types of analyses (e.g., change from 
baseline analysis), other datasets derived from the FAS dataset will be used for the efficacy 
analyses.
5.2
Handling of Missing Data
The mixed-effect model repeated measure (MMRM) assumes data are missing at random 
(MAR), which is a reasonable assumption in longitudinal clinical trials in MDD1.  However, 
the possibility of “missing not at random” (MNAR) data can never be ruled out. As sensitivity 
analyses, selection model2, pattern-mixture model3,4,5,6, and/or shared parameter model7 will 
be used to explore data missing mechanisms of MNAR and investigate the response profile of 
dropout patients by last dropout reason under MNAR mechanism for the following 3 
scenarios:  1) Dropout reasons due to either AE or LOE as MNAR, 2) Dropout reasons due to 
either AE or LOE or subject withdrew consent as MNAR, 3) All dropouts as MNAR using 
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both 1) Delta adjustment imputation method which is to departure from MAR assumption by 
progressively increasing the delta until conclusion from the primary analysis is overturned, 
and 2) Placebo based imputation methods in which missing data for both placebo and drug 
group are imputed based on the imputation model derived from placebo data.  If drug 
improved outcomes prior to dropout, this benefit is carried into subsequent imputed values, 
but will diminish over time in accordance with the correlation structure. Details are provided 
in Section 8.1.3 Sensitivity Analysis.The observed-cases (OC) data set will consist of actual 
observations recorded at each visit during the double-blind treatment period and no missing 
data will be imputed.  MMRM, Wu-Bailey, and pattern-mixture model will be performed on 
the OC dataset. 
The last-observation-carried-forward (LOCF) data set will include data recorded at a 
scheduled double-blind treatment period visit or, if no observation is recorded at that visit, 
data carried forward from the previous scheduled double-blind treatment period visit.  
Baseline data (e.g., the last visit of the single-blind placebo run-in period) will not be carried 
forward to impute missing values for the LOCF data set. The analysis of covariance 
(ANCOVA) analysis will be performed for the change from baseline to the end of the double-
blind treatment period (Day 42, LOCF) in AISRS total score as sensitivity analysis. The 
ANCOVA_LOCF model includes treatment and study center as main effects, and baseline 
value as a covariate. 
ANCOVA analysis with OC data will also be conducted on change from baseline for AISRS 
total score, as well as all continuous change from baseline efficacy endpoints. 
For Clinical Global Impression (CGI) Change from Baseline and categorical 
response/remission variables, OC analyses will be performed in addition to LOCF analyses. 
Study center will not be included in the models for OC analyses. 
6
Study Conduct
6.1
Subject Disposition, Completion Rate and Reasons for Discontinuation
Subject disposition will be summarized for the Randomized Sample by treatment group, and 
by center. 
Subject completion rate and reasons for discontinuation will be summarized for the 
Randomized Sample by treatment group for the double-blind treatment period.  
6.2
Treatment Compliance
For each subject, compliance in taking IMP is calculated by dividing the number of tablets 
taken by the total number of tablets the patients were scheduled to take during the double-blind 
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treatment period. Compliance is calculated on double-blind IMP for the double-blind treatment 
period. For lost-to-follow up patients, the last IMP end date record will be used as the treatment 
end date.  
Summary of Treatment compliance will be provided based on both eCRF data and AiCure 
captured data, respectively.
6.3
Protocol Deviation
Protocol deviations are summarized by center and type of deviation for randomized subjects by 
treatment group. Listing of protocol deviation will list the treatment phases during which the 
deviations occurred. In addition, protocol deviations affected by the COVID-19 will be 
summarized. Listing of subjects with protocol deviations affected by the COVID-19 will also 
be provided.  
7
Baseline Characteristics
7.1
Baseline Definition 
Baseline for the single-blind placebo run-in period refers to last available measurement prior 
to the start of administration of placebo in the single-blind placebo run-in period.
For analyses of the double-blind treatment period data, the baseline is defined as the last 
available measurement prior to the first dose of double-blind Investigational Medicinal 
Product (IMP) in the double-blind treatment period.
7.2
Demographic Characteristics
For the Randomized Sample, demographic characteristics will be summarized by treatment 
group. Age, race, ethnicity, height, weight, waist circumference, and body mass index (BMI) 
will be tabulated by gender and overall using the baseline assessments for the single-blind 
placebo run-in period.
Mean, range and standard deviation will be used to describe continuous variables such as age. 
Frequency distributions will be tabulated for categorical variables such as race.
7.3
Medical and Psychiatric History
A summary of medical and psychiatric history will be presented for the Randomized Sample 
by treatment group and overall. 
A summary of the Adult ADHD Clinical Diagnostic Scale (ACDS) at screening will also be 
presented for the Randomized Sample (by treatment group and overall). The number and 
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percentage of patients with each response to items A23-A41 from Section A (Childhood ADHD 
Symptoms Summary), B22-B39 from Section B (Adult ADHD Symptoms Summary), and  C1-
C5 will be presented.
7.4
Neuropsychiatric Diagnosis
A summary of MINI International Neuropsychiatric Interview (M.I.N.I.) will be presented for 
the Randomized Sample by treatment group and overall. Summarized will be the number and 
percentage of patients who meet each diagnosis criteria, and number and percentage of 
patients with each primary diagnosis. 
7.5
Baseline Psychiatric Evaluation
For the Randomized Sample, baseline for the single-blind placebo run-in period and baseline 
for the double-blind treatment period psychiatric scale evaluation will be summarized by 
treatment group and overall. The mean, median, range and standard deviation will be used to 
summarize the assessments of: AISRS total score, ASRS and CGI - Severity of Illness Score 
(CGI-S). 
8
Efficacy Analysis
All efficacy analyses pertaining to the double-blind treatment period will be performed on the 
Efficacy Sample, and patients will be included in the treatment group as randomized. 
For analysis of the double-blind treatment period data, the baseline for the double-blind 
treatment period defined in Section 7.1 will be used. Statistical comparisons are based on 2-
sided, 0.05 significance levels.
8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from the baseline of the double-blind treatment 
period to Day 42 in AISRS total score.  
8.1.1
Primary Efficacy Analysis
The objective of the primary efficacy analysis is to compare the efficacy between 
centanafadine (SR 200 mg TDD or SR 400 mg TDD) and placebo.  
The primary estimand defining the treatment effect of interest in the trial uses the hypothetical 
strategy specified in the draft ICH E9 (R1) Addendum.  The objective of the primary analysis 
is to evaluate the efficacy of centanafadine SR 400mg TDD in adult subjects with ADHD 
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versus placebo. The estimand, or target of estimation, following the hypothetical strategy is 
the pharmacological effect seen, had no withdrawals occurred.  This hypothetical estimand is 
justifiable in this case, since the focus is on the pharmacological effect of the drug additional 
to non-specific effects.  Subjects who withdraw from a symptomatic IMP treatment either 
could have lost their treatment effect, had the subjects not taken any other symptomatic 
medication after withdrawal, or could have their treatment effect been masked, had the 
subjects taken other symptomatic medication after withdrawal.  This means that any 
observations taken after subjects stop IMP will most likely not contribute relevant information 
about the pharmacological effect of the drug.  Due to this strategy, the last collected efficacy 
assessment after premature trial discontinuation will be done only once at the ET Visit.  Every 
effort will be made to complete all of the ET evaluations prior to administering any additional 
medications for the treatment of ADHD or other prohibited medications.  In the case of 
terminal or lost to follow-up events, no ET evaluations would be expected, and only 
scheduled assessments performed before such an event has occurred. 
The primary estimand for this trial is defined by the following components:

Target Population: Efficacy Sample

Endpoint: Change from baseline to Day 42 in the AISRS total score

Intercurrent Events: Premature treatment discontinuation

Measure of Intervention Effect: Difference in endpoint means between centanafadine 
(SR 200 mg TDD or SR 400 mg TDD) and placebo.
In this hypothetical strategy, the event of withdrawing IMP is considered missing at random 
(MAR), and the primary endpoint of the trial could be considered as a combination of the 
responses of on-treatment completers at Day 42 and the imputation of the endpoint to Day 42 
following the trend in each treatment group using the MMRM method for subjects who 
withdraw IMP during the trial.  All data collected during the trial treatment period will be 
used for statistical analysis.  For the primary efficacy analysis, the treatment effect will be 
estimated using the MMRM method described below.  Under the MAR assumption, MMRM 
provides an unbiased estimate of treatment effect for the treatment period.  Analyses with 
missing values imputed by multiple imputation under MNAR and other methods will be 
performed as sensitivity analyses. The primary analysis will be performed on Efficacy Sample 
which includes all randomized subjects who took at least 1 dose of IMP in the double-blind 
treatment period and who have both a baseline for the double-blind treatment period and at 
least one post-randomization AISRS total score during the double-blind treatment period. The 
primary efficacy analysis will be performed by fitting a MMRM analysis with an unstructured 
(UN) variance covariance structure in which the change from baseline for the double-blind 
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treatment period in AISRS total score at the scheduled double-blind treatment period visits 
will be the dependent variable based on the OC data set. The model will include fixed class 
effect terms for treatment, study center, visit day, and an interaction term of treatment by visit 
day.  The model will also include the interaction term of baseline values for the double-blind 
treatment period of AISRS Total score by visit day as covariates.  The primary comparison 
between centanafadine (400 mg TDD group or 200 mg TDD group) and placebo at Day 42 in 
the double-blind treatment period will be estimated as the difference between Least Squares 
(LS) means utilizing the computing software SAS procedure PROC MIXED. 
In case there is a convergence problem with MMRM model with the unstructured (UN) 
variance covariance matrix, the following structures other than unstructured will be used in 
order of 1) heterogeneous toeplitz (TOEPH), 2) heterogeneous autoregressive of order 1 
(ARH1), and 3) heterogeneous compound symmetry (CSH) and the first (co)variance 
structure converging to the best fit will be used as the primary analysis.  If a structured 
covariance has to be used, the empirical “sandwich” estimator of the standard error of the 
fixed effects parameters will be used in order to deal with possible model misspecification of 
the covariance matrix.
Small centers will be defined as centers that do not have at least one evaluable subject 
(evaluable with regard to the primary efficacy variable) in each treatment arm in the double-
blind treatment period.  All small centers will be pooled to form “pseudo centers” for the 
purpose of analysis according to the following algorithm.  Small centers will be ordered from 
the largest to the smallest based on the number of evaluable subjects (i.e., subjects who have 
baseline and at least one post-baseline value for the primary endpoint in the double-blind 
treatment period).  The process will start by pooling the largest of the small centers with the 
smallest of the small centers until a non-small center is formed.  This process will be repeated 
using the centers left out of the previous pass.  In case of ties in center size, the center with the 
smallest center code will be selected.  If any centers are left out at the end of this process, they 
will be pooled with the smallest pseudo centers, or if no pseudo centers exist, they will be 
pooled with the smallest non-small center.
8.1.2
Technical Computation Details for Primary Efficacy Analysis
The SAS code for the PROC MIXED procedure to carry out the above MMRM analysis with 
an unstructured variance covariance structure is illustrated as follows:
proc mixed;
    class treatment center visit subjid;
   model change=treatment center visit treatment*visit baseline*visit  / s cl  
ddfm=kenwardroger;    
   repeated visit /type=un subject=subjid r rcorr;
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    lsmeans treatment*visit / pdiff cl alpha=0.05 slice=visit;
run;
where baseline is the last AISRS Total score prior to the first dose of double-blind IMP in the 
double-blind treatment period. 
8.1.3
Sensitivity Analyses
8.1.3.1
Sensitivity Analyses for Missing at Random (MAR) Assumption
Traditionally the dropout mechanisms are divided into three types (Little, 1995): (1) Missing 
Completely at Random (MCAR), in which the probability of dropout doesn’t depend on the 
observed data and the missing data; (2) Missing at Random (MAR), in which the probability of 
dropout depends on the observed data, and (3) Missing Not at Random (MNAR), where the 
probability of dropout depends on the missing data and possibly the observed data.
Most of MNAR methods (Diggle P, Kenward MG, 1994) have treated all observations with 
dropout as if they fall within the same dropout type. In practice, we would find that different 
dropout reasons may be related to the outcomes in different ways, for example, detailed dropout 
reasons for this study are:  adverse events (AE), lack of efficacy (LOE), lost to follow-up, 
protocol deviation, sponsor discontinued study, subject met (protocol specified) withdrawal 
criteria, subject was withdrawn from participation by the investigator, and subject withdrew 
consent to participate. Dropout due to an AE and LOE may lead to MNAR dropout. Subject 
withdrew consent may also lead to MNAR dropout. However, it is debatable whether a dropout 
caused by subjects withdrew consent is MAR or MNAR. Except AE, LOE, and subject withdrew 
consent, all the other dropout reasons may be assumed as either MCAR or MAR dropout. Missing 
data due to COVID-19 will also be assumed as MAR. 
As sensitivity analyses for missing at random (MAR) assumption, analyses for missing not at 
random (MNAR) will be carried out.  Pattern Mixture Models (PMM) based on Multiple 
Imputation (MI) with mixed missing data mechanisms will be used to investigate the response 
profile of dropout patients by last dropout reason under MNAR mechanism for the following three 
scenarios:
1) Dropout reasons due to either AE or LOE as MNAR
2) Dropout reasons due to either AE or LOE or subject withdrew consent as MNAR
3) All dropouts as MNAR
Delta Adjustment Imputation Methods
This MNAR sensitivity analysis is to departure from MAR assumption by progressively 
increasing the delta until conclusion from the primary analysis is overturned.  The delta is 0%, 
10%, 20%, 30%, ..., 100% of the expected treatment difference of 5 points and/or the observed 
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treatment difference between centanafadine and Placebo from the primary analysis of MMRM 
model until conclusion of the primary analysis is overturned. When delta=0 it is MAR. When 
delta > 0 it is MNAR.
1) Using Monte Carlo Markov Chain (MCMC) methodology from PROC MI to impute the 
intermittent missing data to a monotone missing pattern;
2) Using a standard MAR-based multiple imputation approach from PROC MI to impute the 
monotone missingness data
3) For patients in the treated group and with a dropout reason of AE or LOE or subject 
withdrew consent, a delta will be added for all the values after the dropout time. 
4) Using MMRM model in the primary analysis to analyze the completed data using PROC 
MIXED on the multiple imputed data
5) Obtaining the overall results using PROC MIANALYZE. 
Placebo Based Imputation Methods
Similar to “Standard” multiple imputations, except parameters for imputation model obtained 
from only the placebo (control) group. Missing data for both placebo and drug group are imputed 
based on the imputation model derived from placebo data. If drug improved outcomes prior to 
dropout, this benefit is carried into subsequent imputed values, but will diminish over time in 
accordance with the correlation structure.
In addition, model based MNAR methods such as the shared parameter model (Wu and Baily, 
1989) and random coefficient pattern mixture model (Hedeker D, Gibbons RD, 1997) will be 
also performed. 
LOCF and OC Analyses
Change from baseline of the double-blind treatment period for the AISRS total score will be 
evaluated using ANCOVA with baseline of the double-blind treatment period value as 
covariate and treatment and, in LOCF analyses, study center as main effects. For the OC 
analyses, study center will not be included in the model.
8.1.3.2
Per Protocol Analyses
Per Protocol analysis will be performed using the Per Protocol Sample. 
8.1.3.3
Other Sensitivity Analyses
The following analyses will be performed to evaluate of the sensitivity of the results due to 
the impact of COVID-19.
1. A MMRM analysis (the same model for the primary efficacy analysis) based on the  
pre-COVID Efficacy Sample using all OC data set during the double-blind treatment 
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period . The pre-COVID Efficacy Sample comprises those subjects in the Efficacy 
Sample who completed or discontinued from the study before March 13, 2020, the 
National Emergency Announcement on COVID-1911.
2. A MMRM analysis (the same model for the primary efficacy analysis) based on the 
Efficacy Sample using pre-COVID data set. The pre-COVID data set consists of 
actual observations recorded at each visit during the double-blind treatment period 
before March 13, 2020, the National Emergency Announcement on COVID-1911.
3. A MMRM analysis (the same model for the primary efficacy analysis) based on the 
non-COVID Efficacy Sample using all OC data set during the double-blind treatment 
period. The non-COVID Efficacy Sample comprises those subjects in the Efficacy 
Sample who had no COVID-19 related PDs.
4. A MMRM analysis (the same model for the primary efficacy analysis) based on the 
Efficacy Sample using non-COVID data set. The non-COVID data set consists of 
actual observations recorded at each visit during the non-COVID treatment period  
which represents the time period where subjects did not have any COVID-19 related 
PDs during the double-blind treatment period. For each subject, the non-COVID 
treatment period starts from randomization and ends on the Day 42/ET date or the 
date before the first COVID-19 related PD (if present), whichever occurs earlier. 
5. A MMRM analysis (the same model for the primary efficacy analysis) based on the 
Efficacy Sample excluding the assessments performed remotely. 
8.1.3.4
Sensitivity Analyses for Violation of Normality Assumption
The primary endpoint MMRM analysis is a maximum likelihood method that relies on 
normality assumption. Residual analyses will be carried out to examine model assumption. 
In the case of gross violations of the normality assumptions, nonparametric van Elteren test8 
(van Elteren, 1960) will be performed to compare treatment effect at Week 14 on both LOCF 
dataset and Multiple Imputation (MI) data. The van Elteren test is a generalized CMH 
procedure useful for stratified continuous data in non-normal setting. It belongs to a general 
family of Mantel-Haenszel mean score tests. The test is performed via SAS procedure PROC 
FREQ, by including CMH2 and SCORES=MODRIDIT options in the TABLE statement. The 
stratification factor is trial center.  
In addition, other methods that are robust to distributional assumption will also be performed 
to provide different views on the primary efficacy result, these include generalized estimating 
equations (GEE), weighted GEE (WGEE), and MI-robust regression9. 
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For MI-van Elteren test and MI-robust regression, imputation datasets will be generated with 
SAS MI procedure, each dataset will be analyzed, then an overall estimate is derived with 
SAS MIANALYZE procedure. 
8.1.4
Subgroup Analyses
Subgroup analyses of change from baseline of the double-blind treatment period in AISRS 
total score to every scheduled visit in the double-blind treatment period will be performed by 
the following factors:

Sex (Based on the biological status)

Race (White and All Other Races) 
All subgroup analyses will be conducted using the same MMRM analysis as for the primary 
efficacy analysis except that the fixed class effect term for trial center will not be included in 
the model.
Interaction effects of treatment-by-subgroup will be assessed at Day 42 for the subgroups 
identified in the previous paragraph. MMRM analyses will be performed by adding addition 
of terms for subgroup-by-day and treatment-by-subgroup-by-day. These treatment-by-
subgroup interaction analyses will be presented in statistical documentation.
8.2
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the change from baseline of the double-blind 
treatment period to Day 42 using the CGI-S. This key secondary efficacy endpoint will be 
analyzed by fitting the same MMRM model described in the primary analysis.
To control the overall experiment-wise type I error at 0.05 level, A fixed sequence testing 
approach will be applied. The statistical test will be performed in the following order:
1) Change from baseline to Day 42 in the double-blind treatment period in AISRS total 
score between centanafadine 400 mg TDD and placebo;
2) Change from baseline to Day 42 in the double-blind treatment period in AISRS total 
score between centanafadine 200 mg TDD and placebo;
3) Change from baseline to Day 42 in CGI-S score between centanafadine 400 mg TDD 
and placebo;
4) Change from baseline to Day 42 in CGI-S score between centanafadine 200 mg TDD 
and placebo.
The testing procedure will stop at the first comparison where the p-value is ≥ 0.05. None of 
the subsequent comparisons will be performed.
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8.3
Other Efficacy Endpoints
Other efficacy analyses are listed below. All other efficacy variables will be evaluated at a 
nominal 0.05 level (2-sided) without adjusting for multiplicity.
1) Change from baseline in AISRS total score for every scheduled visit during the double-
blind treatment period other than the Day 42 visit;
2) Change from baseline for the Inattentive subscale and Hyperactive-Impulsive subscale of 
the AISRS for scheduled visits during the double-blind treatment period, separately at 
every visit
3) Change from baseline in CGI-S for every scheduled visit during the double-blind 
treatment period other than the Day 42 visit
4) CGI Change from Baseline will be collected at each scheduled visit
5) Percentage of responders at each post-baseline visit during the double-blind treatment 
period, where a responder is defined as a subject with a CGI Change from Baseline score 
of 1 or 2 OR a ≥ 30% improvement in ADHD symptoms compared with baseline as 
measured by the AISRS total score
6) Response rate at each post-baseline visit during the double-blind treatment period, where 
response is defined as 
a) a CGI Change from Baseline score of 1 or 2 OR a ≥ 20% improvement in ADHD 
symptoms compared with baseline as measured by the AISRS total score.
b) a CGI Change from Baseline score of 1 or 2 OR a ≥ 40% improvement in ADHD 
symptoms compared with baseline as measured by the AISRS total score.
7) Remission rate for every scheduled visit during the double-blind treatment period, where 
remission is defined as AISRS total score ≤ 18.
Variable (1) through variable (3) will be evaluated using the same MMRM model described 
in the primary analysis. Variable (4) will be evaluated by the Cochran Mantel Haenszel 
(CMH) Row Mean Score Differ Test controlling, in LOCF analysis, for trial center. Variable 
(5) through variable (7) will be evaluated by the CMH General Association Test controlling, 
in LOCF analysis, for study center. An OC analysis will also be conducted for variables (4) 
through (7) but will not control for trial center. Separate summary and statistical test for 
response rate based only on the AISRS improvement and only on the CGI Change from 
Baseline score will be presented for (5) and (6).
8.4
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are listed below. The exploratory efficacy endpoints, when 
applicable, will be evaluated at a nominal 0.05 level (2-sided) without adjusting for 
multiplicity.
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1) Change from baseline for Question 1 (Global Quality of Life) and Questions 9Aa – 
9Ai and 9Ba – 9Bi (Impact of Symptoms) of AIM-A at scheduled visits during the 
double-blind treatment period, separately at every visit
2) Proportion of subjects in each response for the following questions of AIM-A at 
scheduled visits during the double-blind treatment period, separately at every visit  
a.
Questions 2-4 (Global Quality of Life) 
b. Questions 5a-5j (Living with ADHD)
c.
Questions 6a-6k (General Well-Being)
d. Questions 7a-7j (Work, Home and School Performance and Daily Functioning)
e.
Questions 8a-8h (Relationships and Communication)
f.
Economic impact (5 items)
g. Questions 17-23 (Demographics/Medication Status)
3) Change from baseline in the total score of (18 item) ADHD Symptoms score of the 
ASRS and subscale scores for ASRS at scheduled visits during the double-blind 
treatment period, separately at every visit
Variables (1) and (3) will be evaluated using the same MMRM model described in the 
primary analysis. Variable (2) will be summarized by descriptive statistics and no statistical 
comparisons between centanafadine and placebo will be performed.
8.5
Exploratory Analysis
Exploratory efficacy analyses will be presented in Statistical Documentation. 
Treatment-by-center interaction will be assessed at Day 42 by including the treatment-by-
center-by-visit interaction in the model. Results for study centers will be displayed from 
largest center to smallest center. 
Line Item score will be performed for AISRS and ASRS on Change from baseline of the 
double-blind treatment period to Day 42 using the MMRM model for AISRS and ASRS, 
where Cohen's D Effect Size10 is the difference between the two means divided by their 
standard deviation [as defined by Cohen's D and reviewed on pages 4-6 from the Sage book 
"Effect Size for ANOVA Designs" (Vol 129) by Cortina and Nouri]. For MMRM (using SAS 
PROC MIXED), or ANCOVA (Using SAS PROC GLM), LSMean difference of treatment 
effects for the between centanafadine and placebo groups, and the standard error of the 
difference (Stderr) will be obtained with an Estimate statement. Let n1 and n2 denote the 
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respective sample sizes of the two groups to compare, Effect Size = d = (LSMean1 – 
LSMean2) / σ, where 𝜎=
Stderr
1
𝑛1 + 1
𝑛2 .
9
Safety Analysis
Standard safety variables to be analyzed include AEs, clinical laboratory tests, vital signs, 
electrocardiograms (ECGs), body weight, waist circumference, and BMI.  In addition, data 
from the following safety scales will be evaluated: C-SSRS and Study Medication 
Withdrawal Questionnaire (SMWQ).
 Analyses of the double-blind treatment period safety data will be performed on the Safety 
Sample unless indicated otherwise. 
The Safety Sample will also be analyzed for the single-blind placebo lead-in period safety 
data, as applicable, by treatment groups the subjects eventually being assigned in the double-
blind treatment period.
9.1
Adverse Events 
All adverse events (AEs) will be coded by system organ class (SOC) and Medical Dictionary 
for Regulatory Activities (MedDRA) Preferred Term (PT).  The incidence of the following 
events will be summarized:
a)
Treatment-emergent AEs (TEAEs)
b)
TEAEs by severity
c)
TEAEs potentially causally related to the IMP
d)
TEAEs with an outcome of death
e)
Serious TEAEs
f)
TEAEs leading to discontinuation of the IMP 
g)
Treatment-emergent Adverse Events of Special Interest (AESI)
h)
Abuse-related TEAEs and TEAEs involving MHIs (Medication handling irregularities) 
AEs will be classified by Primary SOC and PT according to the MedDRA. AEs that are 
gender-specific, e.g., ovarian cancer, will have their incidence rates evaluated for the specific 
gender. 
Incidence of TEAEs will be summarized by double-blind treatment group for the double-blind 
treatment period. Incidence of TEAEs by SOC and MedDRA PT will be summarized for sex 
and race.
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Adverse Events of Special Interest
Newly acquired skin eruptions that are non-traumatic will be considered AESIs. These may 
include but are not limited to eruptions such as skin rashes, skin irritations, skin reactions, or 
acneiform lesions. This does not include localized contact irritation at ECG lead sites due to 
application or removal of lead adhesive.
Refer to the separate rash workup plan for complete details, including reporting forms, and 
extra measures that must be performed to characterize any skin AESI of a newly acquired skin 
eruption that is non-traumatic. The trial site will have a local designated dermatologist 
available for immediate consultation during the trial for these AESIs.
9.1.1
Adverse Events in the Double-Blind Treatment Period
TEAEs in the double-blind treatment period are defined as AEs with an onset date on or after 
the start of double-blind treatment. In more detail, TEAEs are all adverse events which started 
after start of double-blind IMP; or if the event was continuous from end of the single-blind 
placebo run-in period and was worsening, serious, study drug related, or resulted in death, 
discontinuation, interruption or reduction of study therapy. Adverse Events occurring up to 30 
days after the last day of double-blind dosing will be included in the summary tables. 
The incidence of AEs in the double-blind treatment period will be tabulated by treatment 
group and overall using the Safety Sample. Incidence of TEAE during the double-blind 
treatment period of at least 5% in either centanafadine group and also greater than placebo by 
SOC and MedDRA PT will be provided.
Unless otherwise specified, in general, analysis of safety data will be performed on observed 
case and for last visit.
9.1.2
Adverse Events in the Single-blind Placebo Run-in Period 
Adverse Events in the single-blind placebo run-in period will be summarized for patients in 
the Safety Sample. AEs occurring up to 30 days after the last day of IMP in this period, but 
prior to the start of the double-blind treatment period, will be included in these summary 
tables. The incidence of adverse events in the single-blind placebo run-in period will be 
tabulated by the double-blind treatment patients receive in the double-blind treatment period. 
9.2
Clinical Laboratory Tests
Summary statistics for routine clinical laboratory measurements will be provided. For The 
double-blind treatment period laboratory tests, change from baseline for the double-blind 
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treatment period will be summarized by treatment group. Potentially clinically relevant results 
in laboratory tests will also be summarized.
9.2.1
Clinical Laboratory Tests in Double-Blind Treatment Period
Potentially clinically relevant laboratory measurement test results in the double-blind 
treatment period will be identified for the Safety Sample and will be summarized by treatment 
group and listed. Criteria for identifying laboratory values of potential clinical relevance are 
provided in Appendix 2.
9.2.2
Drug Induced Liver Injury (DILI)
Total bilirubin level should be checked for any subject with increased ALT or AST levels  
three times the upper normal limits (ULN) or baseline. 

