Conditions: Attention Deficit Disorder Attention Deficit Hyperactivity Disorder
Keywords: Centanafadine ADHD ADD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 604
Healthy volunteers: no

Brief summary:
This study evaluates the efficacy, safety, and tolerability of centanafadine sustained-release tablets in adults with attention-deficit/hyperactivity disorder (ADHD). Participants will either receive 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 document:
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: 
NCT03605680 
 
Document Date: 
 
Protocol Version 4.0: 15 January 2020 
 
 
 
 
 
 
 
 




Protocol 405-201-00013
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Protocol Synopsis
Name of Sponsor: Otsuka Pharmaceutical
Development & Commercialization, Inc.
Name of Investigational Medicinal Product: 
Centanafadine (EB-1020)
Protocol No.: 405-201-00013
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 405-201-00013)
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.
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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.
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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.
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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.
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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.
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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.
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.
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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.
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.
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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.
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.
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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.
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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 ..................................................................30
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 ................76
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..................................................................................................78
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..................................................................................79
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...............................................................................................................80
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...................................................................................82
9
Records Management.........................................................................82
9.1
Source Documents.............................................................................................82
9.2
Data Collection..................................................................................................82
9.3
File Management at the Trial Site.....................................................................84
9.4
Records Retention at the Trial Site....................................................................84
10
Quality Control and Quality Assurance...........................................84
10.1
Monitoring.........................................................................................................84
10.2
Auditing.............................................................................................................85
11
Ethics and Responsibility...................................................................85
12
Confidentiality ....................................................................................85
13
Amendment Policy..............................................................................86
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 Identifying 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).
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 
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(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.
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.
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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.
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.
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Table 3.4.3-1 Exclusion Criteria
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.
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).
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Table 3.4.3-1 Exclusion Criteria
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 405-201-00013 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 405-201-00013.
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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 
above-mentioned 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 405-201-00013, 
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, LOE, 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 
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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
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.
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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.
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;
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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.
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.
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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 
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.
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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:
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.
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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. 
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)
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
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
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:
at
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.
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8.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
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, 
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contemporaneous, original, and accurate) as paper records. These data will be collected 
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.
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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. 
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.
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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, 
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.
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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 
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.
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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 
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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Health Organization Adult Attention-Deficit/Hyperactivity Disorder Self-Report
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34 Landgraf JM. Monitoring quality of life in adults with ADHD: reliability and validity 
of a new measure. J of Att Dis. 2007;11(3):351–362.
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Validation of the expanded versions of the adult ADHD self-report scale v1.1 
symptom checklist and the adult ADHD investigator symptom rating scale. J Atten 
Disord. 2018:1087054718756198.
36 Srisurapanont M, Jarusuraisin N, Jittiwutikan J. Amphetamine withdrawal: I. 
Reliability, validity and factor structure of a measure. Aust N Z J Psychiatry. 
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The nature, time course and severity of methamphetamine withdrawal. Addiction. 
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39 Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
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Centre for Drug Evaluation and Research. Assessment of Abuse Potential of Drugs. 
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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 
Assoc. 1993;88:125-134.
43 Little RJA. Modeling the drop-out mechanism in repeated measures studies. J Am 
Stat Assoc. 1995;90:1112-1121.
44 Hedeker D, Gibbons RD. Application of random effects pattern-mixture models for 
missing data in longitudinal studies. Psychological Methods. 1997;2:64-78.
45 Ali MW, Siddiqui O. Multiple imputation compared with some information dropout 
procedures in the estimation and comparison of rates of change in longitudinal 
clinical trials with dropouts. J Biopharmaceutical Stats. 2000;10(2):165-181.
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-
955.
47 van Elteren PH. On the combination of independent two sample tests of Wilcoxon. 
Bull Int Stat Inst. 1960;37:351-361.
48 Mehrotra D, Li X, Liu J, Lu K. Analysis of Longitudinal Clinical Trials with Missing 
Data Using Multiple Imputation in Conjunction with Robust Regression. Biometrics. 
2012;68(4):1250-1259.
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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 405-201-00013, 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 405-201-00013.

Revised the last day of subject contact from Day +14 to Day +10 for subjects that 
do not complete Trial 405-201-00013, 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 urine drug screen should include methylphenidate 
(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.
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
Clarified that SMWQ will be completed by the subject at the site and completed 
remotely for non-site visits.

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.
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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 405-201-00013, 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 that some clinical laboratory assessments (alcohol testing) are not 
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 405-201-00013.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
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Protocol 405-201-00013
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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 405-201-00013, 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. 
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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.
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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
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This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 405-201-00013 Protocol Amendment 2
Document Number: 0001281022
Document Version: 5.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Clinical Pharmacology
Approval
15-Jan-2020
21:01:06
Clinical Approval
15-Jan-2020
19:45:13
Biostatistics Approval
15-Jan-2020
20:18:59
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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: 
NCT03605680 
 
Document Date: 
 
SAP Final Version : 27 April 2020 
 
 
 
 
 
 
 
 