Reporting all DILI as SAE to the FDA based on Hy's Law: 
AST or ALT > 3 x ULN or baseline and 
T_Bili  > 2 x ULN or baseline
A separate incidence table will be provided for DILI cases, and the corresponding listing will 
be provided for Safety Sample during the double-blind treatment period and the single-blind 
placebo run-in period.
9.2.3
Clinical Laboratory Tests in the Single-blind Placebo Run-in Period
Potentially clinically relevant laboratory measurement test results in the Single-blind Placebo 
Run-in Period will be summarized for the Safety Sample by treatment group and overall as 
well as listed by subject and by laboratory test.  
9.3
Vital Signs
Summary statistics for vital signs will be provided. For the double-blind treatment period vital 
signs, change from baseline for the double-blind treatment period will be summarized for the 
Safety Sample by treatment group. Potentially clinically relevant results in vital signs will 
also be summarized. Similar summaries will be provided for the Safety Sample during the 
Single-blind Placebo Run-in Period.
9.3.1
Vital Signs in the Double-Blind Treatment Period
Potentially clinically relevant vital signs measurements identified in the double-blind 
treatment period for the Safety Sample will be summarized by treatment group. Criteria for 
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identifying vital signs of potential clinical relevance are provided in Appendix 1. All 
potentially clinically relevant events or changes will be listed and included in summary tables.
9.3.2
Vital Signs in the Single-blind Placebo Run-in Period
Potentially clinically relevant vital signs measurements identified in the Single-blind Placebo 
Run-in Period for the Safety Sample will be summarized by treatment group. 
9.4
Electrocardiogram (ECG) Data
Summary statistics and incidence of potentially clinically relevant changes will be provided 
for ECG parameters.
For the analysis of QT and QTc, data from three consecutive complexes (representing three 
consecutive heart beats) will be measured to determine average values.  The following QT 
corrections will be used for reporting purposes in the clinical study report:
1) QTcB is the length of the QT interval corrected for heart rate by the Bazett formula: 
QTcB=QT/(RR)0.5 and
2) QTcF is the length of the QT interval corrected for heart rate by the Fridericia formula: 
QTcF=QT/(RR)0.33
3) QTcN is the length of the QT interval corrected for heart rate by the FDA Neuropharm 
Division formula:  QTcN=QT/(RR)0.37 
9.4.1
ECG Data in the Double-Blind Treatment Period
Potentially clinically relevant changes in the 12-lead ECG identified in the double-blind 
treatment period for the Safety Sample will be listed and summarized by treatment group. 
Criteria for identifying ECG measurements of potential clinical relevance are provided in 
Appendix 3.
Categorical changes in ECG parameters during the double-blind treatment period will be 
summarized based on the following criteria:
Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
QT
New Onset (> 450 Msec)
New onset (>450 msec) in QT means a subject who 
attains a value > 450 msec during treatment period 
but not at baseline.
QTc *
New Onset (> 450 Msec)
New onset (> 450 msec) in QTc means a subject 
who attains a value > 450 msec during treatment 
period but not at baseline.
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Categorical Change Criteria in QT/QTc Parameters
Classification
Category
Criteria 
New Onset (> 450 Msec) 
And > 10% Increase
New onset (> 450 msec) and 
> 10% increase in QTc means a subject who attains 
a value > 450 msec and > 10% increase during 
treatment period but not at baseline
New Onset (> 500 Msec)
New onset (> 500 msec) in QTc means a subject 
who attains a value > 500 msec during treatment 
period but not at baseline.
Increase 30 - 60 Msec
Increase from baseline value > 30 and  60 msec in 
QTc
Increase > 60 Msec
Increase from baseline value > 60 msec in QTc
* QTc categorical change criteria apply to QTcB, QTcF and QTcN.
9.4.2
ECG Data in the Single-blind Placebo Run-in Period
Potentially clinically relevant changes in the 12-lead ECG identified in the Single-blind 
Placebo Run-in Period for the Safety Sample will be listed and summarized by treatment 
group. 
9.5
Physical Examinations
By-patient listings will be provided for physical examination.
9.5.1
Body Weight, Waist Circumference and Body Mass Index (BMI) 
Analyses of body weight, waist circumference and BMI will be performed for the Safety 
Sample. The mean change from baseline of the double-blind treatment period to Day 42 (OC) 
and last visit in the double-blind treatment period in body weight will be tabulated and 
analyzed using ANCOVA. The ANCOVA models for both the OC and last visit analyses will 
include the baseline of the double-blind treatment period body weight and the treatment 
group. 
Percentages of patients showing significant weight gain (≥ 7 % increase in weight), as well as 
percentages of patients showing significant weight loss (≥ 7 % decrease in weight) baseline of 
the double-blind treatment period to Day 42 (OC and LOCF) will be analyzed using Cochran-
Mantel-Haenszel (CMH) General Association Test. 
Body mass index is defined as weight in kilograms divided by the square of height in meters.
9.6
Suicidality Data
Suicidality will be monitored during the study using the C-SSRS and will be summarized as 
number and percentage of subjects reporting any suicidal behavior, ideation, behavior by type 
(4 types), ideation by type (5 types) and treatment emergent suicidal behavior and ideation. 
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Summary will be provided for the single-blind placebo run-in period and the double-blind 
treatment period for the Safety Sample.
Suicidality is defined as report of at least one occurrence of any type of suicidal ideation or at 
least one occurrence of any type of suicidal behavior during assessment period (count each 
person only once).
Treatment emergent suicidal behavior and ideation is summarized by four types: Emergence 
of suicidal ideation, Emergence of serious suicidal ideation, Worsening of suicidal ideation, 
Emergence of suicidal behavior. 
Emergence of suicidal behavior/ideation is defined as report of any type of suicidal 
behavior/ideation during treatment when there was no baseline suicidal behavior/ideation.
Emergence of serious suicidal ideation is defined as observation of suicidal ideation severity 
rating of 4 or 5 during treatment when there was no baseline suicidal ideation.                                                   
Worsening of suicidal ideation is defined as a suicidal ideation severity rating that is more 
severe than it was at baseline.
For the double-blind treatment period analyses, the last available measurement prior to the 
first dose of double-blind IMP is being used as “Baseline”.
9.7
SMWQ
Medication withdrawal symptoms assessed by SMWQ total scores at the scheduled visits 
during the double-blind treatment period and follow-up period will be summarized for the 
Safety Sample by treatment group and overall. The number of patients, mean, median, range 
and standard deviation will be presented.
9.8
Medication Handling Irregularities (MHIs) and Events Subject to 
Additional Monitoring (ESAMs)
MHIs and ESAMs will be summarized for the Safety Sample by treatment group and overall. 
By-patient listings will be provided. 
9.9
Concomitant Medications
Number and proportion of patients taking concomitant medications prior to the single-blind 
placebo run-in period, during the single-blind placebo run-in period, during the double-blind 
treatment period, and after study therapy are tabulated by drug classification using the World 
Health Organization (WHO) drug dictionary. For the double-blind treatment period 
Randomized Sample, data will be presented by treatment group and overall.
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9.10 Extent of Exposure
The start date of double-blind IMP - centanafadine or placebo - will be the first day of double-
blind dosing. The number and percentage of subjects who receive double-blind IMP, will be 
presented by week and by treatment group. Each dosing week will be based on the actual 
week; i.e., Day 1-7 in Week 1, Day 8-14 in Week 2, etc. This summary will be performed on 
the Safety Sample. 
The mean daily dosage will be summarized by week and treatment group using descriptive 
statistics. The mean daily dosage per subject per week will be determined for each week of 
the study. This will be calculated by dividing the sum of individual total doses by the number 
of days in the week interval. The summary will contain for each treatment group the number 
of patients receiving double-blind IMP, and the mean and range of the mean daily dose for 
each week.
10 Conventions
10.1 Study Visit Windows
Study visit windows will be used to map visits using study day intervals. This visit window 
convention applies to tables and listings for all efficacy and safety scales (AISRS, CGI-S, 
AIM-A, ASRS and CGI Change from Baseline). This derived study window variable will be 
named as DAY and will be footnoted. In listings it will be listed along with the eCRF study 
visit.
Table 10-1 shows classifications for study day intervals in the double-blind treatment period. 
The variable “target day” is defined using the number of days since the start of double-blind 
dosing in the double-blind treatment period. The first day of double-blind dosing is defined as 
“Day 1”. 
If more than one observation falls within a particular study day interval, then the last
observation within that interval is used. Evaluations occurring more than three days after the 
last double-blind dosing date and evaluations occurring during the follow-up period will not 
be mapped into study visit windows and will be excluded from the double-blind treatment 
period analysis.
Table 10-1: Study Day and Visit Windows in the Double-Blind Treatment Period
Day
Target Day a
Study Day Interval a
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7
7
2-10
14
14
11-17
21
21
18-24
28
28
25-31
35
35
32-38
42
42
39-49 b
a Relative to the first day of double-blind IMP in the double-blind treatment period.
b Evaluations occurring more than three days after the last double-blind dosing date and evaluations occurring 
during the follow-up period will be excluded from the double-blind treatment period analyses.
10.2 Pooling of small centers
Primary efficacy analysis will be performed on the Efficacy Sample which comprises those 
subjects in the Randomized Sample who have a baseline value for the double-blind treatment 
period and at least one post-randomization value for AISRS total score in the double-blind 
treatment period. Small centers will be defined as centers that do not have at least one 
evaluable subject (evaluable with regard to the primary efficacy variable) in each treatment 
arm in the double-blind treatment period. All small centers will be pooled to form “pseudo 
centers” for the purpose of analysis according to the following algorithm. Small centers will 
be ordered from the largest to the smallest based on the number of evaluable subjects (i.e., 
subjects who have a baseline value for the double-blind treatment period value and at least 
one post-randomization value for AISRS total score in the double-blind treatment period).  
The process will start by pooling the largest of the small centers with the smallest of the small 
centers until a non-small center is formed.  This process will be repeated using the centers left 
out of the previous pass.  In case of ties in center size, the center with the smallest center code 
will be selected.  If any centers are left out at the end of this process, they will be pooled with 
the smallest pseudo centers, or if no pseudo centers exist, they will be pooled with the 
smallest non-small center.
10.3 Scales: Rules for Scoring and Handling of Missing Data
10.3.1
Adult ADHD Investigator Symptom Rating Scale (AISRS)
The AISRS is utilized as the primary efficacy assessment of a subject’s level of ADHD 
symptoms. It is a modified version of the ADHD Rating Scale that reflects the impact and 
severity of ADHD among adults and will be administered at each scheduled visit in the 
screening period, the single-blind placebo run-in period, the double-blind treatment period, 
and at 2 and 7 days after the last dose of IMP in the follow-up period. It is a clinician-
administered scale that measures the 18 symptoms of adult ADHD using a Likert scale: 0 
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(none); 1 (mild); 2 (moderate); and 3 (severe) and uses a semi-structured interview 
methodology with suggested prompts for each item to improve interrater reliability. The 
scale's 18 items directly correspond to the 18 DSM-5 symptoms of ADHD where 9 inattentive 
items alternate with 9 hyperactive impulsive items. The maximum total score for the scale is 
54 points, with 27 points for each subscale. The total score is the sum of both the Inattentive 
and Hyperactive Impulsive subscales. 
The AISRS inattentive subscale score and hyperactive-impulsive subscale score, as well as 
the AISRS total score is set to be missing if more than one item of a subscale is missing for 
inattentive subscale or hyperactive-impulsive subscale, separately. If one item is missing for a 
given subscale (inattentive or hyperactive-impulsive), then the subscale score is derived as the 
mean of scores from the 8 non-missing items multiplied by 9. All imputed scores are rounded 
to the first decimal place. The 9 inattentive items consist of the 9 odd numbered items and the 
9 hyperactive impulsive items consist of the 9 even numbered items. 
10.3.2
Clinical Global Impression Severity of Illness Scale – Modified for 
Attention-Deficit Hyperactivity Disorder
The CGI-S modified is an observer-rated scale that will be used to measure symptom severity. 
To perform this assessment, the investigator or rater will respond to the following question: 
“Considering your total clinical experience with adult ADHD, how mentally ill is the patient 
at this time?” Response choices include: 1 = normal, not at all ill; 2 = borderline mentally ill; 
3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most 
extremely ill patients. CGI-S is assessed at each scheduled visit in the double-blind treatment 
period.
10.3.3
Clinical Global Impression Change from Baseline
The CGI Change from Baseline is an observer-rated scale that will be used to measure the 
subject's total improvement compared to before trial drug treatment was initiated. The rater or 
investigator will rate the subject’s total improvement relative to baseline. Response choices 
include: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no 
change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. CGI Change from 
Baseline is assessed at each scheduled visit in the double-blind treatment period except for the 
Day -1 visit. 
10.3.4
Attention-Deficit Hyperactivity Disorder Impact Module – Adult (AIM-
A)
The AIM-A is a subject self-report questionnaire which assesses quality of life in adults with 
ADHD. The questionnaire has 4 global quality of life items, 5 economic impact items, and 
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5 multi-item scales that assess the following key concepts: Living with ADHD, General Well-
Being, Work, Home and School Performance and Daily Functioning. Additionally, 
Relationships and Communication, and Impact of Symptoms are also included.
10.3.5
Adult ADHD Self Report Scale (ASRS)
The ASRS is a self-report questionnaire developed by the WHO. The subject will answer 18 
questions about the frequency of recent ADHD symptoms that are consistent with the DSM-
IV criteria. The ASRS is assessed at the scheduled visits during the screening period, the 
single-blind placebo run-in period, and at Days -1, 28 and 42/ET during the double-blind 
treatment period.
The total score of (18 item) ADHD Symptoms score of the ASRS is set to be missing if more 
than one item of a subscale is missing for inattentive subscale or hyperactive-impulsive 
subscale, separately. If one item is missing for a given subscale (inattentive or hyperactive-
impulsive), then the subscale score is derived as the mean of scores from the 8 non-missing 
items multiplied by 9. All imputed scores are rounded to the first decimal place. The 9 
inattentive items consist of items 1-4 and 7-11 and the 9 hyperactive impulsive items consist 
of items 5-6 and 12-18. 
10.3.6
Study Medication Withdrawal Questionnaire (SMWQ)
The SMWQ is a questionnaire to assess withdrawal symptoms. The SMWQ is a modification 
of the Amphetamine Withdrawal Questionnaire in which the terms “amphetamines and 
methamphetamine” are replaced with the term “the study medication.” The SMWQ is 
assessed at Day 35 and Day 42/ET in the double-blind treatment period and at 1, 2, 3, 5, 7, 
and 10 days after the last dose of IMP in the follow-up period.
10.3.7
Columbia-Suicide Severity Rating Scale (C-SSRS)
Suicidality will be monitored during the trial using the C-SSRS. The C-SSRS is a semi-
structured interview that captures the occurrence, severity, and frequency of suicide-related 
thoughts and behaviors during the assessment period. The interview includes definitions and 
suggested questions to solicit the type of information needed to determine if a suicide-related 
thought or behavior has occurred. The interview and rating for the C-SSRS must be 
completed by a licensed clinician who has been successfully trained to rate this scale by the 
sponsor or a designee and is medically responsible for the subject. Documentation of trial 
training should be maintained in the investigational site’s files.
The C-SSRS has a “Screening/Baseline” version, which will be completed at screening and a 
”Since Last Visit” version that will be completed at all other visits (including the ET visit, if 
applicable). There are a maximum of 19 items to be completed: 7 required, 10 potential 
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additional items if there is a positive response to a required item, and 2 items for 
suicide/suicide behavior present during the interview. The C-SSRS uses dichotomous scales 
(i.e., yes or no), Likert scales, and text or narrative to further describe the thoughts or 
behaviors. 
The C-SSRS is assessed at each scheduled visit in the screening period, the single-blind 
placebo run-in period, the double-blind treatment period, and at 2 and 7 days after the last 
dose of IMP in the follow-up period.
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11
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12 Potential Clinical Relevance Criteria from Protocol
Appendix 1
Criteria for Identifying Vital Signs of Potential Clinical Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Heart Rateb
> 100 bpm
< 50 bpm
 10 bpm increase
 10 bpm decrease
Systolic Blood Pressureb
 140 mmHg
< 90 mmHg
 20 mmHg increase
 20 mmHg decrease
Diastolic Blood Pressureb
 90 mmHg
< 60 mmHg
 10 mmHg increase
 10 mmHg decrease
Orthostatic Hypotension
 30 mmHg decrease in systolic blood 
pressure or a  20 mmHg
in diastolic blood pressure after at least
3 minutes of standing compared to the
previous supine blood pressure.
Not Applicable
(baseline status not considered)
Orthostatic Tachycardia
 25 bpm increase in heart rate from
supine to standing
Not Applicable
(baseline status not considered)
Weight
-
 7% increase
 7% decrease
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the “Criterion 
Value” and also represent a change from the subject’s baseline value of at least the magnitude shown in the 
“Change Relative to Baseline” column.
b As defined in “Supplementary Suggestions for Preparing an Integrated Summary of Safety Information in 
an Original NDA Submission and for Organizing Information in Periodic Safety Updates,” FDA Division 
of Neuropharmacological Drug Products draft (2/27/87).
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Appendix 2
Criteria for Identifying Laboratory Values of Potential Clinical 
Relevance
Laboratory Tests
Criteria
Chemistry
AST (SGOT)
 3 x upper limit of normal (ULN)
ALT (SGPT)
 3 x ULN
Alkaline phosphatase
 3 x ULN
BUN
 30 mg/dL
Creatinine
 2.0 mg/dL
Uric Acid
Men
 10.5 mg/dL
Women
 8.5 mg/dL
Bilirubin (total)
 2.0 mg/dL
Creatine Phosphokinase (CPK)
> 3 x ULN
Hematology
Hematocrit
Men
 37 % and decrease of  3 percentage points from Baseline
Women
 32 % and decrease of  3 percentage points from Baseline
Hemoglobin
Men
 11.5 g/dL
Women
 9.5 g/dL
White blood count
 2,800/ mm3 or  16,000/ mm3
Eosinophils
 10%
Neutrophils
 15%
Absolute neutrophil count
 1,500/ mm3
Platelet count
 75,000/ mm3 or  700,000/ mm3
Urinalysis
Protein
Increase of  2 units
Glucose
Increase of  2 units
Additional Criteria
Chloride
 90 mEq/L or  118 mEq/L
Potassium
 2.5 mEq/L or  6.5 mEq/L
Sodium
 126 mEq/L or  156 mEq/L
Calcium
 8.2 mg/dL or  12 mg/dL
Glucose
Fasting
 100 mg/dL 
Non-Fasting
 200 mg/dL
Total Cholesterol, Fasting
 240 mg/dL 
LDL Cholesterol, Fasting
 160 mg/dL 
HDL Cholesterol, Fasting
Men
< 40 mg/dL
Women
< 50 mg/dL
Triglycerides, Fasting
 150 mg/dL
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Appendix 3
Criteria for Identifying ECG Measurements of Potential Clinical 
Relevance
Variable
Criterion Valuea
Change Relative to Baselinea
Rate
Tachycardia
 120 bpm
increase of   15 bpm
Bradycardia
 50 bpm
decrease of  15 bpm
Rhythm
Sinus tachycardiab
 120 bpm
increase of  15 bpm
Sinus bradycardiac
 50 bpm
decrease of  15 bpm
Supraventricular premature beat
all
not present  present
Ventricular premature beat
all
not present  present
Supraventricular tachycardia
all
not present  present
Ventricular tachycardia
all
not present  present
Atrial fibrillation
all
not present  present
Atrial flutter
all
not present  present
Conduction
1 atrioventricular block
PR  200 msec
increase of   50 msec
2 atrioventricular block
all
not present  present
3 atrioventricular block
all
not present  present
Left bundle-branch block
all
not present  present
Right bundle-branch block
all
not present  present
Pre-excitation syndrome
all
not present  present
Other intraventricular conduction blockd
QRS  120 msec
increase of  20 msec
Infarction
Acute or subacute
all
not present  present
Old
all
not present  present
 12 weeks post study entry
ST/T Morphological
Myocardial Ischemia
all
not present  present
Symmetrical T-wave inversion
all
not present  present
Increase in QTc
QTcF > 450 msec 
(men) 
QTcF > 470 msec 
(women)
a In order to be identified as potentially clinically relevant, an on-treatment value must meet the “Criterion 
Value” and also represent a change from the subject’s baseline value of at least the magnitude shown in the 
“Change Relative to Baseline” column.
b No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial flutter, 
or other rhythm abnormality.
c No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality.
d No current diagnosis of left bundle branch block or right bundle branch block.
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13
Proposed List of Summary Tables
CT-1.1   Subject Disposition 
CT-1.2   Subject Disposition by Center 
CT-1.3   Subject Completion Rates by Week During the Double-Blind Treatment Period (Randomized Sample)
CT-1.4.1   Subject Enrollment by Country (Randomized Sample)
CT-1.4.2   Subject Enrollment by Country by Age Group (Randomized Sample)
CT-2   Reasons for Discontinuation in the Double-Blind Treatment Period (Randomized Sample)
CT-3.1   Demographic Characteristics (Randomized Sample)
CT-3.2.1   Medical History (Randomized Sample)
CT-3.2.2   Psychiatric History (Randomized Sample)
CT-3.2.3   Summary of Adult ADHD Clinical Diagnostic Scale (ACDS) (Randomized Sample)
CT-3.3   MINI International Neuropsychiatric Interview (M.I.N.I.)   (Randomized Sample)
CT-3.4.1   Baseline Psychiatric Scale Evaluations for the Single-Blind Placebo Run-in Period (Randomized 
Sample)
CT-3.4.2   Baseline Psychiatric Scale Evaluations for the Double-Blind Treatment Period (Randomized Sample)
CT-4.1   Concomitant Medications: Medications Taken Prior to Start of Double-Blind Treatment (Safety 
Sample)
CT-4.2   Concomitant Medications: Medications Taken During the Double-Blind Treatment Period (Safety 
Sample)
CT-4.3   Concomitant Medications: Medications Taken Post Study Period (Safety Sample)
CT-5.1     Summary of Efficacy Results at Day 42 in the Double-Blind Treatment Period (Efficacy Sample)
CT-5.2.1.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - MMRM, UN (Efficacy Sample)
CT-5.2.1.2   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - MMRM, UN (Per Protocol Sample)
CT-5.2.1.3   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - MMRM, UN (Pre-COVID Efficacy Sample)
CT-5.2.1.4   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - MMRM, UN – Pre-COVID Data Set (Efficacy Sample)
CT-5.2.1.5   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - MMRM, UN (Non-COVID Efficacy Sample)
CT-5.2.1.6   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - MMRM, UN – Non-COVID Data Set (Efficacy Sample)
CT-5.2.1.7   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - MMRM, UN – Excluding Remote Assessments (Efficacy Sample)
CT-5.2.2   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score - 
MMRM, TOEPH Empirical (Efficacy Sample)
CT-5.2.3   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score - 
MMRM, ARH1 Empirical (Efficacy Sample)
Clinical Study Report 405-201-00014
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CT-5.2.4   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score - 
MMRM, CSH Empirical (Efficacy Sample)
CT-5.2.5   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score - 
MMRM, DDFM=SATTERTHWAITE (Efficacy Sample)
CT-5.2.6.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - LOCF (Efficacy Sample)
CT-5.2.6.2   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - OC (Efficacy Sample)
CT-5.2.7   Summary of Mean Change from Baseline to End of the Single-Blind Run-in Period by Study Day in 
Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score – OC (Efficacy Sample)
CT-5.2.8   Summary of Mean Change from Baseline to End of the Follow-up Period by Study Day in Adult 
ADHD Investigator Symptom Rating Scale (AISRS) Total Score – OC (Efficacy Sample)
CT-5.3.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in AISRS Inattentive Subscale - MMRM, UN (Efficacy Sample)
CT-5.3.2   Summary of Mean Change Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in AISRS Inattentive Subscale - LOCF (Efficacy Sample)
CT-5.3.3   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day AISRS Inattentive Subscale - OC (Efficacy Sample)
CT-5.3.4   Summary of Mean Change from Baseline to End of Single-Blind Placebo Run-in Period in AISRS 
Inattentive Subscale - OC (Efficacy Sample)
CT-5.3.5   Summary of Mean Change from Baseline to End of the Follow-up Period in AISRS Inattentive 
Subscale - OC (Efficacy Sample)
CT-5.3.6   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in AISRS Hyperactive-Impulsive Subscale - MMRM, UN (Efficacy 
Sample)
CT-5.3.7   Summary of Mean Change Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in AISRS Hyperactive-Impulsive Subscale - LOCF (Efficacy Sample)
CT-5.3.8   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day AISRS Hyperactive-Impulsive Subscale - OC (Efficacy Sample)
CT-5.3.9   Summary of Mean Change from Baseline to End of Single-Blind Placebo Run-in Period in AISRS 
Hyperactive-Impulsive Subscale - OC (Efficacy Sample)
CT-5.3.10   Summary of Mean Change from Baseline to End of the Follow-up Period in AISRS Hyperactive-
Impulsive Subscale - OC (Efficacy Sample)
CT-5.4.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Clinical Global Impression - Severity of Illness Modified for ADHD 
(CGI-S) Scale - MMRM, UN (Efficacy Sample)
CT-5.4.2   Summary of Mean Change Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Clinical Global Impression - Severity of Illness Modified for ADHD 
(CGI-S) Scale - LOCF (Efficacy Sample)
CT-5.4.3   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Clinical Global Impression - Severity of Illness Modified for ADHD 
(CGI-S) Scale - OC (Efficacy Sample)
CT-5.5.1   Summary of Mean Clinical Global Impression Change from Baseline Scale by Study Day in the 
Double-Blind Treatment Period - LOCF (Efficacy Sample)
Clinical Study Report 405-201-00014
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CT-5.5.2   Summary of Mean Clinical Global Impression Improvement Change from Baseline Scale by Study 
Day in the Double-Blind Treatment Period - OC (Efficacy Sample)
CT-5.6.1   Summary of Proportion of Responders to Treatment During the Double-Blind Treatment Period   
Relative to the End of the Single-Blind Run-in Period - LOCF (Efficacy Sample)
CT-5.6.2   Summary of Proportion of Responders to Treatment During the Double-Blind Treatment Period   
Relative to the End of the Single-Blind Run-in Period - OC (Efficacy Sample)
CT-5.6.3   Summary of Proportion of Subjects with an Adult ADHD Investigator Symptom Rating Scale 
(AISRS) Total Score or a CGI Change from Baseline Response During the Double-Blind Treatment Period - 
LOCF (Efficacy Sample)
CT-5.6.4   Summary of Proportion of Subjects with an Adult ADHD Investigator Symptom Rating Scale 
(AISRS) Total Score or a CGI Change from Baseline Response During the Double-Blind Treatment Period - 
OC (Efficacy Sample)
CT-5.6.5   Summary of Proportion of Subjects with an Adult ADHD Investigator Symptom Rating Scale 
(AISRS) Total Score Remission During the Double-Blind Treatment Period - LOCF (Efficacy Sample)
CT-5.6.6   Summary of Proportion of Subjects with an Adult ADHD Investigator Symptom Rating Scale 
(AISRS) Total Score Remission During the Double-Blind Treatment Period - OC (Efficacy Sample)
CT-5.7.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Attention-Deficit Hyperactivity Disorder Impact Module - Adult (AIM-
A) Scale - MMRM, UN (Efficacy Sample)
CT-5.7.2   Summary of Mean Change Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Attention-Deficit Hyperactivity Disorder Impact Module - Adult (AIM-
A) Scale - LOCF (Efficacy Sample)
CT-5.7.3   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Attention-Deficit Hyperactivity Disorder Impact Module - Adult (AIM-
A) Scale - OC (Efficacy Sample)
CT-5.7.4   Summary of Mean Change from Baseline to End of Single-Blind Placebo Run-in Period in Attention-
Deficit Hyperactivity Disorder Impact Module - Adult (AIM-A) Scale - OC (Efficacy Sample)
CT-5.7.5   Summary of Proportion of Subjects in Each Category During the Single-Blind Run-in Period and 
Double-Blind Treatment Period by Study Day in in Attention-Deficit Hyperactivity Disorder Impact Module 
- Adult (AIM-A) Scale - OC (Efficacy Sample)
CT-5.8.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Self Report Scale (ASRS) Scale - MMRM, UN (Efficacy 
Sample)
CT-5.8.2   Summary of Mean Change Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Self Report Scale (ASRS) Scale - LOCF (Efficacy Sample)
CT-5.8.3   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Self Report Scale (ASRS) Scale - OC (Efficacy Sample)
CT-5.8.4   Summary of Mean Change from Baseline to End of Single-Blind Placebo Run-in Period in Adult 
ADHD Self Report Scale (ASRS) Scale - OC (Efficacy Sample)
CT-5.9.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in ASRS Inattentive Subscale - MMRM, UN (Efficacy Sample)
CT-5.9.2   Summary of Mean Change Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in ASRS Inattentive Subscale - LOCF (Efficacy Sample)
CT-5.9.3   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in ASRS Inattentive Subscale - OC (Efficacy Sample)
CT-5.9.4   Summary of Mean Change from Baseline to End of Single-Blind Placebo Run-in Period in ASRS 
Inattentive Subscale - OC (Efficacy Sample)
CT-5.9.5   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in ASRS Hyperactive-Impulsive Subscale - MMRM, UN (Efficacy Sample)
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CT-5.9.6   Summary of Mean Change Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in ASRS Hyperactive-Impulsive Subscale - LOCF (Efficacy Sample)
CT-5.9.7   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in ASRS Hyperactive-Impulsive Subscale - OC (Efficacy Sample)
CT-5.9.8   Summary of Mean Change from Baseline to End of Single-Blind Placebo Run-in Period in ASRS 
Hyperactive-Impulsive Subscale - OC (Efficacy Sample)
CT-5.10.1    Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score – MI, VAN ELTEREN TEST (Efficacy Sample)
CT-5.10.2    Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - GEE (Efficacy Sample)
CT-5.10.3    Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-
Blind Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total 
Score - WGEE (Efficacy Sample)
CT-5.11.1 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta Method 
1) in AISRS Total Score Assume All Dropouts as MNAR (Efficacy Sample)
CT-5.11.2 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta Method 
2) in AISRS Total Score Assume All Dropouts as MNAR (Efficacy Sample)
CT-5.11.3 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta Method 
1) in AISRS Total Score Dropout due to AE or LOE or Withdrew Consent as MNAR (Efficacy Sample)
CT-5.11.4 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta Method 
2) in AISRS Total Score Dropout due to AE or LOE or Withdrew Consent as MNAR (Efficacy Sample)
CT-5.11.5 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta Method 
1) in AISRS Total Score Dropouts due to AE or Lack of Efficacy (LOE) as MNAR (Efficacy Sample)
CT-5.11.6 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta Method 
2) in AISRS Total Score Dropouts due to AE or Lack of Efficacy (LOE) as MNAR (Efficacy Sample)
CT-5.11.7 Sensitivity Analysis of MNAR using Placebo Based Imputation in AISRS Total Score (Efficacy 
Sample)
CT-5.11.8 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta Method 
1) in CGI-S Score Assume All Dropouts as MNAR (Efficacy Sample) 
CT-5.11.9 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta Method 
2) in CGI-S Score Assume All Dropouts as MNAR (Efficacy Sample) 
CT-5.11.10 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta 
Method 1) in CGI-S Score Dropout due to AE or LOE or Withdrew Consent as MNAR (Efficacy Sample)
CT-5.11.11 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta 
Method 2) in CGI-S Score Dropout due to AE or LOE or Withdrew Consent as MNAR (Efficacy Sample)
CT-5.11.12 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta 
Method 1) in SDS Mean Score Dropouts due to AE or Lack of Efficacy (LOE) as MNAR (Efficacy Sample)
CT-5.11.13 Sensitivity Analysis of MNAR using Pattern Mixture Model with Multiple Imputation (Delta 
Method 2) in CGI-S Score Dropouts due to AE or Lack of Efficacy (LOE) as MNAR (Efficacy Sample)
CT-5.11.14 Sensitivity Analysis of MNAR using Placebo Based Imputation in CGI-S Score (Efficacy Sample)
CT-5.11.15 Sensitivity Analysis of MNAR Using Model Based Methods: Shared Parameter Model and Random 
Coefficient Pattern Mixture Model –OC (Efficacy Sample)
CT-6.1.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS)Total Score in 
the Subgroup of Females - MMRM (Efficacy Sample)
CT-6.1.2   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score 
in the Subgroup of Males - MMRM (Efficacy Sample)
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CT-6.2.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score 
in the Subgroup of Whites - MMRM (Efficacy Sample)
CT-6.2.2   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Adult ADHD Investigator Symptom Rating Scale (AISRS) Total Score 
in the Subgroup of All Other Races - MMRM (Efficacy Sample)
CT-7.1   Extent of Exposure to Study Medication During the Double-Blind Treatment Period (Safety Sample)
CT-7.2   Number and Percentage of Subjects Receiving Study Medication and Mean and Range of Average 
Daily Dose in the Double-Blind Treatment Period (Safety Sample)
CT-8.1.1   Adverse Events During the Double-Blind Treatment Period (All Causalities) (Safety Sample)
CT-8.1.2   Adverse Events During the Single-Blind Placebo Run-in Period (All Causalities) (Safety Sample)
CT-8.2.1.1   Incidence of TEAEs During the Double-Blind Treatment Period by System Organ Class and 
MedDRA Preferred Term (Safety Sample)
CT-8.2.1.2   Incidence of TEAEs During the Double-Blind Treatment Period by System Organ Class, MedDRA 
Preferred Term and Severity (Safety Sample)
CT-8.2.1.3   Incidence of TEAE During the Double-Blind Treatment Period of at Least 5% in Any 
Centanafadine Group and Greater Than Placebo by System Organ Class and MedDRA Preferred Term 
(Safety Sample)
CT-8.2.1.4   Incidence of TEAEs During the Double-Blind Treatment Period by System Organ Class and 
MedDRA Preferred Term, by Sex (Safety Sample)
CT-8.2.1.5   Incidence of TEAEs During the Double-Blind Treatment Period by System Organ Class and 
MedDRA Preferred Term, by Race (Safety Sample)
CT-8.2.1.6   Incidence of Non-Serious TEAEs During the Double-Blind Treatment Period of at Least 5% in Any 
Centanafadine Group and Greater Than Placebo by System Organ Class and MedDRA Preferred Term 
(Safety Sample)
CT-8.2.1.7   Incidence of TEAE During the Double-Blind Treatment Period of at Least 2% in Any 
Centanafadine Group and Greater Than Placebo by System Organ Class and MedDRA Preferred Term 
(Safety Sample)
CT-8.2.1.8   Incidence and Occurrence (Number of Events) of Serious TEAEs by System Organ Class and 
MedDRA Preferred Term (Safety Sample)
CT-8.2.1.9   Incidence and Occurrence (Number of Events) of Potentially Drug-Related Serious TEAEs by 
System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-8.2.1.10   Incidence and Occurrence (Number of Events) of Non-Serious TEAEs by System Organ Class and 
MedDRA Preferred Term (Safety Sample) 
CT-8.2.2   Incidence of AEs During the Single-Blind Placebo Run-in Period by System Organ Class and 
MedDRA Preferred Term (Safety Sample)
CT-8.3.1   Incidence of Potentially Drug-Related TEAEs During the Double-Blind Treatment Period by System 
Organ Class and MedDRA Preferred Term (Safety Sample)
CT-8.3.2   Incidence of Potentially Drug-Related TEAEs During the Double-Blind Treatment Period by System 
Organ Class, MedDRA Preferred Term and Severity (Safety Sample)
CT-8.4.1.1   Incidence of Deaths Due to TEAEs During the Double-Blind Treatment Period by System Organ 
Class and MedDRA Preferred Term (Safety Sample)
CT-8.4.1.2   Incidence of Deaths Due to TEAEs During the Double-Blind Treatment Period by System Organ 
Class and MedDRA Preferred Term and Severity (Safety Sample)
CT-8.4.2   Incidence of Deaths Due to AEs During the Single-Blind Placebo Run-in Period by System Organ 
Class and MedDRA Preferred Term (Safety Sample)
CT-8.5.1.1   Incidence of Serious TEAEs During the Double-Blind Treatment Period by System Organ Class and 
MedDRA Preferred Term (Safety Sample)
CT-8.5.1.2   Incidence of Serious TEAEs During the Double-Blind Treatment Period by System Organ Class, 
MedDRA Preferred Term and Severity (Safety Sample)
Clinical Study Report 405-201-00014
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CT-8.5.2.1   Incidence of Serious AEs During the Single-Blind Placebo Run-in Period by System Organ Class 
and MedDRA Preferred Term (Safety Sample)
CT-8.6.1   Incidence of TEAEs Resulting in Discontinuation of Study Medication During the Double-Blind 
Treatment Period by System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-8.6.2   Incidence of TEAEs Resulting in Discontinuation of Study Medication During the Double-Blind 
Treatment Period by System Organ Class, MedDRA Preferred Term and Severity (Safety Sample)
CT-8.7.1   Incidence of Treatment-Emergent Adverse Events of Special Interests (AESIs) During the Double-
Blind Treatment Period by System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-8.7.2   Incidence of Treatment-Emergent Adverse Events of Special Interests (AESIs) During the Double-
Blind Treatment Period by System Organ Class and MedDRA Preferred Term and Severity (Safety Sample)
CT-8.7.3   Listing of Treatment-Emergent Adverse Events of Special Interests (AESIs) During the Double-Blind 
Treatment Period (Safety Sample)
CT-8.8.1   Incidence of Treatment-Emergent Abuse Potential-Related Adverse Events During the Double-Blind 
Treatment Period by System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-8.8.2   Incidence of Treatment-Emergent Abuse Potential-Related Adverse Events During the Double-Blind 
Treatment Period by System Organ Class and MedDRA Preferred Term and Severity (Safety Sample)
CT-8.8.3   Listing of Treatment-Emergent Abuse Potential-Related Adverse Events During the Double-Blind 
Treatment Period (Safety Sample)
CT-9.1.1   Listing of Deaths During the Double-Blind Treatment Period
CT-9.1.2   Listing of Deaths During the Single-Blind Placebo Run-in Period
CT-9.2.1   Listing of Serious Adverse Events During the Double-Blind Treatment Period
CT-9.2.2   Listing of Serious Adverse Events During the Single-Blind Placebo Run-in Period
CT-9.3   Listing of Discontinuations of Study Medication Due to Adverse Events During the Double-Blind 
Treatment Period
CT-9.4   Listing of Adverse Events for Subjects Discontinued from Study Due to Adverse Events During the 
Double-Blind Treatment Period
CT-10.1   Criteria for Laboratory Test Values with Potential Clinical Relevance
CT-10.2.1.1   Listing of Laboratory Test Values with Potential Clinical Relevance During the Double-Blind 
Treatment Period by Subject (Safety Sample)
CT-10.2.1.2   Listing of Laboratory Test Values with Potential Clinical Relevance During the Double-Blind 
Treatment Period by Test (Safety Sample)
CT-10.2.2   Incidence of Laboratory Test Values with Potential Clinical Relevance During the Double-Blind 
Treatment Period (Safety Sample)
CT-10.2.3.1   Mean Change from Baseline of the Double-Blind Treatment Period in Clinical Laboratory Test 
Results - Serum Chemistry (Safety Sample)
CT-10.2.3.2   Mean Change from Baseline of the Double-Blind Treatment Period in Clinical Laboratory Test 
Results - Hematology (Safety Sample)
CT-10.2.3.3   Mean Change from Baseline of the Double-Blind Treatment Period in Clinical Laboratory Test 
Results - Urinalysis (Safety Sample)
CT-10.3.1.1   Listing of Laboratory Test Values with Potential Clinical Relevance During the Single-Blind 
Placebo Run-in Period by Subject (Safety Sample)
CT-10.3.1.2   Listing of Laboratory Test Values with Potential Clinical Relevance During the Single-Blind 
Placebo Run-in Period by Test (Safety Sample)
CT-10.3.2   Incidence of Laboratory Test Values with Potential Clinical Relevance During the Single-Blind 
Placebo Run-in Period (Safety Sample)
CT-10.3.3.1   Mean Change from Baseline of the Single-Blind Placebo Run-in Period in Clinical Laboratory 
Test Results During the Single-Blind Placebo Run-in Period - Serum Chemistry (Safety Sample)
CT-10.3.3.2   Mean Change from Baseline of the Single-Blind Placebo Run-in Period in Clinical Laboratory 
Test Results During the Single-Blind Placebo Run-in Period - Hematology (Safety Sample)
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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CT-10.3.3.3   Mean Change from Baseline of the Single-Blind Placebo Run-in Period in Clinical Laboratory 
Test Results During the Single-Blind Placebo Run-in Period - Urinalysis (Safety Sample)
CT-10.4.1   Incidence of Potentially Liver Injury Related Laboratory Test Abnormalities During the Double-
Blind Treatment Period (Safety Sample)
CT-10.4.2   Incidence of Potentially Liver Injury Related Laboratory Test Abnormalities During the Single-
Blind Placebo Run-in Period (Safety Sample)
CT-10.5.1   Listing of Potentially Liver Injury Related Laboratory Test Abnormalities During the Double-Blind 
Treatment Period (Safety Sample)
CT-10.5.2   Listing of Potentially Liver Injury Related Laboratory Test Abnormalities During the Single-Blind 
Placebo Run-in Period (Safety Sample)
CT-11.1   Criteria for Potentially Clinically Relevant Abnormalities in Vital Signs
CT-11.2.1   Listing of Potentially Clinically Relevant Abnormalities in Vital Signs During the Double-Blind 
Treatment Period (Safety Sample)
CT-11.2.2   Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs During the Double-Blind 
Treatment Period (Safety Sample)
CT-11.2.3   Mean Change from Baseline of the Double-Blind Treatment Period in Vital Signs During the 
Double-Blind Treatment Period (Safety Sample)
CT-11.3.1   Listing of Potentially Clinically Relevant Abnormalities in Vital Signs During the Single-Blind 
Placebo Run-in Period (Safety Sample)
CT-11.3.2   Incidence of Potentially Clinically Relevant Abnormalities in Vital Signs During the Single-Blind 
Placebo Run-in Period (Safety Sample)
CT-11.3.3   Mean Change from Baseline of the Single-Blind Placebo Run-in Period in Vital Signs During the 
Single-Blind Placebo Run-in Period (Safety Sample)
CT-12.1   Criteria for Potentially Clinically Relevant Abnormalities in ECG Evaluations
CT-12.2.1   Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations During the Double-
Blind Treatment Period (Safety Sample)
CT-12.2.2   Incidence of Potentially Clinically Relevant Changes in ECG Evaluations During the Double-Blind 
Treatment Period (Safety Sample)
CT-12.2.3   Mean Change from Baseline of the Double-Blind Treatment Period in Electrocardiogram Results 
During the Double-Blind Treatment Period (Safety Sample)
CT-12.3.1   Listing of Categorical Changes in QT/QTc During the Double-Blind Treatment Period (Safety 
Sample)
CT-12.3.2   Incidence of Categorical Changes in QT/QTc During the Double-Blind Treatment Period (Safety 
Sample)
CT-12.4.1   Listing of Potentially Clinically Relevant Abnormalities in ECG Evaluations During the Single-
Blind Placebo Run-in Period (Safety Sample)
CT-12.4.2   Incidence of Potentially Clinically Relevant Changes in ECG Evaluations During the Single-Blind 
Placebo Run-in Period (Safety Sample)
CT-12.4.3   Mean Change from Baseline of the Single-Blind Placebo Run-in Period in Electrocardiogram 
Results During the Single-Blind Placebo Run-in Period (Safety Sample)
CT-12.5.1   Listing of Categorical Changes in QT/QTc During the Single-Blind Placebo Run-in Period (Safety 
Sample)
CT-12.5.2   Incidence of Categorical Changes in QT/QTc During the Single-Blind Placebo Run-in Period 
(Safety Sample)
CT-13.1.1   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Body Weight (kg) (Safety Sample)
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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42
26 May 2020
CT-13.1.2   Summary of Proportion of Patients with Potentially Clinically Relevant Weight Gain or Weight Loss 
During the Double-Blind Treatment Period (Safety Sample)
CT-13.2   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in Waist Circumference (cm) (Safety Sample)
CT-13.3   Summary of Mean Change from Baseline of the Double-Blind Treatment Period to the Double-Blind 
Treatment Period by Study Day in BMI (kg/m2) (Safety Sample)
CT-14.1.1   Columbia-Suicide Severity Rating Scale(C-SSRS) During the Double-Blind Treatment Period, 
Suicidality (Safety Sample)
CT-14.1.2   Columbia-Suicide Severity Rating Scale(C-SSRS) During the Double-Blind Treatment Period, 
Suicidal Behavior by Type (Safety Sample)
CT-14.1.3   Columbia-Suicide Severity Rating Scale(C-SSRS) During the Double-Blind Treatment Period, 
Suicidal Ideation by Type (Safety Sample)
CT-14.1.4   Columbia-Suicide Severity Rating Scale(C-SSRS) During the Double-Blind Treatment Period, 
Treatment Emergent Suicidal Behavior and Ideation (Safety Sample)
CT-14.1.5   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Suicidal 
Ideation During the Double-Blind Treatment Period (Safety Sample)
CT-14.1.6   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Suicidal 
Behavior During the Double-Blind Treatment Period (Safety Sample)
CT-14.1.7   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Serious 
Suicidal Ideation During the Double-Blind Treatment Period (Safety Sample)
CT-14.1.8   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Worsening Suicidal Ideation During 
the Double-Blind Treatment Period (Safety Sample)
CT-14.2.1   Columbia-Suicide Severity Rating Scale (C-SSRS) During the Single-Blind Placebo Run-in Period, 
Suicidality (Safety Sample)
CT-14.2.2   Columbia-Suicide Severity Rating Scale (C-SSRS) During the Single-Blind Placebo Run-in Period, 
Suicidal Behavior by Type (Safety Sample)
CT-14.2.3   Columbia-Suicide Severity Rating Scale (C-SSRS) During the Single-Blind Placebo Run-in Period, 
Suicidal Ideation by Type (Safety Sample)
CT-14.2.4   Columbia-Suicide Severity Rating Scale (C-SSRS) During the Single-Blind Placebo Run-in Period, 
Treatment Emergent Suicidal Behavior and Ideation (Safety Sample)
CT-14.2.5   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Suicidal 
Ideation During the Single-Blind Placebo Run-in Period (Safety Sample)
CT-14.2.6   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Suicidal 
Behavior During the Single-Blind Placebo Run-in Period (Safety Sample)
CT-14.2.7   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Treatment Emergent Serious 
Suicidal Ideation During the Single-Blind Placebo Run-in Period (Safety Sample)
CT-14.2.8   Columbia-Suicide Severity Rating Scale (C-SSRS) – Listing of Worsening Suicidal Ideation During 
the Single-Blind Placebo Run-in Period (Safety Sample)
CT-15   Summary of Mean Study Medication Withdrawal Questionnaire (SMWQ) Total Score During the 
Double-Blind Treatment Period and Follow-up Period by Study Day (Safety Sample)
CT-16   Summary of Medication Handling Irregularity (Safety Sample)
CT-17.1   Summary of ESAMs Reported as Abuse Potential AEs During the Double-Blind Treatment Period by 
System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-17.2   Summary of Non-Adverse Events Reported as Findings (ESAM) During the Double-Blind Treatment 
Period (Safety Sample)
CT-17.3   Summary of ESAMs Reported as Abuse Potential AEs During the Single-Blind Placebo Run-in Period 
by System Organ Class and MedDRA Preferred Term (Safety Sample)
CT-17.4   Summary of Non-Adverse Events Reported as Findings (ESAM) During the Single-Blind Placebo 
Run-in Period (Safety Sample)
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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16.1.9 Documentation of Statistical Methods
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Document Name: 405-201-00014_Statistical_Analysis_Plan
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Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
46


CENTANAFADINE                                                                                                               1 OF 5
PROTOCOL 405-201-00014                                                                                                                               
STAT-1.1  
Adjusted Mean Change from Baseline in AISRS Line Items at Day 42 - MMRM  
(Efficacy Sample)
                                                                                                                                                     
 ----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                  CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
        AISRS                       MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
        Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
        -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                     
        MAKE CARELESS MISTAKES  140  2.15  -0.75   140  2.19  -0.72   141  2.18  -0.44    EB-1020 200mg VS       -0.32     0.0059    -0.33           
                                                                                          PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.29     0.0149    -0.29           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        FIDGET OR SQUIRM WITH   140  2.21  -0.50   140  2.28  -0.51   141  2.18  -0.50    EB-1020 200mg VS       -0.00     0.9973    -0.00           
        YOUR HANDS OR FEET                                                                PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.01     0.9113    -0.01           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        DIFFICULTY KEEPING      140  2.57  -0.78   140  2.54  -0.73   141  2.54  -0.49    EB-1020 200mg VS       -0.29     0.0113    -0.30           
        YOUR ATTENTION                                                                    PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.24     0.0450    -0.24           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        LEAVE YOUR SEAT         140  1.72  -0.59   140  1.78  -0.65   141  1.64  -0.50    EB-1020 200mg VS       -0.09     0.4319    -0.09           
                                                                                          PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.15     0.1936    -0.16           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        DIFFICULTY              140  2.29  -0.80   140  2.30  -0.75   141  2.29  -0.50    EB-1020 200mg VS       -0.30     0.0104    -0.31           
        CONCENTRATING ON                                                                  PLACEBO                                                    
                                                                                                                                                     
                                                                                                                                                     
 ----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: aisrs_itema.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
47


CENTANAFADINE                                                                                                               2 OF 5
PROTOCOL 405-201-00014                                                                                                                               
                                                                      STAT-1.1                                                                      
                                      Adjusted Mean Change from Baseline in AISRS Line Items at Day 42 - MMRM                                       
                                                                 (Efficacy Sample)                                                                  
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                 CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
       AISRS                       MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
       Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
       -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                    
       DIFFICULTY                                                                        EB-1020 400mg VS       -0.25     0.0356    -0.25           
       CONCENTRATING ON                                                                  PLACEBO                                                    
                                                                                                                                                    
       FEEL RESTLESS OR        140  1.93  -0.44   140  2.15  -0.62   141  2.06  -0.41    EB-1020 200mg VS       -0.04     0.7284    -0.04           
       FIDGETY                                                                           PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.22     0.0486    -0.24           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       TROUBLE WRAPPING UP     140  2.40  -0.67   140  2.44  -0.73   141  2.55  -0.47    EB-1020 200mg VS       -0.20     0.0649    -0.22           
       THE FINAL DETAILS                                                                 PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.26     0.0202    -0.28           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       DIFFICULTY UNWINDING    140  1.87  -0.44   140  1.91  -0.41   141  1.80  -0.34    EB-1020 200mg VS       -0.09     0.4355    -0.09           
       AND RELAXING                                                                      PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.06     0.5941    -0.06           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       DIFFICULTY GETTING      140  2.36  -0.74   140  2.54  -0.84   141  2.53  -0.62    EB-1020 200mg VS       -0.13     0.2832    -0.13           
       THINGS IN ORDER                                                                   PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.22     0.0627    -0.22           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: aisrs_itema.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
48


CENTANAFADINE                                                                                                               3 OF 5
PROTOCOL 405-201-00014                                                                                                                               
                                                                      STAT-1.1                                                                      
                                      Adjusted Mean Change from Baseline in AISRS Line Items at Day 42 - MMRM                                       
                                                                 (Efficacy Sample)                                                                  
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                 CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
       AISRS                       MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
       Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
       -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                    
       OVERLY ACTIVE AND       140  1.79  -0.49   140  1.92  -0.61   141  1.75  -0.46    EB-1020 200mg VS       -0.02     0.8394    -0.02           
       COMPELLED TO DO THINGS                                                            PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.14     0.2203    -0.15           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       AVOID OR DELAY          140  2.51  -0.67   140  2.52  -0.59   141  2.50  -0.44    EB-1020 200mg VS       -0.23     0.0473    -0.24           
       GETTING STARTED                                                                   PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.15     0.2113    -0.15           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       TALKING TOO MUCH        140  1.71  -0.61   140  1.85  -0.68   141  1.71  -0.47    EB-1020 200mg VS       -0.14     0.1981    -0.15           
                                                                                         PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.21     0.0668    -0.22           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       MISPLACE OR HAVE        140  2.20  -0.77   140  2.21  -0.78   141  2.12  -0.41    EB-1020 200mg VS       -0.35     0.0022    -0.37           
       DIFFICULTY FINDING                                                                PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.37     0.0017    -0.38           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       FINISHING THE           140  1.90  -0.84   140  1.92  -0.77   141  1.80  -0.42    EB-1020 200mg VS       -0.42     0.0002    -0.45           
       SENTENCES OF THE                                                                  PLACEBO                                                    
       PEOPLE                                                                                                                                       
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: aisrs_itema.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
49


CENTANAFADINE                                                                                                               4 OF 5
PROTOCOL 405-201-00014                                                                                                                               
                                                                      STAT-1.1                                                                      
                                      Adjusted Mean Change from Baseline in AISRS Line Items at Day 42 - MMRM                                       
                                                                 (Efficacy Sample)                                                                  
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                 CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
       AISRS                       MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
       Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
       -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                    
       FINISHING THE                                                                     EB-1020 400mg VS       -0.35     0.0025    -0.36           
       SENTENCES OF THE                                                                  PLACEBO                                                    
       PEOPLE                                                                                                                                       
                                                                                                                                                    
       BEING DISTRACTED BY     140  2.39  -0.75   140  2.47  -0.60   141  2.53  -0.35    EB-1020 200mg VS       -0.41     0.0001    -0.46           
       ACTIVITY OR NOISE                                                                 PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.25     0.0191    -0.28           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       DIFFICULTY WAITING      140  1.87  -0.74   140  1.91  -0.77   141  1.79  -0.48    EB-1020 200mg VS       -0.26     0.0176    -0.28           
       YOUR TURN                                                                         PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.29     0.0100    -0.31           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       PROBLEMS REMEMBERING    140  2.01  -0.81   140  2.11  -0.67   141  2.11  -0.44    EB-1020 200mg VS       -0.37     0.0026    -0.36           
                                                                                         PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.23     0.0648    -0.22           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       INTERRUPT OTHERS WHEN   140  1.71  -0.71   140  1.73  -0.82   141  1.57  -0.43    EB-1020 200mg VS       -0.29     0.0068    -0.32           
       THEY ARE BUSY                                                                     PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.39     0.0004    -0.43           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: aisrs_itema.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
50


CENTANAFADINE                                                                                                               5 OF 5
PROTOCOL 405-201-00014                                                                                                                               
                                                                      STAT-1.1                                                                      
                                      Adjusted Mean Change from Baseline in AISRS Line Items at Day 42 - MMRM                                       
                                                                 (Efficacy Sample)                                                                  
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                 CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
       AISRS                       MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
       Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
       -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                    
       AISRS TOTAL SCORE       140 37.59  -12.1   140 38.76  -12.5   141 37.65  -8.07    EB-1020 200mg VS       -4.01     0.0021    -0.37           
       (DERIVED)                                                                         PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -4.42     0.0009    -0.40           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: aisrs_itema.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
51


CENTANAFADINE                                                                                                               1 OF 5
PROTOCOL 405-201-00014                                                                                                                               
STAT-1.2  
Adjusted Mean Change from Baseline in ASRS Line Items at Day 42 - MMRM  
(Efficacy Sample)
                                                                                                                                                     
 ----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                  CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
        ASRS                        MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
        Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
        -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                     
        ASRS-TROUBLE TO WRAP    124  2.85  -0.67   114  2.73  -0.57   130  2.95  -0.29    EB-1020 200mg VS       -0.38     0.0015    -0.40           
        DETAILS OF PROJECT                                                                PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.29     0.0213    -0.30           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-DIFFICULTY         124  2.81  -0.72   114  2.90  -0.62   130  3.00  -0.30    EB-1020 200mg VS       -0.42     0.0008    -0.43           
        GETTING THINGS IN                                                                 PLACEBO                                                    
        ORDER                                                                                                                                        
                                                                                          EB-1020 400mg VS       -0.33     0.0100    -0.33           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-PROBLEM            124  2.56  -0.82   114  2.67  -0.70   130  2.72  -0.42    EB-1020 200mg VS       -0.40     0.0022    -0.39           
        REMEMBERING                                                                       PLACEBO                                                    
        APPTS/OBLIGATNS                                                                                                                              
                                                                                          EB-1020 400mg VS       -0.28     0.0330    -0.27           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-AVOID/DELAY        124  3.06  -0.63   114  3.22  -0.72   130  3.19  -0.40    EB-1020 200mg VS       -0.22     0.0685    -0.23           
        GETTNG STARTD ON                                                                  PLACEBO                                                    
        THGHTS                                                                                                                                       
                                                                                          EB-1020 400mg VS       -0.32     0.0128    -0.32           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
                                                                                                                                                     
 ----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: aisrs_itemb.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
52


CENTANAFADINE                                                                                                               2 OF 5
PROTOCOL 405-201-00014                                                                                                                               
                                                                      STAT-1.2                                                                      
                                       Adjusted Mean Change from Baseline in ASRS Line Items at Day 42 - MMRM                                       
                                                                 (Efficacy Sample)                                                                  
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                 CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
       ASRS                        MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
       Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
       -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                    
       ASRS-FIDGET/SQUIRM      124  3.01  -0.59   114  2.99  -0.56   130  3.00  -0.47    EB-1020 200mg VS       -0.12     0.3314    -0.12           
       WITH HANDS/FEET                                                                   PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.09     0.4849    -0.09           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-FEEL OVERLY        124  2.56  -0.52   114  2.56  -0.56   130  2.55  -0.46    EB-1020 200mg VS       -0.07     0.6162    -0.06           
       ACTIVE TO DO THINGS                                                               PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.10     0.4410    -0.10           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-MAKE CARELESS      124  2.69  -0.73   114  2.76  -0.79   130  2.81  -0.40    EB-1020 200mg VS       -0.33     0.0104    -0.32           
       MISTAKES                                                                          PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.39     0.0034    -0.38           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-DIFFICULTY         124  3.18  -0.84   114  3.28  -0.75   130  3.38  -0.37    EB-1020 200mg VS       -0.46     0.0004    -0.45           
       KEEPING ATTENTION                                                                 PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.38     0.0042    -0.37           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-DIFFICULTY         124  2.76  -0.81   114  2.89  -0.79   130  2.96  -0.30    EB-1020 200mg VS       -0.50     0.0000    -0.52           
       KEEPING CONCENTRATION                                                             PLACEBO                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: aisrs_itemb.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
53


CENTANAFADINE                                                                                                               3 OF 5
PROTOCOL 405-201-00014                                                                                                                               
                                                                      STAT-1.2                                                                      
                                       Adjusted Mean Change from Baseline in ASRS Line Items at Day 42 - MMRM                                       
                                                                 (Efficacy Sample)                                                                  
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                 CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
       ASRS                        MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
       Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
       -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                    
       ASRS-DIFFICULTY                                                                   EB-1020 400mg VS       -0.49     0.0001    -0.50           
       KEEPING CONCENTRATION                                                             PLACEBO                                                    
                                                                                                                                                    
       ASRS-MISPLACE/DIFFICUL  124  2.74  -0.83   114  3.00  -0.85   130  2.90  -0.40    EB-1020 200mg VS       -0.42     0.0009    -0.42           
       TY FINDING THINGS                                                                 PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.44     0.0007    -0.44           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-DISTRACTED BY      124  3.10  -0.73   114  3.09  -0.61   130  3.15  -0.27    EB-1020 200mg VS       -0.47     0.0001    -0.48           
       ACTIVITY OR NOISE                                                                 PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.35     0.0061    -0.35           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-LEAVE SEAT IN      124  1.95  -0.59   114  2.10  -0.76   130  1.90  -0.32    EB-1020 200mg VS       -0.26     0.0347    -0.27           
       MEETNGS/ORDR SITUATNS                                                             PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.44     0.0008    -0.44           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-FEELING RESTLESS   124  2.92  -0.65   114  2.89  -0.70   130  2.89  -0.46    EB-1020 200mg VS       -0.19     0.1224    -0.19           
       OR FIDGETY                                                                        PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.24     0.0623    -0.24           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: aisrs_itemb.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
54


CENTANAFADINE                                                                                                               4 OF 5
PROTOCOL 405-201-00014                                                                                                                               
                                                                      STAT-1.2                                                                      
                                       Adjusted Mean Change from Baseline in ASRS Line Items at Day 42 - MMRM                                       
                                                                 (Efficacy Sample)                                                                  
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                 CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
       ASRS                        MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
       Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
       -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                    
       ASRS-DIFF UNWINDING     124  2.56  -0.57   114  2.61  -0.61   130  2.64  -0.42    EB-1020 200mg VS       -0.15     0.2810    -0.14           
       AND RELAXING                                                                      PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.19     0.1729    -0.18           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-FIND YOURSELF      124  2.52  -0.75   114  2.61  -0.70   130  2.58  -0.45    EB-1020 200mg VS       -0.31     0.0119    -0.32           
       TALKING TOO MUCH                                                                  PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.26     0.0408    -0.26           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-FINISH SENTENCES   124  2.62  -0.87   114  2.65  -0.86   130  2.68  -0.54    EB-1020 200mg VS       -0.33     0.0103    -0.32           
       OF PEOPLE                                                                         PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.32     0.0165    -0.31           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-DIFFCULTY          124  2.30  -0.72   114  2.55  -0.74   130  2.42  -0.45    EB-1020 200mg VS       -0.26     0.0433    -0.25           
       WAITING YOUR TURN                                                                 PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -0.28     0.0355    -0.27           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
       ASRS-INTERRUPT OTHERS   124  2.21  -0.67   114  2.33  -0.83   130  2.47  -0.54    EB-1020 200mg VS       -0.13     0.2921    -0.13           
       WHEN THEY ARE BUSY                                                                PLACEBO                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: aisrs_itemb.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
55


CENTANAFADINE                                                                                                               5 OF 5
PROTOCOL 405-201-00014                                                                                                                               
                                                                      STAT-1.2                                                                      
                                       Adjusted Mean Change from Baseline in ASRS Line Items at Day 42 - MMRM                                       
                                                                 (Efficacy Sample)                                                                  
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                 CTN SR 200MG       CTN SR 400MG          PLACEBO                             ESTIMATED           COHEN's D         
       ASRS                        MEAN  LSMean       MEAN  LSMean       MEAN  LSMean    TREATMENT            TREATMENT             EFFECT          
       Line Items               N  Base  Change¹   N  Base  Change¹   N  Base  Change¹   COMPARISON            EFFECT ¹  P-VALUE¹    SIZE           
       -------------------------------------------------------------------------------------------------------------------------------------        
                                                                                                                                                    
       ASRS-INTERRUPT OTHERS                                                             EB-1020 400mg VS       -0.28     0.0211    -0.30           
       WHEN THEY ARE BUSY                                                                PLACEBO                                                    
                                                                                                                                                    
       ASRS TOTAL SCORE OF     124 48.39  -12.2   114 49.83  -12.6   130 50.21  -7.28    EB-1020 200mg VS       -4.91     0.0016    -0.40           
       18 ITEMS (DERIVED)                                                                PLACEBO                                                    
                                                                                         EB-1020 400mg VS       -5.33     0.0009    -0.43           
                                                                                         PLACEBO                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ MIXED MODEL REPEATED MEASURES METHOD WITH MODEL TERMS: TREATMENT, (POOLED) STUDY CENTER, VISIT, TREATMENT BY VISIT AND BASELINE BY VISIT INTERACTIO
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: aisrs_itemb.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
56


CENTANAFADINE                                                                                                               1 OF 28
PROTOCOL 405-201-00014                                                                                                                               
STAT-3.1  
MMRM Output for Test on Treatment by Sex Interaction at Day 42  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                Model Information                                                                   
                                                                                                                                                    
                                              Data Set                     WORK.INDATA                                                              
                                              Dependent Variable           CHG                                                                      
                                              Covariance Structure         Unstructured                                                             
                                              Subject Effect               SUBJID                                                                   
                                              Estimation Method            REML                                                                     
                                              Residual Variance Method     None                                                                     
                                              Fixed Effects SE Method      Kenward-Roger                                                            
                                              Degrees of Freedom Method    Kenward-Roger                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                                                                                                    
                                               AVISITN          6    7 14 21 28 35 42                                                               
                                               TRTPN            3    1 2 3                                                                          
                                               POOLCNTR        39   
                                                  
                                                                    
                                                  
                                                                    
                                                  
                                                                    
                                                  
                                                                    
                                                  
                                                                    
                                                  
                                                                    
                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
57


CENTANAFADINE                                                                                                               2 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                    
                                                
                                               SUBJID         421   
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
58


CENTANAFADINE                                                                                                               3 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
59


CENTANAFADINE                                                                                                               4 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                     
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
60


CENTANAFADINE                                                                                                               5 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
61


CENTANAFADINE                                                                                                               6 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
62


CENTANAFADINE                                                                                                               7 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                    
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                SEX              2    F M                                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
63


CENTANAFADINE                                                                                                               8 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                   Dimensions                                                                       
                                                                                                                                                    
                                                       Covariance Parameters            21                                                          
                                                       Columns in X                    129                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        421                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2227                                                      
                                                   Number of Observations Used            2227                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                Iteration History                                                                   
                                                                                                                                                    
                                           Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                    
                                                   0              1     15728.87827870                                                              
                                                   1              2     13520.41397294      0.00033945                                              
                                                   2              1     13518.67561888      0.00000469                                              
                                                   3              1     13518.65293347      0.00000000                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
64


CENTANAFADINE                                                                                                               9 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                            Convergence criteria met.                                                               
                                                                                                                                                    
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(1,1)     SUBJID      43.3236                                                            
                                                         UN(2,1)     SUBJID      38.2897                                                            
                                                         UN(2,2)     SUBJID      70.3806                                                            
                                                         UN(3,1)     SUBJID      37.4535                                                            
                                                         UN(3,2)     SUBJID      60.2826                                                            
                                                         UN(3,3)     SUBJID      81.6833                                                            
                                                         UN(4,1)     SUBJID      38.9483                                                            
                                                         UN(4,2)     SUBJID      59.0458                                                            
                                                         UN(4,3)     SUBJID      73.8743                                                            
                                                         UN(4,4)     SUBJID      89.8024                                                            
                                                         UN(5,1)     SUBJID      38.5482                                                            
                                                         UN(5,2)     SUBJID      60.6062                                                            
                                                         UN(5,3)     SUBJID      72.6270                                                            
                                                         UN(5,4)     SUBJID      82.3083                                                            
                                                         UN(5,5)     SUBJID      97.7229                                                            
                                                         UN(6,1)     SUBJID      37.9468                                                            
                                                         UN(6,2)     SUBJID      60.5956                                                            
                                                         UN(6,3)     SUBJID      74.6496                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
65


CENTANAFADINE                                                                                                               10 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(6,4)     SUBJID      84.5321                                                            
                                                         UN(6,5)     SUBJID      91.9940                                                            
                                                         UN(6,6)     SUBJID       109.35                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood         13518.7                                                         
                                                      AIC (Smaller is Better)       13560.7                                                         
                                                      AICC (Smaller is Better)      13561.1                                                         
                                                      BIC (Smaller is Better)       13645.5                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           20       2210.23          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
66


CENTANAFADINE                                                                                                               11 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                          Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                    
                                                                    Num     Den                                                                     
                                              Effect                 DF      DF    F Value    Pr > F                                                
                                                                                                                                                    
                                              POOLCNTR               38     377       2.08    0.0003                                                
                                              AVISITN                 5     348       1.04    0.3931                                                
                                              TRTPN                   2     375      10.16    <.0001                                                
                                              AVISITN*TRTPN          10     518       1.60    0.1019                                                
                                              SEX                     1     389       0.50    0.4820                                                
                                              AVISITN*SEX             5     346       1.55    0.1739                                                
                                              TRTPN*SEX               2     391       1.17    0.3101                                                
                                              AVISITN*TRTPN*SEX      10     518       0.43    0.9331                                                
                                              BASE*AVISITN            6     376       1.86    0.0859                                                
                                                                                                                                                    
                                                                                                                                                    
                                                    Coefficients for 1 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      Intercept           
                                                                                     
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                                          
                                                                                     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
67


CENTANAFADINE                                                                                                               12 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 1 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                          
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                                          
                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
68


CENTANAFADINE                                                                                                               13 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 1 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                          
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      AVISITN            
             7                                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
69


CENTANAFADINE                                                                                                               14 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 1 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN                               14                                                                      
                                      AVISITN                               21                                                                      
                                      AVISITN                               28                                                                      
                                      AVISITN                               35                                                                      
                                      AVISITN                               42                                                                      
                                      TRTPN                                             1                                                           
                                      TRTPN                                             2                                                           
                                      TRTPN                                             3                                                           
                                      AVISITN*TRTPN                          7          1                                                           
                                      AVISITN*TRTPN                          7          2                                                           
                                      AVISITN*TRTPN                          7          3                                                           
                                      AVISITN*TRTPN                         14          1                                                           
                                      AVISITN*TRTPN                         14          2                                                           
                                      AVISITN*TRTPN                         14          3                                                           
                                      AVISITN*TRTPN                         21          1                                                           
                                      AVISITN*TRTPN                         21          2                                                           
                                      AVISITN*TRTPN                         21          3                                                           
                                      AVISITN*TRTPN                         28          1                                                           
                                      AVISITN*TRTPN                         28          2                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
70


CENTANAFADINE                                                                                                               15 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 1 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN*TRTPN                         28          3                                                           
                                      AVISITN*TRTPN                         35          1                                                           
                                      AVISITN*TRTPN                         35          2                                                           
                                      AVISITN*TRTPN                         35          3                                                           
                                      AVISITN*TRTPN                         42          1                                                           
                                      AVISITN*TRTPN                         42          2                                                           
                                      AVISITN*TRTPN                         42          3                                                           
                                      SEX                            F                                                                              
                                      SEX                            M                                                                              
                                      AVISITN*SEX                    F       7                                                                      
                                      AVISITN*SEX                    M       7                                                                      
                                      AVISITN*SEX                    F      14                                                                      
                                      AVISITN*SEX                    M      14                                                                      
                                      AVISITN*SEX                    F      21                                                                      
                                      AVISITN*SEX                    M      21                                                                      
                                      AVISITN*SEX                    F      28                                                                      
                                      AVISITN*SEX                    M      28                                                                      
                                      AVISITN*SEX                    F      35                                                                      
                                      AVISITN*SEX                    M      35                                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
71


CENTANAFADINE                                                                                                               16 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 1 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN*SEX                    F      42                                                                      
                                      AVISITN*SEX                    M      42                                                                      
                                      TRTPN*SEX                      F                  1                 1                                         
                                      TRTPN*SEX                      M                  1                -1                                         
                                      TRTPN*SEX                      F                  2                                                           
                                      TRTPN*SEX                      M                  2                                                           
                                      TRTPN*SEX                      F                  3                -1                                         
                                      TRTPN*SEX                      M                  3                 1                                         
                                      AVISITN*TRTPN*SEX              F       7          1                                                           
                                      AVISITN*TRTPN*SEX              M       7          1                                                           
                                      AVISITN*TRTPN*SEX              F       7          2                                                           
                                      AVISITN*TRTPN*SEX              M       7          2                                                           
                                      AVISITN*TRTPN*SEX              F       7          3                                                           
                                      AVISITN*TRTPN*SEX              M       7          3                                                           
                                      AVISITN*TRTPN*SEX              F      14          1                                                           
                                      AVISITN*TRTPN*SEX              M      14          1                                                           
                                      AVISITN*TRTPN*SEX              F      14          2                                                           
                                      AVISITN*TRTPN*SEX              M      14          2                                                           
                                      AVISITN*TRTPN*SEX              F      14          3                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
72


CENTANAFADINE                                                                                                               17 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 1 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN*TRTPN*SEX              M      14          3                                                           
                                      AVISITN*TRTPN*SEX              F      21          1                                                           
                                      AVISITN*TRTPN*SEX              M      21          1                                                           
                                      AVISITN*TRTPN*SEX              F      21          2                                                           
                                      AVISITN*TRTPN*SEX              M      21          2                                                           
                                      AVISITN*TRTPN*SEX              F      21          3                                                           
                                      AVISITN*TRTPN*SEX              M      21          3                                                           
                                      AVISITN*TRTPN*SEX              F      28          1                                                           
                                      AVISITN*TRTPN*SEX              M      28          1                                                           
                                      AVISITN*TRTPN*SEX              F      28          2                                                           
                                      AVISITN*TRTPN*SEX              M      28          2                                                           
                                      AVISITN*TRTPN*SEX              F      28          3                                                           
                                      AVISITN*TRTPN*SEX              M      28          3                                                           
                                      AVISITN*TRTPN*SEX              F      35          1                                                           
                                      AVISITN*TRTPN*SEX              M      35          1                                                           
                                      AVISITN*TRTPN*SEX              F      35          2                                                           
                                      AVISITN*TRTPN*SEX              M      35          2                                                           
                                      AVISITN*TRTPN*SEX              F      35          3                                                           
                                      AVISITN*TRTPN*SEX              M      35          3                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
73


CENTANAFADINE                                                                                                               18 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 1 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN*TRTPN*SEX              F      42          1                 1                                         
                                      AVISITN*TRTPN*SEX              M      42          1                -1                                         
                                      AVISITN*TRTPN*SEX              F      42          2                                                           
                                      AVISITN*TRTPN*SEX              M      42          2                                                           
                                      AVISITN*TRTPN*SEX              F      42          3                -1                                         
                                      AVISITN*TRTPN*SEX              M      42          3                 1                                         
                                      BASE*AVISITN                           7                                                                      
                                      BASE*AVISITN                          14                                                                      
                                      BASE*AVISITN                          21                                                                      
                                      BASE*AVISITN                          28                                                                      
                                      BASE*AVISITN                          35                                                                      
                                      BASE*AVISITN                          42                                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
74


CENTANAFADINE                                                                                                               19 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 2 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      Intercept           
                                                                                     
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                                         
                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
75


CENTANAFADINE                                                                                                               20 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 2 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                                         
                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
76


CENTANAFADINE                                                                                                               21 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 2 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                           
                                                                                     
                                      POOLCNTR            
                                                                                    
                                      POOLCNTR            
                                                                                    
                                      AVISITN             
             7                                                                      
                                      AVISITN                               14                                                                      
                                      AVISITN                               21                                                                      
                                      AVISITN                               28                                                                      
                                      AVISITN                               35                                                                      
                                      AVISITN                               42                                                                      
                                      TRTPN                                             1                                                           
                                      TRTPN                                             2                                                           
                                      TRTPN                                             3                                                           
                                      AVISITN*TRTPN                          7          1                                                           
                                      AVISITN*TRTPN                          7          2                                                           
                                      AVISITN*TRTPN                          7          3                                                           
                                      AVISITN*TRTPN                         14          1                                                           
                                      AVISITN*TRTPN                         14          2                                                           
                                      AVISITN*TRTPN                         14          3                                                           
                                      AVISITN*TRTPN                         21          1                                                           
                                      AVISITN*TRTPN                         21          2                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
77


CENTANAFADINE                                                                                                               22 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 2 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN*TRTPN                         21          3                                                           
                                      AVISITN*TRTPN                         28          1                                                           
                                      AVISITN*TRTPN                         28          2                                                           
                                      AVISITN*TRTPN                         28          3                                                           
                                      AVISITN*TRTPN                         35          1                                                           
                                      AVISITN*TRTPN                         35          2                                                           
                                      AVISITN*TRTPN                         35          3                                                           
                                      AVISITN*TRTPN                         42          1                                                           
                                      AVISITN*TRTPN                         42          2                                                           
                                      AVISITN*TRTPN                         42          3                                                           
                                      SEX                            F                                                                              
                                      SEX                            M                                                                              
                                      AVISITN*SEX                    F       7                                                                      
                                      AVISITN*SEX                    M       7                                                                      
                                      AVISITN*SEX                    F      14                                                                      
                                      AVISITN*SEX                    M      14                                                                      
                                      AVISITN*SEX                    F      21                                                                      
                                      AVISITN*SEX                    M      21                                                                      
                                      AVISITN*SEX                    F      28                                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
78


CENTANAFADINE                                                                                                               23 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 2 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN*SEX                    M      28                                                                      
                                      AVISITN*SEX                    F      35                                                                      
                                      AVISITN*SEX                    M      35                                                                      
                                      AVISITN*SEX                    F      42                                                                      
                                      AVISITN*SEX                    M      42                                                                      
                                      TRTPN*SEX                      F                  1                                                           
                                      TRTPN*SEX                      M                  1                                                           
                                      TRTPN*SEX                      F                  2                 1                                         
                                      TRTPN*SEX                      M                  2                -1                                         
                                      TRTPN*SEX                      F                  3                -1                                         
                                      TRTPN*SEX                      M                  3                 1                                         
                                      AVISITN*TRTPN*SEX              F       7          1                                                           
                                      AVISITN*TRTPN*SEX              M       7          1                                                           
                                      AVISITN*TRTPN*SEX              F       7          2                                                           
                                      AVISITN*TRTPN*SEX              M       7          2                                                           
                                      AVISITN*TRTPN*SEX              F       7          3                                                           
                                      AVISITN*TRTPN*SEX              M       7          3                                                           
                                      AVISITN*TRTPN*SEX              F      14          1                                                           
                                      AVISITN*TRTPN*SEX              M      14          1                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
79


CENTANAFADINE                                                                                                               24 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 2 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN*TRTPN*SEX              F      14          2                                                           
                                      AVISITN*TRTPN*SEX              M      14          2                                                           
                                      AVISITN*TRTPN*SEX              F      14          3                                                           
                                      AVISITN*TRTPN*SEX              M      14          3                                                           
                                      AVISITN*TRTPN*SEX              F      21          1                                                           
                                      AVISITN*TRTPN*SEX              M      21          1                                                           
                                      AVISITN*TRTPN*SEX              F      21          2                                                           
                                      AVISITN*TRTPN*SEX              M      21          2                                                           
                                      AVISITN*TRTPN*SEX              F      21          3                                                           
                                      AVISITN*TRTPN*SEX              M      21          3                                                           
                                      AVISITN*TRTPN*SEX              F      28          1                                                           
                                      AVISITN*TRTPN*SEX              M      28          1                                                           
                                      AVISITN*TRTPN*SEX              F      28          2                                                           
                                      AVISITN*TRTPN*SEX              M      28          2                                                           
                                      AVISITN*TRTPN*SEX              F      28          3                                                           
                                      AVISITN*TRTPN*SEX              M      28          3                                                           
                                      AVISITN*TRTPN*SEX              F      35          1                                                           
                                      AVISITN*TRTPN*SEX              M      35          1                                                           
                                      AVISITN*TRTPN*SEX              F      35          2                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
80


CENTANAFADINE                                                                                                               25 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                    Coefficients for 2 vs. 3 BY SEX AT DAY 42                                                       
                                                                                                                                                    
                                                           Pooled           Analysis    Planned                                                     
                                                           Center           Visit       Treatment                                                   
                                      Effect               Number    Sex    (N)         (N)            Row1                                         
                                                                                                                                                    
                                      AVISITN*TRTPN*SEX              M      35          2                                                           
                                      AVISITN*TRTPN*SEX              F      35          3                                                           
                                      AVISITN*TRTPN*SEX              M      35          3                                                           
                                      AVISITN*TRTPN*SEX              F      42          1                                                           
                                      AVISITN*TRTPN*SEX              M      42          1                                                           
                                      AVISITN*TRTPN*SEX              F      42          2                 1                                         
                                      AVISITN*TRTPN*SEX              M      42          2                -1                                         
                                      AVISITN*TRTPN*SEX              F      42          3                -1                                         
                                      AVISITN*TRTPN*SEX              M      42          3                 1                                         
                                      BASE*AVISITN                           7                                                                      
                                      BASE*AVISITN                          14                                                                      
                                      BASE*AVISITN                          21                                                                      
                                      BASE*AVISITN                          28                                                                      
                                      BASE*AVISITN                          35                                                                      
                                      BASE*AVISITN                          42                                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
81


CENTANAFADINE                                                                                                               26 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                                         Standard                                                                   
                                 Label                       Estimate       Error      DF    t Value    Pr > |t|                                    
                                                                                                                                                    
                                 1 vs. 3 BY SEX AT DAY 42      0.2939      2.6567     383       0.11      0.9120                                    
                                 2 vs. 3 BY SEX AT DAY 42     -2.4115      2.6901     387      -0.90      0.3706                                    
                                                                                                                                                    
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                Analysis    Planned                                                                                                 
                                Visit       Treatment                Standard                                                                       
    Effect               Sex    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper      
                                                                                                                                                    
    AVISITN*TRTPN*SEX    F       7          1             -5.4027      0.8667     378      -6.23      <.0001      0.05     -7.1068     -3.6986      
    AVISITN*TRTPN*SEX    M       7          1             -6.9479      0.8409     383      -8.26      <.0001      0.05     -8.6013     -5.2946      
    AVISITN*TRTPN*SEX    F       7          2             -7.1868      0.8594     376      -8.36      <.0001      0.05     -8.8767     -5.4969      
    AVISITN*TRTPN*SEX    M       7          2             -5.0335      0.8496     379      -5.92      <.0001      0.05     -6.7041     -3.3629      
    AVISITN*TRTPN*SEX    F       7          3             -3.7852      0.8669     378      -4.37      <.0001      0.05     -5.4897     -2.0807      
    AVISITN*TRTPN*SEX    M       7          3             -4.6461      0.8279     378      -5.61      <.0001      0.05     -6.2739     -3.0183      
    AVISITN*TRTPN*SEX    F      14          1             -7.8481      1.0852     397      -7.23      <.0001      0.05     -9.9815     -5.7147      
    AVISITN*TRTPN*SEX    M      14          1            -10.2218      1.0454     386      -9.78      <.0001      0.05    -12.2771     -8.1665      
    AVISITN*TRTPN*SEX    F      14          2             -9.4956      1.1164     412      -8.51      <.0001      0.05    -11.6901     -7.3010      
    AVISITN*TRTPN*SEX    M      14          2             -8.6092      1.0577     399      -8.14      <.0001      0.05    -10.6885     -6.5298      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
82


CENTANAFADINE                                                                                                               27 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                Analysis    Planned                                                                                                 
                                Visit       Treatment                Standard                                                                       
    Effect               Sex    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper      
                                                                                                                                                    
    AVISITN*TRTPN*SEX    F      14          3             -5.3059      1.0908     381      -4.86      <.0001      0.05     -7.4506     -3.1612      
    AVISITN*TRTPN*SEX    M      14          3             -5.5124      1.0340     407      -5.33      <.0001      0.05     -7.5451     -3.4797      
    AVISITN*TRTPN*SEX    F      21          1            -10.5355      1.1670     394      -9.03      <.0001      0.05    -12.8298     -8.2411      
    AVISITN*TRTPN*SEX    M      21          1            -11.0775      1.1325     393      -9.78      <.0001      0.05    -13.3040     -8.8510      
    AVISITN*TRTPN*SEX    F      21          2            -12.3262      1.2227     419     -10.08      <.0001      0.05    -14.7295     -9.9229      
    AVISITN*TRTPN*SEX    M      21          2            -10.3736      1.1476     408      -9.04      <.0001      0.05    -12.6295     -8.1176      
    AVISITN*TRTPN*SEX    F      21          3             -6.9788      1.1675     374      -5.98      <.0001      0.05     -9.2745     -4.6830      
    AVISITN*TRTPN*SEX    M      21          3             -6.6063      1.1096     403      -5.95      <.0001      0.05     -8.7877     -4.4249      
    AVISITN*TRTPN*SEX    F      28          1            -10.4794      1.2327     400      -8.50      <.0001      0.05    -12.9028     -8.0561      
    AVISITN*TRTPN*SEX    M      28          1            -11.4879      1.1864     390      -9.68      <.0001      0.05    -13.8205     -9.1553      
    AVISITN*TRTPN*SEX    F      28          2            -12.7682      1.2871     416      -9.92      <.0001      0.05    -15.2983    -10.2381      
    AVISITN*TRTPN*SEX    M      28          2            -10.4550      1.2036     406      -8.69      <.0001      0.05    -12.8211     -8.0890      
    AVISITN*TRTPN*SEX    F      28          3             -7.5212      1.2256     373      -6.14      <.0001      0.05     -9.9311     -5.1113      
    AVISITN*TRTPN*SEX    M      28          3             -6.6440      1.1591     399      -5.73      <.0001      0.05     -8.9227     -4.3652      
    AVISITN*TRTPN*SEX    F      35          1            -11.4369      1.2920     398      -8.85      <.0001      0.05    -13.9769     -8.8969      
    AVISITN*TRTPN*SEX    M      35          1            -11.7373      1.2478     391      -9.41      <.0001      0.05    -14.1904     -9.2842      
    AVISITN*TRTPN*SEX    F      35          2            -14.6552      1.3521     409     -10.84      <.0001      0.05    -17.3132    -11.9971      
    AVISITN*TRTPN*SEX    M      35          2            -11.6595      1.2727     414      -9.16      <.0001      0.05    -14.1614     -9.1577      
    AVISITN*TRTPN*SEX    F      35          3             -8.5420      1.2828     371      -6.66      <.0001      0.05    -11.0644     -6.0196      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
83


CENTANAFADINE                                                                                                               28 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.1                                                                       
                                          MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                Analysis    Planned                                                                                                 
                                Visit       Treatment                Standard                                                                       
    Effect               Sex    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper      
                                                                                                                                                    
    AVISITN*TRTPN*SEX    M      35          3             -7.1620      1.2125     396      -5.91      <.0001      0.05     -9.5458     -4.7783      
    AVISITN*TRTPN*SEX    F      42          1            -12.3096      1.3743     401      -8.96      <.0001      0.05    -15.0112     -9.6079      
    AVISITN*TRTPN*SEX    M      42          1            -11.8471      1.3215     389      -8.96      <.0001      0.05    -14.4454     -9.2489      
    AVISITN*TRTPN*SEX    F      42          2            -14.1591      1.4448     408      -9.80      <.0001      0.05    -16.9992    -11.3190      
    AVISITN*TRTPN*SEX    M      42          2            -10.9912      1.3502     412      -8.14      <.0001      0.05    -13.6453     -8.3372      
    AVISITN*TRTPN*SEX    F      42          3             -8.4423      1.3593     370      -6.21      <.0001      0.05    -11.1152     -5.7695      
    AVISITN*TRTPN*SEX    M      42          3             -7.6860      1.2832     394      -5.99      <.0001      0.05    -10.2088     -5.1632      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
84


CENTANAFADINE                                                                                                               1 OF 28
PROTOCOL 405-201-00014                                                                                                                               
STAT-3.2  
MMRM Output for Test on Treatment by Race Interaction at Day 42  
(Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                     
                                                                The Mixed Procedure                                                                  
                                                                                                                                                     
                                                                 Model Information                                                                   
                                                                                                                                                     
                                               Data Set                     WORK.INDATA                                                              
                                               Dependent Variable           CHG                                                                      
                                               Covariance Structure         Unstructured                                                             
                                               Subject Effect               SUBJID                                                                   
                                               Estimation Method            REML                                                                     
                                               Residual Variance Method     None                                                                     
                                               Fixed Effects SE Method      Kenward-Roger                                                            
                                               Degrees of Freedom Method    Kenward-Roger                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                              Class Level Information                                                                
                                                                                                                                                     
                                                Class       Levels    Values                                                                         
                                                                                                                                                     
                                                AVISITN          6    7 14 21 28 35 42                                                               
                                                TRTPN            3    1 2 3                                                                          
                                                POOLCNTR        39   
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
85


CENTANAFADINE                                                                                                               2 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                    
                                                  
                                                SUBJID         421  
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
86


CENTANAFADINE                                                                                                               3 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
87


CENTANAFADINE                                                                                                               4 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
88


CENTANAFADINE                                                                                                               5 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
89


CENTANAFADINE                                                                                                               6 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
90


CENTANAFADINE                                                                                                               7 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                               RACEGRP          2    All Other Races White                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
91


CENTANAFADINE                                                                                                               8 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                   Dimensions                                                                       
                                                                                                                                                    
                                                       Covariance Parameters            21                                                          
                                                       Columns in X                    129                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        421                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2227                                                      
                                                   Number of Observations Used            2227                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                Iteration History                                                                   
                                                                                                                                                    
                                           Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                    
                                                   0              1     15704.36373766                                                              
                                                   1              2     13498.26971465      0.00024380                                              
                                                   2              1     13497.03266047      0.00000273                                              
                                                   3              1     13497.01951942      0.00000000                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
92


CENTANAFADINE                                                                                                               9 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                            Convergence criteria met.                                                               
                                                                                                                                                    
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(1,1)     SUBJID      43.3078                                                            
                                                         UN(2,1)     SUBJID      37.9417                                                            
                                                         UN(2,2)     SUBJID      69.5782                                                            
                                                         UN(3,1)     SUBJID      36.8986                                                            
                                                         UN(3,2)     SUBJID      59.1553                                                            
                                                         UN(3,3)     SUBJID      80.0027                                                            
                                                         UN(4,1)     SUBJID      38.6686                                                            
                                                         UN(4,2)     SUBJID      58.2307                                                            
                                                         UN(4,3)     SUBJID      72.5007                                                            
                                                         UN(4,4)     SUBJID      88.6310                                                            
                                                         UN(5,1)     SUBJID      38.3557                                                            
                                                         UN(5,2)     SUBJID      59.4955                                                            
                                                         UN(5,3)     SUBJID      71.0718                                                            
                                                         UN(5,4)     SUBJID      81.0660                                                            
                                                         UN(5,5)     SUBJID      96.3614                                                            
                                                         UN(6,1)     SUBJID      37.6519                                                            
                                                         UN(6,2)     SUBJID      59.1146                                                            
                                                         UN(6,3)     SUBJID      72.6172                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
93


CENTANAFADINE                                                                                                               10 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(6,4)     SUBJID      82.6569                                                            
                                                         UN(6,5)     SUBJID      90.2016                                                            
                                                         UN(6,6)     SUBJID       106.64                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood         13497.0                                                         
                                                      AIC (Smaller is Better)       13539.0                                                         
                                                      AICC (Smaller is Better)      13539.5                                                         
                                                      BIC (Smaller is Better)       13623.9                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           20       2207.34          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
94


CENTANAFADINE                                                                                                               11 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                          Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                    
                                                                     Num     Den                                                                    
                                            Effect                    DF      DF    F Value    Pr > F                                               
                                                                                                                                                    
                                            POOLCNTR                  38     377       2.15    0.0002                                               
                                            AVISITN                    5     352       1.25    0.2856                                               
                                            TRTPN                      2     389       9.82    <.0001                                               
                                            AVISITN*TRTPN             10     527       2.05    0.0272                                               
                                            RACEGRP                    1     414       8.58    0.0036                                               
                                            AVISITN*RACEGRP            5     353       2.06    0.0695                                               
                                            TRTPN*RACEGRP              2     394       0.85    0.4284                                               
                                            AVISIT*TRTPN*RACEGRP      10     526       1.21    0.2828                                               
                                            BASE*AVISITN               6     380       2.09    0.0534                                               
                                                                                                                                                    
                                                                                                                                                    
                                                  Coefficients for 1 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               Intercept             
                                                                                         
                               POOLCNTR              
                                                                                         
                               POOLCNTR              
                                                                                         
                                                     
                                                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
95


CENTANAFADINE                                                                                                               12 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 1 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                      
                                                                                         
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                                                      
                                                                                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
96


CENTANAFADINE                                                                                                               13 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 1 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               AVISITN                
                         7                                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
97


CENTANAFADINE                                                                                                               14 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 1 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISITN                                              14                                                              
                               AVISITN                                              21                                                              
                               AVISITN                                              28                                                              
                               AVISITN                                              35                                                              
                               AVISITN                                              42                                                              
                               TRTPN                                                            1                                                   
                               TRTPN                                                            2                                                   
                               TRTPN                                                            3                                                   
                               AVISITN*TRTPN                                         7          1                                                   
                               AVISITN*TRTPN                                         7          2                                                   
                               AVISITN*TRTPN                                         7          3                                                   
                               AVISITN*TRTPN                                        14          1                                                   
                               AVISITN*TRTPN                                        14          2                                                   
                               AVISITN*TRTPN                                        14          3                                                   
                               AVISITN*TRTPN                                        21          1                                                   
                               AVISITN*TRTPN                                        21          2                                                   
                               AVISITN*TRTPN                                        21          3                                                   
                               AVISITN*TRTPN                                        28          1                                                   
                               AVISITN*TRTPN                                        28          2                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
98


CENTANAFADINE                                                                                                               15 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 1 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISITN*TRTPN                                        28          3                                                   
                               AVISITN*TRTPN                                        35          1                                                   
                               AVISITN*TRTPN                                        35          2                                                   
                               AVISITN*TRTPN                                        35          3                                                   
                               AVISITN*TRTPN                                        42          1                                                   
                               AVISITN*TRTPN                                        42          2                                                   
                               AVISITN*TRTPN                                        42          3                                                   
                               RACEGRP                           All Other Races                                                                    
                               RACEGRP                           White                                                                              
                               AVISITN*RACEGRP                   All Other Races     7                                                              
                               AVISITN*RACEGRP                   White               7                                                              
                               AVISITN*RACEGRP                   All Other Races    14                                                              
                               AVISITN*RACEGRP                   White              14                                                              
                               AVISITN*RACEGRP                   All Other Races    21                                                              
                               AVISITN*RACEGRP                   White              21                                                              
                               AVISITN*RACEGRP                   All Other Races    28                                                              
                               AVISITN*RACEGRP                   White              28                                                              
                               AVISITN*RACEGRP                   All Other Races    35                                                              
                               AVISITN*RACEGRP                   White              35                                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
99