Table of Contents
Table of Contents..................................................................................................................... 1
Statistical Analysis Plan; Final: 27 April 2020........................................................................ 3
STAT-1.1 Adjusted Mean Change from Baseline in AISRS Line Items at Day 42 -
MMRM (Efficacy Sample)...................................................................................................... 45
STAT-1.2 Adjusted Mean Change from Baseline in ASRS Line Items at Day 42 - MMRM
(Efficacy Sample).....................................................................................................................50
STAT-3.1 MMRM Output for Test on Treatment by Sex Interaction at Day 42 (Efficacy
Sample).................................................................................................................................... 55
STAT-3.2 MMRM Output for Test on Treatment by Race Interaction at Day 42 (Efficacy
Sample).................................................................................................................................... 83
STAT-4.1.1 Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM
(UN), DDFM=KENWARDROGER (Efficacy Sample)......................................................... 111
STAT-4.1.2 Proc Mixed Output for Change from Baseline in AISRS Total Score, MMRM
(UN), DDFM=SATTERTHWAITE (Efficacy Sample).......................................................... 129
STAT-4.2 Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score,
LOCF (Efficacy Sample)......................................................................................................... 143
STAT-4.3 Proc GLM Output for Change from Baseline to Day 42 in AISRS Total Score,
OC (Efficacy Sample).............................................................................................................. 149
STAT-4.4 Proc GLM Output for Treatment by Center Interaction at Day 42 in AISRS
Total Score, LOCF (Efficacy Sample).....................................................................................155
STAT-4.5.1 Summary of Mean Change at Day 42 from Baseline in AISRS Total Score
By Center - LOCF (Efficacy Sample)......................................................................................157
STAT-4.5.2 Differences in Unadjusted Mean Changes of AISRS Total Score at Day 42
Among Treatment Groups By Center - LOCF (Efficacy Sample).......................................... 161
STAT-4.6 Unadjusted Mean Change from Baseline to Double Blind Treatment Period by
Study Day in AISRS Total Score, LOCF (Efficacy Sample).................................................. 163
STAT-4.7 Unadjusted Mean Change from Baseline to Double Blind Treatment Period by
Study Day in AISRS Total Score, OC (Efficacy Sample)....................................................... 187
STAT-4.8 Non-Parametric Stratified by Center Analysis of Mean Change from Baseline
to Double Blind Treatment Period by Study Day in AISRS Total Score, LOCF (Efficacy
Sample).................................................................................................................................... 211
STAT-4.9 Residual at Day 42 from Proc Mixed for Change from Baseline in AISRS Total
Score, Primary Efficacy Analysis Model (Efficacy Sample)...................................................217
STAT-4.10 Proc Mixed Output Using Heterogeneous Variance Structure for Treatment
Groups (Efficacy Sample)........................................................................................................226
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STAT-5.1 Proc Mixed Output for Change from Baseline in CGI-S Scale, MMRM (UN)
(Efficacy Sample).....................................................................................................................252
STAT-5.2 Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, LOCF
(Efficacy Sample).....................................................................................................................266
STAT-5.3 Proc GLM Output for Change from Baseline to Day 42 in CGI-S Scale, OC
(Efficacy Sample).....................................................................................................................272
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).......... 278
STAT-6.1.2 Residual by Week from Proc Mixed for Change from Baseline in AISRS
Total Score, Primary Efficacy Analysis Model (Efficacy Sample)......................................... 279
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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. 405-201-00013
IND No. 119,361
Statistical Analysis Plan
Version: Final
Date: April 27, 2020
CONFIDENTIAL – PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
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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 405-201-00013. 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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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. Dropout 
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
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 
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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. 
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;
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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.
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) 
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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.
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.
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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 
respective sample sizes of the two groups to compare, Effect Size = d = (LSMean1 –
LSMean2) / σ, where ߪൌ
ୗ୲ୢୣ୰୰
ටభ
೙భାభ
೙మ
.
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 
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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.
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.
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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 
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.
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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 
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
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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.
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 
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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. 
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.
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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.
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 
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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
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 
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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 
(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.
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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 
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.
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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 
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
References
1
Siddiqui O, Hung JHM, O'Neill R. MMRM vs. LOCF:  A comprehensive comparison 
based on simulation study and 25 NDA datasets. J Biopharmaceutical Stats. 2009; 
19(2):227-46.
2
Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis. Applied 
Statistics. 1994; 43:49-93.
3
Little RJA. Pattern-mixture models for multivariate incomplete data. J Am Stat Assoc. 
1993; 88:125-34.
4
Little RJA. Modeling the drop-out mechanism in repeated measures studies. J Am Stat 
Assoc. 1995; 90:1112-21.
5
Hedeker D, Gibbons RD. Application of random effects pattern-mixture models for 
missing data in longitudinal studies. Psychological Methods. 1997; 2:64-78.
6
Ali MW, Siddiqui O. Multiple imputation compared with some information dropout 
procedures in the estimation and comparison of rates of change in longitudinal clinical 
trials with dropouts. J Biopharmaceutical Stats. 2000;10(2):165-81.
7
Wu MC, Bailey KR. Estimation and comparison of changes in the presence of informative 
right censoring:  Conditional linear model. Biometrics. 1989; 45:939-55.
8
van Elteren, PH. On the combination of independent two sample tests of Wilcoxon. Bull 
Int Stat Inst. 1960; 37:351-61.
9
Mehrotra D, Li X, Liu J, Lu K. Analysis of Longitudinal Clinical Trials with Missing 
Data Using Multiple Imputation in Conjunction with Robust Regression. Biometrics 
2012; 68:1250-1259.    
10 Cortina, J. M., & Nouri, H. (2000). Effect size for ANOVA designs. Thousand Oaks, 
Calif.: Sage Publications.
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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-5.2.2   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)
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)
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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)
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)
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
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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)
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)
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
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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)
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)
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
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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)
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)
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
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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)
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)
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
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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)
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)
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
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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 405-201-00013
16.1.9 Documentation of Statistical Methods
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Clinical Approval
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19:49:24
Biostatistics Approval
27-Apr-2020
22:34:44
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
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CENTANAFADINE                                                                                                               2 OF 5
PROTOCOL 405-201-00013                                                                                                                               
                                                                       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       -0.12     0.2531    -0.13           
        CONCENTRATING ON                                                                  PLACEBO                                                    
                                                                                                                                                     
        FEEL RESTLESS OR        147  2.18  -0.47   147  2.20  -0.54   144  2.10  -0.36    EB-1020 200mg VS       -0.10     0.3769    -0.10           
        FIDGETY                                                                           PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.18     0.1134    -0.19           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        TROUBLE WRAPPING UP     147 2.58  -0.69   147  2.52  -0.54   144  2.51  -0.35    EB-1020 200mg VS       -0.34     0.0040    -0.34           
        THE FINAL DETAILS                                                                 PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.19     0.1020    -0.19           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        DIFFICULTY UNWINDING    147  1.84  -0.47   147  1.96  -0.40   144  1.86  -0.39    EB-1020 200mg VS       -0.08     0.4738    -0.08           
        AND RELAXING                                                                      PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.02     0.8874    -0.02           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        DIFFICULTY GETTING      147  2.50  -0.60   147  2.49  -0.64   144  2.47  -0.38    EB-1020 200mg VS       -0.21     0.0691    -0.21           
        THINGS IN ORDER                                                                   PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.26     0.0256    -0.26           
                                                                                          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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
46


CENTANAFADINE                                                                                                              3 OF 5
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       147  2.05  -0.55   147  2.08  -0.55   144  1.93  -0.38    EB-1020 200mg VS       -0.17     0.1608    -0.16           
        COMPELLED TO DO THINGS                                                            PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.17     0.1541    -0.17           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        AVOID OR DELAY          147  2.63  -0.71   147  2.52  -0.55   144  2.65  -0.45    EB-1020 200mg VS       -0.26     0.0348    -0.25           
        GETTING STARTED                                                                   PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.10     0.3848    -0.10           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        TALKING TOO MUCH        147  1.89  -0.62   147  1.75  -0.50   144  1.80  -0.34    EB-1020 200mg VS       -0.27     0.0148    -0.29           
                                                                                          PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.15     0.1649    -0.16           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        MISPLACE OR HAVE        147  2.23  -0.54   147  2.16  -0.49   144  2.35  -0.47    EB-1020 200mg VS       -0.07     0.5480    -0.07           
        DIFFICULTY FINDING                                                                PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.02     0.8648    -0.02           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        FINISHING THE           147  1.89  -0.64   147  1.93  -0.65   144  2.00  -0.53    EB-1020 200mg VS       -0.11     0.3294    -0.11           
        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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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
4 OF 5
PROTOCOL 405-201-00013
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
-0.12
0.2683
-0.13
SENTENCES OF THE
PLACEBO
PEOPLE
BEING DISTRACTED BY
147
2.59
-0.56
147
2.58
-0.55
144
2.59
-0.30
EB-1020 200mg VS
-0.26
0.0229
-0.27
ACTIVITY OR NOISE
PLACEBO
EB-1020 400mg VS
-0.24
0.0311
-0.25
PLACEBO
DIFFICULTY WAITING
147
1.91
-0.39
147
1.99
-0.55
144
1.88
-0.39
EB-1020 200mg VS
-0.01
0.9533
-0.01
YOUR TURN
PLACEBO
EB-1020 400mg VS
-0.16
0.1284
-0.18
PLACEBO
PROBLEMS REMEMBERING
147
2.13
-0.54
147
2.18
-0.77
144
2.26
-0.63
EB-1020 200mg VS
0.09
0.4350
0.09
PLACEBO
EB-1020 400mg VS
-0.14
0.2301
-0.14
PLACEBO
INTERRUPT OTHERS WHEN
147
1.69
-0.62
147
1.82
-0.58
144
1.80
-0.54
EB-1020 200mg VS
-0.08
0.4580
-0.09
THEY ARE BUSY
PLACEBO
EB-1020 400mg VS
-0.04
0.7183
-0.04
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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/aisrs_item.sas
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 5
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       147 39.60  -10.1   147 39.56  -9.73   144 39.53  -6.98    EB-1020 200mg VS       -3.15     0.0193    -0.28           
        (DERIVED)                                                                         PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -2.74     0.0392    -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_itema.lis, RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 5
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      118  3.11  -0.56   127  3.18  -0.56   131  3.10  -0.31    EB-1020 200mg VS       -0.26     0.0490    -0.25           
        WITH HANDS/FEET                                                                   PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.25     0.0497    -0.25           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-FEEL OVERLY        118  2.58  -0.56   127  2.76  -0.72   131  2.66 -0.35    EB-1020 200mg VS       -0.20     0.1266    -0.19           
        ACTIVE TO DO THINGS                                                               PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.37     0.0047    -0.35           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-MAKE CARELESS      118  2.98  -0.65   127  2.72  -0.67   131  2.97  -0.38    EB-1020 200mg VS       -0.26     0.0357    -0.27           
        MISTAKES                                                                          PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.29     0.0216    -0.29           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-DIFFICULTY         118  3.45  -0.61   127  3.36  -0.66   131  3.32  -0.37    EB-1020 200mg VS       -0.24     0.0717    -0.23           
        KEEPING ATTENTION                                                                 PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.29     0.0235    -0.28           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-DIFFICULTY         118  3.02  -0.80   127  3.09  -0.80   131  3.12  -0.47    EB-1020 200mg VS       -0.33     0.0129    -0.32           
        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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 5
PROTOCOL 405-201-00013                                                                                                                               
                                                                       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       -0.33     0.0107    -0.32           
        KEEPING CONCENTRATION                                                             PLACEBO                                                    
                                                                                                                                                     