CENTANAFADINE                                                                                                               16 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 1 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISITN*RACEGRP                   All Other Races    42                                                              
                               AVISITN*RACEGRP                   White              42                                                              
                               TRTPN*RACEGRP                     All Other Races                1                 1                                 
                               TRTPN*RACEGRP                     White                          1                -1                                 
                               TRTPN*RACEGRP                     All Other Races                2                                                   
                               TRTPN*RACEGRP                     White                          2                                                   
                               TRTPN*RACEGRP                     All Other Races                3                -1                                 
                               TRTPN*RACEGRP                     White                          3                 1                                 
                               AVISIT*TRTPN*RACEGRP              All Other Races     7          1                                                   
                               AVISIT*TRTPN*RACEGRP              White               7          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races     7          2                                                   
                               AVISIT*TRTPN*RACEGRP              White               7          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races     7          3                                                   
                               AVISIT*TRTPN*RACEGRP              White               7          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    14          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              14          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    14          2                                                   
                               AVISIT*TRTPN*RACEGRP              White              14          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    14          3                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
100


CENTANAFADINE                                                                                                               17 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 1 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISIT*TRTPN*RACEGRP              White              14          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    21          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              21          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    21          2                                                   
                               AVISIT*TRTPN*RACEGRP              White              21          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    21          3                                                   
                               AVISIT*TRTPN*RACEGRP              White              21          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    28          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              28          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    28          2                                                   
                               AVISIT*TRTPN*RACEGRP              White              28          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    28          3                                                   
                               AVISIT*TRTPN*RACEGRP              White              28          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    35          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              35          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    35          2                                                   
                               AVISIT*TRTPN*RACEGRP              White              35          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    35          3                                                   
                               AVISIT*TRTPN*RACEGRP              White              35          3                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
101


CENTANAFADINE                                                                                                               18 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 1 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISIT*TRTPN*RACEGRP              All Other Races    42          1                 1                                 
                               AVISIT*TRTPN*RACEGRP              White              42          1                -1                                 
                               AVISIT*TRTPN*RACEGRP              All Other Races    42          2                                                   
                               AVISIT*TRTPN*RACEGRP              White              42          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    42          3                -1                                 
                               AVISIT*TRTPN*RACEGRP              White              42          3                 1                                 
                               BASE*AVISITN                                          7                                                              
                               BASE*AVISITN                                         14                                                              
                               BASE*AVISITN                                         21                                                              
                               BASE*AVISITN                                         28                                                              
                               BASE*AVISITN                                         35                                                              
                               BASE*AVISITN                                         42                                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
102


CENTANAFADINE                                                                                                               19 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 2 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               Intercept              
                                                                                         
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                               POOLCNTR               
                                                                                        
                                                      
                                                                                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
103


CENTANAFADINE                                                                                                               20 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 2 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                      
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                               POOLCNTR              
                                                                                        
                                                     
                                                                                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
104


CENTANAFADINE                                                                                                               21 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 2 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                      
                                                                                          
                               POOLCNTR               
                                                                                         
                               POOLCNTR               
                                                                                         
                               AVISITN                
                          7                                                              
                               AVISITN                                              14                                                              
                               AVISITN                                              21                                                              
                               AVISITN                                              28                                                              
                               AVISITN                                              35                                                              
                               AVISITN                                              42                                                              
                               TRTPN                                                            1                                                   
                               TRTPN                                                            2                                                   
                               TRTPN                                                            3                                                   
                               AVISITN*TRTPN                                         7          1                                                   
                               AVISITN*TRTPN                                         7          2                                                   
                               AVISITN*TRTPN                                         7          3                                                   
                               AVISITN*TRTPN                                        14          1                                                   
                               AVISITN*TRTPN                                        14          2                                                   
                               AVISITN*TRTPN                                        14          3                                                   
                               AVISITN*TRTPN                                        21          1                                                   
                               AVISITN*TRTPN                                        21          2                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
105


CENTANAFADINE                                                                                                               22 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 2 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISITN*TRTPN                                        21          3                                                   
                               AVISITN*TRTPN                                        28          1                                                   
                               AVISITN*TRTPN                                        28          2                                                   
                               AVISITN*TRTPN                                        28          3                                                   
                               AVISITN*TRTPN                                        35          1                                                   
                               AVISITN*TRTPN                                        35          2                                                   
                               AVISITN*TRTPN                                        35          3                                                   
                               AVISITN*TRTPN                                        42          1                                                   
                               AVISITN*TRTPN                                        42          2                                                   
                               AVISITN*TRTPN                                        42          3                                                   
                               RACEGRP                           All Other Races                                                                    
                               RACEGRP                           White                                                                              
                               AVISITN*RACEGRP                   All Other Races     7                                                              
                               AVISITN*RACEGRP                   White               7                                                              
                               AVISITN*RACEGRP                   All Other Races    14                                                              
                               AVISITN*RACEGRP                   White              14                                                              
                               AVISITN*RACEGRP                   All Other Races    21                                                              
                               AVISITN*RACEGRP                   White              21                                                              
                               AVISITN*RACEGRP                   All Other Races    28                                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
106


CENTANAFADINE                                                                                                               23 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 2 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISITN*RACEGRP                   White              28                                                              
                               AVISITN*RACEGRP                   All Other Races    35                                                              
                               AVISITN*RACEGRP                   White              35                                                              
                               AVISITN*RACEGRP                   All Other Races    42                                                              
                               AVISITN*RACEGRP                   White              42                                                              
                               TRTPN*RACEGRP                     All Other Races                1                                                   
                               TRTPN*RACEGRP                     White                          1                                                   
                               TRTPN*RACEGRP                     All Other Races                2                 1                                 
                               TRTPN*RACEGRP                     White                          2                -1                                 
                               TRTPN*RACEGRP                     All Other Races                3                -1                                 
                               TRTPN*RACEGRP                     White                          3                 1                                 
                               AVISIT*TRTPN*RACEGRP              All Other Races     7          1                                                   
                               AVISIT*TRTPN*RACEGRP              White               7          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races     7          2                                                   
                               AVISIT*TRTPN*RACEGRP              White               7          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races     7          3                                                   
                               AVISIT*TRTPN*RACEGRP              White               7          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    14          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              14          1                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
107


CENTANAFADINE                                                                                                               24 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 2 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISIT*TRTPN*RACEGRP              All Other Races    14          2                                                   
                               AVISIT*TRTPN*RACEGRP              White              14          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    14          3                                                   
                               AVISIT*TRTPN*RACEGRP              White              14          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    21          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              21          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    21          2                                                   
                               AVISIT*TRTPN*RACEGRP              White              21          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    21          3                                                   
                               AVISIT*TRTPN*RACEGRP              White              21          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    28          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              28          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    28          2                                                   
                               AVISIT*TRTPN*RACEGRP              White              28          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    28          3                                                   
                               AVISIT*TRTPN*RACEGRP              White              28          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    35          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              35          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    35          2                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
108


CENTANAFADINE                                                                                                               25 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                  Coefficients for 2 vs. 3 BY RACEGRP AT DAY 42                                                     
                                                                                                                                                    
                                                       Pooled                       Analysis    Planned                                             
                                                       Center                       Visit       Treatment                                           
                               Effect                  Number    RACEGRP            (N)         (N)            Row1                                 
                                                                                                                                                    
                               AVISIT*TRTPN*RACEGRP              White              35          2                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    35          3                                                   
                               AVISIT*TRTPN*RACEGRP              White              35          3                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    42          1                                                   
                               AVISIT*TRTPN*RACEGRP              White              42          1                                                   
                               AVISIT*TRTPN*RACEGRP              All Other Races    42          2                 1                                 
                               AVISIT*TRTPN*RACEGRP              White              42          2                -1                                 
                               AVISIT*TRTPN*RACEGRP              All Other Races    42          3                -1                                 
                               AVISIT*TRTPN*RACEGRP              White              42          3                 1                                 
                               BASE*AVISITN                                          7                                                              
                               BASE*AVISITN                                         14                                                              
                               BASE*AVISITN                                         21                                                              
                               BASE*AVISITN                                         28                                                              
                               BASE*AVISITN                                         35                                                              
                               BASE*AVISITN                                         42                                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
109


CENTANAFADINE                                                                                                               26 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                                           Standard                                                                 
                               Label                           Estimate       Error      DF    t Value    Pr > |t|                                  
                                                                                                                                                    
                               1 vs. 3 BY RACEGRP AT DAY 42     -1.8375      3.1294     385      -0.59      0.5574                                  
                               2 vs. 3 BY RACEGRP AT DAY 42     -1.0598      3.3731     395      -0.31      0.7535                                  
                                                                                                                                                    
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                           Analysis   Planned                                                                                       
                                           Visit      Treatment              Standard                                                               
  Effect                 RACEGRP           (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper    
                                                                                                                                                    
  AVISIT*TRTPN*RACEGRP   All Other Races    7         1            -7.0994     1.2575    381     -5.65     <.0001     0.05    -9.5720    -4.6268    
  AVISIT*TRTPN*RACEGRP   White              7         1            -5.9784     0.6928    382     -8.63     <.0001     0.05    -7.3405    -4.6163    
  AVISIT*TRTPN*RACEGRP   All Other Races    7         2            -9.0250     1.3770    376     -6.55     <.0001     0.05   -11.7327    -6.3173    
  AVISIT*TRTPN*RACEGRP   White              7         2            -5.4838     0.6732    378     -8.15     <.0001     0.05    -6.8075    -4.1602    
  AVISIT*TRTPN*RACEGRP   All Other Races    7         3            -4.0554     1.2955    376     -3.13     0.0019     0.05    -6.6028    -1.5080    
  AVISIT*TRTPN*RACEGRP   White              7         3            -4.3810     0.6867    378     -6.38     <.0001     0.05    -5.7311    -3.0309    
  AVISIT*TRTPN*RACEGRP   All Other Races   14         1           -11.5844     1.5470    394     -7.49     <.0001     0.05   -14.6259    -8.5429    
  AVISIT*TRTPN*RACEGRP   White             14         1            -8.3630     0.8593    397     -9.73     <.0001     0.05   -10.0523    -6.6737    
  AVISIT*TRTPN*RACEGRP   All Other Races   14         2           -12.1861     1.7791    416     -6.85     <.0001     0.05   -15.6834    -8.6889    
  AVISIT*TRTPN*RACEGRP   White             14         2            -8.4720     0.8445    407    -10.03     <.0001     0.05   -10.1321    -6.8120    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
110


CENTANAFADINE                                                                                                               27 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                           Analysis   Planned                                                                                       
                                           Visit      Treatment              Standard                                                               
  Effect                 RACEGRP           (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper    
                                                                                                                                                    
  AVISIT*TRTPN*RACEGRP   All Other Races   14         3            -4.3684     1.6060    390     -2.72     0.0068     0.05    -7.5259    -1.2109    
  AVISIT*TRTPN*RACEGRP   White             14         3            -5.7832     0.8529    406     -6.78     <.0001     0.05    -7.4599    -4.1064    
  AVISIT*TRTPN*RACEGRP   All Other Races   21         1           -13.4900     1.6638    398     -8.11     <.0001     0.05   -16.7608   -10.2191    
  AVISIT*TRTPN*RACEGRP   White             21         1           -10.0518     0.9235    400    -10.88     <.0001     0.05   -11.8674    -8.2363    
  AVISIT*TRTPN*RACEGRP   All Other Races   21         2           -15.6552     1.9656    433     -7.96     <.0001     0.05   -19.5185   -11.7918    
  AVISIT*TRTPN*RACEGRP   White             21         2           -10.4459     0.9123    409    -11.45     <.0001     0.05   -12.2393    -8.6525    
  AVISIT*TRTPN*RACEGRP   All Other Races   21         3            -8.2352     1.7156    389     -4.80     <.0001     0.05   -11.6083    -4.8622    
  AVISIT*TRTPN*RACEGRP   White             21         3            -6.4527     0.9087    398     -7.10     <.0001     0.05    -8.2391    -4.6662    
  AVISIT*TRTPN*RACEGRP   All Other Races   28         1           -13.8665     1.7467    394     -7.94     <.0001     0.05   -17.3004   -10.4326    
  AVISIT*TRTPN*RACEGRP   White             28         1           -10.1758     0.9760    404    -10.43     <.0001     0.05   -12.0944    -8.2572    
  AVISIT*TRTPN*RACEGRP   All Other Races   28         2           -14.8643     2.0891    437     -7.12     <.0001     0.05   -18.9702   -10.7584    
  AVISIT*TRTPN*RACEGRP   White             28         2           -10.8890     0.9603    407    -11.34     <.0001     0.05   -12.7767    -9.0013    
  AVISIT*TRTPN*RACEGRP   All Other Races   28         3            -8.8032     1.8058    391     -4.87     <.0001     0.05   -12.3536    -5.2529    
  AVISIT*TRTPN*RACEGRP   White             28         3            -6.6365     0.9533    395     -6.96     <.0001     0.05    -8.5106    -4.7624    
  AVISIT*TRTPN*RACEGRP   All Other Races   35         1           -14.0585     1.8441    403     -7.62     <.0001     0.05   -17.6837   -10.4333    
  AVISIT*TRTPN*RACEGRP   White             35         1           -10.8714     1.0221    400    -10.64     <.0001     0.05   -12.8808    -8.8621    
  AVISIT*TRTPN*RACEGRP   All Other Races   35         2           -18.2432     2.2321    447     -8.17     <.0001     0.05   -22.6299   -13.8565    
  AVISIT*TRTPN*RACEGRP   White             35         2           -12.0993     1.0101    407    -11.98     <.0001     0.05   -14.0849   -10.1137    
  AVISIT*TRTPN*RACEGRP   All Other Races   35         3            -9.4821     1.8927    392     -5.01     <.0001     0.05   -13.2032    -5.7609    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
111


CENTANAFADINE                                                                                                               28 OF 28
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                           Analysis   Planned                                                                                       
                                           Visit      Treatment              Standard                                                               
  Effect                 RACEGRP           (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper    
                                                                                                                                                    
  AVISIT*TRTPN*RACEGRP   White             35         3            -7.4198     0.9957    392     -7.45     <.0001     0.05    -9.3775    -5.4622    
  AVISIT*TRTPN*RACEGRP   All Other Races   42         1           -16.2801     1.9359    397     -8.41     <.0001     0.05   -20.0860   -12.4743    
  AVISIT*TRTPN*RACEGRP   White             42         1           -10.8032     1.0812    402     -9.99     <.0001     0.05   -12.9286    -8.6777    
  AVISIT*TRTPN*RACEGRP   All Other Races   42         2           -16.4160     2.3407    424     -7.01     <.0001     0.05   -21.0168   -11.8152    
  AVISIT*TRTPN*RACEGRP   White             42         2           -11.7167     1.0708    409    -10.94     <.0001     0.05   -13.8216    -9.6118    
  AVISIT*TRTPN*RACEGRP   All Other Races   42         3           -10.9567     1.9920    390     -5.50     <.0001     0.05   -14.8731    -7.0403    
  AVISIT*TRTPN*RACEGRP   White             42         3            -7.3172     1.0483    390     -6.98     <.0001     0.05    -9.3781    -5.2562    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
112


CENTANAFADINE                                                                                                               1 OF 18
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.1.1  
Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER  
(Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                     
                                                                The Mixed Procedure                                                                  
                                                                                                                                                     
                                                                 Model Information                                                                   
                                                                                                                                                     
                                               Data Set                     WORK.INDATA                                                              
                                               Dependent Variable           CHG                                                                      
                                               Covariance Structure         Unstructured                                                             
                                               Subject Effect               SUBJID                                                                   
                                               Estimation Method            REML                                                                     
                                               Residual Variance Method     None                                                                     
                                               Fixed Effects SE Method      Kenward-Roger                                                            
                                               Degrees of Freedom Method    Kenward-Roger                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                              Class Level Information                                                                
                                                                                                                                                     
                                                Class       Levels    Values                                                                         
                                                                                                                                                     
                                                AVISITN          6    7 14 21 28 35 42                                                               
                                                TRTPN            3    1 2 3                                                                          
                                                POOLCNTR        39   
                                                  
                                                                     
                                                  
                                                                     
                                                  
                                                                     
                                                  
                                                                     
                                                  
                                                                     
                                                  
                                                                     
                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
113


CENTANAFADINE                                                                                                               2 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                     
                                                 
                                                SUBJID         421   
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                      
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
114


CENTANAFADINE                                                                                                               3 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                     
                                                 
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
115


CENTANAFADINE                                                                                                               4 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
116


CENTANAFADINE                                                                                                               5 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                    
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
117


CENTANAFADINE                                                                                                               6 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                     
                                                 
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
118


CENTANAFADINE                                                                                                               7 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                     
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
119


CENTANAFADINE                                                                                                               8 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                   Dimensions                                                                       
                                                                                                                                                    
                                                       Covariance Parameters            21                                                          
                                                       Columns in X                     73                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        421                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2227                                                      
                                                   Number of Observations Used            2227                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                Iteration History                                                                   
                                                                                                                                                    
                                           Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                    
                                                   0              1     15800.38727426                                                              
                                                   1              2     13568.79752107      0.00031679                                              
                                                   2              1     13567.17482444      0.00000418                                              
                                                   3              1     13567.15460435      0.00000000                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
120


CENTANAFADINE                                                                                                               9 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                            Convergence criteria met.                                                               
                                                                                                                                                    
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(1,1)     SUBJID      43.6133                                                            
                                                         UN(2,1)     SUBJID      38.4610                                                            
                                                         UN(2,2)     SUBJID      70.3656                                                            
                                                         UN(3,1)     SUBJID      37.5232                                                            
                                                         UN(3,2)     SUBJID      59.9507                                                            
                                                         UN(3,3)     SUBJID      81.2761                                                            
                                                         UN(4,1)     SUBJID      39.2740                                                            
                                                         UN(4,2)     SUBJID      59.0315                                                            
                                                         UN(4,3)     SUBJID      73.7748                                                            
                                                         UN(4,4)     SUBJID      89.8567                                                            
                                                         UN(5,1)     SUBJID      38.9775                                                            
                                                         UN(5,2)     SUBJID      60.4118                                                            
                                                         UN(5,3)     SUBJID      72.5077                                                            
                                                         UN(5,4)     SUBJID      82.3971                                                            
                                                         UN(5,5)     SUBJID      97.7856                                                            
                                                         UN(6,1)     SUBJID      38.2789                                                            
                                                         UN(6,2)     SUBJID      60.0226                                                            
                                                         UN(6,3)     SUBJID      74.3151                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
121


CENTANAFADINE                                                                                                               10 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(6,4)     SUBJID      84.3266                                                            
                                                         UN(6,5)     SUBJID      91.8307                                                            
                                                         UN(6,6)     SUBJID       108.84                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood         13567.2                                                         
                                                      AIC (Smaller is Better)       13609.2                                                         
                                                      AICC (Smaller is Better)      13609.6                                                         
                                                      BIC (Smaller is Better)       13694.0                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           20       2233.23          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
122


CENTANAFADINE                                                                                                               11 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                           Solution for Fixed Effects                                                               
                                                                                                                                                    
                                      Pooled    Analysis    Planned                                                                                 
                                      Center    Visit       Treatment                Standard                                                       
                     Effect           Number    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|                        
                                                                                                                                                    
                     Intercept                                             1.1270      4.7691     581       0.24      0.8133                        
                     AVISITN                     7                         0.5954      2.6832     341       0.22      0.8245                        
                     AVISITN                    14                        -1.3583      2.4093     363      -0.56      0.5733                        
                     AVISITN                    21                         0.8510      2.0449     353       0.42      0.6775                        
                     AVISITN                    28                        -1.3535      1.7676     346      -0.77      0.4444                        
                     AVISITN                    35                        -0.6029      1.5610     337      -0.39      0.6996                        
                     AVISITN                    42                              0                                                                   
                     TRTPN                                  1             -4.0055      1.2937     368      -3.10      0.0021                        
                     TRTPN                                  2             -4.4192      1.3220     378      -3.34      0.0009                        
                     TRTPN                                  3                   0                                                                   
                     AVISITN*TRTPN               7          1              2.0743      1.0975     335       1.89      0.0596                        
                     AVISITN*TRTPN               7          2              2.6082      1.1265     339       2.32      0.0212                        
                     AVISITN*TRTPN               7          3                   0                                                                   
                     AVISITN*TRTPN              14          1              0.3557      0.9813     357       0.36      0.7172                        
                     AVISITN*TRTPN              14          2              0.7686      1.0094     356       0.76      0.4469                        
                     AVISITN*TRTPN              14          3                   0                                                                   
                     AVISITN*TRTPN              21          1            -0.01500      0.8285     348      -0.02      0.9856                        
                     AVISITN*TRTPN              21          2            -0.07966      0.8542     350      -0.09      0.9258                        
                     AVISITN*TRTPN              21          3                   0                                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
123


CENTANAFADINE                                                                                                               12 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                           Solution for Fixed Effects                                                               
                                                                                                                                                    
                                      Pooled    Analysis    Planned                                                                                 
                                      Center    Visit       Treatment                Standard                                                       
                     Effect           Number    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|                        
                                                                                                                                                    
                     AVISITN*TRTPN              28          1             0.06611      0.7137     344       0.09      0.9263                        
                     AVISITN*TRTPN              28          2            -0.05910      0.7352     343      -0.08      0.9360                        
                     AVISITN*TRTPN              28          3                   0                                                                   
                     AVISITN*TRTPN              35          1              0.2307      0.6270     335       0.37      0.7131                        
                     AVISITN*TRTPN              35          2             -0.8321      0.6479     335      -1.28      0.1999                        
                     AVISITN*TRTPN              35          3                   0                                                                   
                     AVISITN*TRTPN              42          1                   0                                                                   
                     AVISITN*TRTPN              42          2                   0                                                                   
                     AVISITN*TRTPN   
      42          3                   0                                                                   
                     POOLCNTR       
                                1.7152      3.7658     428       0.46      0.6490                        
                     POOLCNTR       
                               -5.1572      5.2435     403      -0.98      0.3259                        
                     POOLCNTR       
                                1.6504      3.6560     432       0.45      0.6519                        
                     POOLCNTR       
                                0.5885      4.4348     413       0.13      0.8945                        
                     POOLCNTR       
                               -3.9263      4.4129     414      -0.89      0.3741                        
                     POOLCNTR       
                                1.2240      3.7770     428       0.32      0.7460                        
                     POOLCNTR       
                                0.8833      3.7274     429       0.24      0.8128                        
                     POOLCNTR       
                               -2.1241      4.2789     416      -0.50      0.6199                        
                     POOLCNTR       
                                1.9882      5.1695     403       0.38      0.7007                        
                     POOLCNTR       
                               -3.3736      3.8277     426      -0.88      0.3786                        
                                     
                                                                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
124


CENTANAFADINE                                                                                                               13 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                           Solution for Fixed Effects                                                               
                                                                                                                                                    
                                      Pooled    Analysis    Planned                                                                                 
                                      Center    Visit       Treatment                Standard                                                       
                     Effect           Number    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|                        
                                                                                                                                                    
                     POOLCNTR        
                               -2.6399      4.1913     418      -0.63      0.5291                        
                     POOLCNTR        
                               -9.4424      5.1658     404      -1.83      0.0683                        
                     POOLCNTR        
                               -3.1314      4.3052     416      -0.73      0.4674                        
                     POOLCNTR        
                                3.6852      4.0316     425       0.91      0.3612                        
                     POOLCNTR        
                               -1.5147      4.0615     421      -0.37      0.7094                        
                     POOLCNTR        
                               -0.7002      4.5899     411      -0.15      0.8788                        
                     POOLCNTR        
                               -3.9140      4.1883     418      -0.93      0.3506                        
                     POOLCNTR        
                                2.1512      4.8016     408       0.45      0.6544                        
                     POOLCNTR        
                               -2.5698      4.8033     408      -0.54      0.5929                        
                     POOLCNTR        
                                0.4082      3.9332     424       0.10      0.9174                        
                     POOLCNTR        
                               -2.0848      4.1288     419      -0.50      0.6139                        
                     POOLCNTR        
                                9.2093      4.8043     408       1.92      0.0560                        
                     POOLCNTR        
                                3.0940      3.9314     423       0.79      0.4317                        
                     POOLCNTR        
                               -3.5346      3.9635     422      -0.89      0.3730                        
                     POOLCNTR        
                               -2.2842      4.1174     419      -0.55      0.5793                        
                     POOLCNTR        
                                6.8249      4.3486     415       1.57      0.1173                        
                     POOLCNTR        
                               -5.2814      4.4034     414      -1.20      0.2311                        
                     POOLCNTR        
                               -2.7571      4.2019     417      -0.66      0.5121                        
                     POOLCNTR        
                                2.0058      3.6634     432       0.55      0.5843                        
                                     
                                                                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
125


CENTANAFADINE                                                                                                               14 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                           Solution for Fixed Effects                                                               
                                                                                                                                                    
                                      Pooled    Analysis    Planned                                                                                 
                                      Center    Visit       Treatment                Standard                                                       
                     Effect           Number    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|                        
                                     
                                                                                                          
                     POOLCNTR        
                                 3.0549      3.6512     431       0.84      0.4032                        
                     POOLCNTR        
                                -2.0401      4.5650     411      -0.45      0.6552                        
                     POOLCNTR        
                                 1.7734      4.5671     411       0.39      0.6980                        
                     POOLCNTR        
                                -4.4210      3.9066     427      -1.13      0.2584                        
                     POOLCNTR        
                                 0.6462      4.4087     414       0.15      0.8835                        
                     POOLCNTR        
                                -0.5512      3.8270     427      -0.14      0.8855                        
                     POOLCNTR        
                                -1.6096      5.1715     403      -0.31      0.7558                        
                     POOLCNTR        
                                -3.2196      4.4113     414      -0.73      0.4659                        
                     POOLCNTR        
                                -3.8034      4.4030     413      -0.86      0.3882                        
                     POOLCNTR        
                                      0                                                                   
                     BASE*AVISITN    
       7                        -0.1387     0.05917     381      -2.34      0.0196                        
                     BASE*AVISITN               14                        -0.1179     0.07108     437      -1.66      0.0979                        
                     BASE*AVISITN               21                        -0.2124     0.07568     436      -2.81      0.0052                        
                     BASE*AVISITN               28                        -0.1613     0.07907     439      -2.04      0.0419                        
                     BASE*AVISITN               35                        -0.2010     0.08284     444      -2.43      0.0156                        
                     BASE*AVISITN               42                        -0.2232     0.08730     443      -2.56      0.0109                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
126


CENTANAFADINE                                                                                                               15 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                          Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                    
                                                                  Num     Den                                                                       
                                                Effect             DF      DF    F Value    Pr > F                                                  
                                                                                                                                                    
                                                AVISITN             5     353       1.23    0.2932                                                  
                                                TRTPN               2     379      10.09    <.0001                                                  
                                                AVISITN*TRTPN      10     524       1.66    0.0881                                                  
                                                POOLCNTR           38     380       2.12    0.0002                                                  
                                                BASE*AVISITN        6     382       2.15    0.0468                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                   Standard                                                                                         
                      Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                        
                                                                                                                                                    
                      DAY7  1 vs 3      -1.9312      0.7960     381      -2.43      0.0157      0.05     -3.4963     -0.3661                        
                      DAY7  2 vs 3      -1.8111      0.7992     379      -2.27      0.0240      0.05     -3.3825     -0.2396                        
                      DAY14  1 vs 3     -3.6498      1.0171     373      -3.59      0.0004      0.05     -5.6498     -1.6497                        
                      DAY14  2 vs 3     -3.6506      1.0304     381      -3.54      0.0004      0.05     -5.6766     -1.6246                        
                      DAY21  1 vs 3     -4.0205      1.0982     369      -3.66      0.0003      0.05     -6.1801     -1.8609                        
                      DAY21  2 vs 3     -4.4989      1.1183     380      -4.02      <.0001      0.05     -6.6978     -2.2999                        
                      DAY28  1 vs 3     -3.9394      1.1597     369      -3.40      0.0008      0.05     -6.2198     -1.6589                        
                      DAY28  2 vs 3     -4.4783      1.1797     378      -3.80      0.0002      0.05     -6.7980     -2.1586                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
127


CENTANAFADINE                                                                                                               16 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                   Standard                                                                                         
                      Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                        
                                                                                                                                                    
                      DAY35  1 vs 3     -3.7747      1.2192     368      -3.10      0.0021      0.05     -6.1721     -1.3774                        
                      DAY35  2 vs 3     -5.2513      1.2437     378      -4.22      <.0001      0.05     -7.6968     -2.8058                        
                      DAY42  1 vs 3     -4.0055      1.2937     368      -3.10      0.0021      0.05     -6.5494     -1.4615                        
                      DAY42  2 vs 3     -4.4192      1.3220     378      -3.34      0.0009      0.05     -7.0186     -1.8198                        
                                                                                                                                                    
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                          Analysis    Planned                                                                                                       
                          Visit       Treatment                Standard                                                                             
         Effect           (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper            
                                                                                                                                                    
         AVISITN*TRTPN     7          1             -6.2099      0.6181     385     -10.05      <.0001      0.05     -7.4251     -4.9947            
         AVISITN*TRTPN     7          2             -6.0897      0.6199     381      -9.82      <.0001      0.05     -7.3085     -4.8709            
         AVISITN*TRTPN     7          3             -4.2786      0.6120     381      -6.99      <.0001      0.05     -5.4820     -3.0753            
         AVISITN*TRTPN    14          1             -9.0936      0.7625     402     -11.93      <.0001      0.05    -10.5925     -7.5947            
         AVISITN*TRTPN    14          2             -9.0945      0.7770     415     -11.70      <.0001      0.05    -10.6218     -7.5672            
         AVISITN*TRTPN    14          3             -5.4438      0.7599     405      -7.16      <.0001      0.05     -6.9376     -3.9501            
         AVISITN*TRTPN    21          1            -10.8348      0.8200     407     -13.21      <.0001      0.05    -12.4468     -9.2228            
         AVISITN*TRTPN    21          2            -11.3132      0.8431     423     -13.42      <.0001      0.05    -12.9703     -9.6560            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
128


CENTANAFADINE                                                                                                               17 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                          Analysis    Planned                                                                                                       
                          Visit       Treatment                Standard                                                                             
         Effect           (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper            
                                                                                                                                                    
         AVISITN*TRTPN    21          3             -6.8143      0.8114     399      -8.40      <.0001      0.05     -8.4095     -5.2191            
         AVISITN*TRTPN    28          1            -11.0222      0.8636     409     -12.76      <.0001      0.05    -12.7198     -9.3245            
         AVISITN*TRTPN    28          2            -11.5611      0.8869     422     -13.04      <.0001      0.05    -13.3044     -9.8179            
         AVISITN*TRTPN    28          3             -7.0828      0.8508     396      -8.33      <.0001      0.05     -8.7554     -5.4102            
         AVISITN*TRTPN    35          1            -11.6110      0.9058     407     -12.82      <.0001      0.05    -13.3916     -9.8304            
         AVISITN*TRTPN    35          2            -13.0876      0.9345     423     -14.00      <.0001      0.05    -14.9245    -11.2507            
         AVISITN*TRTPN    35          3             -7.8362      0.8895     394      -8.81      <.0001      0.05     -9.5850     -6.0875            
         AVISITN*TRTPN    42          1            -12.0791      0.9584     409     -12.60      <.0001      0.05    -13.9632    -10.1951            
         AVISITN*TRTPN    42          2            -12.4928      0.9915     422     -12.60      <.0001      0.05    -14.4418    -10.5439            
         AVISITN*TRTPN    42          3             -8.0736      0.9387     393      -8.60      <.0001      0.05     -9.9192     -6.2281            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
129


CENTANAFADINE                                                                                                               18 OF 18
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.1                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=KENWARDROGER                             
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                              Tests of Effect Slices                                                                
                                                                                                                                                    
                                                           Analysis                                                                                 
                                                           Visit        Num     Den                                                                 
                                          Effect           (N)           DF      DF    F Value    Pr > F                                            
                                                                                                                                                    
                                          AVISITN*TRTPN     7             2     380       3.70    0.0257                                            
                                          AVISITN*TRTPN    14             2     378       8.52    0.0002                                            
                                          AVISITN*TRTPN    21             2     377      10.00    <.0001                                            
                                          AVISITN*TRTPN    28             2     377       8.80    0.0002                                            
                                          AVISITN*TRTPN    35             2     377       9.66    <.0001                                            
                                          AVISITN*TRTPN    42             2     377       7.04    0.0010                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
130


CENTANAFADINE                                                                                                               1 OF 14
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.1.2  
Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE  
(Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                     
                                                                The Mixed Procedure                                                                  
                                                                                                                                                     
                                                                 Model Information                                                                   
                                                                                                                                                     
                                               Data Set                     WORK.INDATA                                                              
                                               Dependent Variable           CHG                                                                      
                                               Covariance Structure         Unstructured                                                             
                                               Subject Effect               SUBJID                                                                   
                                               Estimation Method            REML                                                                     
                                               Residual Variance Method     None                                                                     
                                               Fixed Effects SE Method      Model-Based                                                              
                                               Degrees of Freedom Method    Satterthwaite                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                              Class Level Information                                                                
                                                                                                                                                     
                                                Class       Levels    Values                                                                         
                                                                                                                                                     
                                                AVISITN          6    7 14 21 28 35 42                                                               
                                                TRTPN            3    1 2 3                                                                          
                                                POOLCNTR        39   
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
131


CENTANAFADINE                                                                                                               2 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                    
                                                
                                               SUBJID         421   
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
132


CENTANAFADINE                                                                                                               3 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
133


CENTANAFADINE                                                                                                               4 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
134


CENTANAFADINE                                                                                                               5 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
135


CENTANAFADINE                                                                                                               6 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
136


CENTANAFADINE                                                                                                               7 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
137


CENTANAFADINE                                                                                                               8 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                   Dimensions                                                                       
                                                                                                                                                    
                                                       Covariance Parameters            21                                                          
                                                       Columns in X                     73                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        421                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2227                                                      
                                                   Number of Observations Used            2227                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                Iteration History                                                                   
                                                                                                                                                    
                                           Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                    
                                                   0              1     15800.38727426                                                              
                                                   1              2     13568.79752107      0.00031679                                              
                                                   2              1     13567.17482444      0.00000418                                              
                                                   3              1     13567.15460435      0.00000000                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
138


CENTANAFADINE                                                                                                               9 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                            Convergence criteria met.                                                               
                                                                                                                                                    
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(1,1)     SUBJID      43.6133                                                            
                                                         UN(2,1)     SUBJID      38.4610                                                            
                                                         UN(2,2)     SUBJID      70.3656                                                            
                                                         UN(3,1)     SUBJID      37.5232                                                            
                                                         UN(3,2)     SUBJID      59.9507                                                            
                                                         UN(3,3)     SUBJID      81.2761                                                            
                                                         UN(4,1)     SUBJID      39.2740                                                            
                                                         UN(4,2)     SUBJID      59.0315                                                            
                                                         UN(4,3)     SUBJID      73.7748                                                            
                                                         UN(4,4)     SUBJID      89.8567                                                            
                                                         UN(5,1)     SUBJID      38.9775                                                            
                                                         UN(5,2)     SUBJID      60.4118                                                            
                                                         UN(5,3)     SUBJID      72.5077                                                            
                                                         UN(5,4)     SUBJID      82.3971                                                            
                                                         UN(5,5)     SUBJID      97.7856                                                            
                                                         UN(6,1)     SUBJID      38.2789                                                            
                                                         UN(6,2)     SUBJID      60.0226                                                            
                                                         UN(6,3)     SUBJID      74.3151                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
139


CENTANAFADINE                                                                                                               10 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(6,4)     SUBJID      84.3266                                                            
                                                         UN(6,5)     SUBJID      91.8307                                                            
                                                         UN(6,6)     SUBJID       108.84                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood         13567.2                                                         
                                                      AIC (Smaller is Better)       13609.2                                                         
                                                      AICC (Smaller is Better)      13609.6                                                         
                                                      BIC (Smaller is Better)       13694.0                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           20       2233.23          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
140


CENTANAFADINE                                                                                                               11 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                          Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                    
                                                                  Num     Den                                                                       
                                                Effect             DF      DF    F Value    Pr > F                                                  
                                                                                                                                                    
                                                AVISITN             5     357       1.25    0.2860                                                  
                                                TRTPN               2     379      10.10    <.0001                                                  
                                                AVISITN*TRTPN      10     356       1.68    0.0835                                                  
                                                POOLCNTR           38     380       2.18    0.0001                                                  
                                                BASE*AVISITN        6     378       2.19    0.0430                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                   Standard                                                                                         
                      Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                        
                                                                                                                                                    
                      DAY7  1 vs 3      -1.9312      0.7958     381      -2.43      0.0157      0.05     -3.4959     -0.3665                        
                      DAY7  2 vs 3      -1.8111      0.7989     379      -2.27      0.0240      0.05     -3.3820     -0.2401                        
                      DAY14  1 vs 3     -3.6498      1.0169     373      -3.59      0.0004      0.05     -5.6493     -1.6502                        
                      DAY14  2 vs 3     -3.6506      1.0301     381      -3.54      0.0004      0.05     -5.6760     -1.6253                        
                      DAY21  1 vs 3     -4.0205      1.0980     369      -3.66      0.0003      0.05     -6.1796     -1.8614                        
                      DAY21  2 vs 3     -4.4989      1.1179     380      -4.02      <.0001      0.05     -6.6970     -2.3008                        
                      DAY28  1 vs 3     -3.9394      1.1594     369      -3.40      0.0008      0.05     -6.2192     -1.6596                        
                      DAY28  2 vs 3     -4.4783      1.1792     378      -3.80      0.0002      0.05     -6.7970     -2.1596                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
141


CENTANAFADINE                                                                                                               12 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                   Standard                                                                                         
                      Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                        
                                                                                                                                                    
                      DAY35  1 vs 3     -3.7747      1.2186     368      -3.10      0.0021      0.05     -6.1711     -1.3784                        
                      DAY35  2 vs 3     -5.2513      1.2430     378      -4.22      <.0001      0.05     -7.6953     -2.8074                        
                      DAY42  1 vs 3     -4.0055      1.2930     368      -3.10      0.0021      0.05     -6.5480     -1.4630                        
                      DAY42  2 vs 3     -4.4192      1.3210     378      -3.35      0.0009      0.05     -7.0167     -1.8217                        
                                                                                                                                                    
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                          Analysis    Planned                                                                                                       
                          Visit       Treatment                Standard                                                                             
         Effect           (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper            
                                                                                                                                                    
         AVISITN*TRTPN     7          1             -6.2099      0.6166     385     -10.07      <.0001      0.05     -7.4223     -4.9975            
         AVISITN*TRTPN     7          2             -6.0897      0.6184     381      -9.85      <.0001      0.05     -7.3056     -4.8738            
         AVISITN*TRTPN     7          3             -4.2786      0.6107     381      -7.01      <.0001      0.05     -5.4793     -3.0780            
         AVISITN*TRTPN    14          1             -9.0936      0.7613     402     -11.95      <.0001      0.05    -10.5902     -7.5971            
         AVISITN*TRTPN    14          2             -9.0945      0.7757     415     -11.72      <.0001      0.05    -10.6193     -7.5697            
         AVISITN*TRTPN    14          3             -5.4438      0.7587     405      -7.18      <.0001      0.05     -6.9353     -3.9524            
         AVISITN*TRTPN    21          1            -10.8348      0.8189     407     -13.23      <.0001      0.05    -12.4445     -9.2251            
         AVISITN*TRTPN    21          2            -11.3132      0.8418     423     -13.44      <.0001      0.05    -12.9677     -9.6586            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
142


CENTANAFADINE                                                                                                               13 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                          Analysis    Planned                                                                                                       
                          Visit       Treatment                Standard                                                                             
         Effect           (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper            
                                                                                                                                                    
         AVISITN*TRTPN    21          3             -6.8143      0.8103     399      -8.41      <.0001      0.05     -8.4073     -5.2213            
         AVISITN*TRTPN    28          1            -11.0222      0.8624     409     -12.78      <.0001      0.05    -12.7175     -9.3269            
         AVISITN*TRTPN    28          2            -11.5611      0.8855     422     -13.06      <.0001      0.05    -13.3017     -9.8205            
         AVISITN*TRTPN    28          3             -7.0828      0.8497     396      -8.34      <.0001      0.05     -8.7533     -5.4124            
         AVISITN*TRTPN    35          1            -11.6110      0.9044     407     -12.84      <.0001      0.05    -13.3890     -9.8330            
         AVISITN*TRTPN    35          2            -13.0876      0.9329     423     -14.03      <.0001      0.05    -14.9214    -11.2538            
         AVISITN*TRTPN    35          3             -7.8362      0.8884     394      -8.82      <.0001      0.05     -9.5828     -6.0897            
         AVISITN*TRTPN    42          1            -12.0791      0.9570     409     -12.62      <.0001      0.05    -13.9603    -10.1979            
         AVISITN*TRTPN    42          2            -12.4928      0.9898     422     -12.62      <.0001      0.05    -14.4384    -10.5473            
         AVISITN*TRTPN    42          3             -8.0736      0.9375     393      -8.61      <.0001      0.05     -9.9168     -6.2304            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
143


CENTANAFADINE                                                                                                               14 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.1.2                                                                      
                          Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM (UN), DDFM=SATTERTHWAITE                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                              Tests of Effect Slices                                                                
                                                                                                                                                    
                                                           Analysis                                                                                 
                                                           Visit        Num     Den                                                                 
                                          Effect           (N)           DF      DF    F Value    Pr > F                                            
                                                                                                                                                    
                                          AVISITN*TRTPN     7             2     380       3.70    0.0257                                            
                                          AVISITN*TRTPN    14             2     378       8.52    0.0002                                            
                                          AVISITN*TRTPN    21             2     377      10.01    <.0001                                            
                                          AVISITN*TRTPN    28             2     377       8.80    0.0002                                            
                                          AVISITN*TRTPN    35             2     377       9.67    <.0001                                            
                                          AVISITN*TRTPN    42             2     377       7.05    0.0010                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
144


CENTANAFADINE                                                                                                               1 OF 6
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.2  
Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, LOCF  
(Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                     
                                                                 The GLM Procedure                                                                   
                                                                                                                                                     
                                                              Class Level Information                                                                
                                                                                                                                                     
Class       Levels  Values                                                                                                                           
                                                                                                                                                     
TRTPN            3  1 2 3                                                                                                                            
                                                                                                                                                     
POOLCNTR        39 
                   
                                                                                                                                                     
                                                                                                                                                     
                                                      Number of Observations Read         421                                                        
                                                      Number of Observations Used         421                                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
145


CENTANAFADINE                                                                                                               2 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.2                                                                       
                                  Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, LOCF                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                       Sum of                                                                       
                               Source                      DF         Squares     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               Model                       41      8805.99497       214.78037       2.07    0.0002                                  
                                                                                                                                                    
                               Error                      379     39250.45633       103.56321                                                       
                                                                                                                                                    
                               Corrected Total            420     48056.45131                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.183243     -105.7081      10.17660     -9.627078                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2     1454.328052      727.164026       7.02    0.0010                                  
                               POOLCNTR                    38     6862.153762      180.582994       1.74    0.0053                                  
                               BASE                         1      280.694601      280.694601       2.71    0.1005                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
146


CENTANAFADINE                                                                                                               3 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.2                                                                       
                                  Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, LOCF                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                               Level of             -------------CHG-------------     -------------BASE------------                                 
                               TRTPN          N             Mean          Std Dev             Mean          Std Dev                                 
                                                                                                                                                    
                               1            140      -10.7071429       10.8359224       37.5857143       6.75041775                                 
                               2            140      -11.0571429       10.7125768       38.7642857       6.95578090                                 
                               3            141       -7.1347518       10.1624096       37.6453901       6.34837972                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
147


CENTANAFADINE                                                                                                               4 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.2                                                                       
                                  Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, LOCF                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                                                       Standard                  LSMEAN                                             
                                          TRTPN      CHG LSMEAN           Error    Pr > |t|      Number                                             
                                                                                                                                                    
                                          1         -11.6211087       0.9465643      <.0001           1                                             
                                          2         -11.7874384       0.9518103      <.0001           2                                             
                                          3          -7.7408197       0.9407099      <.0001           3                                             
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for effect TRTPN                                                         
                                                       Pr > |t| for H0: LSMean(i)=LSMean(j)                                                         
                                                                                                                                                    
                                                             Dependent Variable: CHG                                                                
                                                                                                                                                    
                                                  i/j              1             2             3                                                    
                                                                                                                                                    
                                                     1                      0.8926        0.0016                                                    
                                                     2        0.8926                      0.0011                                                    
                                                     3        0.0016        0.0011                                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                    
                                                1          -11.621109      -13.482284    -9.759933                                                  
                                                2          -11.787438      -13.658929    -9.915948                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
148


CENTANAFADINE                                                                                                               5 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.2                                                                       
                                  Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, LOCF                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                                TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                    
                                                3           -7.740820       -9.590484    -5.891156                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for Effect TRTPN                                                         
                                                                                                                                                    
                                                           Difference                                                                               
                                                              Between    95% Confidence Limits for                                                  
                                               i    j           Means       LSMean(i)-LSMean(j)                                                     
                                                                                                                                                    
                                               1    2        0.166330       -2.253380     2.586039                                                  
                                               1    3       -3.880289       -6.279048    -1.481530                                                  
                                               2    3       -4.046619       -6.461174    -1.632064                                                  
                                                                                                                                                    
                                                                                                                                                    
NOTE: To ensure overall protection level, only probabilities associated with pre-planned comparisons should be used.                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
149


CENTANAFADINE                                                                                                               6 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.2                                                                       
                                  Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, LOCF                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                               Standard                                                             
                                   Parameter                   Estimate           Error    t Value    Pr > |t|                                      
                                                                                                                                                    
                                   1 vs 3                   -3.88028896      1.21997068      -3.18      0.0016                                      
                                   2 vs 3                   -4.04661870      1.22800435      -3.30      0.0011                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
150


CENTANAFADINE                                                                                                               1 OF 6
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.3  
Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, OC  
(Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                     
                                                                 The GLM Procedure                                                                   
                                                                                                                                                     
                                                              Class Level Information                                                                
                                                                                                                                                     
                                                           Class         Levels    Values                                                            
                                                                                                                                                     
                                                           TRTPN              3    1 2 3                                                             
                                                                                                                                                     
                                                                                                                                                     
                                                      Number of Observations Read         421                                                        
                                                      Number of Observations Used         421                                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
151


CENTANAFADINE                                                                                                               2 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.3                                                                       
                                   Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, OC                                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                       Sum of                                                                       
                               Source                      DF         Squares     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               Model                        3      1943.84121       647.94707       5.86    0.0006                                  
                                                                                                                                                    
                               Error                      417     46112.61010       110.58180                                                       
                                                                                                                                                    
                               Corrected Total            420     48056.45131                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.040449     -109.2314      10.51579     -9.627078                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2     1249.405044      624.702522       5.65    0.0038                                  
                               BASE                         1      618.365333      618.365333       5.59    0.0185                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
152


CENTANAFADINE                                                                                                               3 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.3                                                                       
                                   Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, OC                                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                               Level of             -------------CHG-------------     -------------BASE------------                                 
                               TRTPN          N             Mean          Std Dev             Mean          Std Dev                                 
                                                                                                                                                    
                               1            140      -10.7071429       10.8359224       37.5857143       6.75041775                                 
                               2            140      -11.0571429       10.7125768       38.7642857       6.95578090                                 
                               3            141       -7.1347518       10.1624096       37.6453901       6.34837972                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
153


CENTANAFADINE                                                                                                               4 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.3                                                                       
                                   Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, OC                                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                                                       Standard                  LSMEAN                                             
                                          TRTPN      CHG LSMEAN           Error    Pr > |t|      Number                                             
                                                                                                                                                    
                                          1         -10.7820438       0.8893105      <.0001           1                                             
                                          2         -10.9177347       0.8906994      <.0001           2                                             
                                          3          -7.1988014       0.8860032      <.0001           3                                             
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for effect TRTPN                                                         
                                                       Pr > |t| for H0: LSMean(i)=LSMean(j)                                                         
                                                                                                                                                    
                                                             Dependent Variable: CHG                                                                
                                                                                                                                                    
                                                  i/j              1             2             3                                                    
                                                                                                                                                    
                                                     1                      0.9143        0.0045                                                    
                                                     2        0.9143                      0.0033                                                    
                                                     3        0.0045        0.0033                                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                    
                                                1          -10.782044      -12.530134    -9.033954                                                  
                                                2          -10.917735      -12.668555    -9.166914                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
154


CENTANAFADINE                                                                                                               5 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.3                                                                       
                                   Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, OC                                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                                TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                    
                                                3           -7.198801       -8.940391    -5.457212                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for Effect TRTPN                                                         
                                                                                                                                                    
                                                           Difference                                                                               
                                                              Between    95% Confidence Limits for                                                  
                                               i    j           Means       LSMean(i)-LSMean(j)                                                     
                                                                                                                                                    
                                               1    2        0.135691       -2.341328     2.612710                                                  
                                               1    3       -3.583242       -6.049479    -1.117006                                                  
                                               2    3       -3.718933       -6.190945    -1.246921                                                  
                                                                                                                                                    
                                                                                                                                                    
NOTE: To ensure overall protection level, only probabilities associated with pre-planned comparisons should be used.                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
155


CENTANAFADINE                                                                                                               6 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.3                                                                       
                                   Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score, OC                                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                               Standard                                                             
                                   Parameter                   Estimate           Error    t Value    Pr > |t|                                      
                                                                                                                                                    
                                   1 vs 3                   -3.58324241      1.25465498      -2.86      0.0045                                      
                                   2 vs 3                   -3.71893327      1.25759322      -2.96      0.0033                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
156


CENTANAFADINE                                                                                                               1 OF 2
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.4  
Proc GLM Output for Treatment by Center Interaction at Day 42 in AISRS Total Score, LOCF  
(Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                     
                                                                 The GLM Procedure                                                                   
                                                                                                                                                     
                                                              Class Level Information                                                                
                                                                                                                                                     
Class       Levels  Values                                                                                                                           
                                                                                                                                                     
TRTPN            3  1 2 3                                                                                                                            
                   
  
POOLCNTR        39 
 
                   
 
                   
 
                                                                                                                                                     
                                                      Number of Observations Read         421                                                        
                                                      Number of Observations Used         421                                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMCNTR; TABLE: stat1d.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.4      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
157


CENTANAFADINE                                                                                                               2 OF 2
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.4                                                                       
                             Proc GLM Output for Treatment by Center Interaction at Day 42 in AISRS Total Score, LOCF                               
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------- Parameter Code=AISRSTOT Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                       Sum of                                                                       
                               Source                      DF         Squares     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               Model                      117     17215.30877       147.13939       1.45    0.0067                                  
                                                                                                                                                    
                               Error                      303     30841.14254       101.78595                                                       
                                                                                                                                                    
                               Corrected Total            420     48056.45131                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.358231     -104.7971      10.08890     -9.627078                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2      475.234975      237.617487       2.33    0.0986                                  
                               POOLCNTR                    38     6881.047923      181.080208       1.78    0.0046                                  
                               TRTPN*POOLCNTR              76     8409.313799      110.648866       1.09    0.3087                                  
                               BASE                         1      246.568428      246.568428       2.42    0.1207                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMCNTR; TABLE: stat1d.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.4      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
158


CENTANAFADINE                                                                                                               1 OF 4
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.5.1  
Summary of Mean Change at Day 42 from Baseline in AISRS Total Score  
By Center - LOCF (Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                               ____________________AISRS TOTAL SCORE____________________                                                             
                               __CTN SR 200MG___   __CTN SR 400MG___   _____PLACEBO_____                                                             
                                                                                          TREATMENT                                                  
        CENTER                   N  LS MEAN (SE)     N  LS MEAN (SE)     N  LS MEAN (SE)  COMPARISON                   LS MEAN DIFFERENCE¹           
        -----------------------------------------------------------------------------------------------------------------------------------          
        OVERALL                140  -11.6 (0.95)   140  -11.8 (0.95)   141  -7.74 (0.94)  CTN SR 200MG VS. PLACEBO    -3.88 (-6.28, -1.48)           
                                                                                          CTN SR 400MG VS. PLACEBO    -4.05 (-6.46, -1.63)           
      
                   8  -5.26 (3.63)     6  -10.1 (4.15)     7  -5.83 (3.85)  CTN SR 200MG VS. PLACEBO     0.57 (-9.71, 10.85)           
      
                                                                            CTN SR 400MG VS. PLACEBO    -4.23 (-15.3,  6.82)           
      
                   1  -48.7 (10.2)     1  -8.22 (10.2)     1  -32.6 (10.2)  CTN SR 200MG VS. PLACEBO    -16.2 (-44.2, 11.92)           
      
                                                                            CTN SR 400MG VS. PLACEBO    24.35 (-3.73, 52.44)           
      
                  11  -9.62 (3.06)    13  -9.01 (2.81)    12  -6.45 (2.91)  CTN SR 200MG VS. PLACEBO    -3.18 (-11.5,  5.13)           
      
                                                                            CTN SR 400MG VS. PLACEBO    -2.57 (-10.5,  5.39)           
      
                   2  -12.6 (7.24)     1  -2.74 (10.2)     3  -7.95 (5.82)  CTN SR 200MG VS. PLACEBO    -4.62 (-22.9, 13.66)           
      
                                                                            CTN SR 400MG VS. PLACEBO     5.21 (-17.9, 28.30)           
      
                   2  -17.5 (7.14)     2  -30.1 (7.24)     2  -2.90 (7.14)  CTN SR 200MG VS. PLACEBO    -14.6 (-34.5,  5.27)           
      
                                                                            CTN SR 400MG VS. PLACEBO    -27.2 (-47.2, -7.09)           
      
                   7  -13.7 (3.84)     8  -9.60 (3.58)     6  -1.71 (4.13)  CTN SR 200MG VS. PLACEBO    -12.0 (-23.0, -0.93)           
      
                                                                            CTN SR 400MG VS. PLACEBO    -7.89 (-18.6,  2.84)           
      
                   8  -6.71 (3.57)     8  -11.4 (3.57)     8  -7.37 (3.60)  CTN SR 200MG VS. PLACEBO     0.66 (-9.33, 10.65)           
      
                                                                            CTN SR 400MG VS. PLACEBO    -4.05 (-14.1,  5.95)           
      
                   3  -8.54 (5.84)     2  -7.61 (7.16)     2  -2.89 (7.16)  CTN SR 200MG VS. PLACEBO    -5.65 (-23.8, 12.48)           
      
                                                                            CTN SR 400MG VS. PLACEBO    -4.72 (-24.7, 15.26)           
      
                   1  -18.5 (10.1)     1  6.32 (10.1)      1  -4.45 (10.1)  CTN SR 200MG VS. PLACEBO    -14.1 (-42.2, 14.12)           
      
                                                                            CTN SR 400MG VS. PLACEBO    10.78 (-17.4, 38.94)           
      
                   5  -16.8 (4.52)     6  -9.67 (4.12)     6  -11.4 (4.12)  CTN SR 200MG VS. PLACEBO    -5.37 (-17.4,  6.67)           
      
                                                                            CTN SR 400MG VS. PLACEBO     1.75 (-9.72, 13.21)           
      
                   3  -13.7 (5.87)     3  -11.1 (5.89)     2  -3.10 (7.14)  CTN SR 200MG VS. PLACEBO    -10.6 (-28.9,  7.57)           
      
                                                                            CTN SR 400MG VS. PLACEBO    -7.97 (-26.2, 10.30)           
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ OVERALL TREATMENT DIFFERENCE IS DERIVED USING ANCOVA MODEL, WITH TREATMENT AND CENTER AS MAIN EFFECT AND BASELINE VALUE AS                         
  COVARIATE; BY CENTER DIFFERENCES ARE DERIVED USING ANCOVA MODEL, WITH TREATMENT AND CENTER AS MAIN EFFECT, TREATMENT BY CENTER INTERACTION,        
  AND BASELINE VALUE AS COVARIATE.                                                                                                                   
NOTE: FOR ANALYSIS PURPOSE, SMALL CENTERS ARE POOLED TOGETHER.                                                                                       
                                                                                                                                                     
FILE: centera.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
159


CENTANAFADINE                                                                                                               2 OF 4
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.5.1                                                                      
                                       Summary of Mean Change at Day 42 from Baseline in AISRS Total Score                                          
                                                        By Center - LOCF (Efficacy Sample)                                                          
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                              ____________________AISRS TOTAL SCORE____________________                                                             
                              __CTN SR 200MG___   __CTN SR 400MG___   _____PLACEBO_____                                                             
                                                                                         TREATMENT                                                  
       CENTER                   N  LS MEAN (SE)     N  LS MEAN (SE)     N  LS MEAN (SE)  COMPARISON                   LS MEAN DIFFERENCE¹           
      
------------------------------------------------------------------------------------------------------------------------------          
     
                    1  -1.84 (10.1)     1  -19.7 (10.1)     1  -18.7 (10.1)  CTN SR 200MG VS. PLACEBO    16.84 (-11.2, 44.92)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -1.00 (-29.1, 27.08)           
     
                    2  -25.0 (7.14)     2  -15.6 (7.19)     3  -1.25 (5.84)  CTN SR 200MG VS. PLACEBO    -23.8 (-41.9, -5.64)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -14.4 (-32.5,  3.76)           
     
                    3  -10.5 (5.85)     4  -8.93 (5.05)     4  -5.67 (5.04)  CTN SR 200MG VS. PLACEBO    -4.80 (-20.0, 10.39)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -3.26 (-17.3, 10.78)           
     
                    3  -10.4 (5.84)     4  -11.4 (5.04)     3  -6.21 (5.83)  CTN SR 200MG VS. PLACEBO    -4.19 (-20.4, 12.05)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -5.20 (-20.4,  9.96)           
     
                    2  -1.69 (7.15)     1  -17.7 (10.1)     2  -29.9 (7.15)  CTN SR 200MG VS. PLACEBO    28.16 ( 8.31, 48.02)           
     
                                                                             CTN SR 400MG VS. PLACEBO    12.15 (-12.2, 36.47)           
     
                    3  -16.3 (5.83)     2  -7.29 (7.18)     3  -10.2 (5.83)  CTN SR 200MG VS. PLACEBO    -6.14 (-22.4, 10.10)           
     
                                                                             CTN SR 400MG VS. PLACEBO     2.89 (-15.4, 21.15)           
     
                    1  0.55 (10.1)      2  -7.98 (7.14)     1  -9.32 (10.1)  CTN SR 200MG VS. PLACEBO     9.87 (-18.2, 37.98)           
     
                                                                             CTN SR 400MG VS. PLACEBO     1.34 (-23.0, 25.65)           
     
                    1  -10.6 (10.1)     2  -4.48 (7.14)     1  -20.1 (10.1)  CTN SR 200MG VS. PLACEBO     9.52 (-18.6, 37.60)           
     
                                                                             CTN SR 400MG VS. PLACEBO    15.65 (-8.68, 39.97)           
     
                    5  -11.2 (4.54)     5  -10.6 (4.53)     4  1.78 (5.17)   CTN SR 200MG VS. PLACEBO    -13.0 (-26.4,  0.38)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -12.3 (-25.7,  1.06)           
     
                    3  -14.6 (5.88)     3  -14.9 (5.91)     3  -12.1 (5.87)  CTN SR 200MG VS. PLACEBO    -2.49 (-18.7, 13.72)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -2.76 (-19.0, 13.46)           
     
                    2  -3.18 (7.14)     1  -13.3 (10.1)     1  6.39 (10.1)   CTN SR 200MG VS. PLACEBO    -9.56 (-34.0, 14.87)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -19.7 (-47.8,  8.40)           
     
                    4  -14.2 (5.08)     5  -4.19 (4.53)     4  -2.45 (5.05)  CTN SR 200MG VS. PLACEBO    -11.7 (-25.8,  2.34)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -1.73 (-15.1, 11.62)           
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ OVERALL TREATMENT DIFFERENCE IS DERIVED USING ANCOVA MODEL, WITH TREATMENT AND CENTER AS MAIN EFFECT AND BASELINE VALUE AS                         
 COVARIATE; BY CENTER DIFFERENCES ARE DERIVED USING ANCOVA MODEL, WITH TREATMENT AND CENTER AS MAIN EFFECT, TREATMENT BY CENTER INTERACTION,        
 AND BASELINE VALUE AS COVARIATE.                                                                                                                   
NOTE: FOR ANALYSIS PURPOSE, SMALL CENTERS ARE POOLED TOGETHER.                                                                                       
                                                                                                                                                    
FILE: centera.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
160


CENTANAFADINE                                                                                                               3 OF 4
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.5.1                                                                      
                                       Summary of Mean Change at Day 42 from Baseline in AISRS Total Score                                          
                                                        By Center - LOCF (Efficacy Sample)                                                          
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                              ____________________AISRS TOTAL SCORE____________________                                                             
                              __CTN SR 200MG___   __CTN SR 400MG___   _____PLACEBO_____                                                             
                                                                                         TREATMENT                                                  
       CENTER                   N  LS MEAN (SE)     N  LS MEAN (SE)     N  LS MEAN (SE)  COMPARISON                   LS MEAN DIFFERENCE¹           
      
-------------------------------------------------------------------------------------------------------------------------------          
     
                    3  -10.2 (5.90)     5  -14.2 (4.52)     4  -17.8 (5.05)  CTN SR 200MG VS. PLACEBO     7.58 (-7.74, 22.91)           
     
                                                                             CTN SR 400MG VS. PLACEBO     3.54 (-9.81, 16.88)           
     
                    3  -10.8 (5.85)     3  -14.5 (5.83)     3  -2.23 (5.83)  CTN SR 200MG VS. PLACEBO    -8.58 (-24.8,  7.67)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -12.2 (-28.4,  3.98)           
     
                    2  2.03 (7.20)      3  3.22 (5.95)      2  -2.39 (7.21)  CTN SR 200MG VS. PLACEBO     4.42 (-15.4, 24.27)           
     
                                                                             CTN SR 400MG VS. PLACEBO     5.60 (-12.5, 23.73)           
     
                    2  -13.9 (7.14)     2  -19.0 (7.19)     2  -20.2 (7.13)  CTN SR 200MG VS. PLACEBO     6.23 (-13.6, 26.10)           
     
                                                                             CTN SR 400MG VS. PLACEBO     1.21 (-18.7, 21.13)           
     
                    2  -13.0 (7.19)     3  -7.01 (5.89)     3  -11.3 (5.88)  CTN SR 200MG VS. PLACEBO    -1.66 (-19.8, 16.46)           
     
                                                                             CTN SR 400MG VS. PLACEBO     4.28 (-11.9, 20.49)           
     
                   12  -9.45 (2.91)    10  -14.6 (3.19)    11  -0.87 (3.05)  CTN SR 200MG VS. PLACEBO    -8.58 (-16.9, -0.29)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -13.7 (-22.4, -5.01)           
     
                   12  -5.08 (2.91)    11  -7.96 (3.04)    12  -5.60 (2.91)  CTN SR 200MG VS. PLACEBO     0.52 (-7.59,  8.62)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -2.37 (-10.7,  5.93)           
     
                    2  -10.7 (7.15)     1  -0.39 (10.1)     2  -10.1 (7.14)  CTN SR 200MG VS. PLACEBO    -0.66 (-20.5, 19.19)           
     
                                                                             CTN SR 400MG VS. PLACEBO     9.68 (-14.8, 34.15)           
     
                    2  -17.0 (7.19)     1  -0.29 (10.1)     2  -0.69 (7.15)  CTN SR 200MG VS. PLACEBO    -16.3 (-36.3,  3.80)           
     
                                                                             CTN SR 400MG VS. PLACEBO     0.40 (-24.1, 24.86)           
     
                    5  -15.9 (4.52)     5  -26.3 (4.59)     5  -12.3 (4.55)  CTN SR 200MG VS. PLACEBO    -3.55 (-16.1,  9.03)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -14.0 (-26.5, -1.41)           
     
                    2  0.08 (7.13)      3  -8.71 (5.83)     1  -13.6 (10.1)  CTN SR 200MG VS. PLACEBO    13.69 (-10.7, 38.10)           
     
                                                                             CTN SR 400MG VS. PLACEBO     4.90 (-18.1, 27.88)           
     
                    6  -16.2 (4.12)     5  -13.8 (4.52)     6  -5.68 (4.13)  CTN SR 200MG VS. PLACEBO    -10.5 (-22.0,  0.93)           
     
                                                                             CTN SR 400MG VS. PLACEBO    -8.17 (-20.2,  3.90)           
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ OVERALL TREATMENT DIFFERENCE IS DERIVED USING ANCOVA MODEL, WITH TREATMENT AND CENTER AS MAIN EFFECT AND BASELINE VALUE AS                         
 COVARIATE; BY CENTER DIFFERENCES ARE DERIVED USING ANCOVA MODEL, WITH TREATMENT AND CENTER AS MAIN EFFECT, TREATMENT BY CENTER INTERACTION,        
 AND BASELINE VALUE AS COVARIATE.                                                                                                                   
NOTE: FOR ANALYSIS PURPOSE, SMALL CENTERS ARE POOLED TOGETHER.                                                                                       
                                                                                                                                                    
FILE: centera.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
161


CENTANAFADINE                                                                                                               4 OF 4
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.5.1                                                                      
                                       Summary of Mean Change at Day 42 from Baseline in AISRS Total Score                                          
                                                        By Center - LOCF (Efficacy Sample)                                                          
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                              ____________________AISRS TOTAL SCORE____________________                                                             
                              __CTN SR 200MG___   __CTN SR 400MG___   _____PLACEBO_____                                                             
                                                                                         TREATMENT                                                  
       CENTER                   N  LS MEAN (SE)     N  LS MEAN (SE)     N  LS MEAN (SE)  COMPARISON                   LS MEAN DIFFERENCE¹           
       -----------------------------------------------------------------------------------------------------------------------------------          
      
         1  -6.32 (10.1)     1  -15.6 (10.1)     1  -1.48 (10.1)  CTN SR 200MG VS. PLACEBO    -4.84 (-32.9, 23.24)           
       
                                                                  CTN SR 400MG VS. PLACEBO    -14.1 (-42.2, 13.98)           
       
         3  -7.77 (5.83)     1  -27.8 (10.1)     2  -14.0 (7.14)  CTN SR 200MG VS. PLACEBO     6.24 (-11.9, 24.38)           
       
                                                                  CTN SR 400MG VS. PLACEBO    -13.8 (-38.1, 10.50)           
       
         1  -25.6 (10.1)     2  -13.8 (7.14)     3  -16.8 (5.84)  CTN SR 200MG VS. PLACEBO    -8.86 (-31.8, 14.09)           
       
                                                                  CTN SR 400MG VS. PLACEBO     2.93 (-15.2, 21.06)           
       
         1  -18.5 (10.1)     1  3.16 (10.1)      2  -9.65 (7.15)  CTN SR 200MG VS. PLACEBO    -8.84 (-33.2, 15.48)           
       
                                                                  CTN SR 400MG VS. PLACEBO    12.81 (-11.5, 37.14)           
       
                                                                                                                             
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ OVERALL TREATMENT DIFFERENCE IS DERIVED USING ANCOVA MODEL, WITH TREATMENT AND CENTER AS MAIN EFFECT AND BASELINE VALUE AS                         
  COVARIATE; BY CENTER DIFFERENCES ARE DERIVED USING ANCOVA MODEL, WITH TREATMENT AND CENTER AS MAIN EFFECT, TREATMENT BY CENTER INTERACTION,        
  AND BASELINE VALUE AS COVARIATE.                                                                                                                   
NOTE: FOR ANALYSIS PURPOSE, SMALL CENTERS ARE POOLED TOGETHER.                                                                                       
                                                                                                                                                     
FILE: centera.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
162


CENTANAFADINE                                                                                                               1 OF 2
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.5.2  
Differences in Unadjusted Mean Changes of AISRS Total Score at Day 42 Among Treatment Groups  
By Center - LOCF (Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                                                                                                CTN SR 200MG VS.   CTN SR 400MG VS.                  
                                                     _CTN SR 200M  CTN SR 400MG  __PLACEBO___            PLACEBO            PLACEBO                  
                                                                                                                                                     
                 CENTER                    COUNTRY    N     MEAN¹   N     MEAN¹   N     MEAN¹              DIFF²              DIFF²                  
                 ------------------------------------------------------------------------------------------------------------------                  
                
                                                                                                                            
               
                    USA      2    -18.00   2    -32.00   2     -2.50             -15.50             -29.50                  
               
                    USA      2     -3.50   1    -12.00   1      8.00             -11.50             -20.00                  
               
                    USA      2    -25.50   2    -17.00   3     -2.00             -23.50             -15.00                  
               
                    USA      5    -16.20   5    -27.60   5    -13.20              -3.00             -14.40                  
               
                    USA     12     -9.33  10    -14.70  11     -0.64              -8.70             -14.06                  
               
                    USA      3     -7.67   1    -28.00   2    -14.50               6.83             -13.50                  
               
                    USA      1     -6.00   1    -14.00   1     -1.00              -5.00             -13.00                  
               
                    USA      3    -10.00   3    -14.67   3     -2.33              -7.67             -12.33                  
               
                    USA      5    -12.00   5    -11.20   4      0.00             -12.00             -11.20                  
               
                    USA      6    -16.00   5    -14.20   6     -5.17             -10.83              -9.03                  
               
                    USA      7    -14.43   8    -10.00   6     -2.17             -12.26              -7.83                  
               
                    USA      3     -8.00   2     -8.50   2     -2.00              -6.00              -6.50                  
               
                    USA      3    -12.67   3     -9.67   2     -3.50              -9.17              -6.17                  
               
                    USA      3    -11.00   4    -11.50   3     -6.00              -5.00              -5.50                  
               
                    USA      8     -6.88   8    -11.63   8     -6.63              -0.25              -5.00                  
               
                    USA      8     -4.25   6     -9.33   7     -5.00               0.75              -4.33                  
               
                    USA      3    -11.33   4     -9.25   4     -5.75              -5.58              -3.50                  
               
                    USA     11    -10.09  13     -9.46  12     -6.50              -3.59              -2.96                  
               
                    USA      4    -13.25   5     -4.80   4     -2.25             -11.00              -2.55                  
               
                    USA      3    -13.33   3    -13.33   3    -11.00              -2.33              -2.33                  
               
                    USA     12     -5.08  11     -7.82  12     -5.67               0.58              -2.15                  
               
                    USA      1     -2.00   1    -20.00   1    -19.00              17.00              -1.00                  
                
                                                                                                                            
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ MEAN CHANGE FROM BASELINE AT DAY 42 (LOCF).                                                                                                        
² DIFFERENCE IN MEAN CHANGES AT DAY 42 BETWEEN TWO TREATMENT GROUPS.                                                                                 
NOTE: FOR ANALYSIS PURPOSE, SMALL CENTERS ARE POOLED TOGETHER.                                                                                       
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: centerb.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
163


CENTANAFADINE                                                                                                               2 OF 2
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.5.2                                                                      
                           Differences in Unadjusted Mean Changes of AISRS Total Score at Day 42 Among Treatment Groups                             
                                                        By Center - LOCF (Efficacy Sample)                                                          
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                               CTN SR 200MG VS.   CTN SR 400MG VS.                  
                                                    _CTN SR 200M  CTN SR 400MG  __PLACEBO___            PLACEBO            PLACEBO                  
                                                                                                                                                    
                CENTER                    COUNTRY    N     MEAN¹   N     MEAN¹   N     MEAN¹              DIFF²              DIFF²                  
                ------------------------------------------------------------------------------------------------------------------                  
               
                                                                                                                    
               
            USA      1      2.00   2     -7.50   1     -9.00              11.00               1.50                  
               
            USA      5    -16.40   6     -9.83   6    -11.50              -4.90               1.67                  
               
            USA      2    -14.50   2    -17.50   2    -20.00               5.50               2.50                  
               
            USA      2    -15.50   1      1.00   2     -1.50             -14.00               2.50                  
               
            USA      1    -24.00   2    -13.50   3    -16.00              -8.00               2.50                  
               
            USA      2    -14.50   1     -5.00   3     -8.00              -6.50               3.00                  
               
            USA      2      0.00   3     -8.33   1    -12.00              12.00               3.67                  
               
            USA      3     -8.67   5    -13.80   4    -18.00               9.33               4.20                  
               
            USA      2    -11.50   3     -5.67   3    -10.00              -1.50               4.33                  
               
            USA      3    -16.00   2     -6.00   3    -10.67              -5.33               4.67                  
               
            USA      2      0.50   3      1.33   2     -4.00               4.50               5.33                  
               
            USA      2    -10.00   1     -2.00   2     -9.50              -0.50               7.50                  
               
            USA      1    -19.00   1      6.00   1     -3.00             -16.00               9.00                  
               
            USA      2     -2.50   1    -19.00   2    -30.50              28.00              11.50                  
               
            USA      1    -18.00   1      3.00   2     -9.00              -9.00              12.00                  
               
            USA      1     -9.00   2     -4.00   1    -19.00              10.00              15.00                  
               
            USA      1    -51.00   1    -10.00   1    -35.00             -16.00              25.00                  
               
                                                                                                                    
               
                                                                                                                    
               
                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ MEAN CHANGE FROM BASELINE AT DAY 42 (LOCF).                                                                                                        
² DIFFERENCE IN MEAN CHANGES AT DAY 42 BETWEEN TWO TREATMENT GROUPS.                                                                                 
NOTE: FOR ANALYSIS PURPOSE, SMALL CENTERS ARE POOLED TOGETHER.                                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: centerb.lis, RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
164


CENTANAFADINE                                                                                                               1 OF 24
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.6  
Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              137     -5.3431      7.5542      0.6454    -27.0000     12.0000                                    
                                  3              139     -3.5612      6.6693      0.5657    -31.0000     10.0000                                    
                                  Diff (1-2)             -1.7819      7.1223      0.8574                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                               -5.3431     -6.6194  -4.0668      7.5542      6.7532   8.5724                             
                          3                               -3.5612     -4.6797  -2.4426      6.6693      5.9667   7.5609                             
                          Diff (1-2)    Pooled            -1.7819     -3.4699  -0.0939      7.1223      6.5726   7.7730                             
                          Diff (1-2)    Satterthwaite     -1.7819     -3.4716  -0.0922                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           274      -2.08      0.0386                                              
                                           Satterthwaite    Unequal      268.85      -2.08      0.0388                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
165


CENTANAFADINE                                                                                                               2 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       136       138       1.28    0.1458                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
166


CENTANAFADINE                                                                                                               3 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              140     -8.1429      9.6018      0.8115    -48.0000     10.0000                                    
                                  3              141     -4.6879      7.7994      0.6568    -38.0000      8.0000                                    
                                  Diff (1-2)             -3.4549      8.7440      1.0432                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                               -8.1429     -9.7473  -6.5384      9.6018      8.5936  10.8803                             
                          3                               -4.6879     -5.9865  -3.3894      7.7994      6.9830   8.8336                             
                          Diff (1-2)    Pooled            -3.4549     -5.5085  -1.4013      8.7440      8.0747   9.5351                             
                          Diff (1-2)    Satterthwaite     -3.4549     -5.5105  -1.3994                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -3.31      0.0010                                              
                                           Satterthwaite    Unequal         267      -3.31      0.0011                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
167


CENTANAFADINE                                                                                                               4 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.52    0.0146                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
168


CENTANAFADINE                                                                                                               5 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              140     -9.5857     10.1450      0.8574    -45.0000     10.0000                                    
                                  3              141     -5.8582      8.7436      0.7363    -40.0000     11.0000                                    
                                  Diff (1-2)             -3.7276      9.4678      1.1296                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                               -9.5857    -11.2810  -7.8905     10.1450      9.0797  11.4957                             
                          3                               -5.8582     -7.3140  -4.4024      8.7436      7.8284   9.9031                             
                          Diff (1-2)    Pooled            -3.7276     -5.9512  -1.5039      9.4678      8.7431  10.3244                             
                          Diff (1-2)    Satterthwaite     -3.7276     -5.9526  -1.5025                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -3.30      0.0011                                              
                                           Satterthwaite    Unequal      272.48      -3.30      0.0011                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
169


CENTANAFADINE                                                                                                               6 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.35    0.0801                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
170


CENTANAFADINE                                                                                                               7 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              140     -9.8000     10.4587      0.8839    -44.0000     13.0000                                    
                                  3              141     -6.2553      8.9836      0.7566    -37.0000     13.0000                                    
                                  Diff (1-2)             -3.5447      9.7465      1.1629                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                               -9.8000    -11.5477  -8.0523     10.4587      9.3605  11.8512                             
                          3                               -6.2553     -7.7511  -4.7596      8.9836      8.0433  10.1749                             
                          Diff (1-2)    Pooled            -3.5447     -5.8338  -1.2556      9.7465      9.0005  10.6283                             
                          Diff (1-2)    Satterthwaite     -3.5447     -5.8353  -1.2541                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -3.05      0.0025                                              
                                           Satterthwaite    Unequal      272.21      -3.05      0.0025                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
171


CENTANAFADINE                                                                                                               8 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.36    0.0735                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
172


CENTANAFADINE                                                                                                               9 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              140    -10.2929     10.6376      0.8990    -51.0000     11.0000                                    
                                  3              141     -6.9716      9.5086      0.8008    -37.0000     12.0000                                    
                                  Diff (1-2)             -3.3212     10.0869      1.2035                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                              -10.2929    -12.0704  -8.5153     10.6376      9.5206  12.0539                             
                          3                               -6.9716     -8.5548  -5.3885      9.5086      8.5133  10.7695                             
                          Diff (1-2)    Pooled            -3.3212     -5.6903  -0.9522     10.0869      9.3149  10.9995                             
                          Diff (1-2)    Satterthwaite     -3.3212     -5.6914  -0.9511                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -2.76      0.0062                                              
                                           Satterthwaite    Unequal      275.12      -2.76      0.0062                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
173


CENTANAFADINE                                                                                                               10 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.25    0.1862                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
174


CENTANAFADINE                                                                                                               11 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              140    -10.7071     10.8359      0.9158    -51.0000     11.0000                                    
                                  3              141     -7.1348     10.1624      0.8558    -39.0000     12.0000                                    
                                  Diff (1-2)             -3.5724     10.5034      1.2532                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                              -10.7071    -12.5178  -8.8964     10.8359      9.6981  12.2787                             
                          3                               -7.1348     -8.8268  -5.4427     10.1624      9.0987  11.5100                             
                          Diff (1-2)    Pooled            -3.5724     -6.0392  -1.1055     10.5034      9.6995  11.4537                             
                          Diff (1-2)    Satterthwaite     -3.5724     -6.0399  -1.1049                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -2.85      0.0047                                              
                                           Satterthwaite    Unequal      277.59      -2.85      0.0047                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
175


CENTANAFADINE                                                                                                               12 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.14    0.4493                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
176


CENTANAFADINE                                                                                                               13 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              139     -5.4460      6.6389      0.5631    -24.0000      9.0000                                    
                                  3              139     -3.5612      6.6693      0.5657    -31.0000     10.0000                                    
                                  Diff (1-2)             -1.8849      6.6541      0.7982                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                               -5.4460     -6.5595  -4.3326      6.6389      5.9395   7.5264                             
                          3                               -3.5612     -4.6797  -2.4426      6.6693      5.9667   7.5609                             
                          Diff (1-2)    Pooled            -1.8849     -3.4562  -0.3136      6.6541      6.1423   7.2597                             
                          Diff (1-2)    Satterthwaite     -1.8849     -3.4562  -0.3136                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           276      -2.36      0.0189                                              
                                           Satterthwaite    Unequal      275.99      -2.36      0.0189                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
177


CENTANAFADINE                                                                                                               14 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       138       138       1.01    0.9572                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
178


CENTANAFADINE                                                                                                               15 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              140     -8.1143      8.1850      0.6918    -35.0000     12.0000                                    
                                  3              141     -4.6879      7.7994      0.6568    -38.0000      8.0000                                    
                                  Diff (1-2)             -3.4263      7.9938      0.9537                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                               -8.1143     -9.4820  -6.7466      8.1850      7.3255   9.2748                             
                          3                               -4.6879     -5.9865  -3.3894      7.7994      6.9830   8.8336                             
                          Diff (1-2)    Pooled            -3.4263     -5.3038  -1.5489      7.9938      7.3820   8.7171                             
                          Diff (1-2)    Satterthwaite     -3.4263     -5.3041  -1.5485                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -3.59      0.0004                                              
                                           Satterthwaite    Unequal      278.15      -3.59      0.0004                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
179


CENTANAFADINE                                                                                                               16 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.10    0.5693                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
180


CENTANAFADINE                                                                                                               17 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              140    -10.1071      9.2088      0.7783    -34.0000     17.0000                                    
                                  3              141     -5.8582      8.7436      0.7363    -40.0000     11.0000                                    
                                  Diff (1-2)             -4.2490      8.9784      1.0712                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                              -10.1071    -11.6459  -8.5683      9.2088      8.2418  10.4349                             
                          3                               -5.8582     -7.3140  -4.4024      8.7436      7.8284   9.9031                             
                          Diff (1-2)    Pooled            -4.2490     -6.3577  -2.1403      8.9784      8.2912   9.7907                             
                          Diff (1-2)    Satterthwaite     -4.2490     -6.3581  -2.1399                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -3.97      <.0001                                              
                                           Satterthwaite    Unequal      278.03      -3.97      <.0001                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
181


CENTANAFADINE                                                                                                               18 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.11    0.5411                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
182