        ASRS-MISPLACE/DIFFICUL  118  3.05  -0.63   127  2.98  -0.69   131  3.07  -0.50    EB-1020 200mg VS       -0.13     0.3334    -0.12           
        TY FINDING THINGS                                                                 PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.19     0.1470    -0.18           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-DISTRACTED BY      118  3.25  -0.63   127  3.28  -0.61   131  3.30  -0.28    EB-1020 200mg VS       -0.35     0.0130    -0.32           
        ACTIVITY OR NOISE                                                                 PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.32     0.0184    -0.29           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-LEAVE SEAT IN      118  2.26  -0.59   127  2.14  -0.70   131  2.02  -0.32    EB-1020 200mg VS       -0.27     0.0307    -0.28           
        MEETNGS/ORDR SITUATNS                                                             PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.39     0.0015    -0.40           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-FEELING RESTLESS   118 2.97  -0.56   127  3.02  -0.68   131  2.98  -0.34    EB-1020 200mg VS       -0.22     0.0909    -0.22           
        OR FIDGETY                                                                        PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.34     0.0093    -0.33           
                                                                                          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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 5
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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     118 2.60  -0.55   127  2.91  -0.55   131  2.76  -0.32    EB-1020 200mg VS       -0.23     0.0946    -0.21           
        AND RELAXING                                                                      PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.23     0.0835    -0.22           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-FIND YOURSELF      118  2.64  -0.70   127  2.59  -0.68   131  2.66  -0.38    EB-1020 200mg VS       -0.32     0.0170    -0.30           
        TALKING TOO MUCH                                                                  PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.29     0.0251    -0.28           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-FINISH SENTENCES   118  2.70  -0.78   127  2.66  -0.78   131  2.73  -0.50    EB-1020 200mg VS       -0.28     0.0417    -0.26           
        OF PEOPLE                                                                         PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.28     0.0405    -0.26           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-DIFFCULTY          118  2.57  -0.60   127  2.65  -0.82   131  2.44  -0.40    EB-1020 200mg VS       -0.20     0.1576    -0.18           
        WAITING YOUR TURN                                                                 PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -0.42     0.0028    -0.38           
                                                                                          PLACEBO                                                    
                                                                                                                                                     
        ASRS-INTERRUPT OTHERS   118  2.46  -0.82   127  2.48  -0.81   131  2.46  -0.62    EB-1020 200mg VS       -0.20     0.1216    -0.20           
        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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 5
PROTOCOL 405-201-00013                                                                                                                               
                                                                       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       -0.19     0.1325    -0.19           
        WHEN THEY ARE BUSY                                                                PLACEBO                                                    
                                                                                                                                                     
        ASRS TOTAL SCORE OF     118 52.22  -11.3   127 52.06  -12.0   131 51.67  -6.70    EB-1020 200mg VS       -4.60     0.0062    -0.35           
        18 ITEMS (DERIVED)                                                                PLACEBO                                                    
                                                                                          EB-1020 400mg VS       -5.28     0.0014    -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_itemb.lis, RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/aisrs_item.sas                                                              
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-1.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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         438   
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                              6 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                                                         
                                                                                                                                                    
                                               SEX              2    F M                                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                   Dimensions                                                                       
                                                                                                                                                    
                                                       Covariance Parameters            21                                                          
                                                       Columns in X                    128                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        438                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2292                                                      
                                                   Number of Observations Used            2292                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      STAT-3.1                                                                       
                                           MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                 (Efficacy Sample)                                                                   
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
------------------------------------------------------------- Parameter Code=AISRSTOT --------------------------------------------------------------
                                                                                                                                                     
                                                                The Mixed Procedure                                                                  
                                                                                                                                                     
                                                                 Iteration History                                                                   
                                                                                                                                                     
                                            Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                     
                                                    0              1     16471.93771301                                                              
                                                    1              2     14206.06433817      0.00014910                                              
                                                    2              1     14205.26506836      0.00000141                                              
                                                    3              1     14205.25788280      0.00000000                                              
                                                                                                                                                     
                                                                                                                                                     
                                                            Convergence criteria met.                                                               
                                                                                                                                                     
                                                                                                                                                     
                                                          Covariance Parameter Estimates                                                             
                                                                                                                                                     
                                                          Cov Parm    Subject    Estimate                                                            
                                                                                                                                                     
                                                          UN(1,1)     SUBJID      52.3976                                                            
                                                          UN(2,1)     SUBJID      40.2284                                                            
                                                          UN(2,2)     SUBJID      72.6755                                                            
                                                          UN(3,1)     SUBJID      38.1964                                                            
                                                          UN(3,2)     SUBJID      62.4528                                                            
                                                          UN(3,3)     SUBJID      81.8612                                                            
                                                          UN(4,1)     SUBJID      37.6894                                                            
                                                          UN(4,2)     SUBJID      63.0768                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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(4,3)     SUBJID      77.7325                                                            
                                                         UN(4,4)     SUBJID       105.92                                                            
                                                         UN(5,1)     SUBJID      38.4856                                                            
                                                         UN(5,2)     SUBJID      63.7432                                                            
                                                         UN(5,3)     SUBJID      81.2609                                                            
                                                         UN(5,4)     SUBJID      96.6536                                                            
                                                         UN(5,5)     SUBJID       111.49                                                            
                                                         UN(6,1)     SUBJID      38.7755                                                            
                                                         UN(6,2)     SUBJID      64.7203                                                            
                                                         UN(6,3)     SUBJID      79.0855                                                            
                                                         UN(6,4)     SUBJID      96.9247                                                            
                                                         UN(6,5)     SUBJID      99.9728                                                            
                                                         UN(6,6)     SUBJID       118.03                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood         14205.3                                                         
                                                      AIC (Smaller is Better)       14247.3                                                         
                                                      AICC (Smaller is Better)      14247.7                                                         
                                                      BIC (Smaller is Better)       14333.0                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      STAT-3.1                                                                       
                                           MMRM Output for Test on Treatment by Sex Interaction at Day 42                                            
                                                                 (Efficacy Sample)                                                                   
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
------------------------------------------------------------- Parameter Code=AISRSTOT --------------------------------------------------------------
                                                                                                                                                     
                                                                The Mixed Procedure                                                                  
                                                                                                                                                     
                                                          Null Model Likelihood Ratio Test                                                           
                                                                                                                                                     
                                                            DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                     
                                                            20       2266.68          <.0001                                                         
                                                                                                                                                     
                                                                                                                                                     
                                                           Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                     
                                                                     Num     Den                                                                     
                                               Effect                 DF      DF    F Value    Pr > F                                                
                                                                                                                                                     
                                               POOLCNTR               37     393       2.24    <.0001                                                
                                               AVISITN                 5     377       2.31    0.0434                                                
                                               TRTPN                   2     396       3.03    0.0495                                                
                                               AVISITN*TRTPN          10     558       1.63    0.0954                                                
                                               SEX                     1     412       0.02    0.8821                                                
                                               AVISITN*SEX             5     376       1.58    0.1649                                                
                                               TRTPN*SEX               2     408       0.17    0.8404                                                
                                               AVISITN*TRTPN*SEX      10     558       0.54    0.8603                                                
                                               BASE*AVISITN            6     402       2.38    0.0287                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                         
                                                                                                                                                    
                                      Intercept          
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                      POOLCNTR           
                                                                                    
                                                         
                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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             
                                                                                     
                                      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                                                           
                                      AVISITN*TRTPN                         21          3                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               15 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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          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                                                                      
                                      AVISITN*SEX                    M      28                                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               16 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      35                                                                      
                                       AVISITN*SEX                    M      35                                                                      
                                       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                                                           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               17 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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          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                                                           
                                      AVISITN*TRTPN*SEX              M      35          2                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               18 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      35          3                                                           
                                       AVISITN*TRTPN*SEX              M      35          3                                                           
                                       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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               19 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               20 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               21 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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            
                                                                                     
                                      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                                                           
                                      AVISITN*TRTPN                         21          3                                                           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               22 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                         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                                                                      
                                       AVISITN*SEX                    M      28                                                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               23 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                    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                                                           
                                       AVISITN*TRTPN*SEX              F      14          2                                                           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               24 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      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                                                           
                                       AVISITN*TRTPN*SEX              M      35          2                                                           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               25 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               26 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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    0.008634      2.7164     405       0.00      0.9975                                    
                                 2 vs. 3 BY SEX AT DAY 42      1.0223      2.7042     403       0.38      0.7056                                    
                                                                                                                                                    
                                                                                                                                                    
                                                               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             -5.5125      0.9145     398      -6.03      <.0001      0.05     -7.3104     -3.7146      
    AVISITN*TRTPN*SEX    M       7          1             -5.4466      0.9030     402      -6.03      <.0001      0.05     -7.2219     -3.6713      
    AVISITN*TRTPN*SEX    F       7          2             -3.7780      0.9336     400      -4.05      <.0001      0.05     -5.6133     -1.9427      
    AVISITN*TRTPN*SEX    M       7          2             -4.3169      0.9075     402      -4.76      <.0001      0.05     -6.1010     -2.5329      
    AVISITN*TRTPN*SEX    F       7          3             -5.2355      0.9157     396      -5.72      <.0001      0.05     -7.0357     -3.4352      
    AVISITN*TRTPN*SEX    M       7          3             -3.0663      0.9328     400      -3.29      0.0011      0.05     -4.9001     -1.2324      
    AVISITN*TRTPN*SEX    F      14          1             -7.9530      1.0866     431      -7.32      <.0001      0.05    -10.0887     -5.8173      
    AVISITN*TRTPN*SEX    M      14          1             -6.9443      1.0453     415      -6.64      <.0001      0.05     -8.9991     -4.8895      
    AVISITN*TRTPN*SEX    F      14          2             -6.6749      1.0980     431      -6.08      <.0001      0.05     -8.8330     -4.5169      
    AVISITN*TRTPN*SEX    M      14          2             -6.7586      1.0477     416      -6.45      <.0001      0.05     -8.8180     -4.6993      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               27 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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             -7.0864      1.0693     422      -6.63      <.0001      0.05     -9.1883     -4.9846      
     AVISITN*TRTPN*SEX    M      14          3             -5.8234      1.0854     422      -5.37      <.0001      0.05     -7.9569     -3.6899      
     AVISITN*TRTPN*SEX    F      21          1             -8.8044      1.1479     418      -7.67      <.0001      0.05    -11.0608     -6.5480      
     AVISITN*TRTPN*SEX    M      21          1             -8.1444      1.1330     432      -7.19      <.0001      0.05    -10.3713     -5.9176      
     AVISITN*TRTPN*SEX    F      21          2             -8.2616      1.1716     434      -7.05      <.0001      0.05    -10.5644     -5.9589      
     AVISITN*TRTPN*SEX    M      21          2             -8.3214      1.1086     410      -7.51      <.0001      0.05    -10.5007     -6.1422      
     AVISITN*TRTPN*SEX    F      21          3             -6.5243      1.1292     415      -5.78      <.0001      0.05     -8.7439     -4.3047      
     AVISITN*TRTPN*SEX    M      21          3             -6.5280      1.1518     416      -5.67      <.0001      0.05     -8.7920     -4.2640      
     AVISITN*TRTPN*SEX    F      28          1             -9.7129      1.3221     429      -7.35      <.0001      0.05    -12.3114     -7.1143      
     AVISITN*TRTPN*SEX    M      28          1             -9.5818      1.2976     433      -7.38      <.0001      0.05    -12.1321     -7.0315      
     AVISITN*TRTPN*SEX    F      28          2             -8.5617      1.3340     435      -6.42      <.0001      0.05    -11.1835     -5.9398      
     AVISITN*TRTPN*SEX    M      28          2            -10.5997      1.2679     423      -8.36      <.0001      0.05    -13.0919     -8.1075      
     AVISITN*TRTPN*SEX    F      28          3             -5.7966      1.2745     413      -4.55      <.0001      0.05     -8.3020     -3.2913      
     AVISITN*TRTPN*SEX    M      28          3             -6.8225      1.3154     423      -5.19      <.0001      0.05     -9.4081     -4.2369      
     AVISITN*TRTPN*SEX    F      35          1            -10.3738      1.3557     421      -7.65      <.0001      0.05    -13.0386     -7.7090      
     AVISITN*TRTPN*SEX    M      35          1            -10.1739      1.3368     429      -7.61      <.0001      0.05    -12.8014     -7.5463      
     AVISITN*TRTPN*SEX    F      35          2            -10.6335      1.3813     440      -7.70      <.0001      0.05    -13.3484     -7.9187      
     AVISITN*TRTPN*SEX    M      35          2            -10.7772      1.3026     417      -8.27      <.0001      0.05    -13.3378     -8.2166      
     AVISITN*TRTPN*SEX    F      35          3             -7.3509      1.3131     412      -5.60      <.0001      0.05     -9.9321     -4.7697      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               28 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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             -7.0325      1.3507     417      -5.21      <.0001      0.05     -9.6875     -4.3774      
    AVISITN*TRTPN*SEX    F      42          1            -10.3674      1.4025     421      -7.39      <.0001      0.05    -13.1242     -7.6106      
     AVISITN*TRTPN*SEX    M      42          1             -9.9078      1.3872     433      -7.14      <.0001      0.05    -12.6343     -7.1814      
     AVISITN*TRTPN*SEX    F      42          2             -9.4500      1.4201     434      -6.65      <.0001      0.05    -12.2411     -6.6589      
     AVISITN*TRTPN*SEX    M      42          2            -10.0041      1.3380     410      -7.48      <.0001      0.05    -12.6344     -7.3738      
     AVISITN*TRTPN*SEX    F      42          3             -7.2141      1.3547     411      -5.33      <.0001      0.05     -9.8771     -4.5510      
     AVISITN*TRTPN*SEX    M      42          3             -6.7459      1.3983     419      -4.82      <.0001      0.05     -9.4945     -3.9972      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2a.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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         438  
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                   
                                               