CENTANAFADINE                                                                                                               19 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              140    -10.2714      9.6387      0.8146    -42.0000      7.0000                                    
                                  3              141     -6.2553      8.9836      0.7566    -37.0000     13.0000                                    
                                  Diff (1-2)             -4.0161      9.3157      1.1115                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                              -10.2714    -11.8821  -8.6608      9.6387      8.6266  10.9220                             
                          3                               -6.2553     -7.7511  -4.7596      8.9836      8.0433  10.1749                             
                          Diff (1-2)    Pooled            -4.0161     -6.2040  -1.8282      9.3157      8.6028  10.1586                             
                          Diff (1-2)    Satterthwaite     -4.0161     -6.2046  -1.8276                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -3.61      0.0004                                              
                                           Satterthwaite    Unequal      277.34      -3.61      0.0004                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
183


CENTANAFADINE                                                                                                               20 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.15    0.4067                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
184


CENTANAFADINE                                                                                                               21 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              140    -11.4000     10.1689      0.8594    -40.0000     10.0000                                    
                                  3              141     -6.9716      9.5086      0.8008    -37.0000     12.0000                                    
                                  Diff (1-2)             -4.4284      9.8431      1.1744                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                              -11.4000    -13.0992  -9.7008     10.1689      9.1011  11.5229                             
                          3                               -6.9716     -8.5548  -5.3885      9.5086      8.5133  10.7695                             
                          Diff (1-2)    Pooled            -4.4284     -6.7402  -2.1166      9.8431      9.0898  10.7337                             
                          Diff (1-2)    Satterthwaite     -4.4284     -6.7408  -2.1160                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -3.77      0.0002                                              
                                           Satterthwaite    Unequal      277.47      -3.77      0.0002                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
185


CENTANAFADINE                                                                                                               22 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.14    0.4286                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
186


CENTANAFADINE                                                                                                               23 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              140    -11.0571     10.7126      0.9054    -41.0000     11.0000                                    
                                  3              141     -7.1348     10.1624      0.8558    -39.0000     12.0000                                    
                                  Diff (1-2)             -3.9224     10.4401      1.2456                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                              -11.0571    -12.8472  -9.2670     10.7126      9.5877  12.1389                             
                          3                               -7.1348     -8.8268  -5.4427     10.1624      9.0987  11.5100                             
                          Diff (1-2)    Pooled            -3.9224     -6.3744  -1.4704     10.4401      9.6411  11.3847                             
                          Diff (1-2)    Satterthwaite     -3.9224     -6.3749  -1.4699                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           279      -3.15      0.0018                                              
                                           Satterthwaite    Unequal      278.01      -3.15      0.0018                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
187


CENTANAFADINE                                                                                                               24 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.6                                                                       
                   Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       139       140       1.11    0.5341                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
188


CENTANAFADINE                                                                                                               1 OF 24
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.7  
Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              137     -5.3431      7.5542      0.6454    -27.0000     12.0000                                    
                                  3              139     -3.5612      6.6693      0.5657    -31.0000     10.0000                                    
                                  Diff (1-2)             -1.7819      7.1223      0.8574                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                               -5.3431     -6.6194  -4.0668      7.5542      6.7532   8.5724                             
                          3                               -3.5612     -4.6797  -2.4426      6.6693      5.9667   7.5609                             
                          Diff (1-2)    Pooled            -1.7819     -3.4699  -0.0939      7.1223      6.5726   7.7730                             
                          Diff (1-2)    Satterthwaite     -1.7819     -3.4716  -0.0922                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           274      -2.08      0.0386                                              
                                           Satterthwaite    Unequal      268.85      -2.08      0.0388                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
189


CENTANAFADINE                                                                                                               2 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       136       138       1.28    0.1458                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
190


CENTANAFADINE                                                                                                               3 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              132     -8.5606      9.7042      0.8446    -48.0000     10.0000                                    
                                  3              132     -4.8561      7.9070      0.6882    -38.0000      8.0000                                    
                                  Diff (1-2)             -3.7045      8.8514      1.0895                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                               -8.5606    -10.2315  -6.8897      9.7042      8.6579  11.0404                             
                          3                               -4.8561     -6.2175  -3.4946      7.9070      7.0545   8.9958                             
                          Diff (1-2)    Pooled            -3.7045     -5.8499  -1.5592      8.8514      8.1540   9.6801                             
                          Diff (1-2)    Satterthwaite     -3.7045     -5.8503  -1.5588                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           262      -3.40      0.0008                                              
                                           Satterthwaite    Unequal      251.73      -3.40      0.0008                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
191


CENTANAFADINE                                                                                                               4 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       131       131       1.51    0.0197                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
192


CENTANAFADINE                                                                                                               5 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              127     -9.9685     10.4501      0.9273    -45.0000     10.0000                                    
                                  3              132     -5.9924      8.8925      0.7740    -40.0000     11.0000                                    
                                  Diff (1-2)             -3.9761      9.6875      1.2041                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                               -9.9685    -11.8036  -8.1334     10.4501      9.3038  11.9212                             
                          3                               -5.9924     -7.5236  -4.4613      8.8925      7.9337  10.1169                             
                          Diff (1-2)    Pooled            -3.9761     -6.3473  -1.6049      9.6875      8.9175  10.6042                             
                          Diff (1-2)    Satterthwaite     -3.9761     -6.3551  -1.5971                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           257      -3.30      0.0011                                              
                                           Satterthwaite    Unequal      247.28      -3.29      0.0011                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
193


CENTANAFADINE                                                                                                               6 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       126       131       1.38    0.0680                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
194


CENTANAFADINE                                                                                                               7 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              122    -10.0492     10.4580      0.9468    -44.0000     13.0000                                    
                                  3              130     -6.4462      9.1313      0.8009    -37.0000     13.0000                                    
                                  Diff (1-2)             -3.6030      9.7959      1.2348                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                              -10.0492    -11.9237  -8.1747     10.4580      9.2900  11.9645                             
                          3                               -6.4462     -8.0307  -4.8616      9.1313      8.1400  10.3996                             
                          Diff (1-2)    Pooled            -3.6030     -6.0349  -1.1711      9.7959      9.0073  10.7369                             
                          Diff (1-2)    Satterthwaite     -3.6030     -6.0459  -1.1602                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           250      -2.92      0.0038                                              
                                           Satterthwaite    Unequal      240.57      -2.91      0.0040                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
195


CENTANAFADINE                                                                                                               8 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       121       129       1.31    0.1299                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
196


CENTANAFADINE                                                                                                               9 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              115    -10.1391     10.5945      0.9879    -51.0000     11.0000                                    
                                  3              125     -7.1840      9.3657      0.8377    -37.0000     12.0000                                    
                                  Diff (1-2)             -2.9551      9.9732      1.2887                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                              -10.1391    -12.0962  -8.1820     10.5945      9.3797  12.1737                             
                          3                               -7.1840     -8.8420  -5.5260      9.3657      8.3310  10.6962                             
                          Diff (1-2)    Pooled            -2.9551     -5.4938  -0.4165      9.9732      9.1521  10.9574                             
                          Diff (1-2)    Satterthwaite     -2.9551     -5.5074  -0.4029                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           238      -2.29      0.0227                                              
                                           Satterthwaite    Unequal      228.34      -2.28      0.0234                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
197


CENTANAFADINE                                                                                                               10 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       114       124       1.28    0.1789                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
198


CENTANAFADINE                                                                                                               11 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  1              113    -10.5841     10.5117      0.9889    -40.0000     11.0000                                    
                                  3              123     -7.3008     10.1658      0.9166    -39.0000     12.0000                                    
                                  Diff (1-2)             -3.2833     10.3328      1.3464                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          1                              -10.5841    -12.5434  -8.6248     10.5117      9.2969  12.0944                             
                          3                               -7.3008     -9.1153  -5.4863     10.1658      9.0346  11.6234                             
                          Diff (1-2)    Pooled            -3.2833     -5.9359  -0.6306     10.3328      9.4754  11.3621                             
                          Diff (1-2)    Satterthwaite     -3.2833     -5.9399  -0.6266                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           234      -2.44      0.0155                                              
                                           Satterthwaite    Unequal      230.76      -2.44      0.0156                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
199


CENTANAFADINE                                                                                                               12 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       112       122       1.07    0.7162                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
200


CENTANAFADINE                                                                                                               13 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              139     -5.4460      6.6389      0.5631    -24.0000      9.0000                                    
                                  3              139     -3.5612      6.6693      0.5657    -31.0000     10.0000                                    
                                  Diff (1-2)             -1.8849      6.6541      0.7982                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                               -5.4460     -6.5595  -4.3326      6.6389      5.9395   7.5264                             
                          3                               -3.5612     -4.6797  -2.4426      6.6693      5.9667   7.5609                             
                          Diff (1-2)    Pooled            -1.8849     -3.4562  -0.3136      6.6541      6.1423   7.2597                             
                          Diff (1-2)    Satterthwaite     -1.8849     -3.4562  -0.3136                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           276      -2.36      0.0189                                              
                                           Satterthwaite    Unequal      275.99      -2.36      0.0189                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
201


CENTANAFADINE                                                                                                               14 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       138       138       1.01    0.9572                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
202


CENTANAFADINE                                                                                                               15 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              125     -8.0880      8.3396      0.7459    -35.0000     12.0000                                    
                                  3              132     -4.8561      7.9070      0.6882    -38.0000      8.0000                                    
                                  Diff (1-2)             -3.2319      8.1202      1.0134                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                               -8.0880     -9.5644  -6.6116      8.3396      7.4182   9.5243                             
                          3                               -4.8561     -6.2175  -3.4946      7.9070      7.0545   8.9958                             
                          Diff (1-2)    Pooled            -3.2319     -5.2277  -1.2362      8.1202      7.4725   8.8919                             
                          Diff (1-2)    Satterthwaite     -3.2319     -5.2307  -1.2332                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           255      -3.19      0.0016                                              
                                           Satterthwaite    Unequal      252.07      -3.18      0.0016                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
203


CENTANAFADINE                                                                                                               16 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       124       131       1.11    0.5473                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
204


CENTANAFADINE                                                                                                               17 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              116    -10.5690      9.5555      0.8872    -34.0000     17.0000                                    
                                  3              132     -5.9924      8.8925      0.7740    -40.0000     11.0000                                    
                                  Diff (1-2)             -4.5765      9.2084      1.1719                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                              -10.5690    -12.3264  -8.8116      9.5555      8.4641  10.9727                             
                          3                               -5.9924     -7.5236  -4.4613      8.8925      7.9337  10.1169                             
                          Diff (1-2)    Pooled            -4.5765     -6.8848  -2.2683      9.2084      8.4616  10.1008                             
                          Diff (1-2)    Satterthwaite     -4.5765     -6.8960  -2.2571                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           246      -3.91      0.0001                                              
                                           Satterthwaite    Unequal      236.43      -3.89      0.0001                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
205


CENTANAFADINE                                                                                                               18 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       115       131       1.15    0.4242                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
206


CENTANAFADINE                                                                                                               19 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              114    -10.4298     10.0344      0.9398    -42.0000      7.0000                                    
                                  3              130     -6.4462      9.1313      0.8009    -37.0000     13.0000                                    
                                  Diff (1-2)             -3.9837      9.5636      1.2271                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                              -10.4298    -12.2918  -8.5679     10.0344      8.8794  11.5377                             
                          3                               -6.4462     -8.0307  -4.8616      9.1313      8.1400  10.3996                             
                          Diff (1-2)    Pooled            -3.9837     -6.4009  -1.5664      9.5636      8.7822  10.4989                             
                          Diff (1-2)    Satterthwaite     -3.9837     -6.4165  -1.5508                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           242      -3.25      0.0013                                              
                                           Satterthwaite    Unequal      230.32      -3.23      0.0014                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
207


CENTANAFADINE                                                                                                               20 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       113       129       1.21    0.2991                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
208


CENTANAFADINE                                                                                                               21 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              104    -12.0577     10.7666      1.0557    -40.0000     10.0000                                    
                                  3              125     -7.1840      9.3657      0.8377    -37.0000     12.0000                                    
                                  Diff (1-2)             -4.8737     10.0256      1.3306                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                              -12.0577    -14.1515  -9.9639     10.7666      9.4757  12.4678                             
                          3                               -7.1840     -8.8420  -5.5260      9.3657      8.3310  10.6962                             
                          Diff (1-2)    Pooled            -4.8737     -7.4957  -2.2517     10.0256      9.1821  11.0411                             
                          Diff (1-2)    Satterthwaite     -4.8737     -7.5308  -2.2166                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           227      -3.66      0.0003                                              
                                           Satterthwaite    Unequal      205.77      -3.62      0.0004                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
209


CENTANAFADINE                                                                                                               22 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       103       124       1.32    0.1375                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
210


CENTANAFADINE                                                                                                               23 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                  TRTPN            N        Mean     Std Dev     Std Err     Minimum     Maximum                                    
                                                                                                                                                    
                                  2              102    -11.5490     11.6293      1.1515    -41.0000     11.0000                                    
                                  3              123     -7.3008     10.1658      0.9166    -39.0000     12.0000                                    
                                  Diff (1-2)             -4.2482     10.8531      1.4534                                                            
                                                                                                                                                    
                          TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                    
                          2                              -11.5490    -13.8332  -9.2648     11.6293     10.2229  13.4878                             
                          3                               -7.3008     -9.1153  -5.4863     10.1658      9.0346  11.6234                             
                          Diff (1-2)    Pooled            -4.2482     -7.1124  -1.3840     10.8531      9.9325  11.9632                             
                          Diff (1-2)    Satterthwaite     -4.2482     -7.1502  -1.3463                                                              
                                                                                                                                                    
                                           Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                    
                                           Pooled           Equal           223      -2.92      0.0038                                              
                                           Satterthwaite    Unequal      202.31      -2.89      0.0043                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
211


CENTANAFADINE                                                                                                               24 OF 24
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.7                                                                       
                    Unadjusted Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, OC                      
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                               The TTEST Procedure                                                                  
                                                                                                                                                    
                                                      Variable:  CHG  (Change from Baseline)                                                        
                                                                                                                                                    
                                                              Equality of Variances                                                                 
                                                                                                                                                    
                                                Method      Num DF    Den DF    F Value    Pr > F                                                   
                                                                                                                                                    
                                                Folded F       101       122       1.31    0.1554                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
212


CENTANAFADINE                                                                                                               1 OF 6
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.8  
Non-Parametric Stratified by Center Analysis of Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                                The FREQ Procedure                                                                  
                                                                                                                                                    
                                                        Summary Statistics for TRTP by CHG                                                          
                                                             Controlling for POOLCNTR                                                               
                                                                                                                                                    
                                            Cochran-Mantel-Haenszel Statistics (Based on Rank Scores)                                               
                                                                                                                                                    
                                         Statistic    Alternative Hypothesis    DF       Value      Prob                                            
                                         ---------------------------------------------------------------                                            
                                             1        Nonzero Correlation        1      0.4550    0.5000                                            
                                             2        Row Mean Scores Differ     2      4.9054    0.0861                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
213


CENTANAFADINE                                                                                                               2 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.8                                                                       
Non-Parametric Stratified by Center Analysis of Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                                The FREQ Procedure                                                                  
                                                                                                                                                    
                                                        Summary Statistics for TRTP by CHG                                                          
                                                             Controlling for POOLCNTR                                                               
                                                                                                                                                    
                                            Cochran-Mantel-Haenszel Statistics (Based on Rank Scores)                                               
                                                                                                                                                    
                                         Statistic    Alternative Hypothesis    DF       Value      Prob                                            
                                         ---------------------------------------------------------------                                            
                                             1        Nonzero Correlation        1      6.1912    0.0128                                            
                                             2        Row Mean Scores Differ     2     14.3978    0.0007                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
214


CENTANAFADINE                                                                                                               3 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.8                                                                       
Non-Parametric Stratified by Center Analysis of Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                                The FREQ Procedure                                                                  
                                                                                                                                                    
                                                        Summary Statistics for TRTP by CHG                                                          
                                                             Controlling for POOLCNTR                                                               
                                                                                                                                                    
                                            Cochran-Mantel-Haenszel Statistics (Based on Rank Scores)                                               
                                                                                                                                                    
                                         Statistic    Alternative Hypothesis    DF       Value      Prob                                            
                                         ---------------------------------------------------------------                                            
                                             1        Nonzero Correlation        1      7.3934    0.0065                                            
                                             2        Row Mean Scores Differ     2     17.6867    0.0001                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
215


CENTANAFADINE                                                                                                               4 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.8                                                                       
Non-Parametric Stratified by Center Analysis of Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                                The FREQ Procedure                                                                  
                                                                                                                                                    
                                                        Summary Statistics for TRTP by CHG                                                          
                                                             Controlling for POOLCNTR                                                               
                                                                                                                                                    
                                            Cochran-Mantel-Haenszel Statistics (Based on Rank Scores)                                               
                                                                                                                                                    
                                         Statistic    Alternative Hypothesis    DF       Value      Prob                                            
                                         ---------------------------------------------------------------                                            
                                             1        Nonzero Correlation        1      6.0289    0.0141                                            
                                             2        Row Mean Scores Differ     2     14.5765    0.0007                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
216


CENTANAFADINE                                                                                                               5 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.8                                                                       
Non-Parametric Stratified by Center Analysis of Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                                The FREQ Procedure                                                                  
                                                                                                                                                    
                                                        Summary Statistics for TRTP by CHG                                                          
                                                             Controlling for POOLCNTR                                                               
                                                                                                                                                    
                                            Cochran-Mantel-Haenszel Statistics (Based on Rank Scores)                                               
                                                                                                                                                    
                                         Statistic    Alternative Hypothesis    DF       Value      Prob                                            
                                         ---------------------------------------------------------------                                            
                                             1        Nonzero Correlation        1      3.2902    0.0697                                            
                                             2        Row Mean Scores Differ     2     11.9563    0.0025                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
217


CENTANAFADINE                                                                                                               6 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.8                                                                       
Non-Parametric Stratified by Center Analysis of Mean Change from Baseline to Double Blind Tretmnet Period by Study Day in AISRS Total Score, LOCF   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                                The FREQ Procedure                                                                  
                                                                                                                                                    
                                                        Summary Statistics for TRTP by CHG                                                          
                                                             Controlling for POOLCNTR                                                               
                                                                                                                                                    
                                            Cochran-Mantel-Haenszel Statistics (Based on Rank Scores)                                               
                                                                                                                                                    
                                         Statistic    Alternative Hypothesis    DF       Value      Prob                                            
                                         ---------------------------------------------------------------                                            
                                             1        Nonzero Correlation        1      2.7238    0.0989                                            
                                             2        Row Mean Scores Differ     2     10.7158    0.0047                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
218


CENTANAFADINE                                                                                                               1 OF 11
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.9  
Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         338    Sum Weights                338                                            
                                         Mean               0.21994106    Sum Observations    74.3400787                                            
                                         Std Deviation       10.206485    Variance            104.172337                                            
                                         Skewness           -0.4662637    Kurtosis            -0.2816581                                            
                                         Uncorrected SS      35122.428    Corrected SS        35106.0776                                            
                                         Coeff Variation     4640.5546    Std Error Mean       0.5551596                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.219941     Std Deviation           10.20649                                                
                                              Median   2.116541     Variance               104.17234                                                
                                              Mode     7.859023     Range                   51.41794                                                
                                                                    Interquartile Range     14.95136                                                
                                                                                                                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.396176    Pr > |t|    0.6922                                                   
                                                 Sign           M        21    Pr >= |M|   0.0256                                                   
                                                 Signed Rank    S    1936.5    Pr >= |S|   0.2821                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
219


CENTANAFADINE                                                                                                               2 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       21.91943                                                                
                                                             99%            20.45404                                                                
                                                             95%            14.85949                                                                
                                                             90%            12.11174                                                                
                                                             75% Q3          7.82680                                                                
                                                             50% Median      2.11654                                                                
                                                             25% Q1         -7.12456                                                                
                                                             10%           -14.10923                                                                
                                                             5%            -18.33244                                                                
                                                             1%            -27.07807                                                                
                                                             0% Min        -29.49851                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
                                                    ------Lowest-----        -----Highest-----                                                      
                                                                                                                                                    
                                                       Value      Obs           Value      Obs                                                      
                                                                                                                                                    
                                                    -29.4985      961         19.4617     1608                                                      
                                                    -27.6116      257         20.4540      298                                                      
                                                    -27.3096     1412         20.7976     1491                                                      
                                                    -27.0781      401         21.6142      973                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
220


CENTANAFADINE                                                                                                               3 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
                                                    ------Lowest-----        -----Highest-----                                                      
                                                                                                                                                    
                                                       Value      Obs           Value      Obs                                                      
                                                                                                                                                    
                                                    -25.9557     1117         21.9194     1066                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
221


CENTANAFADINE                                                                                                               4 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
     Stem Leaf                                    #             Boxplot                                   Normal Probability Plot                   
       20 5869                                    4                |                     21+                                             ++ ***     
       18 95                                      2                |                       |                                           ++ **        
       16 023709                                  6                |                       |                                         ++****         
       14 003899946                               9                |                       |                                       +****            
       12 01245678891238                         14                |                       |                                     +***               
       10 11123799911225888                      17                |                     11+                                   ****                 
        8 00115566678990012222234566789          29                |                       |                                ****                    
        6 00012223345566780001234567778888999    35             +-----+                    |                             ****                       
        4 23344677990122334455577788             26             |     |                    |                           ***+                         
        2 00222334577888990111244456899          29             *-----*                    |                         ***+                           
        0 0144555668880035779                    19             |  +  |                   1+                       ***+                             
       -0 87544421098873331100                   20             |     |                    |                      **+                               
       -2 7322098543222110                       16             |     |                    |                     **                                 
       -4 87532119976544210                      17             |     |                    |                   ***                                  
       -6 87765317766431000                      17             +-----+                    |                 +**                                    
       -8 9772110096541                          13                |                     -9+               +***                                     
      -10 986321007766554300                     18                |                       |              ***                                       
      -12 9866421986520                          13                |                       |            ***                                         
      -14 95287544431                            11                |                       |          ***                                           
      -16 65510                                   5                |                       |        +**                                             
      -18 00966533                                8                |                    -19+      ****                                              
      -20 3                                       1                |                       |    ++*                                                 
      -22 932                                     3                |                       |  ++**                                                  
      -24 1                                       1                |                       |++ **                                                   
      -26 6310                                    4                |                       |***                                                     
      -28 5                                       1                |                    -29+*                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
222


CENTANAFADINE                                                                                                               5 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
          ----+----+----+----+----+----+----+                                               +----+----+----+----+----+----+----+----+----+----+     
                                                                                                -2        -1         0        +1        +2          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
223


CENTANAFADINE                                                                                                               6 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         338    Sum Weights                338                                            
                                         Mean               0.02186339    Sum Observations    7.38982701                                            
                                         Std Deviation      1.00255899    Variance            1.00512453                                            
                                         Skewness           -0.4654092    Kurtosis            -0.2701205                                            
                                         Uncorrected SS     338.888534    Corrected SS        338.726967                                            
                                         Coeff Variation    4585.55983    Std Error Mean      0.05453202                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.021863     Std Deviation            1.00256                                                
                                              Median   0.204955     Variance                 1.00512                                                
                                              Mode     0.760366     Range                    5.13076                                                
                                                                    Interquartile Range      1.45333                                                
                                                                                                                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.400928    Pr > |t|    0.6887                                                   
                                                 Sign           M        21    Pr >= |M|   0.0256                                                   
                                                 Signed Rank    S    1930.5    Pr >= |S|   0.2836                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
224


CENTANAFADINE                                                                                                               7 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       2.170595                                                                
                                                             99%            1.980822                                                                
                                                             95%            1.444907                                                                
                                                             90%            1.182725                                                                
                                                             75% Q3         0.762961                                                                
                                                             50% Median     0.204955                                                                
                                                             25% Q1        -0.690365                                                                
                                                             10%           -1.369158                                                                
                                                             5%            -1.794783                                                                
                                                             1%            -2.635345                                                                
                                                             0% Min        -2.960170                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
                                                    ------Lowest-----        -----Highest-----                                                      
                                                                                                                                                    
                                                       Value      Obs           Value      Obs                                                      
                                                                                                                                                    
                                                    -2.96017      961         1.88413     1608                                                      
                                                    -2.72302     1412         1.98082      298                                                      
                                                    -2.68489      257         2.07185     1491                                                      
                                                    -2.63534      401         2.14336     1066                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
225


CENTANAFADINE                                                                                                               8 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
                                                    ------Lowest-----        -----Highest-----                                                      
                                                                                                                                                    
                                                       Value      Obs           Value      Obs                                                      
                                                                                                                                                    
                                                    -2.54132     1117         2.17059      973                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
226


CENTANAFADINE                                                                                                               9 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
      Stem Leaf                                   #             Boxplot                                   Normal Probability Plot                   
        20 747                                    3                |                    2.1+                                             ++  **     
        18 488                                    3                |                       |                                           ++ ***       
        16 35884                                  5                |                       |                                         ++ ***         
        14 224456938                              9                |                       |                                       ++***            
        12 113355688346                          12                |                       |                                     +***               
        10 0122778889923566789                   19                |                    1.1+                                   +***                 
         8 0123445568888800133344466679          28                |                       |                                ****                    
         6 0011122345578889001355666666677888    34             +-----+                    |                             ****                       
         4 012223566799011222333455567999        30             |     |                    |                           ***+                         
         2 0012223457778889900023344678          28             *-----*                    |                         ***+                           
         0 0144455667880035678                   19             |  +  |                 0.1+                       ***+                             
        -0 987444411988863331100                 21             |     |                    |                      **+                               
        -2 9621109854221110                      16             |     |                    |                     **                                 
        -4 9886642200887554330                   19             |     |                    |                   ***                                  
        -6 975555397654220                       15             +-----+                    |                 +**                                    
        -8 86644309877331                        14                |                   -0.9+               +**                                      
       -10 98442108777332200                     17                |                       |             +***                                       
       -12 87765322877310                        14                |                       |           +***                                         
       -14 76509743310                           11                |                       |         +***                                           
       -16 98101                                  5                |                       |       +***                                             
       -18 9985420                                7                |                   -1.9+     +***                                               
       -20 6                                      1                |                       |   ++*                                                  
       -22 532                                    3                |                       | ++ **                                                  
       -24 4                                      1                |                       |+  *                                                    
       -26 284                                    3                |                       |***                                                     
       -28 6                                      1                0                   -2.9+*                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
227


CENTANAFADINE                                                                                                               10 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                   AVISITN = 42                                                                     
                                                                 AVISIT = DAY 42                                                                    
                                                                                                                                                    
           ----+----+----+----+----+----+----                                               +----+----+----+----+----+----+----+----+----+----+     
       Multiply Stem.Leaf by 10**-1                                                             -2        -1         0        +1        +2          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
228


CENTANAFADINE                                                                                                               11 OF 11
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-4.9                                                                       
                Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                   
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                             Plot of RESID*PRED.  Legend: A = 1 obs, B = 2 obs, etc.                                                
                                                                                                                                                    
       |                                                                                                                                            
       |                                                                                                                                            
    40 +                                                                                                                                            
       |                                                                                                                                            
       |                                                                                                                                            
       |                                                                                                                                            
       |                                      A             A AA               A                                                                    
    20 +                                            A     B  B    AB A  B                                                                           
 R     |                      B A    AA  A A   AB A AABB   B  A BC   CC   CAAA ABABA BAB  AA A                                                      
 e     |              A      A A  A  A C   BAAACBADABCDEEFDEDFCG GEFEACEFEAADE BD BBA  AAC B BAAA  A  A                                             
 s     |                A         A  ACAA ACCDBACACACDDBHEFGIFEGJHCEFFHMMNRMQJJKJFEBKEEBADDDBCDEBEAAAAA   B                                         
 i     |   A      A          AAB B  AC A AABBCACCCBCBEFFGEJIHEGFGBHGEFGGKIGIHJIPDGHLJLCNLKKDLIJHGNINKCDAABBAB AB               A            A       
 d   0 +      A          A     A ACBBA   ADABACCCADBGEDDHBEECEEGDEHGFEEFFEKELGKFFFJGJIFGKBDLEEDDIEGDCJDFGFDADBABB  B           AAA AA               
 u     |           A             A  AABA AA ABB BAECCAADCD GDEIHBFCIGFEGCGKHGGEFEECCBBEFIFECFCHCEFADCBD BCABA A    A A AA             A             
 a     |                   A     AB C AAB   B ACBAC CAACDFAEHDBCAJFAEDGEHIBFECECBBADDDCBDBFF AEBCAADABBA B A   A                                    
 l     |                 A    B      A  A AAA BAAAB BBDACCAADABB  BACDDCBEFEDBFBCCCBGD CADAA  A B A   B  AA A                                       
       |                        BA   AA   BAA  AA    ABB  CBAEAB  CECDADBC  CC DABDAB  A A DA B A A AB     AA                                       
   -20 +                 A A          A  A  ABA A   BAB  A C AB BABAAA   B    A  A     AA   AB   A    A                                             
       |                  A       A            C    A  A AAA AAAA A        AAA   A                                                                  
       |                     A A                      A  AA    B        BA   A                                                                      
       |                  A               A                                                                                                         
       |                                                                                                                                            
   -40 +                                                                                                                                            
       |                                                                                                                                            
       ---+----------+----------+----------+----------+----------+----------+----------+----------+----------+----------+----------+----------+--   
        -22.5      -20.0      -17.5      -15.0      -12.5      -10.0      -7.5       -5.0       -2.5        0.0        2.5        5.0        7.5    
                                                                                                                                                    
                                                                        Predicted                                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
229


CENTANAFADINE                                                                                                               1 OF 26
PROTOCOL 405-201-00014                                                                                                                               
STAT-4.10  
Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                Model Information                                                                   
                                                                                                                                                    
                                              Data Set                     WORK.INDATA                                                              
                                              Dependent Variable           CHG                                                                      
                                              Covariance Structure         Unstructured                                                             
                                              Subject Effect               SUBJID                                                                   
                                              Group Effect                 TRTPN                                                                    
                                              Estimation Method            REML                                                                     
                                              Residual Variance Method     None                                                                     
                                              Fixed Effects SE Method      Kenward-Roger                                                            
                                              Degrees of Freedom Method    Kenward-Roger                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                                                                                                    
                                               AVISITN          6    7 14 21 28 35 42                                                               
                                               TRTPN            3    1 2 3                                                                          
                                               POOLCNTR        39   
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
230


CENTANAFADINE                                                                                                               2 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                                                                                                    
                                               SUBJID         421   
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                    
                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
231


CENTANAFADINE                                                                                                               3 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
232


CENTANAFADINE                                                                                                               4 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
233


CENTANAFADINE                                                                                                               5 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
234


CENTANAFADINE                                                                                                               6 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
235


CENTANAFADINE                                                                                                               7 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                                                                                                    
                                                                   Dimensions                                                                       
                                                                                                                                                    
                                                       Covariance Parameters            63                                                          
                                                       Columns in X                     73                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        421                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2227                                                      
                                                   Number of Observations Used            2227                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
236


CENTANAFADINE                                                                                                               8 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                Iteration History                                                                   
                                                                                                                                                    
                                           Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                    
                                                   0              1     15800.38727426                                                              
                                                   1              4     13478.73670114      0.00213540                                              
                                                   2              1     13467.00275618      0.00024731                                              
                                                   3              1     13465.70016597      0.00001037                                              
                                                   4              1     13465.64921223      0.00000003                                              
                                                   5              1     13465.64904810      0.00000000                                              
                                                                                                                                                    
                                                                                                                                                    
                                                            Convergence criteria met.                                                               
                                                                                                                                                    
                                                                                                                                                    
                                                      Estimated R Matrix for SUBJID 
                                                       
                                                                                                                                                    
                                                Row        Col1        Col2        Col3        Col4                                                 
                                                                                                                                                    
                                                  1     36.9737     26.0068     31.4785     33.3871                                                 
                                                  2     26.0068     59.7634     55.9805     56.6731                                                 
                                                  3     31.4785     55.9805     78.9073     73.4766                                                 
                                                  4     33.3871     56.6731     73.4766     94.5512                                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
237


CENTANAFADINE                                                                                                               9 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                Estimated R Correlation Matrix for SUBJID 
                                                 
                                                                                                                                                     
                                                 Row        Col1        Col2        Col3        Col4                                                 
                                                                                                                                                     
                                                   1      1.0000      0.5533      0.5828      0.5647                                                 
                                                   2      0.5533      1.0000      0.8152      0.7539                                                 
                                                   3      0.5828      0.8152      1.0000      0.8507                                                 
                                                   4      0.5647      0.7539      0.8507      1.0000                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                       Estimated R Matrix for SUBJID 
                                                       
                                                                                                                                                     
                                     Row        Col1        Col2        Col3        Col4        Col5        Col6                                     
                                                                                                                                                     
                                       1     48.7945     45.9963     44.9550     46.9027     44.0988     44.7419                                     
                                       2     45.9963     92.0313     77.3240     75.1467     71.7701     69.6304                                     
                                       3     44.9550     77.3240     93.5276     87.1175     77.8069     80.6325                                     
                                       4     46.9027     75.1467     87.1175      101.83     91.1218     92.2892                                     
                                       5     44.0988     71.7701     77.8069     91.1218      101.52     89.0164                                     
                                       6     44.7419     69.6304     80.6325     92.2892     89.0164      109.05                                     
                                                                                                                                                     
                                                                                                                                                     
                                                       Estimated R Matrix for SUBJID 
                                                       
                                                                                                                                                     
                                     Row        Col1        Col2        Col3        Col4        Col5        Col6                                     
                                                                                                                                                     
                                       1     45.3296     42.2715     36.0407     39.1670     40.8245     39.9697                                     
                                       2     42.2715     58.5296     46.1505     46.4824     51.7087     50.9898                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
238


CENTANAFADINE                                                                                                               10 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                      Estimated R Matrix for SUBJID 
                                                       
                                                                                                                                                    
                                    Row        Col1        Col2        Col3        Col4        Col5        Col6                                     
                                                                                                                                                    
                                      3     36.0407     46.1505     71.3771     62.2249     65.8373     69.3392                                     
                                      4     39.1670     46.4824     62.2249     75.8237     70.2194     74.6922                                     
                                      5     40.8245     51.7087     65.8373     70.2194     84.4321     83.9356                                     
                                      6     39.9697     50.9898     69.3392     74.6922     83.9356     97.8853                                     
                                                                                                                                                    
                                                                                                                                                    
                                                          Covariance Parameter Estimates                                                            
                                                                                                                                                    
                                                    Cov Parm    Subject    Group      Estimate                                                      
                                                                                                                                                    
                                                    UN(1,1)     SUBJID     TRTPN 1     48.7945                                                      
                                                    UN(2,1)     SUBJID     TRTPN 1     45.9963                                                      
                                                    UN(2,2)     SUBJID     TRTPN 1     92.0313                                                      
                                                    UN(3,1)     SUBJID     TRTPN 1     44.9550                                                      
                                                    UN(3,2)     SUBJID     TRTPN 1     77.3240                                                      
                                                    UN(3,3)     SUBJID     TRTPN 1     93.5276                                                      
                                                    UN(4,1)     SUBJID     TRTPN 1     46.9027                                                      
                                                    UN(4,2)     SUBJID     TRTPN 1     75.1467                                                      
                                                    UN(4,3)     SUBJID     TRTPN 1     87.1175                                                      
                                                    UN(4,4)     SUBJID     TRTPN 1      101.83                                                      
                                                    UN(5,1)     SUBJID     TRTPN 1     44.0988                                                      
                                                    UN(5,2)     SUBJID     TRTPN 1     71.7701                                                      
                                                    UN(5,3)     SUBJID     TRTPN 1     77.8069                                                      
                                                    UN(5,4)     SUBJID     TRTPN 1     91.1218                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
239


CENTANAFADINE                                                                                                               11 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                          Covariance Parameter Estimates                                                            
                                                                                                                                                    
                                                    Cov Parm    Subject    Group      Estimate                                                      
                                                                                                                                                    
                                                    UN(5,5)     SUBJID     TRTPN 1      101.52                                                      
                                                    UN(6,1)     SUBJID     TRTPN 1     44.7419                                                      
                                                    UN(6,2)     SUBJID     TRTPN 1     69.6304                                                      
                                                    UN(6,3)     SUBJID     TRTPN 1     80.6325                                                      
                                                    UN(6,4)     SUBJID     TRTPN 1     92.2892                                                      
                                                    UN(6,5)     SUBJID     TRTPN 1     89.0164                                                      
                                                    UN(6,6)     SUBJID     TRTPN 1      109.05                                                      
                                                    UN(1,1)     SUBJID     TRTPN 2     36.9737                                                      
                                                    UN(2,1)     SUBJID     TRTPN 2     26.0068                                                      
                                                    UN(2,2)     SUBJID     TRTPN 2     59.7634                                                      
                                                    UN(3,1)     SUBJID     TRTPN 2     31.4785                                                      
                                                    UN(3,2)     SUBJID     TRTPN 2     55.9805                                                      
                                                    UN(3,3)     SUBJID     TRTPN 2     78.9073                                                      
                                                    UN(4,1)     SUBJID     TRTPN 2     33.3871                                                      
                                                    UN(4,2)     SUBJID     TRTPN 2     56.6731                                                      
                                                    UN(4,3)     SUBJID     TRTPN 2     73.4766                                                      
                                                    UN(4,4)     SUBJID     TRTPN 2     94.5512                                                      
                                                    UN(5,1)     SUBJID     TRTPN 2     32.3181                                                      
                                                    UN(5,2)     SUBJID     TRTPN 2     56.3760                                                      
                                                    UN(5,3)     SUBJID     TRTPN 2     72.7477                                                      
                                                    UN(5,4)     SUBJID     TRTPN 2     86.8002                                                      
                                                    UN(5,5)     SUBJID     TRTPN 2      107.38                                                      
                                                    UN(6,1)     SUBJID     TRTPN 2     30.4643                                                      
                                                    UN(6,2)     SUBJID     TRTPN 2     56.8611                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
240


CENTANAFADINE                                                                                                               12 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                          Covariance Parameter Estimates                                                            
                                                                                                                                                    
                                                    Cov Parm    Subject    Group      Estimate                                                      
                                                                                                                                                    
                                                    UN(6,3)     SUBJID     TRTPN 2     70.9567                                                      
                                                    UN(6,4)     SUBJID     TRTPN 2     85.9523                                                      
                                                    UN(6,5)     SUBJID     TRTPN 2      101.05                                                      
                                                    UN(6,6)     SUBJID     TRTPN 2      117.94                                                      
                                                    UN(1,1)     SUBJID     TRTPN 3     45.3296                                                      
                                                    UN(2,1)     SUBJID     TRTPN 3     42.2715                                                      
                                                    UN(2,2)     SUBJID     TRTPN 3     58.5296                                                      
                                                    UN(3,1)     SUBJID     TRTPN 3     36.0407                                                      
                                                    UN(3,2)     SUBJID     TRTPN 3     46.1505                                                      
                                                    UN(3,3)     SUBJID     TRTPN 3     71.3771                                                      
                                                    UN(4,1)     SUBJID     TRTPN 3     39.1670                                                      
                                                    UN(4,2)     SUBJID     TRTPN 3     46.4824                                                      
                                                    UN(4,3)     SUBJID     TRTPN 3     62.2249                                                      
                                                    UN(4,4)     SUBJID     TRTPN 3     75.8237                                                      
                                                    UN(5,1)     SUBJID     TRTPN 3     40.8245                                                      
                                                    UN(5,2)     SUBJID     TRTPN 3     51.7087                                                      
                                                    UN(5,3)     SUBJID     TRTPN 3     65.8373                                                      
                                                    UN(5,4)     SUBJID     TRTPN 3     70.2194                                                      
                                                    UN(5,5)     SUBJID     TRTPN 3     84.4321                                                      
                                                    UN(6,1)     SUBJID     TRTPN 3     39.9697                                                      
                                                    UN(6,2)     SUBJID     TRTPN 3     50.9898                                                      
                                                    UN(6,3)     SUBJID     TRTPN 3     69.3392                                                      
                                                    UN(6,4)     SUBJID     TRTPN 3     74.6922                                                      
                                                    UN(6,5)     SUBJID     TRTPN 3     83.9356                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
241


CENTANAFADINE                                                                                                               13 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                          Covariance Parameter Estimates                                                            
                                                                                                                                                    
                                                    Cov Parm    Subject    Group      Estimate                                                      
                                                                                                                                                    
                                                    UN(6,6)     SUBJID     TRTPN 3     97.8853                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood         13465.6                                                         
                                                      AIC (Smaller is Better)       13591.6                                                         
                                                      AICC (Smaller is Better)      13595.5                                                         
                                                      BIC (Smaller is Better)       13846.3                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           62       2334.74          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
242


CENTANAFADINE                                                                                                               14 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                           Solution for Fixed Effects                                                               
                                                                                                                                                    