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                                                         
                                                                                                                                                    
                                               RACEGRP          2    All Other Races White                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                   Dimensions                                                                       
                                                                                                                                                    
                                                       Covariance Parameters            21                                                          
                                                       Columns in X                    128                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        438                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2292                                                      
                                                   Number of Observations Used            2292                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      STAT-3.2                                                                       
                                          MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                 (Efficacy Sample)                                                                   
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
------------------------------------------------------------- Parameter Code=AISRSTOT --------------------------------------------------------------
                                                                                                                                                     
                                                                The Mixed Procedure                                                                  
                                                                                                                                                     
                                                                 Iteration History                                                                   
                                                                                                                                                    
                                            Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                     
                                                    0              1     16457.56446856                                                              
                                                    1              2     14194.15343914      0.00015243                                              
                                                    2              1     14193.34064068      0.00000121                                              
                                                    3              1     14193.33447925      0.00000000                                              
                                                                                                                                                     
                                                                                                                                                     
                                                             Convergence criteria met.                                                               
                                                                                                                                                     
                                                                                                                                                     
                                                          Covariance Parameter Estimates                                                             
                                                                                                                                                     
                                                          Cov Parm    Subject    Estimate                                                            
                                                                                                                                                     
                                                          UN(1,1)     SUBJID      52.6274                                                            
                                                          UN(2,1)     SUBJID      40.2457                                                            
                                                          UN(2,2)     SUBJID      72.4424                                                            
                                                          UN(3,1)     SUBJID      37.9044                                                            
                                                          UN(3,2)     SUBJID      62.1116                                                            
                                                          UN(3,3)     SUBJID      81.4367                                                            
                                                          UN(4,1)     SUBJID      37.1824                                                            
                                                          UN(4,2)     SUBJID      62.6074                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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(4,3)     SUBJID      77.2494                                                            
                                                          UN(4,4)     SUBJID       105.45                                                            
                                                          UN(5,1)     SUBJID      38.0335                                                            
                                                          UN(5,2)     SUBJID      63.1832                                                            
                                                          UN(5,3)     SUBJID      80.6593                                                            
                                                          UN(5,4)     SUBJID      95.9188                                                            
                                                          UN(5,5)     SUBJID       110.56                                                            
                                                          UN(6,1)     SUBJID      38.5893                                                            
                                                         UN(6,2)     SUBJID      64.3249                                                            
                                                          UN(6,3)     SUBJID      78.5308                                                            
                                                          UN(6,4)     SUBJID      96.2386                                                            
                                                          UN(6,5)     SUBJID      99.4627                                                            
                                                          UN(6,6)     SUBJID       117.27                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                  Fit Statistics                                                                     
                                                                                                                                                     
                                                       -2 Res Log Likelihood         14193.3                                                         
                                                       AIC (Smaller is Better)       14235.3                                                         
                                                       AICC (Smaller is Better)      14235.8                                                         
                                                       BIC (Smaller is Better)       14321.1                                                         
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     STAT-3.2                                                                       
                                         MMRM Output for Test on Treatment by Race Interaction at Day 42                                            
                                                                (Efficacy Sample)                                                                   
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
------------------------------------------------------------- Parameter Code=AISRSTOT --------------------------------------------------------------
                                                                                                                                                    
                                                               The Mixed Procedure                                                                  
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           20       2264.23          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                          Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                    
                                                                     Num     Den                                                                    
                                            Effect                    DF      DF    F Value    Pr > F                                               
                                                                                                                                                    
                                            POOLCNTR                  37     393       2.25    <.0001                                               
                                            AVISITN                    5     377       1.96    0.0837                                               
                                            TRTPN                      2     402       2.69    0.0690                                               
                                            AVISITN*TRTPN             10     559       1.68    0.0821                                               
                                            RACEGRP                    1     415       1.14    0.2857                                               
                                            AVISITN*RACEGRP            5     376       1.25    0.2836                                               
                                            TRTPN*RACEGRP              2     410       0.44    0.6436                                               
                                            AVISIT*TRTPN*RACEGRP      10     559       1.01    0.4349                                               
                                            BASE*AVISITN               6     402       2.39    0.0280                                               
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                 
                                                                                                                                                     
                                Intercept              
                                                                                         
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                POOLCNTR              
                                                                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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               
                                                                                         
                               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                                                   
                               AVISITN*TRTPN                                        21          3                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               15 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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          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                                                              
                               AVISITN*RACEGRP                   White              28                                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               16 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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    35                                                              
                                AVISITN*RACEGRP                   White              35                                                              
                                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                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               17 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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          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                                                   
                               AVISIT*TRTPN*RACEGRP              White              35          2                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               18 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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    35          3                                                   
                               AVISIT*TRTPN*RACEGRP              White              35          3                                                   
                               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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               19 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                              20 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               21 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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               
                                                                                         
                                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                                                   
                                AVISITN*TRTPN                                        21          3                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               22 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                        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                                                              
                               AVISITN*RACEGRP                   White              28                                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               23 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                   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                                                   
                                AVISIT*TRTPN*RACEGRP              All Other Races    14          2                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               24 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              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                                                   
                               AVISIT*TRTPN*RACEGRP              White              35          2                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               25 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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    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: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               26 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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     -4.2107      3.6531     413      -1.15      0.2497                                  
                               2 vs. 3 BY RACEGRP AT DAY 42     -4.6414      3.5664     405      -1.30      0.1939                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                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            -5.4070     1.4741    402     -3.67     0.0003     0.05    -8.3049    -2.5092    
   AVISIT*TRTPN*RACEGRP   White              7         1            -5.5130     0.7191    401     -7.67     <.0001     0.05    -6.9267    -4.0993    
   AVISIT*TRTPN*RACEGRP   All Other Races    7         2            -5.5362     1.4286    409     -3.88     0.0001     0.05    -8.3446    -2.7278    
   AVISIT*TRTPN*RACEGRP   White              7         2            -3.6971     0.7401    399     -5.00     <.0001     0.05    -5.1521    -2.2421    
   AVISIT*TRTPN*RACEGRP   All Other Races    7         3            -4.4167     1.6472    402     -2.68     0.0076     0.05    -7.6548    -1.1786    
   AVISIT*TRTPN*RACEGRP   White              7         3            -4.1607     0.7267    399     -5.73     <.0001     0.05    -5.5893    -2.7320    
   AVISIT*TRTPN*RACEGRP   All Other Races   14         1            -9.1406     1.7282    425     -5.29     <.0001     0.05   -12.5375    -5.7437    
   AVISIT*TRTPN*RACEGRP   White             14         1            -7.0447     0.8377    421     -8.41     <.0001     0.05    -8.6913    -5.3981    
   AVISIT*TRTPN*RACEGRP   All Other Races   14         2            -7.7555     1.6612    425     -4.67     <.0001     0.05   -11.0208    -4.4903    
   AVISIT*TRTPN*RACEGRP   White             14         2            -6.4603     0.8573    427     -7.54     <.0001     0.05    -8.1453    -4.7753    
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               27 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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            -6.8926     1.8839    401     -3.66     0.0003     0.05   -10.5961    -3.1891    
   AVISIT*TRTPN*RACEGRP   White             14         3            -6.4045     0.8426    433     -7.60     <.0001     0.05    -8.0607    -4.7484    
   AVISIT*TRTPN*RACEGRP   All Other Races   21         1            -9.1324     1.8815    447     -4.85     <.0001     0.05   -12.8302    -5.4346    
   AVISIT*TRTPN*RACEGRP   White             21         1            -8.3083     0.8926    424     -9.31     <.0001     0.05   -10.0626    -6.5539    
   AVISIT*TRTPN*RACEGRP   All Other Races   21         2            -9.6889     1.7502    409     -5.54     <.0001     0.05   -13.1294    -6.2483    
   AVISIT*TRTPN*RACEGRP   White             21         2            -7.9419     0.9105    430     -8.72     <.0001     0.05    -9.7315    -6.1523    
   AVISIT*TRTPN*RACEGRP   All Other Races   21         3            -6.4777     2.0044    400     -3.23     0.0013     0.05   -10.4181    -2.5374    
   AVISIT*TRTPN*RACEGRP   White             21         3            -6.5518     0.8889    429     -7.37     <.0001     0.05    -8.2989    -4.8047    
   AVISIT*TRTPN*RACEGRP   All Other Races   28         1           -11.3582     2.1608    444     -5.26     <.0001     0.05   -15.6049    -7.1116    
   AVISIT*TRTPN*RACEGRP   White             28         1            -9.2681     1.0250    433     -9.04     <.0001     0.05   -11.2826    -7.2535    
   AVISIT*TRTPN*RACEGRP   All Other Races   28        2           -12.7159     1.9930    408     -6.38     <.0001     0.05   -16.6337    -8.7982    
   AVISIT*TRTPN*RACEGRP   White             28         2            -8.7879     1.0386    442     -8.46     <.0001     0.05   -10.8291    -6.7467    
   AVISIT*TRTPN*RACEGRP   All Other Races   28         3            -5.5914     2.3069    414     -2.42     0.0158     0.05   -10.1261    -1.0567    
   AVISIT*TRTPN*RACEGRP   White             28         3            -6.4036     1.0037    428     -6.38     <.0001     0.05    -8.3764    -4.4308    
   AVISIT*TRTPN*RACEGRP   All Other Races   35         1           -11.5318     2.2200    440     -5.19     <.0001     0.05   -15.8948    -7.1687    
   AVISIT*TRTPN*RACEGRP   White             35         1            -9.9860     1.0509    427     -9.50     <.0001     0.05   -12.0515    -7.9204    
   AVISIT*TRTPN*RACEGRP   All Other Races   35         2           -13.1394     2.0655    417     -6.36     <.0001     0.05   -17.1995    -9.0793    
   AVISIT*TRTPN*RACEGRP   White             35         2           -10.0665     1.0666    439     -9.44     <.0001     0.05   -12.1627    -7.9703    
   AVISIT*TRTPN*RACEGRP   All Other Races   35         3            -8.4240     2.3575    405     -3.57     0.0004     0.05   -13.0585    -3.7896    
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               28 OF 28
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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            -6.9780     1.0307    426     -6.77     <.0001     0.05    -9.0039    -4.9521    
   AVISIT*TRTPN*RACEGRP   All Other Races   42         1           -11.5976     2.2803    430     -5.09     <.0001     0.05   -16.0795    -7.1158    
   AVISIT*TRTPN*RACEGRP   White             42         1            -9.8108     1.0918    431     -8.99     <.0001     0.05   -11.9568    -7.6648    
   AVISIT*TRTPN*RACEGRP   All Other Races   42         2           -11.4938     2.1175    406     -5.43     <.0001     0.05   -15.6564    -7.3313    
   AVISIT*TRTPN*RACEGRP   White             42         2            -9.2764     1.0974    433     -8.45     <.0001     0.05   -11.4333    -7.1195    
   AVISIT*TRTPN*RACEGRP   All Other Races   42         3            -4.9221     2.4639    416     -2.00     0.0464     0.05    -9.7653   -0.07897    
   AVISIT*TRTPN*RACEGRP   White             42         3            -7.3460     1.0634    424     -6.91     <.0001     0.05    -9.4363    -5.2558    
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: stat2b.lis, RUN: 18JUN2020 10:01; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                    
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat2.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-3.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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         438   
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                     
                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                     72                                                          
                                                        Columns in Z                     0                                                          
                                                        Subjects                        438                                                          
                                                        Max Obs per Subject               6                                                          
                                                                                                                                                     
                                                                                                                                                    
                                                              Number of Observations                                                                 
                                                                                                                                                     
                                                    Number of Observations Read            2292                                                      
                                                    Number of Observations Used            2292                                                      
                                                    Number of Observations Not Used           0                                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                 Iteration History                                                                   
                                                                                                                                                     
                                            Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                     
                                                    0              1     16529.25629156                                                              
                                                    1              2     14254.41720522      0.00013099                                              
                                                    2              1     14253.71654441      0.00000106                                              
                                                    3              1     14253.71110309      0.00000000                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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      52.4121                                                            
                                                         UN(2,1)     SUBJID      40.1625                                                            
                                                         UN(2,2)     SUBJID      72.3841                                                            
                                                         UN(3,1)     SUBJID      37.8797                                                            
                                                         UN(3,2)     SUBJID      62.0385                                                            
                                                         UN(3,3)     SUBJID      81.2283                                                            
                                                         UN(4,1)     SUBJID      37.2709                                                            
                                                         UN(4,2)     SUBJID      62.5977                                                            
                                                         UN(4,3)     SUBJID      77.1568                                                            
                                                         UN(4,4)     SUBJID       105.57                                                            
                                                         UN(5,1)     SUBJID      38.1278                                                            
                                                         UN(5,2)     SUBJID      63.2146                                                            
                                                         UN(5,3)     SUBJID      80.4768                                                            
                                                         UN(5,4)     SUBJID      95.8339                                                            
                                                         UN(5,5)     SUBJID       110.37                                                            
                                                         UN(6,1)     SUBJID      38.5259                                                            
                                                         UN(6,2)     SUBJID      64.2868                                                            
                                                         UN(6,3)     SUBJID      78.4374                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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      96.1387                                                            
                                                          UN(6,5)     SUBJID      99.0726                                                            
                                                          UN(6,6)     SUBJID       117.05                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                  Fit Statistics                                                                     
                                                                                                                                                     
                                                       -2 Res Log Likelihood         14253.7                                                         
                                                       AIC (Smaller is Better)       14295.7                                                         
                                                       AICC (Smaller is Better)      14296.1                                                         
                                                       BIC (Smaller is Better)       14381.4                                                         
                                                                                                                                                     