                                      Pooled    Analysis    Planned                                                                                 
                                      Center    Visit       Treatment                Standard                                                       
                     Effect           Number    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|                        
                                                                                                                                                    
                     Intercept                                             2.2570      4.8279     484       0.47      0.6404                        
                     AVISITN                     7                         0.1158      2.6468     338       0.04      0.9651                        
                     AVISITN                    14                        -1.0804      2.4063     361      -0.45      0.6537                        
                     AVISITN                    21                         1.3469      2.0492     336       0.66      0.5115                        
                     AVISITN                    28                        -1.3671      1.7371     334      -0.79      0.4318                        
                     AVISITN                    35                        -1.2228      1.5148     307      -0.81      0.4202                        
                     AVISITN                    42                              0                                                                   
                     TRTPN                                  1             -3.9849      1.2601     249      -3.16      0.0018                        
                     TRTPN                                  2             -4.4036      1.3262     243      -3.32      0.0010                        
                     TRTPN                                  3                   0                                                                   
                     AVISITN*TRTPN               7          1              2.0812      1.0252     214       2.03      0.0436                        
                     AVISITN*TRTPN               7          2              2.5703      1.1536     220       2.23      0.0269                        
                     AVISITN*TRTPN               7          3                   0                                                                   
                     AVISITN*TRTPN              14          1              0.3743      0.9708     239       0.39      0.7002                        
                     AVISITN*TRTPN              14          2              0.8059      1.0165     221       0.79      0.4288                        
                     AVISITN*TRTPN              14          3                   0                                                                   
                     AVISITN*TRTPN              21          1            -0.03336      0.7740     225      -0.04      0.9657                        
                     AVISITN*TRTPN              21          2            -0.05933      0.8789     200      -0.07      0.9462                        
                     AVISITN*TRTPN              21          3                   0                                                                   
                     AVISITN*TRTPN              28          1             0.04623      0.6580     232       0.07      0.9440                        
                     AVISITN*TRTPN              28          2            -0.08429      0.7725     199      -0.11      0.9132                        
                     AVISITN*TRTPN              28          3                   0                                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
243


CENTANAFADINE                                                                                                               15 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                           Solution for Fixed Effects                                                               
                                                                                                                                                    
                                      Pooled    Analysis    Planned                                                                                 
                                      Center    Visit       Treatment                Standard                                                       
                     Effect           Number    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|                        
                                                                                                                                                    
                     AVISITN*TRTPN              35          1              0.2367      0.6395     189       0.37      0.7117                        
                     AVISITN*TRTPN              35          2             -0.9126      0.5964     187      -1.53      0.1276                        
                     AVISITN*TRTPN              35          3                   0                                                                   
                     AVISITN*TRTPN              42          1                   0                                                                   
                     AVISITN*TRTPN              42          2                   0                                                                   
                     AVISITN*TRTPN              42          3                   0                                                                   
                     POOLCNTR        
                                0.8283      3.8363     321       0.22      0.8292                        
                     POOLCNTR        
                               -6.1914      5.3240     366      -1.16      0.2456                        
                     POOLCNTR        
                                1.0964      3.7183     309       0.29      0.7683                        
                     POOLCNTR        
                               -1.6031      4.5459     325      -0.35      0.7246                        
                     POOLCNTR        
                               -4.5469      4.4902     349      -1.01      0.3119                        
                     POOLCNTR        
                                0.4501      3.8364     321       0.12      0.9067                        
                     POOLCNTR        
                               -0.1036      3.7924     316      -0.03      0.9782                        
                     POOLCNTR        
                               -3.2912      4.3656     360      -0.75      0.4514                        
                     POOLCNTR        
                                1.9748      5.2591     363       0.38      0.7075                        
                     POOLCNTR        
                               -4.1388      3.8918     320      -1.06      0.2884                        
                     POOLCNTR        
                               -3.1507      4.2517     350      -0.74      0.4592                        
                     POOLCNTR        
                              -10.6697      5.2445     363      -2.03      0.0426                        
                     POOLCNTR        
                               -4.3208      4.3847     332      -0.99      0.3251                        
                     POOLCNTR        
                                2.8042      4.0999     331       0.68      0.4945                        
                     POOLCNTR        
                               -2.4878      4.1211     333      -0.60      0.5465                        
                     POOLCNTR        
                               -3.2434      4.7088     355      -0.69      0.4914                        
                                     
                                                                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
244


CENTANAFADINE                                                                                                               16 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                           Solution for Fixed Effects                                                               
                                                                                                                                                    
                                      Pooled    Analysis    Planned                                                                                 
                                      Center    Visit       Treatment                Standard                                                       
                     Effect           Number    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|                        
                                     
                                                                                                          
                     POOLCNTR        
                               -4.6400      4.2765     342      -1.08      0.2787                        
                     POOLCNTR        
                                0.3984      4.8159     338       0.08      0.9341                        
                     POOLCNTR        
                               -1.9005      4.8163     339      -0.39      0.6934                        
                     POOLCNTR        
                               -1.4595      3.9964     336      -0.37      0.7152                        
                     POOLCNTR        
                               -4.0268      4.1976     338      -0.96      0.3381                        
                     POOLCNTR        
                                8.7760      4.9299     391       1.78      0.0758                        
                     POOLCNTR        
                                2.1905      3.9947     328       0.55      0.5838                        
                     POOLCNTR        
                               -5.0765      4.0162     322      -1.26      0.2071                        
                     POOLCNTR        
                               -3.2253      4.1899     338      -0.77      0.4420                        
                     POOLCNTR        
                                5.7015      4.3994     342       1.30      0.1959                        
                     POOLCNTR        
                               -7.0249      4.4804     348      -1.57      0.1178                        
                     POOLCNTR        
                               -4.1895      4.2580     328      -0.98      0.3259                        
                     POOLCNTR        
                                1.1537      3.7287     314       0.31      0.7572                        
                     POOLCNTR        
                                2.2150      3.7161     311       0.60      0.5516                        
                     POOLCNTR        
                               -2.3843      4.6802     355      -0.51      0.6108                        
                     POOLCNTR        
                                1.3772      4.6860     354       0.29      0.7690                        
                     POOLCNTR        
                               -5.2391      3.9702     332      -1.32      0.1879                        
                     POOLCNTR        
                               -0.5364      4.4506     351      -0.12      0.9041                        
                     POOLCNTR        
                               -1.5627      3.8965     323      -0.40      0.6886                        
                     POOLCNTR        
                               -3.9649      5.2626     363      -0.75      0.4517                        
                     POOLCNTR        
                               -5.0626      4.5384     368      -1.12      0.2654                        
                     POOLCNTR        
                               -4.3025      4.4648     310      -0.96      0.3360                        
                                     
                                                                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
245


CENTANAFADINE                                                                                                               17 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                           Solution for Fixed Effects                                                               
                                                                                                                                                    
                                      Pooled    Analysis    Planned                                                                                 
                                      Center    Visit       Treatment                Standard                                                       
                     Effect           Number    (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|                        
                                                                                                                                                    
                     POOLCNTR        
                                      0                                                                   
                     BASE*AVISITN     
        7                        -0.1300     0.06016     371      -2.16      0.0313                        
                     BASE*AVISITN               14                        -0.1294     0.07004     408      -1.85      0.0655                        
                     BASE*AVISITN               21                        -0.2303     0.07607     431      -3.03      0.0026                        
                     BASE*AVISITN               28                        -0.1649     0.08037     436      -2.05      0.0408                        
                     BASE*AVISITN               35                        -0.1882     0.08325     439      -2.26      0.0243                        
                     BASE*AVISITN               42                        -0.2273     0.08808     441      -2.58      0.0102                        
                                                                                                                                                    
                                                                                                                                                    
                                                          Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                    
                                                                  Num     Den                                                                       
                                                Effect             DF      DF    F Value    Pr > F                                                  
                                                                                                                                                    
                                                AVISITN             5     347       1.35    0.2432                                                  
                                                TRTPN               2     247      10.64    <.0001                                                  
                                                AVISITN*TRTPN      10     288       1.85    0.0523                                                  
                                                POOLCNTR           38     361       2.24    <.0001                                                  
                                                BASE*AVISITN        6     372       2.28    0.0359                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
246


CENTANAFADINE                                                                                                               18 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                          Analysis    Planned                                                                                                       
                          Visit       Treatment                Standard                                                                             
         Effect           (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper            
                                                                                                                                                    
         AVISITN*TRTPN     7          1             -6.2343      0.6492     143      -9.60      <.0001      0.05     -7.5175     -4.9510            
         AVISITN*TRTPN     7          2             -6.1638      0.5830     159     -10.57      <.0001      0.05     -7.3153     -5.0123            
         AVISITN*TRTPN     7          3             -4.3306      0.6230     146      -6.95      <.0001      0.05     -5.5618     -3.0994            
         AVISITN*TRTPN    14          1             -9.1119      0.8613     144     -10.58      <.0001      0.05    -10.8143     -7.4095            
         AVISITN*TRTPN    14          2             -9.0991      0.7308     140     -12.45      <.0001      0.05    -10.5441     -7.6541            
         AVISITN*TRTPN    14          3             -5.5013      0.6996     153      -7.86      <.0001      0.05     -6.8835     -4.1192            
         AVISITN*TRTPN    21          1            -10.9137      0.8728     148     -12.50      <.0001      0.05    -12.6385     -9.1890            
         AVISITN*TRTPN    21          2            -11.3585      0.8343     140     -13.61      <.0001      0.05    -13.0079     -9.7090            
         AVISITN*TRTPN    21          3             -6.8955      0.7677     143      -8.98      <.0001      0.05     -8.4130     -5.3780            
         AVISITN*TRTPN    28          1            -11.0717      0.9127     144     -12.13      <.0001      0.05    -12.8758     -9.2676            
         AVISITN*TRTPN    28          2            -11.6209      0.9119     136     -12.74      <.0001      0.05    -13.4243     -9.8176            
         AVISITN*TRTPN    28          3             -7.1331      0.7890     146      -9.04      <.0001      0.05     -8.6924     -5.5737            
         AVISITN*TRTPN    35          1            -11.6202      0.9220     138     -12.60      <.0001      0.05    -13.4433     -9.7972            
         AVISITN*TRTPN    35          2            -13.1883      0.9849     137     -13.39      <.0001      0.05    -15.1358    -11.2407            
         AVISITN*TRTPN    35          3             -7.8720      0.8310     144      -9.47      <.0001      0.05     -9.5146     -6.2295            
         AVISITN*TRTPN    42          1            -12.1124      0.9593     140     -12.63      <.0001      0.05    -14.0089    -10.2158            
         AVISITN*TRTPN    42          2            -12.5311      1.0402     135     -12.05      <.0001      0.05    -14.5884    -10.4738            
         AVISITN*TRTPN    42          3             -8.1275      0.8928     142      -9.10      <.0001      0.05     -9.8925     -6.3625            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
247


CENTANAFADINE                                                                                                               19 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                        Differences of Least Squares Means                                                          
                                                                                                                                                    
                   Analysis   Planned     Analysis   Planned                                                                                        
                   Visit      Treatment   Visit      Treatment              Standard                                                                
   Effect          (N)        (N)         (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper     
                                                                                                                                                    
   AVISITN*TRTPN    7         1            7         2           -0.07041     0.7962    240     -0.09     0.9296     0.05    -1.6389     1.4980     
   AVISITN*TRTPN    7         1            7         3            -1.9037     0.8264    248     -2.30     0.0221     0.05    -3.5313    -0.2761     
   AVISITN*TRTPN    7         1           14         1             2.8777     0.6083    130      4.73     <.0001     0.05     1.6742     4.0812     
   AVISITN*TRTPN    7         1           14         2             2.8648     0.9105    235      3.15     0.0019     0.05     1.0711     4.6586     
   AVISITN*TRTPN    7         1           14         3            -0.7329     0.8853    251     -0.83     0.4086     0.05    -2.4765     1.0107     
   AVISITN*TRTPN    7         1           21         1             4.6795     0.6357    125      7.36     <.0001     0.05     3.4213     5.9376     
   AVISITN*TRTPN    7         1           21         2             5.1242     0.9953    223      5.15     <.0001     0.05     3.1629     7.0855     
   AVISITN*TRTPN    7         1           21         3             0.6613     0.9401    234      0.70     0.4825     0.05    -1.1909     2.5134     
   AVISITN*TRTPN    7         1           28         1             4.8374     0.6689    107      7.23     <.0001     0.05     3.5114     6.1635     
   AVISITN*TRTPN    7         1           28         2             5.3867     1.0612    209      5.08     <.0001     0.05     3.2946     7.4788     
   AVISITN*TRTPN    7         1           28         3             0.8988     0.9577    232      0.94     0.3489     0.05    -0.9880     2.7856     
   AVISITN*TRTPN    7         1           35         1             5.3860     0.7106    103      7.58     <.0001     0.05     3.9767     6.7953     
   AVISITN*TRTPN    7         1           35         2             6.9540     1.1245    205      6.18     <.0001     0.05     4.7370     9.1711     
   AVISITN*TRTPN    7         1           35         3             1.6378     0.9925    229      1.65     0.1003     0.05    -0.3178     3.5934     
   AVISITN*TRTPN    7         1           42         1             5.8781     0.7520    100      7.82     <.0001     0.05     4.3862     7.3700     
   AVISITN*TRTPN    7         1           42         2             6.2968     1.1733    197      5.37     <.0001     0.05     3.9829     8.6107     
   AVISITN*TRTPN    7         1           42         3             1.8932     1.0448    220      1.81     0.0713     0.05    -0.1659     3.9523     
   AVISITN*TRTPN    7         2            7         3            -1.8333     0.7769    236     -2.36     0.0191     0.05    -3.3638    -0.3028     
   AVISITN*TRTPN    7         2           14         1             2.9481     0.9769    217      3.02     0.0029     0.05     1.0226     4.8736     
   AVISITN*TRTPN    7         2           14         2             2.9352     0.5957    124      4.93     <.0001     0.05     1.7563     4.1142     
   AVISITN*TRTPN    7         2           14         3            -0.6625     0.8392    237     -0.79     0.4306     0.05    -2.3157     0.9907     
   AVISITN*TRTPN    7         2           21         1             4.7499     0.9872    222      4.81     <.0001     0.05     2.8045     6.6953     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
248


CENTANAFADINE                                                                                                               20 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                        Differences of Least Squares Means                                                          
                                                                                                                                                    
                   Analysis   Planned     Analysis   Planned                                                                                        
                   Visit      Treatment   Visit      Treatment              Standard                                                                
   Effect          (N)        (N)         (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper     
                                                                                                                                                    
   AVISITN*TRTPN    7         2           21         2             5.1946     0.6623    127      7.84     <.0001     0.05     3.8840     6.5052     
   AVISITN*TRTPN    7         2           21         3             0.7317     0.8968    222      0.82     0.4154     0.05    -1.0357     2.4990     
   AVISITN*TRTPN    7         2           28         1             4.9078     1.0227    212      4.80     <.0001     0.05     2.8918     6.9238     
   AVISITN*TRTPN    7         2           28         2             5.4571     0.7394    123      7.38     <.0001     0.05     3.9936     6.9207     
   AVISITN*TRTPN    7         2           28         3             0.9692     0.9152    226      1.06     0.2907     0.05    -0.8343     2.7727     
   AVISITN*TRTPN    7         2           35         1             5.4564     1.0312    202      5.29     <.0001     0.05     3.4231     7.4897     
   AVISITN*TRTPN    7         2           35         2             7.0244     0.8369    117      8.39     <.0001     0.05     5.3670     8.6819     
   AVISITN*TRTPN    7         2           35         3             1.7082     0.9516    218      1.80     0.0740     0.05    -0.1674     3.5838     
   AVISITN*TRTPN    7         2           42         1             5.9485     1.0645    201      5.59     <.0001     0.05     3.8495     8.0475     
   AVISITN*TRTPN    7         2           42         2             6.3673     0.9160    116      6.95     <.0001     0.05     4.5531     8.1814     
   AVISITN*TRTPN    7         2           42         3             1.9637     1.0060    208      1.95     0.0523     0.05   -0.01970     3.9470     
   AVISITN*TRTPN    7         3           14         1             4.7814     1.0016    225      4.77     <.0001     0.05     2.8076     6.7551     
   AVISITN*TRTPN    7         3           14         2             4.7685     0.8936    227      5.34     <.0001     0.05     3.0077     6.5293     
   AVISITN*TRTPN    7         3           14         3             1.1708     0.3843    131      3.05     0.0028     0.05     0.4106     1.9310     
   AVISITN*TRTPN    7         3           21         1             6.5832     1.0115    226      6.51     <.0001     0.05     4.5899     8.5764     
   AVISITN*TRTPN    7         3           21         2             7.0279     0.9799    219      7.17     <.0001     0.05     5.0966     8.9592     
   AVISITN*TRTPN    7         3           21         3             2.5650     0.5796    122      4.43     <.0001     0.05     1.4176     3.7124     
   AVISITN*TRTPN    7         3           28         1             6.7411     1.0463    218      6.44     <.0001     0.05     4.6790     8.8032     
   AVISITN*TRTPN    7         3           28         2             7.2904     1.0468    207      6.96     <.0001     0.05     5.2266     9.3542     
   AVISITN*TRTPN    7         3           28         3             2.8025     0.5700    132      4.92     <.0001     0.05     1.6749     3.9301     
   AVISITN*TRTPN    7         3           35         1             7.2897     1.0544    212      6.91     <.0001     0.05     5.2111     9.3682     
   AVISITN*TRTPN    7         3           35         2             8.8577     1.1109    201      7.97     <.0001     0.05     6.6671    11.0483     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
249


CENTANAFADINE                                                                                                               21 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                        Differences of Least Squares Means                                                          
                                                                                                                                                    
                   Analysis   Planned     Analysis   Planned                                                                                        
                   Visit      Treatment   Visit      Treatment              Standard                                                                
   Effect          (N)        (N)         (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper     
                                                                                                                                                    
   AVISITN*TRTPN    7         3           35         3             3.5415     0.6078    121      5.83     <.0001     0.05     2.3383     4.7447     
   AVISITN*TRTPN    7         3           42         1             7.7818     1.0871    208      7.16     <.0001     0.05     5.6387     9.9249     
   AVISITN*TRTPN    7         3           42         2             8.2005     1.1603    193      7.07     <.0001     0.05     5.9120    10.4891     
   AVISITN*TRTPN    7         3           42         3             3.7969     0.6986    121      5.44     <.0001     0.05     2.4139     5.1800     
   AVISITN*TRTPN   14         1           14         2           -0.01284     1.0728    241     -0.01     0.9905     0.05    -2.1262     2.1005     
   AVISITN*TRTPN   14         1           14         3            -3.6106     1.0505    244     -3.44     0.0007     0.05    -5.6798    -1.5414     
   AVISITN*TRTPN   14         1           21         1             1.8018     0.4983    124      3.62     0.0004     0.05     0.8156     2.7880     
   AVISITN*TRTPN   14         1           21         2             2.2465     1.1457    246      1.96     0.0510     0.05   -0.01000     4.5031     
   AVISITN*TRTPN   14         1           21         3            -2.2164     1.0971    248     -2.02     0.0444     0.05    -4.3773   -0.05549     
   AVISITN*TRTPN   14         1           28         1             1.9598     0.5937    126      3.30     0.0013     0.05     0.7848     3.1347     
   AVISITN*TRTPN   14         1           28         2             2.5090     1.2033    242      2.09     0.0381     0.05     0.1387     4.8793     
   AVISITN*TRTPN   14         1           28         3            -1.9789     1.1122    246     -1.78     0.0764     0.05    -4.1696     0.2119     
   AVISITN*TRTPN   14         1           35         1             2.5083     0.6469    124      3.88     0.0002     0.05     1.2279     3.7887     
   AVISITN*TRTPN   14         1           35         2             4.0764     1.2595    241      3.24     0.0014     0.05     1.5953     6.5574     
   AVISITN*TRTPN   14         1           35         3            -1.2399     1.1423    252     -1.09     0.2788     0.05    -3.4897     1.0099     
   AVISITN*TRTPN   14         1           42         1             3.0004     0.7209    123      4.16     <.0001     0.05     1.5735     4.4274     
   AVISITN*TRTPN   14         1           42         2             3.4192     1.3033    235      2.62     0.0093     0.05     0.8516     5.9868     
   AVISITN*TRTPN   14         1           42         3            -0.9844     1.1881    252     -0.83     0.4081     0.05    -3.3243     1.3554     
   AVISITN*TRTPN   14         2           14         3            -3.5977     0.9490    240     -3.79     0.0002     0.05    -5.4672    -1.7283     
   AVISITN*TRTPN   14         2           21         1             1.8147     1.0821    244      1.68     0.0948     0.05    -0.3168     3.9461     
   AVISITN*TRTPN   14         2           21         2             2.2594     0.4852    117      4.66     <.0001     0.05     1.2985     3.2202     
   AVISITN*TRTPN   14         2           21         3            -2.2036     1.0001    237     -2.20     0.0285     0.05    -4.1737    -0.2334     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
250


CENTANAFADINE                                                                                                               22 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                        Differences of Least Squares Means                                                          
                                                                                                                                                    
                   Analysis   Planned     Analysis   Planned                                                                                        
                   Visit      Treatment   Visit      Treatment              Standard                                                                
   Effect          (N)        (N)         (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper     
                                                                                                                                                    
   AVISITN*TRTPN   14         2           28         1             1.9726     1.1146    237      1.77     0.0780     0.05    -0.2231     4.1683     
   AVISITN*TRTPN   14         2           28         2             2.5219     0.6012    117      4.19     <.0001     0.05     1.3313     3.7125     
   AVISITN*TRTPN   14         2           28         3            -1.9660     1.0166    246     -1.93     0.0543     0.05    -3.9684    0.03631     
   AVISITN*TRTPN   14         2           35         1             2.5211     1.1224    230      2.25     0.0256     0.05     0.3096     4.7327     
   AVISITN*TRTPN   14         2           35         2             4.0892     0.7094    112      5.76     <.0001     0.05     2.6836     5.4949     
   AVISITN*TRTPN   14         2           35         3            -1.2270     1.0495    241     -1.17     0.2435     0.05    -3.2945     0.8404     
   AVISITN*TRTPN   14         2           42         1             3.0133     1.1531    228      2.61     0.0096     0.05     0.7411     5.2855     
   AVISITN*TRTPN   14         2           42         2             3.4320     0.7779    110      4.41     <.0001     0.05     1.8903     4.9737     
   AVISITN*TRTPN   14         2           42         3            -0.9716     1.0991    236     -0.88     0.3776     0.05    -3.1369     1.1937     
   AVISITN*TRTPN   14         3           21         1             5.4124     1.0600    245      5.11     <.0001     0.05     3.3245     7.5003     
   AVISITN*TRTPN   14         3           21         2             5.8571     1.0305    236      5.68     <.0001     0.05     3.8269     7.8873     
   AVISITN*TRTPN   14         3           21         3             1.3942     0.5352    124      2.61     0.0103     0.05     0.3349     2.4535     
   AVISITN*TRTPN   14         3           28         1             5.5703     1.0932    237      5.10     <.0001     0.05     3.4167     7.7240     
   AVISITN*TRTPN   14         3           28         2             6.1196     1.0943    225      5.59     <.0001     0.05     3.9632     8.2760     
   AVISITN*TRTPN   14         3           28         3             1.6317     0.5625    130      2.90     0.0044     0.05     0.5189     2.7446     
   AVISITN*TRTPN   14         3           35         1             6.1189     1.1010    230      5.56     <.0001     0.05     3.9495     8.2882     
   AVISITN*TRTPN   14         3           35         2             7.6869     1.1558    218      6.65     <.0001     0.05     5.4090     9.9649     
   AVISITN*TRTPN   14         3           35         3             2.3707     0.5550    119      4.27     <.0001     0.05     1.2717     3.4697     
   AVISITN*TRTPN   14         3           42         1             6.6110     1.1323    226      5.84     <.0001     0.05     4.3799     8.8421     
   AVISITN*TRTPN   14         3           42         2             7.0298     1.2033    210      5.84     <.0001     0.05     4.6576     9.4019     
   AVISITN*TRTPN   14         3           42         3             2.6262     0.6518    120      4.03     <.0001     0.05     1.3357     3.9166     
   AVISITN*TRTPN   21         1           21         2             0.4447     1.1553    250      0.38     0.7006     0.05    -1.8307     2.7201     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
251


CENTANAFADINE                                                                                                               23 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                        Differences of Least Squares Means                                                          
                                                                                                                                                    
                   Analysis   Planned     Analysis   Planned                                                                                        
                   Visit      Treatment   Visit      Treatment              Standard                                                                
   Effect          (N)        (N)         (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper     
                                                                                                                                                    
   AVISITN*TRTPN   21         1           21         3            -4.0182     1.1060    249     -3.63     0.0003     0.05    -6.1964    -1.8400     
   AVISITN*TRTPN   21         1           28         1             0.1579     0.4168    121      0.38     0.7054     0.05    -0.6672     0.9831     
   AVISITN*TRTPN   21         1           28         2             0.7072     1.2123    246      0.58     0.5602     0.05    -1.6806     3.0950     
   AVISITN*TRTPN   21         1           28         3            -3.7807     1.1210    249     -3.37     0.0009     0.05    -5.9886    -1.5728     
   AVISITN*TRTPN   21         1           35         1             0.7065     0.5769    114      1.22     0.2232     0.05    -0.4362     1.8492     
   AVISITN*TRTPN   21         1           35         2             2.2745     1.2680    245      1.79     0.0741     0.05    -0.2230     4.7721     
   AVISITN*TRTPN   21         1           35         3            -3.0417     1.1509    253     -2.64     0.0087     0.05    -5.3083    -0.7751     
   AVISITN*TRTPN   21         1           42         1             1.1986     0.5977    115      2.01     0.0473     0.05    0.01472     2.3825     
   AVISITN*TRTPN   21         1           42         2             1.6174     1.3116    239      1.23     0.2187     0.05    -0.9664     4.2011     
   AVISITN*TRTPN   21         1           42         3            -2.7862     1.1963    253     -2.33     0.0206     0.05    -5.1422    -0.4303     
   AVISITN*TRTPN   21         2           21         3            -4.4629     1.0784    244     -4.14     <.0001     0.05    -6.5872    -2.3387     
   AVISITN*TRTPN   21         2           28         1            -0.2868     1.1855    247     -0.24     0.8091     0.05    -2.6218     2.0482     
   AVISITN*TRTPN   21         2           28         2             0.2625     0.4862    114      0.54     0.5903     0.05    -0.7006     1.2256     
   AVISITN*TRTPN   21         2           28         3            -4.2254     1.0936    251     -3.86     0.0001     0.05    -6.3792    -2.0716     
   AVISITN*TRTPN   21         2           35         1             0.2618     1.1929    242      0.22     0.8265     0.05    -2.0880     2.6115     
   AVISITN*TRTPN   21         2           35         2             1.8298     0.6210    112      2.95     0.0039     0.05     0.5995     3.0602     
   AVISITN*TRTPN   21         2           35         3            -3.4864     1.1242    250     -3.10     0.0021     0.05    -5.7006    -1.2723     
   AVISITN*TRTPN   21         2           42         1             0.7539     1.2219    242      0.62     0.5378     0.05    -1.6529     3.1607     
   AVISITN*TRTPN   21         2           42         2             1.1726     0.7252    110      1.62     0.1087     0.05    -0.2645     2.6098     
   AVISITN*TRTPN   21         2           42         3            -3.2310     1.1706    250     -2.76     0.0062     0.05    -5.5365    -0.9254     
   AVISITN*TRTPN   21         3           28         1             4.1762     1.1379    246      3.67     0.0003     0.05     1.9348     6.4175     
   AVISITN*TRTPN   21         3           28         2             4.7254     1.1393    234      4.15     <.0001     0.05     2.4808     6.9701     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
252


CENTANAFADINE                                                                                                               24 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                        Differences of Least Squares Means                                                          
                                                                                                                                                    
                   Analysis   Planned     Analysis   Planned                                                                                        
                   Visit      Treatment   Visit      Treatment              Standard                                                                
   Effect          (N)        (N)         (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper     
                                                                                                                                                    
   AVISITN*TRTPN   21         3           28         3             0.2375     0.4197    124      0.57     0.5725     0.05    -0.5932     1.0683     
   AVISITN*TRTPN   21         3           35         1             4.7247     1.1454    239      4.12     <.0001     0.05     2.4683     6.9811     
   AVISITN*TRTPN   21         3           35         2             6.2928     1.1985    231      5.25     <.0001     0.05     3.9314     8.6541     
   AVISITN*TRTPN   21         3           35         3             0.9765     0.4363    125      2.24     0.0270     0.05     0.1131     1.8399     
   AVISITN*TRTPN   21         3           42         1             5.2168     1.1755    237      4.44     <.0001     0.05     2.9011     7.5326     
   AVISITN*TRTPN   21         3           42         2             5.6356     1.2444    223      4.53     <.0001     0.05     3.1832     8.0880     
   AVISITN*TRTPN   21         3           42         3             1.2320     0.4938    124      2.49     0.0139     0.05     0.2546     2.2093     
   AVISITN*TRTPN   28         1           28         2             0.5493     1.2420    246      0.44     0.6587     0.05    -1.8971     2.9956     
   AVISITN*TRTPN   28         1           28         3            -3.9386     1.1523    245     -3.42     0.0007     0.05    -6.2082    -1.6690     
   AVISITN*TRTPN   28         1           35         1             0.5486     0.4314    115      1.27     0.2061     0.05    -0.3059     1.4030     
   AVISITN*TRTPN   28         1           35         2             2.1166     1.2961    246      1.63     0.1037     0.05    -0.4363     4.6695     
   AVISITN*TRTPN   28         1           35         3            -3.1996     1.1814    251     -2.71     0.0072     0.05    -5.5264    -0.8728     
   AVISITN*TRTPN   28         1           42         1             1.0407     0.4870    114      2.14     0.0347     0.05    0.07594     2.0054     
   AVISITN*TRTPN   28         1           42         2             1.4594     1.3388    242      1.09     0.2768     0.05    -1.1778     4.0967     
   AVISITN*TRTPN   28         1           42         3            -2.9442     1.2257    253     -2.40     0.0170     0.05    -5.3581    -0.5303     
   AVISITN*TRTPN   28         2           28         3            -4.4879     1.1541    240     -3.89     0.0001     0.05    -6.7614    -2.2144     
   AVISITN*TRTPN   28         2           35         1           -0.00071     1.2487    244     -0.00     0.9995     0.05    -2.4604     2.4590     
   AVISITN*TRTPN   28         2           35         2             1.5673     0.5233    106      3.00     0.0034     0.05     0.5299     2.6047     
   AVISITN*TRTPN   28         2           35         3            -3.7489     1.1831    243     -3.17     0.0017     0.05    -6.0794    -1.4184     
   AVISITN*TRTPN   28         2           42         1             0.4914     1.2765    245      0.38     0.7006     0.05    -2.0229     3.0057     
   AVISITN*TRTPN   28         2           42         2             0.9101     0.6303    107      1.44     0.1516     0.05    -0.3393     2.1596     
   AVISITN*TRTPN   28         2           42         3            -3.4934     1.2273    247     -2.85     0.0048     0.05    -5.9108    -1.0761     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
253


CENTANAFADINE                                                                                                               25 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                        Differences of Least Squares Means                                                          
                                                                                                                                                    
                   Analysis   Planned     Analysis   Planned                                                                                        
                   Visit      Treatment   Visit      Treatment              Standard                                                                
   Effect          (N)        (N)         (N)        (N)         Estimate      Error     DF   t Value   Pr > |t|    Alpha      Lower      Upper     
                                                                                                                                                    
   AVISITN*TRTPN   28         3           35         1             4.4872     1.1598    240      3.87     0.0001     0.05     2.2026     6.7718     
   AVISITN*TRTPN   28         3           35         2             6.0552     1.2125    237      4.99     <.0001     0.05     3.6666     8.4439     
   AVISITN*TRTPN   28         3           35         3             0.7390     0.3985    123      1.85     0.0661     0.05   -0.04985     1.5278     
   AVISITN*TRTPN   28         3           42         1             4.9793     1.1895    239      4.19     <.0001     0.05     2.6361     7.3225     
   AVISITN*TRTPN   28         3           42         2             5.3980     1.2579    229      4.29     <.0001     0.05     2.9194     7.8766     
   AVISITN*TRTPN   28         3           42         3             0.9944     0.4443    125      2.24     0.0270     0.05     0.1151     1.8738     
   AVISITN*TRTPN   35         1           35         2             1.5681     1.3037    244      1.20     0.2302     0.05    -1.0000     4.1361     
   AVISITN*TRTPN   35         1           35         3            -3.7482     1.1884    246     -3.15     0.0018     0.05    -6.0888    -1.4075     
   AVISITN*TRTPN   35         1           42         1             0.4921     0.5403    111      0.91     0.3644     0.05    -0.5785     1.5628     
   AVISITN*TRTPN   35         1           42         2             0.9109     1.3458    239      0.68     0.4992     0.05    -1.7403     3.5620     
   AVISITN*TRTPN   35         1           42         3            -3.4927     1.2325    249     -2.83     0.0050     0.05    -5.9203    -1.0652     
   AVISITN*TRTPN   35         2           35         3            -5.3162     1.2406    241     -4.29     <.0001     0.05    -7.7601    -2.8724     
   AVISITN*TRTPN   35         2           42         1            -1.0759     1.3301    247     -0.81     0.4193     0.05    -3.6956     1.5438     
   AVISITN*TRTPN   35         2           42         2            -0.6572     0.4852   99.7     -1.35     0.1786     0.05    -1.6198     0.3054     
   AVISITN*TRTPN   35         2           42         3            -5.0608     1.2827    247     -3.95     0.0001     0.05    -7.5871    -2.5344     
   AVISITN*TRTPN   35         3           42         1             4.2403     1.2175    244      3.48     0.0006     0.05     1.8421     6.6385     
   AVISITN*TRTPN   35         3           42         2             4.6591     1.2849    235      3.63     0.0004     0.05     2.1277     7.1905     
   AVISITN*TRTPN   35         3           42         3             0.2555     0.3442    121      0.74     0.4594     0.05    -0.4260     0.9369     
   AVISITN*TRTPN   42         1           42         2             0.4187     1.3727    245      0.31     0.7606     0.05    -2.2850     3.1225     
   AVISITN*TRTPN   42         1           42         3            -3.9849     1.2601    249     -3.16     0.0018     0.05    -6.4667    -1.5030     
   AVISITN*TRTPN   42         2           42         3            -4.4036     1.3262    243     -3.32     0.0010     0.05    -7.0159    -1.7913     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
254


CENTANAFADINE                                                                                                               26 OF 26
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-4.10                                                                       
                                  Proc Mixed Output Using Heterogeneous Variance Structure for Treatment Groups                                     
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                              Tests of Effect Slices                                                                
                                                                                                                                                    
                                                           Analysis                                                                                 
                                                           Visit        Num     Den                                                                 
                                          Effect           (N)           DF      DF    F Value    Pr > F                                            
                                                                                                                                                    
                                          AVISITN*TRTPN     7             2     243       3.60    0.0289                                            
                                          AVISITN*TRTPN    14             2     246       9.18    0.0001                                            
                                          AVISITN*TRTPN    21             2     248      10.57    <.0001                                            
                                          AVISITN*TRTPN    28             2     246       9.47    0.0001                                            
                                          AVISITN*TRTPN    35             2     246      10.24    <.0001                                            
                                          AVISITN*TRTPN    42             2     247       7.30    0.0008                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
255


CENTANAFADINE                                                                                                               1 OF 14
PROTOCOL 405-201-00014                                                                                                                               
STAT-5.1  
Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                Model Information                                                                   
                                                                                                                                                    
                                              Data Set                     WORK.INDATA                                                              
                                              Dependent Variable           CHG                                                                      
                                              Covariance Structure         Unstructured                                                             
                                              Subject Effect               SUBJID                                                                   
                                              Estimation Method            REML                                                                     
                                              Residual Variance Method     None                                                                     
                                              Fixed Effects SE Method      Kenward-Roger                                                            
                                              Degrees of Freedom Method    Kenward-Roger                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                                                                                                    
                                               AVISITN          6    7 14 21 28 35 42                                                               
                                               TRTPN            3    1 2 3                                                                          
                                               POOLCNTR        39   
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                    
                                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
256


CENTANAFADINE                                                                                                               2 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                               Class       Levels    Values                                                                         
                                                                                                                                                    
                                               SUBJID         421   
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
257


CENTANAFADINE                                                                                                               3 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
258


CENTANAFADINE                                                                                                               4 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                    
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
259


CENTANAFADINE                                                                                                               5 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
260


CENTANAFADINE                                                                                                               6 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
261


CENTANAFADINE                                                                                                               7 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                    
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                     
                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
262


CENTANAFADINE                                                                                                               8 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                   Dimensions                                                                       
                                                                                                                                                    
                                                       Covariance Parameters            21                                                          
                                                       Columns in X                     73                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        421                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2220                                                      
                                                   Number of Observations Used            2220                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                Iteration History                                                                   
                                                                                                                                                    
                                           Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                    
                                                   0              1      5534.17561525                                                              
                                                   1              2      3687.88676445      0.00358545                                              
                                                   2              1      3687.36668372      0.00001709                                              
                                                   3              1      3687.36429296      0.00000000                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
263


CENTANAFADINE                                                                                                               9 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                            Convergence criteria met.                                                               
                                                                                                                                                    
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(1,1)     SUBJID       0.3911                                                            
                                                         UN(2,1)     SUBJID       0.2991                                                            
                                                         UN(2,2)     SUBJID       0.6117                                                            
                                                         UN(3,1)     SUBJID       0.3110                                                            
                                                         UN(3,2)     SUBJID       0.5237                                                            
                                                         UN(3,3)     SUBJID       0.7431                                                            
                                                         UN(4,1)     SUBJID       0.2804                                                            
                                                         UN(4,2)     SUBJID       0.5001                                                            
                                                         UN(4,3)     SUBJID       0.5893                                                            
                                                         UN(4,4)     SUBJID       0.7650                                                            
                                                         UN(5,1)     SUBJID       0.3206                                                            
                                                         UN(5,2)     SUBJID       0.5243                                                            
                                                         UN(5,3)     SUBJID       0.6146                                                            
                                                         UN(5,4)     SUBJID       0.6923                                                            
                                                         UN(5,5)     SUBJID       0.9120                                                            
                                                         UN(6,1)     SUBJID       0.2947                                                            
                                                         UN(6,2)     SUBJID       0.5097                                                            
                                                         UN(6,3)     SUBJID       0.5999                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
264


CENTANAFADINE                                                                                                               10 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                         Covariance Parameter Estimates                                                             
                                                                                                                                                    
                                                         Cov Parm    Subject    Estimate                                                            
                                                                                                                                                    
                                                         UN(6,4)     SUBJID       0.7026                                                            
                                                         UN(6,5)     SUBJID       0.8049                                                            
                                                         UN(6,6)     SUBJID       0.9541                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood          3687.4                                                         
                                                      AIC (Smaller is Better)        3729.4                                                         
                                                      AICC (Smaller is Better)       3729.8                                                         
                                                      BIC (Smaller is Better)        3814.3                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           20       1846.81          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
265


CENTANAFADINE                                                                                                               11 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                          Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                    
                                                                  Num     Den                                                                       
                                                Effect             DF      DF    F Value    Pr > F                                                  
                                                                                                                                                    
                                                AVISITN             5     352       0.16    0.9771                                                  
                                                TRTPN               2     377       4.07    0.0179                                                  
                                                AVISITN*TRTPN      10     522       1.44    0.1591                                                  
                                                POOLCNTR           38     379       1.62    0.0135                                                  
                                                BASE*AVISITN        6     378       6.13    <.0001                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                   Standard                                                                                         
                      Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                        
                                                                                                                                                    
                      DAY7  1 vs 3     -0.05184     0.07546     381      -0.69      0.4925      0.05     -0.2002     0.09652                        
                      DAY7  2 vs 3     -0.03062     0.07587     379      -0.40      0.6868      0.05     -0.1798      0.1186                        
                      DAY14  1 vs 3     -0.1951     0.09505     376      -2.05      0.0408      0.05     -0.3820    -0.00824                        
                      DAY14  2 vs 3     -0.1611     0.09681     384      -1.66      0.0968      0.05     -0.3515     0.02920                        
                      DAY21  1 vs 3     -0.2313      0.1053     367      -2.20      0.0286      0.05     -0.4383    -0.02432                        
                      DAY21  2 vs 3     -0.2400      0.1076     376      -2.23      0.0262      0.05     -0.4515    -0.02852                        
                      DAY28  1 vs 3     -0.2650      0.1076     364      -2.46      0.0142      0.05     -0.4766    -0.05345                        
                      DAY28  2 vs 3     -0.2665      0.1099     371      -2.42      0.0158      0.05     -0.4827    -0.05034                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
266