                                                                                                                                                     
                                                          Null Model Likelihood Ratio Test                                                           
                                                                                                                                                     
                                                            DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                     
                                                            20       2275.55          <.0001                                                         
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                             0.4831      4.8082     567       0.10      0.9200                        
                      AVISITN                     7                        -0.7357      2.9385     398      -0.25      0.8024                        
                      AVISITN                    14                        -0.8075      2.4473     388      -0.33      0.7416                        
                      AVISITN                    21                        -2.8674      2.0446     361      -1.40      0.1616                        
                      AVISITN                    28                         2.9224      1.7765     345       1.64      0.1009                        
                      AVISITN                    35                         0.5711      1.7576     352       0.32      0.7454                        
                     AVISITN                    42                              0                                                                   
                      TRTPN                                  1             -3.1497      1.3407     400     -2.35      0.0193                        
                      TRTPN                                  2             -2.7448      1.3267     392      -2.07      0.0392                        
                      TRTPN                                  3                   0                                                                   
                      AVISITN*TRTPN               7          1              1.8448      1.2086     398       1.53      0.1277                        
                      AVISITN*TRTPN               7          2              2.8699      1.1928     393       2.41      0.0166                        
                      AVISITN*TRTPN               7          3                   0                                                                   
                      AVISITN*TRTPN              14          1              2.1849      1.0072     387       2.17      0.0307                        
                      AVISITN*TRTPN              14          2              2.4905      0.9856     382       2.53      0.0119                        
                      AVISITN*TRTPN              14          3                   0                                                                   
                      AVISITN*TRTPN              21          1              1.2025      0.8417     362       1.43      0.1540                        
                      AVISITN*TRTPN              21          2              0.9723      0.8240     360       1.18      0.2388                        
                      AVISITN*TRTPN              21          3                   0                                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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             -0.2340      0.7283     342      -0.32      0.7481                        
                     AVISITN*TRTPN              28          2             -0.6011      0.7150     343      -0.84      0.4011                        
                     AVISITN*TRTPN              28          3                   0                                                                   
                     AVISITN*TRTPN              35          1             0.07206      0.7186     348       0.10      0.9202                        
                     AVISITN*TRTPN              35          2             -0.7607      0.7085     349      -1.07      0.2837                        
                     AVISITN*TRTPN              35          3                   0                                                                   
                     AVISITN*TRTPN              42          1                   0                                                                   
                     AVISITN*TRTPN              42          2                   0                                                                   
                     AVISITN*TRTPN   
      42          3                   0                                                                   
                     POOLCNTR        
                               -1.5781      3.9342     391      -0.40      0.6885                        
                     POOLCNTR        
                               -1.0310      3.8358     391      -0.27      0.7882                        
                     POOLCNTR        
                               -2.1594      3.9655     391      -0.54      0.5864                        
                     POOLCNTR        
                               -1.5289      3.7488     393      -0.41      0.6836                        
                     POOLCNTR        
                               -1.5067      3.8012     392      -0.40      0.6920                        
                     POOLCNTR        
                               -2.4888      4.2744     391      -0.58      0.5607                        
                     POOLCNTR        
                               -8.3662      4.3446     393      -1.93      0.0549                        
                     POOLCNTR        
                               -6.3243      5.3927     393      -1.17      0.2416                        
                     POOLCNTR        
                               -5.4404      3.9685     392      -1.37      0.1712                        
                     POOLCNTR        
                               -1.9497      4.7926     406      -0.41      0.6844                        
                                     
                                                                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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        
                               -3.3328      3.7186     392      -0.90      0.3707                        
                      POOLCNTR        
                               -5.6893      4.1349     391      -1.38      0.1696                        
                      POOLCNTR        
                                0.8859      4.2071     397       0.21      0.8333                        
                      POOLCNTR        
                               -3.4584      4.1907     393      -0.83      0.4097                        
                      POOLCNTR        
                               -2.1719      4.2744     391      -0.51      0.6117                        
                      POOLCNTR        
                               -3.4300      4.7326     392      -0.72      0.4690                        
                      POOLCNTR        
                               -3.1079      3.9681     391      -0.78      0.4340                        
                      POOLCNTR        
                               -4.5105      4.3481     391      -1.04      0.3002                        
                      POOLCNTR        
                               -0.4554      5.3811     393      -0.08      0.9326                        
                      POOLCNTR        
                               -1.5914      4.4306     394      -0.36      0.7197                        
                      POOLCNTR        
                               -5.6339      5.0120     390      -1.12      0.2617                        
                      POOLCNTR        
                                0.2294      4.7268     391       0.05      0.9613                        
                      POOLCNTR        
                               -1.1086      4.7948     392      -0.23      0.8173                        
                      POOLCNTR        
                               -3.8392      4.5625     394      -0.84      0.4006                        
                      POOLCNTR        
                               -1.8688      3.8721     393      -0.48      0.6296                        
                      POOLCNTR        
                               -4.7987      4.2584     393      -1.13      0.2605                        
                      POOLCNTR        
                               -4.5967      4.1713     391      -1.10      0.2712                        
                      POOLCNTR        
                               -4.0969      4.7405    397      -0.86      0.3880                        
                      POOLCNTR        
                              -12.4605      3.8212     392      -3.26      0.0012                        
                                      
                                                                                                         
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       
                                 2.2378      5.3865     390       0.42      0.6780                        
                      POOLCNTR       
                                 3.2557      4.5695     390       0.71      0.4766                        
                      POOLCNTR       
                                -2.8411      4.9870     390      -0.57      0.5692                        
                      POOLCNTR       
                                -2.4274      5.0523     397      -0.48      0.6312                        
                      POOLCNTR       
                                -1.0008      3.9085     391      -0.26      0.7980                        
                      POOLCNTR       
                                -5.1075      3.8314     391      -1.33      0.1833                        
                      POOLCNTR       
                                -1.5870      4.9866     392      -0.32      0.7505                        
                      POOLCNTR       
                                -1.6255      4.9908     392      -0.33      0.7448                        
                      POOLCNTR       
                                      0                                                                   
                      BASE*AVISITN                7                       -0.02833     0.06074     406      -0.47      0.6411                        
                      BASE*AVISITN               14                       -0.08413     0.06890     455      -1.22      0.2227                        
                      BASE*AVISITN               21                       -0.03354     0.07241     456      -0.46      0.6434                        
                      BASE*AVISITN               28                        -0.1732     0.08145     469      -2.13      0.0340                        
                      BASE*AVISITN               35                        -0.1373     0.08324     466      -1.65      0.0998                        
                      BASE*AVISITN               42                        -0.1177     0.08570     465      -1.37      0.1704                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               15 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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     380       2.06    0.0694                                                  
                                                TRTPN               2     400       3.05    0.0482                                                  
                                                AVISITN*TRTPN      10     563       1.68    0.0815                                                  
                                                POOLCNTR           37     396       2.25    <.0001                                                  
                                                BASE*AVISITN        6     405       2.18    0.0443                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                   Standard                                                                                         
                      Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                       
                                                                                                                                                    