CENTANAFADINE                                                                                                               12 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                   Standard                                                                                         
                      Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                        
                                                                                                                                                    
                      DAY35  1 vs 3     -0.2626      0.1183     364      -2.22      0.0271      0.05     -0.4952    -0.02991                        
                      DAY35  2 vs 3     -0.3555      0.1212     373      -2.93      0.0036      0.05     -0.5938     -0.1173                        
                      DAY42  1 vs 3     -0.3287      0.1219     365      -2.70      0.0073      0.05     -0.5684    -0.08902                        
                      DAY42  2 vs 3     -0.2820      0.1249     372      -2.26      0.0245      0.05     -0.5276    -0.03644                        
                                                                                                                                                    
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                          Analysis    Planned                                                                                                       
                          Visit       Treatment                Standard                                                                             
         Effect           (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper            
                                                                                                                                                    
         AVISITN*TRTPN     7          1             -0.4635     0.05831     389      -7.95      <.0001      0.05     -0.5781     -0.3488            
         AVISITN*TRTPN     7          2             -0.4422     0.05866     386      -7.54      <.0001      0.05     -0.5576     -0.3269            
         AVISITN*TRTPN     7          3             -0.4116     0.05774     385      -7.13      <.0001      0.05     -0.5251     -0.2981            
         AVISITN*TRTPN    14          1             -0.7240     0.07107     405     -10.19      <.0001      0.05     -0.8637     -0.5843            
         AVISITN*TRTPN    14          2             -0.6900     0.07311     420      -9.44      <.0001      0.05     -0.8337     -0.5463            
         AVISITN*TRTPN    14          3             -0.5289     0.07093     407      -7.46      <.0001      0.05     -0.6683     -0.3894            
         AVISITN*TRTPN    21          1             -0.8550     0.07830     405     -10.92      <.0001      0.05     -1.0089     -0.7010            
         AVISITN*TRTPN    21          2             -0.8637     0.08093     419     -10.67      <.0001      0.05     -1.0227     -0.7046            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
267


CENTANAFADINE                                                                                                               13 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                          Analysis    Planned                                                                                                       
                          Visit       Treatment                Standard                                                                             
         Effect           (N)         (N)          Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper            
                                                                                                                                                    
         AVISITN*TRTPN    21          3             -0.6236     0.07749     396      -8.05      <.0001      0.05     -0.7760     -0.4713            
         AVISITN*TRTPN    28          1             -0.9048     0.08001     403     -11.31      <.0001      0.05     -1.0621     -0.7475            
         AVISITN*TRTPN    28          2             -0.9063     0.08273     413     -10.96      <.0001      0.05     -1.0689     -0.7437            
         AVISITN*TRTPN    28          3             -0.6398     0.07895     392      -8.10      <.0001      0.05     -0.7950     -0.4846            
         AVISITN*TRTPN    35          1             -0.9406     0.08760     403     -10.74      <.0001      0.05     -1.1128     -0.7684            
         AVISITN*TRTPN    35          2             -1.0336     0.09091     418     -11.37      <.0001      0.05     -1.2123     -0.8549            
         AVISITN*TRTPN    35          3             -0.6781     0.08597     389      -7.89      <.0001      0.05     -0.8471     -0.5090            
         AVISITN*TRTPN    42          1             -1.0402     0.09021     406     -11.53      <.0001      0.05     -1.2176     -0.8629            
         AVISITN*TRTPN    42          2             -0.9935     0.09365     415     -10.61      <.0001      0.05     -1.1776     -0.8095            
         AVISITN*TRTPN    42          3             -0.7115     0.08826     388      -8.06      <.0001      0.05     -0.8851     -0.5380            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
268


CENTANAFADINE                                                                                                               14 OF 14
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.1                                                                       
                                       Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)                                         
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Parameter Code=CGI0201 -------------------------------------------------------------- 
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                              Tests of Effect Slices                                                                
                                                                                                                                                    
                                                           Analysis                                                                                 
                                                           Visit        Num     Den                                                                 
                                          Effect           (N)           DF      DF    F Value    Pr > F                                            
                                                                                                                                                    
                                          AVISITN*TRTPN     7             2     380       0.24    0.7878                                            
                                          AVISITN*TRTPN    14             2     381       2.39    0.0931                                            
                                          AVISITN*TRTPN    21             2     374       3.30    0.0379                                            
                                          AVISITN*TRTPN    28             2     370       4.03    0.0186                                            
                                          AVISITN*TRTPN    35             2     372       4.73    0.0094                                            
                                          AVISITN*TRTPN    42             2     372       4.24    0.0150                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
269


CENTANAFADINE                                                                                                               1 OF 6
PROTOCOL 405-201-00014                                                                                                                               
STAT-5.2  
Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, LOCF  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
Class       Levels  Values                                                                                                                           
                                                                                                                                                    
TRTPN            3  1 2 3                                                                                                                            
                                                                                                                                                    
POOLCNTR        39 
 
                  
 
                                                                                                                                                    
                                                                                                                                                    
                                                     Number of Observations Read         421                                                        
                                                     Number of Observations Used         421                                                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
270


CENTANAFADINE                                                                                                               2 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.2                                                                       
                                     Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, LOCF                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                       Sum of                                                                       
                               Source                      DF         Squares     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               Model                       41      75.2669725       1.8357798       1.97    0.0006                                  
                                                                                                                                                    
                               Error                      379     352.9087994       0.9311578                                                       
                                                                                                                                                    
                               Corrected Total            420     428.1757720                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.175785     -118.7866      0.964965     -0.812352                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2      6.97064551      3.48532275       3.74    0.0246                                  
                               POOLCNTR                    38     46.93646590      1.23517016       1.33    0.0997                                  
                               BASE                         1     17.18753428     17.18753428      18.46    <.0001                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
271


CENTANAFADINE                                                                                                               3 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.2                                                                       
                                     Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, LOCF                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                               Level of             -------------CHG-------------     -------------BASE------------                                 
                               TRTPN          N             Mean          Std Dev             Mean          Std Dev                                 
                                                                                                                                                    
                               1            140      -0.92142857       1.10634441       4.55714286       0.56608498                                 
                               2            140      -0.89285714       0.97225118       4.65714286       0.54668956                                 
                               3            141      -0.62411348       0.92225660       4.52482270       0.55525490                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
272


CENTANAFADINE                                                                                                               4 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.2                                                                       
                                     Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, LOCF                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                                                       Standard                  LSMEAN                                             
                                          TRTPN      CHG LSMEAN           Error    Pr > |t|      Number                                             
                                                                                                                                                    
                                          1         -0.99635472      0.08963644      <.0001           1                                             
                                          2         -0.93139660      0.09048002      <.0001           2                                             
                                          3         -0.69523223      0.08917989      <.0001           3                                             
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for effect TRTPN                                                         
                                                       Pr > |t| for H0: LSMean(i)=LSMean(j)                                                         
                                                                                                                                                    
                                                             Dependent Variable: CHG                                                                
                                                                                                                                                    
                                                  i/j              1             2             3                                                    
                                                                                                                                                    
                                                     1                      0.5780        0.0096                                                    
                                                     2        0.5780                      0.0437                                                    
                                                     3        0.0096        0.0437                                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                    
                                                1           -0.996355       -1.172602    -0.820108                                                  
                                                2           -0.931397       -1.109302    -0.753491                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
273


CENTANAFADINE                                                                                                               5 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.2                                                                       
                                     Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, LOCF                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                                TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                    
                                                3           -0.695232       -0.870582    -0.519883                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for Effect TRTPN                                                         
                                                                                                                                                    
                                                           Difference                                                                               
                                                              Between    95% Confidence Limits for                                                  
                                               i    j           Means       LSMean(i)-LSMean(j)                                                     
                                                                                                                                                    
                                               1    2       -0.064958       -0.294343     0.164427                                                  
                                               1    3       -0.301122       -0.528624    -0.073621                                                  
                                               2    3       -0.236164       -0.465593    -0.006735                                                  
                                                                                                                                                    
                                                                                                                                                    
NOTE: To ensure overall protection level, only probabilities associated with pre-planned comparisons should be used.                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
274


CENTANAFADINE                                                                                                               6 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.2                                                                       
                                     Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, LOCF                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                               Standard                                                             
                                   Parameter                   Estimate           Error    t Value    Pr > |t|                                      
                                                                                                                                                    
                                   1 vs 3                   -0.30112249      0.11570382      -2.60      0.0096                                      
                                   2 vs 3                   -0.23616436      0.11668402      -2.02      0.0437                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
275


CENTANAFADINE                                                                                                               1 OF 6
PROTOCOL 405-201-00014                                                                                                                               
STAT-5.3  
Proc GLM Output for Change from Baseline to Day 42 in  CGI-S Scale, OC  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                             Class Level Information                                                                
                                                                                                                                                    
                                                          Class         Levels    Values                                                            
                                                                                                                                                    
                                                          TRTPN              3    1 2 3                                                             
                                                                                                                                                    
                                                                                                                                                    
                                                     Number of Observations Read         421                                                        
                                                     Number of Observations Used         421                                                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
276


CENTANAFADINE                                                                                                               2 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.3                                                                       
                                      Proc GLM Output for Change from Baseline to Day 42 in  CGI-S Scale, OC                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                       Sum of                                                                       
                               Source                      DF         Squares     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               Model                        3      28.3305066       9.4435022       9.85    <.0001                                  
                                                                                                                                                    
                               Error                      417     399.8452653       0.9588615                                                       
                                                                                                                                                    
                               Corrected Total            420     428.1757720                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.066166     -120.5408      0.979215     -0.812352                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2      6.17656237      3.08828118       3.22    0.0409                                  
                               BASE                         1     20.76132028     20.76132028      21.65    <.0001                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
277


CENTANAFADINE                                                                                                               3 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.3                                                                       
                                      Proc GLM Output for Change from Baseline to Day 42 in  CGI-S Scale, OC                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                               Level of             -------------CHG-------------     -------------BASE------------                                 
                               TRTPN          N             Mean          Std Dev             Mean          Std Dev                                 
                                                                                                                                                    
                               1            140      -0.92142857       1.10634441       4.55714286       0.56608498                                 
                               2            140      -0.89285714       0.97225118       4.65714286       0.54668956                                 
                               3            141      -0.62411348       0.92225660       4.52482270       0.55525490                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
278


CENTANAFADINE                                                                                                               4 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.3                                                                       
                                      Proc GLM Output for Change from Baseline to Day 42 in  CGI-S Scale, OC                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                                                       Standard                  LSMEAN                                             
                                          TRTPN      CHG LSMEAN           Error    Pr > |t|      Number                                             
                                                                                                                                                    
                                          1         -0.93041807      0.08278130      <.0001           1                                             
                                          2         -0.86176789      0.08302801      <.0001           2                                             
                                          3         -0.64605649      0.08259948      <.0001           3                                             
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for effect TRTPN                                                         
                                                       Pr > |t| for H0: LSMean(i)=LSMean(j)                                                         
                                                                                                                                                    
                                                             Dependent Variable: CHG                                                                
                                                                                                                                                    
                                                  i/j              1             2             3                                                    
                                                                                                                                                    
                                                     1                      0.5589        0.0154                                                    
                                                     2        0.5589                      0.0668                                                    
                                                     3        0.0154        0.0668                                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                    
                                                1           -0.930418       -1.093139    -0.767697                                                  
                                                2           -0.861768       -1.024973    -0.698562                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
279


CENTANAFADINE                                                                                                               5 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.3                                                                       
                                      Proc GLM Output for Change from Baseline to Day 42 in  CGI-S Scale, OC                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                               Least Squares Means                                                                  
                                                                                                                                                    
                                                TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                    
                                                3           -0.646056       -0.808420    -0.483693                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for Effect TRTPN                                                         
                                                                                                                                                    
                                                           Difference                                                                               
                                                              Between    95% Confidence Limits for                                                  
                                               i    j           Means       LSMean(i)-LSMean(j)                                                     
                                                                                                                                                    
                                               1    2       -0.068650       -0.299331     0.162031                                                  
                                               1    3       -0.284362       -0.514078    -0.054646                                                  
                                               2    3       -0.215711       -0.446452     0.015030                                                  
                                                                                                                                                    
                                                                                                                                                    
NOTE: To ensure overall protection level, only probabilities associated with pre-planned comparisons should be used.                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
280


CENTANAFADINE                                                                                                               6 OF 6
PROTOCOL 405-201-00014                                                                                                                               
                                                                     STAT-5.3                                                                       
                                      Proc GLM Output for Change from Baseline to Day 42 in  CGI-S Scale, OC                                        
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------- Parameter Code=CGI0201 Analysis Visit (N)=42 --------------------------------------------------- 
                                                                                                                                                    
                                                                The GLM Procedure                                                                   
                                                                                                                                                    
                                                  Dependent Variable: CHG   Change from Baseline                                                    
                                                                                                                                                    
                                                                               Standard                                                             
                                   Parameter                   Estimate           Error    t Value    Pr > |t|                                      
                                                                                                                                                    
                                   1 vs 3                   -0.28436158      0.11686401      -2.43      0.0154                                      
                                   2 vs 3                   -0.21571140      0.11738543      -1.84      0.0668                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 31AUG2020 08:32; ANALYSIS DATASET CREATED: 16JUN2020 08:14                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
281


CENTANAFADINE                                                                                                               1 OF 1
PROTOCOL 405-201-00014                                                                                                                               
STAT-6.1.1  
Shapiro-Wilk Test for Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model  
(Efficacy Sample)
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                                                                                                  GOODNESS OF FIT                                    
                                                              TEST              GOODNESS OF FIT              TEST                                    
                       PROTOCOL           Day                 VARIABLE          TEST                   STATISTICS  Pvalue                            
                       ------------------------------------------------------------------------------------------------------                        
                       40520100014        DAY 7               RESID             Shapiro-Wilk               0.9618  <0.0001                           
                                                              STUDENTRESID      Shapiro-Wilk               0.9619  <0.0001                           
                                          DAY 14              RESID             Shapiro-Wilk               0.9742  <0.0001                           
                                                              STUDENTRESID      Shapiro-Wilk               0.9729  <0.0001                           
                                          DAY 21              RESID             Shapiro-Wilk               0.9755  <0.0001                           
                                                              STUDENTRESID      Shapiro-Wilk               0.9754  <0.0001                           
                                          DAY 28              RESID             Shapiro-Wilk               0.9780  <0.0001                           
                                                              STUDENTRESID      Shapiro-Wilk               0.9785  <0.0001                           
                                          DAY 35              RESID             Shapiro-Wilk               0.9772  <0.0001                           
                                                              STUDENTRESID      Shapiro-Wilk               0.9776  <0.0001                           
                                          DAY 42              RESID             Shapiro-Wilk               0.9767  <0.0001                           
                                                              STUDENTRESID      Shapiro-Wilk               0.9772  <0.0001                           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normality_ba.lis, RUN: 31AUG2020 08:32                                                                                                         
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality_b.sas                                                             
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.1      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
282


CENTANAFADINE                                                                                                               1 OF 48
PROTOCOL 405-201-00014                                                                                                                               
STAT-6.1.2  
Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model  
(Efficacy Sample)
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         415    Sum Weights                415                                            
                                         Mean               0.00590733    Sum Observations    2.45154156                                            
                                         Std Deviation      6.29621838    Variance            39.6423659                                            
                                         Skewness           -0.7622497    Kurtosis            1.20879183                                            
                                         Uncorrected SS     16411.9539    Corrected SS        16411.9395                                            
                                         Coeff Variation    106583.167    Std Error Mean       0.3090692                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.005907     Std Deviation            6.29622                                                
                                              Median   0.890327     Variance                39.64237                                                
                                              Mode     2.147650     Range                   41.51301                                                
                                                                    Interquartile Range      6.74509                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
283


CENTANAFADINE                                                                                                               2 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.019113    Pr > |t|    0.9848                                                   
                                                 Sign           M      31.5    Pr >= |M|   0.0023                                                   
                                                 Signed Rank    S      4203    Pr >= |S|   0.0856                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.961785    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.084284    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.900816    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  5.031644    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
284


CENTANAFADINE                                                                                                               3 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level           Quantile                                                               
                                                                                                                                                    
                                                             100% Max       17.902786                                                               
                                                             99%            11.786668                                                               
                                                             95%             8.673196                                                               
                                                             90%             6.633776                                                               
                                                             75% Q3          3.932496                                                               
                                                             50% Median      0.890327                                                               
                                                             25% Q1         -2.812590                                                               
                                                             10%            -8.383850                                                               
                                                             5%            -12.326090                                                               
                                                             1%            -17.376429                                                               
                                                             0% Min        -23.610226                                                               
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
285


CENTANAFADINE                                                                                                               4 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -23.6102   40520100014-
                        253         11.7867   40520100014-
                        24           
          -23.5381   40520100014-
                        267         12.5707   40520100014-
                        44           
          -20.6914   40520100014-
                        395         14.6909   40520100014-
                        36           
          -18.3791   40520100014-
                         48         15.9070   40520100014-
                       281           
          -17.3764   40520100014-
                        381         17.9028   40520100014-
                       186           
                                 
                                                          
                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
286


CENTANAFADINE                                                                                                               5 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         415    Sum Weights                415                                            
                                         Mean               0.00076876    Sum Observations    0.31903492                                            
                                         Std Deviation      1.01663979    Variance            1.03355646                                            
                                         Skewness           -0.7470648    Kurtosis            1.26177724                                            
                                         Uncorrected SS     427.892621    Corrected SS        427.892376                                            
                                         Coeff Variation    132244.305    Std Error Mean      0.04990488                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.000769     Std Deviation            1.01664                                                
                                              Median   0.138127     Variance                 1.03356                                                
                                              Mode     0.330816     Range                    6.97281                                                
                                                                    Interquartile Range      1.04756                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
287


CENTANAFADINE                                                                                                               6 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.015404    Pr > |t|    0.9877                                                   
                                                 Sign           M      31.5    Pr >= |M|   0.0023                                                   
                                                 Signed Rank    S      4190    Pr >= |S|   0.0866                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.961929    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.086473    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.912147    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  5.104489    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
288


CENTANAFADINE                                                                                                               7 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       3.049245                                                                
                                                             99%            1.938606                                                                
                                                             95%            1.444558                                                                
                                                             90%            1.079590                                                                
                                                             75% Q3         0.613816                                                                
                                                             50% Median     0.138127                                                                
                                                             25% Q1        -0.433740                                                                
                                                             10%           -1.322380                                                                
                                                             5%            -2.093381                                                                
                                                             1%            -2.777724                                                                
                                                             0% Min        -3.923569                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
289


CENTANAFADINE                                                                                                               8 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
--------------------------------------------------------------- Analysis Visit (N)=7 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -3.92357   40520100014-
                        267         1.93861   40520100014-
                       328           
          -3.74529   40520100014-
                        253         2.19553   40520100014-
                        24           
          -3.23957   40520100014-
                        395         2.26410   40520100014-
                        36           
          -2.83208   40520100014-
                         48         2.64914   40520100014-
                       281           
          -2.77772   40520100014-
                        414         3.04925   40520100014-
                       186           
                                                                                                     
                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
290


CENTANAFADINE                                                                                                               9 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         389    Sum Weights                389                                            
                                         Mean               -0.0478972    Sum Observations    -18.632024                                            
                                         Std Deviation      8.10987026    Variance            65.7699957                                            
                                         Skewness           -0.6462853    Kurtosis            0.96373179                                            
                                         Uncorrected SS     25519.6508    Corrected SS        25518.7583                                            
                                         Coeff Variation    -16931.814    Std Error Mean      0.41118674                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     -0.04790     Std Deviation            8.10987                                                
                                              Median    1.17581     Variance                65.77000                                                
                                              Mode      5.07029     Range                   55.06309                                                
                                                                    Interquartile Range     10.14964                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
291


CENTANAFADINE                                                                                                               10 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  -0.11649    Pr > |t|    0.9073                                                   
                                                 Sign           M      25.5    Pr >= |M|   0.0111                                                   
                                                 Signed Rank    S    2399.5    Pr >= |S|   0.2801                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.974232    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.075075    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.543451    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  2.960271    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
292


CENTANAFADINE                                                                                                               11 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       22.23178                                                                
                                                             99%            16.59354                                                                
                                                             95%            11.12111                                                                
                                                             90%             9.36192                                                                
                                                             75% Q3          5.23846                                                                
                                                             50% Median      1.17581                                                                
                                                             25% Q1         -4.91118                                                                
                                                             10%           -10.67147                                                                
                                                             5%            -15.17154                                                                
                                                             1%            -23.34365                                                                
                                                             0% Min        -32.83131                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
293


CENTANAFADINE                                                                                                               12 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -32.8313   40520100014
                       437         16.5927   40520100014-
                        451           
          -29.4798   40520100014
                       665         16.5935   40520100014-
                        459           
          -25.1439   40520100014
                       796         17.5325   40520100014-
                        470           
          -23.3436   40520100014
                       651         17.8254   40520100014-
                        589           
          -22.7128   40520100014
                       482         22.2318   40520100014-
                        678           
                                 
                                                                                                          
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
294


CENTANAFADINE                                                                                                               13 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         389    Sum Weights                389                                            
                                         Mean               -0.0058977    Sum Observations    -2.2942086                                            
                                         Std Deviation      1.00702053    Variance            1.01409034                                            
                                         Skewness           -0.6687682    Kurtosis            1.22213191                                            
                                         Uncorrected SS     393.480582    Corrected SS        393.467052                                            
                                         Coeff Variation    -17074.776    Std Error Mean      0.05105797                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     -0.00590     Std Deviation            1.00702                                                
                                              Median    0.14300     Variance                 1.01409                                                
                                              Mode      0.61175     Range                    7.23960                                                
                                                                    Interquartile Range      1.23899                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
295


CENTANAFADINE                                                                                                               14 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  -0.11551    Pr > |t|    0.9081                                                   
                                                 Sign           M      25.5    Pr >= |M|   0.0111                                                   
                                                 Signed Rank    S    2371.5    Pr >= |S|   0.2858                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.972919    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.075857    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.550481    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq   2.96986    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
296


CENTANAFADINE                                                                                                               15 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       2.814987                                                                
                                                             99%            2.126709                                                                
                                                             95%            1.349592                                                                
                                                             90%            1.156538                                                                
                                                             75% Q3         0.635037                                                                
                                                             50% Median     0.142997                                                                
                                                             25% Q1        -0.603950                                                                
                                                             10%           -1.376566                                                                
                                                             5%            -1.830571                                                                
                                                             1%            -2.869759                                                                
                                                             0% Min        -4.424614                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
297


CENTANAFADINE                                                                                                               16 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=14 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -4.42461   40520100014-
                        437         2.00259   40520100014-
                        459           
         -3.72916   40520100014-
                        665         2.12671   40520100014-
                        470           
         -3.07149   40520100014-
                        796         2.13944   40520100014-
                        558           
         -2.86976   40520100014-
                        482         2.28195   40520100014-
                        589           
         -2.86776   40520100014-
                        651         2.81499   40520100014-
                        678           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
298


CENTANAFADINE                                                                                                               17 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         375    Sum Weights                375                                            
                                         Mean               0.04424235    Sum Observations    16.5908809                                            
                                         Std Deviation      8.77628273    Variance            77.0231386                                            
                                         Skewness           -0.5795826    Kurtosis            0.26916873                                            
                                         Uncorrected SS     28807.3879    Corrected SS        28806.6538                                            
                                         Coeff Variation    19836.8372    Std Error Mean      0.45320529                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean      0.04424     Std Deviation            8.77628                                                
                                              Median    0.97708     Variance                77.02314                                                
                                              Mode     -4.26252     Range                   53.44257                                                
                                                                    Interquartile Range     12.23517                                                
                                                                                                                                                    
                                      Note: The mode displayed is the smallest of 3 modes with a count of 2.                                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
299


CENTANAFADINE                                                                                                               18 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.097621    Pr > |t|    0.9223                                                   
                                                 Sign           M      14.5    Pr >= |M|   0.1481                                                   
                                                 Signed Rank    S      2381    Pr >= |S|   0.2575                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.975477    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.067214    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.379476    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  2.479975    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
300


CENTANAFADINE                                                                                                               19 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level           Quantile                                                               
                                                                                                                                                    
                                                             100% Max       23.818333                                                               
                                                             99%            15.303207                                                               
                                                             95%            12.320121                                                               
                                                             90%            10.028486                                                               
                                                             75% Q3          6.741001                                                               
                                                             50% Median      0.977085                                                               
                                                             25% Q1         -5.494165                                                               
                                                             10%           -11.975058                                                               
                                                             5%            -16.506856                                                               
                                                             1%            -25.986745                                                               
                                                             0% Min        -29.624234                                                               
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
301


CENTANAFADINE                                                                                                               20 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -29.6242   40520100014-
                       1043         14.0883   40520100014-
                      1081           
          -26.7808   40520100014-
                        966         15.3032   40520100014-
                       921           
          -26.7543   40520100014-
                        825         17.2591   40520100014-
                      1076           
          -25.9867   40520100014-
                        848         20.5261   40520100014-
                      1056           
          -23.7829   40520100014-
                        832         23.8183   40520100014-
                       856           
                                                                                                     
                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
302


CENTANAFADINE                                                                                                               21 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         375    Sum Weights                375                                            
                                         Mean               0.00487939    Sum Observations    1.82977148                                            
                                         Std Deviation      1.00562938    Variance            1.01129045                                            
                                         Skewness           -0.5952846    Kurtosis            0.35653957                                            
                                         Uncorrected SS     378.231556    Corrected SS        378.222628                                            
                                         Coeff Variation    20609.7331    Std Error Mean      0.05193048                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean      0.00488     Std Deviation            1.00563                                                
                                              Median    0.11437     Variance                 1.01129                                                
                                              Mode     -0.47879     Range                    6.14534                                                
                                                                    Interquartile Range      1.39912                                                
                                                                                                                                                    
                                      Note: The mode displayed is the smallest of 3 modes with a count of 2.                                        
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
303


CENTANAFADINE                                                                                                               22 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t   0.09396    Pr > |t|    0.9252                                                   
                                                 Sign           M      14.5    Pr >= |M|   0.1481                                                   
                                                 Signed Rank    S      2414    Pr >= |S|   0.2510                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W      0.97535    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.067951    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.375553    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  2.435138    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
304


CENTANAFADINE                                                                                                               23 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       2.685261                                                                
                                                             99%            1.737520                                                                
                                                             95%            1.409697                                                                
                                                             90%            1.150881                                                                
                                                             75% Q3         0.773889                                                                
                                                             50% Median     0.114367                                                                
                                                             25% Q1        -0.625233                                                                
                                                             10%           -1.363214                                                                
                                                             5%            -1.907909                                                                
                                                             1%            -2.928031                                                                
                                                             0% Min        -3.460083                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
305


CENTANAFADINE                                                                                                               24 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=21 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -3.46008   40520100014-
                       1043         1.72616   40520100014-
                       914           
          -3.30052   40520100014-
                        825         1.73752   40520100014-
                       921           
          -3.15665   40520100014-
                        966         1.93699   40520100014-
                      1076           
          -2.92803   40520100014-
                        848         2.39535   40520100014-
                      1056           
          -2.67885   40520100014-
                        868         2.68526   40520100014-
                       856           
                                 
                                                                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
306


CENTANAFADINE                                                                                                               25 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         366    Sum Weights                366                                            
                                         Mean               0.10619435    Sum Observations    38.8671306                                            
                                         Std Deviation      9.24929929    Variance            85.5495374                                            
                                         Skewness            -0.504134    Kurtosis            -0.0661248                                            
                                         Uncorrected SS     31229.7086    Corrected SS        31225.5812                                            
                                         Coeff Variation    8709.78509    Std Error Mean      0.48346862                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.106194     Std Deviation            9.24930                                                
                                              Median   1.270199     Variance                85.54954                                                
                                              Mode     6.917760     Range                   50.29097                                                
                                                                    Interquartile Range     12.74462                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
307


CENTANAFADINE                                                                                                               26 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.219651    Pr > |t|    0.8263                                                   
                                                 Sign           M        24    Pr >= |M|   0.0139                                                   
                                                 Signed Rank    S    2320.5    Pr >= |S|   0.2525                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.977981    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.069596    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.475034    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  2.720452    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
308


CENTANAFADINE                                                                                                               27 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       23.67290                                                                
                                                             99%            17.88792                                                                
                                                             95%            13.05207                                                                
                                                             90%            10.51949                                                                
                                                             75% Q3          7.10617                                                                
                                                             50% Median      1.27020                                                                
                                                             25% Q1         -5.63845                                                                
                                                             10%           -12.94030                                                                
                                                             5%            -16.83098                                                                
                                                             1%            -24.63841                                                                
                                                             0% Min        -26.61808                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
309


CENTANAFADINE                                                                                                               28 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -26.6181   40520100014-
                       1408         17.6443   40520100014-
                       1440           
         -26.2893   40520100014-
                       1199         17.8879   40520100014-
                       1350           
         -24.9814   40520100014-
                       1242         18.4836   40520100014-
                       1213           
         -24.6384   40520100014-
                       1245         20.7367   40520100014-
                       1421           
         -24.6213   40520100014-
                       1334         23.6729   40520100014-
                       1336           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
310


CENTANAFADINE                                                                                                               29 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         366    Sum Weights                366                                            
                                         Mean                 0.010984    Sum Observations    4.02014573                                            
                                         Std Deviation      1.00683954    Variance            1.01372586                                            
                                         Skewness           -0.5138819    Kurtosis            0.01054228                                            
                                         Uncorrected SS     370.054095    Corrected SS        370.009937                                            
                                         Coeff Variation    9166.41575    Std Error Mean      0.05262835                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.010984     Std Deviation            1.00684                                                
                                              Median   0.140686     Variance                 1.01373                                                
                                              Mode     0.737348     Range                    5.69482                                                
                                                                    Interquartile Range      1.37277                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
311


CENTANAFADINE                                                                                                               30 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.208709    Pr > |t|    0.8348                                                   
                                                 Sign           M        24    Pr >= |M|   0.0139                                                   
                                                 Signed Rank    S    2326.5    Pr >= |S|   0.2513                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.978466    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.069808    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.472312    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  2.687998    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
312


CENTANAFADINE                                                                                                               31 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       2.640998                                                                
                                                             99%            1.970411                                                                
                                                             95%            1.401831                                                                
                                                             90%            1.157699                                                                
                                                             75% Q3         0.763652                                                                
                                                             50% Median     0.140686                                                                
                                                             25% Q1        -0.609115                                                                
                                                             10%           -1.386098                                                                
                                                             5%            -1.825071                                                                
                                                             1%            -2.744377                                                                
                                                             0% Min        -3.053825                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
313


CENTANAFADINE                                                                                                               32 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=28 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -3.05383   40520100014-
                       1199         1.88200   40520100014-
                      1440           
          -2.94301   40520100014-
                       1408         1.97041   40520100014-
                      1213           
          -2.77174   40520100014-
                       1242         2.02350   40520100014-
                      1350           
          -2.74438   40520100014-
                       1334         2.29077   40520100014-
                      1421           
          -2.64333   40520100014-
                       1245         2.64100   40520100014-
                      1336           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
314


CENTANAFADINE                                                                                                               33 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         344    Sum Weights                344                                            
                                         Mean               0.22073119    Sum Observations    75.9315287                                            
                                         Std Deviation      9.61866843    Variance            92.5187824                                            
                                         Skewness           -0.4952975    Kurtosis            -0.1237985                                            
                                         Uncorrected SS     31750.7028    Corrected SS        31733.9424                                            
                                         Coeff Variation    4357.63905    Std Error Mean      0.51860385                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.220731     Std Deviation            9.61867                                                
                                              Median   1.701746     Variance                92.51878                                                
                                              Mode     7.432365     Range                   54.67437                                                
                                                                    Interquartile Range     14.33341                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
315


CENTANAFADINE                                                                                                               34 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.425626    Pr > |t|    0.6706                                                   
                                                 Sign           M        16    Pr >= |M|   0.0945                                                   
                                                 Signed Rank    S      2217    Pr >= |S|   0.2302                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.977242    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.067652    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.438875    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  2.629038    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
316


CENTANAFADINE                                                                                                               35 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       22.53512                                                                
                                                             99%            18.03788                                                                
                                                             95%            13.41618                                                                
                                                             90%            11.23166                                                                
                                                             75% Q3          7.76020                                                                
                                                             50% Median      1.70175                                                                
                                                             25% Q1         -6.57321                                                                
                                                             10%           -13.76659                                                                
                                                             5%            -16.80512                                                                
                                                             1%            -23.07843                                                                
                                                             0% Min        -32.13925                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
317


CENTANAFADINE                                                                                                               36 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -32.1393   40520100014-
                       1562         17.1124   40520100014-
                       1590           
         -28.7832   40520100014-
                       1691         18.0379   40520100014-
                       1575           
         -24.7266   40520100014-
                       1606         21.5556   40520100014-
                       1707           
         -23.0784   40520100014-
                       1569         22.1875   40520100014-
                       1693           
         -21.5722   40520100014-
                       1663         22.5351   40520100014-
                       1775           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
318


CENTANAFADINE                                                                                                               37 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         344    Sum Weights                344                                            
                                         Mean               0.02322776    Sum Observations    7.99034796                                            
                                         Std Deviation      1.00148516    Variance            1.00297252                                            
                                         Skewness           -0.5068561    Kurtosis            -0.0234398                                            
                                         Uncorrected SS     344.205173    Corrected SS        344.019575                                            
                                         Coeff Variation    4311.58814    Std Error Mean      0.05399646                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.023228     Std Deviation            1.00149                                                
                                              Median   0.176296     Variance                 1.00297                                                
                                              Mode     0.759057     Range                    5.93096                                                
                                                                    Interquartile Range      1.49444                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
319


CENTANAFADINE                                                                                                               38 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.430172    Pr > |t|    0.6673                                                   
                                                 Sign           M        16    Pr >= |M|   0.0945                                                   
                                                 Signed Rank    S      2252    Pr >= |S|   0.2230                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.977591    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.069272    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.428574    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  2.550366    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
320


CENTANAFADINE                                                                                                               39 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       2.378000                                                                
                                                             99%            1.842423                                                                
                                                             95%            1.414009                                                                
                                                             90%            1.195080                                                                
                                                             75% Q3         0.813832                                                                
                                                             50% Median     0.176296                                                                
                                                             25% Q1        -0.680604                                                                
                                                             10%           -1.427671                                                                
                                                             5%            -1.744891                                                                
                                                             1%            -2.358551                                                                
                                                             0% Min        -3.552963                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
321


CENTANAFADINE                                                                                                               40 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=35 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -3.55296   40520100014-
                       1562         1.74930   40520100014-
                      1590           
          -3.06229   40520100014-
                       1691         1.84242   40520100014-
                      1575           
          -2.54111   40520100014-
                       1606         2.22747   40520100014-
                      1707           
          -2.35855   40520100014-
                       1569         2.36251   40520100014-
                      1693           
          -2.26636   40520100014-
                       1663         2.37800   40520100014-
                      1775           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
322


CENTANAFADINE                                                                                                               41 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         338    Sum Weights                338                                            
                                         Mean               0.21994106    Sum Observations    74.3400787                                            
                                         Std Deviation       10.206485    Variance            104.172337                                            
                                         Skewness           -0.4662637    Kurtosis            -0.2816581                                            
                                         Uncorrected SS      35122.428    Corrected SS        35106.0776                                            
                                         Coeff Variation     4640.5546    Std Error Mean       0.5551596                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.219941     Std Deviation           10.20649                                                
                                              Median   2.116541     Variance               104.17234                                                
                                              Mode     7.859023     Range                   51.41794                                                
                                                                    Interquartile Range     14.95136                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
323


CENTANAFADINE                                                                                                               42 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.396176    Pr > |t|    0.6922                                                   
                                                 Sign           M        21    Pr >= |M|   0.0256                                                   
                                                 Signed Rank    S    1936.5    Pr >= |S|   0.2821                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.976668    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.076295    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.500683    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq  2.723085    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
324


CENTANAFADINE                                                                                                               43 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       21.91943                                                                
                                                             99%            20.45404                                                                
                                                             95%            14.85949                                                                
                                                             90%            12.11174                                                                
                                                             75% Q3          7.82680                                                                
                                                             50% Median      2.11654                                                                
                                                             25% Q1         -7.12456                                                                
                                                             10%           -14.10923                                                                
                                                             5%            -18.33244                                                                
                                                             1%            -27.07807                                                                
                                                             0% Min        -29.49851                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
325


CENTANAFADINE                                                                                                               44 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                           Variable:  RESID  (Residual)                                                             
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -29.4985   40520100014-
                       2031         19.4617   40520100014-
                       2128           
         -27.6116   40520100014-
                       1928         20.4540   40520100014-
                       1934           
         -27.3096   40520100014-
                       2099         20.7976   40520100014-
                       2111           
         -27.0781   40520100014-
                       1950         21.6142   40520100014-
                       2033           
         -25.9557   40520100014-
                       2054         21.9194   40520100014-
                       2046           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
326


CENTANAFADINE                                                                                                               45 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                                     Moments                                                                        
                                                                                                                                                    
                                         N                         338    Sum Weights                338                                            
                                         Mean               0.02186339    Sum Observations    7.38982701                                            
                                         Std Deviation      1.00255899    Variance            1.00512453                                            
                                         Skewness           -0.4654092    Kurtosis            -0.2701205                                            
                                         Uncorrected SS     338.888534    Corrected SS        338.726967                                            
                                         Coeff Variation    4585.55983    Std Error Mean      0.05453202                                            
                                                                                                                                                    
                                                                                                                                                    
                                                            Basic Statistical Measures                                                              
                                                                                                                                                    
                                                  Location                    Variability                                                           
                                                                                                                                                    
                                              Mean     0.021863     Std Deviation            1.00256                                                
                                              Median   0.204955     Variance                 1.00512                                                
                                              Mode     0.760366     Range                    5.13076                                                
                                                                    Interquartile Range      1.45333                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
327


CENTANAFADINE                                                                                                               46 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t  0.400928    Pr > |t|    0.6887                                                   
                                                 Sign           M        21    Pr >= |M|   0.0256                                                   
                                                 Signed Rank    S    1930.5    Pr >= |S|   0.2836                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.977218    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.075766    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.494181    Pr > W-Sq  <0.0050                                              
                                            Anderson-Darling      A-Sq   2.68251    Pr > A-Sq  <0.0050                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
328


CENTANAFADINE                                                                                                               47 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       2.170595                                                                
                                                             99%            1.980822                                                                
                                                             95%            1.444907                                                                
                                                             90%            1.182725                                                                
                                                             75% Q3         0.762961                                                                
                                                             50% Median     0.204955                                                                
                                                             25% Q1        -0.690365                                                                
                                                             10%           -1.369158                                                                
                                                             5%            -1.794783                                                                
                                                             1%            -2.635345                                                                
                                                             0% Min        -2.960170                                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
329


CENTANAFADINE                                                                                                               48 OF 48
PROTOCOL 405-201-00014                                                                                                                               
                                                                    STAT-6.1.2                                                                      
                 Residual by Week from Proc Mixed for Change from Baseline in AISRS Total Score, Primary Efficacy Analysis Model                    
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
-------------------------------------------------------------- Analysis Visit (N)=42 --------------------------------------------------------------- 
                                                                                                                                                    
                                                             The UNIVARIATE Procedure                                                               
                                                 Variable:  STUDENTRESID  (Studentized Residual)                                                    
                                                                                                                                                    
                                                               Extreme Observations                                                                 
                                                                                                                                                    
         ---------------------------Lowest---------------------------        ---------------------------Highest--------------------------           
                                                                                                                                                    
            Value   USUBJID                                       Obs           Value   USUBJID                                       Obs           
                                                                                                                                                    
         -2.96017   40520100014
                       2031         1.88413   40520100014-
                       2128           
         -2.72302   40520100014
                       2099         1.98082   40520100014-
                       1934           
         -2.68489   40520100014
                       1928         2.07185   40520100014-
                       2111           
         -2.63534   40520100014
                       1950         2.14336   40520100014-
                       2046           
         -2.54132   40520100014
                       2054         2.17059   40520100014-
                       2033           
                                
                                                                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
---------------------------------------------------------------------------------------------------------------------------------------------------- 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 31AUG2020 08:32                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100014/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
330


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Document Name: P40520100014_DOC_STAT
Document Number: 1000088241
Document Version: 3.0
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yyyy hh:min) -
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Safety Approval
22-Sep-2020
14:15:24
Biostatistics Approval
22-Sep-2020
00:48:53
Clinical Programming
Approval
22-Sep-2020
16:17:04
Clinical Approval
23-Sep-2020
00:10:52
Clinical Study Report 405-201-00014
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
331