                      DAY7  1 vs 3      -1.3049      0.8584     396      -1.52      0.1292      0.05     -2.9924      0.3826                        
                      DAY7  2 vs 3       0.1251      0.8581     396       0.15      0.8841      0.05     -1.5618      1.8121                        
                       DAY14  1 vs 3     -0.9648      1.0193     403      -0.95      0.3444      0.05     -2.9686      1.0390                        
                       DAY14  2 vs 3     -0.2542      1.0168     400      -0.25      0.8027      0.05     -2.2531      1.7446                        
                       DAY21  1 vs 3     -1.9472      1.0892     398      -1.79      0.0746      0.05     -4.0885      0.1941                        
                       DAY21  2 vs 3     -1.7725      1.0824     391      -1.64      0.1023      0.05     -3.9006      0.3556                        
                       DAY28  1 vs 3     -3.3837      1.2590     401      -2.69      0.0075      0.05     -5.8587     -0.9087                        
                       DAY28  2 vs 3     -3.3458      1.2483     395      -2.68      0.0077      0.05     -5.8000     -0.8917                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               16 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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     -3.0776      1.2921     398      -2.38      0.0177      0.05     -5.6178     -0.5375                        
                       DAY35  2 vs 3     -3.5055      1.2838     394      -2.73      0.0066      0.05     -6.0294     -0.9816                        
                       DAY42  1 vs 3     -3.1497      1.3407     400      -2.35      0.0193      0.05     -5.7855     -0.5139                        
                       DAY42  2 vs 3     -2.7448      1.3267     392      -2.07      0.0392      0.05     -5.3532     -0.1364                        
                                                                                                                                                     
                                                                                                                                                     
                                                                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             -5.4832      0.6575     405      -8.34      <.0001      0.05     -6.7757     -4.1907            
          AVISITN*TRTPN     7          2             -4.0531      0.6710     406      -6.04      <.0001      0.05     -5.3721     -2.7341            
          AVISITN*TRTPN     7          3             -4.1783      0.6708     402      -6.23      <.0001      0.05     -5.4970     -2.8596            
          AVISITN*TRTPN    14          1             -7.4261      0.7642     431      -9.72      <.0001      0.05     -8.9281     -5.9242            
          AVISITN*TRTPN    14          2             -6.7156      0.7740     436      -8.68      <.0001      0.05     -8.2368     -5.1943            
          AVISITN*TRTPN    14          3             -6.4613      0.7759     437      -8.33      <.0001      0.05     -7.9862     -4.9364            
          AVISITN*TRTPN    21          1             -8.4638      0.8150     436     -10.39      <.0001      0.05    -10.0655     -6.8620            
          AVISITN*TRTPN    21          2             -8.2891      0.8186     436     -10.13      <.0001      0.05     -9.8980     -6.6801            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               17 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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             -6.5166      0.8184     435      -7.96      <.0001      0.05     -8.1251     -4.9080            
          AVISITN*TRTPN    28          1             -9.6450      0.9350     444     -10.32      <.0001      0.05    -11.4825     -7.8075            
          AVISITN*TRTPN    28          2             -9.6071      0.9317     446     -10.31      <.0001      0.05    -11.4382     -7.7761            
          AVISITN*TRTPN    28          3             -6.2613      0.9266     437      -6.76      <.0001      0.05     -8.0825     -4.4401            
          AVISITN*TRTPN    35          1            -10.2665      0.9572     438     -10.73      <.0001      0.05    -12.1478     -8.3852            
          AVISITN*TRTPN    35          2            -10.6944      0.9567     446     -11.18      <.0001      0.05    -12.5746     -8.8143            
          AVISITN*TRTPN    35          3             -7.1889      0.9493     434      -7.57      <.0001      0.05     -9.0547     -5.3231            
          AVISITN*TRTPN    42          1            -10.1321      0.9918     440     -10.22      <.0001      0.05    -12.0814     -8.1829            
          AVISITN*TRTPN    42          2             -9.7272      0.9830     439      -9.89      <.0001      0.05   -11.6593     -7.7951            
          AVISITN*TRTPN    42          3             -6.9824      0.9807     436      -7.12      <.0001      0.05     -8.9099     -5.0549            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               18 OF 18
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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     397       1.71    0.1821                                            
                                          AVISITN*TRTPN    14             2     402       0.48    0.6181                                            
                                          AVISITN*TRTPN    21             2     397       1.97    0.1409                                            
                                          AVISITN*TRTPN    28             2     400       4.82    0.0085                                            
                                          AVISITN*TRTPN    35             2     399       4.44    0.0124                                            
                                          AVISITN*TRTPN    42             2     398       3.30    0.0377                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1aa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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         438  
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                   
                                                
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                     72                                                          
                                                        Columns in Z                      0                                                          
                                                       Subjects                        438                                                          
                                                        Max Obs per Subject               6                                                          
                                                                                                                                                     
                                                                                                                                                     
                                                              Number of Observations                                                                 
                                                                                                                                                     
                                                    Number of Observations Read            2292                                                      
                                                    Number of Observations Used            2292                                                      
                                                    Number of Observations Not Used           0                                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                 Iteration History                                                                   
                                                                                                                                                     
                                            Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                     
                                                    0              1     16529.25629156                                                              
                                                    1              2     14254.41720522      0.00013099                                              
                                                    2              1     14253.71654441      0.00000106                                              
                                                    3              1     14253.71110309      0.00000000                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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      52.4121                                                            
                                                          UN(2,1)     SUBJID      40.1625                                                            
                                                          UN(2,2)     SUBJID      72.3841                                                            
                                                          UN(3,1)     SUBJID      37.8797                                                            
                                                          UN(3,2)     SUBJID      62.0385                                                            
                                                          UN(3,3)     SUBJID      81.2283                                                            
                                                          UN(4,1)     SUBJID      37.2709                                                            
                                                          UN(4,2)     SUBJID      62.5977                                                            
                                                          UN(4,3)     SUBJID      77.1568                                                            
                                                          UN(4,4)     SUBJID       105.57                                                            
                                                          UN(5,1)     SUBJID      38.1278                                                            
                                                          UN(5,2)     SUBJID      63.2146                                                            
                                                          UN(5,3)     SUBJID      80.4768                                                            
                                                          UN(5,4)     SUBJID      95.8339                                                            
                                                          UN(5,5)     SUBJID       110.37                                                            
                                                          UN(6,1)     SUBJID      38.5259                                                            
                                                          UN(6,2)     SUBJID      64.2868                                                            
                                                          UN(6,3)     SUBJID      78.4374                                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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      96.1387                                                            
                                                         UN(6,5)     SUBJID      99.0726                                                            
                                                         UN(6,6)     SUBJID       117.05                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood         14253.7                                                         
                                                      AIC (Smaller is Better)       14295.7                                                         
                                                      AICC (Smaller is Better)      14296.1                                                         
                                                      BIC (Smaller is Better)       14381.4                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           20       2275.55          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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     384       2.09    0.0662                                                  
                                                TRTPN               2     400       3.06    0.0482                                                  
                                                AVISITN*TRTPN      10     396       1.71    0.0774                                                  
                                                POOLCNTR           37     396       2.31    <.0001                                                  
                                                BASE*AVISITN        6     404       2.21    0.0415                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                    Estimates                                                                       
                                                                                                                                                    
                                                   Standard                                                                                         
                      Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                        
                                                                                                                                                    
                      DAY7  1 vs 3      -1.3049      0.8582     396      -1.52      0.1291      0.05     -2.9920      0.3822                        
                      DAY7  2 vs 3       0.1251      0.8578     396       0.15      0.8841      0.05     -1.5614      1.8116                        
                       DAY14  1 vs 3     -0.9648      1.0190     403      -0.95      0.3443      0.05     -2.9680      1.0384                        
                       DAY14  2 vs 3     -0.2542      1.0165     400      -0.25      0.8026      0.05     -2.2526      1.7442                        
                       DAY21  1 vs 3     -1.9472      1.0889     398      -1.79      0.0745      0.05     -4.0879      0.1935                        
                       DAY21  2 vs 3     -1.7725      1.0822     391      -1.64      0.1022      0.05     -3.9001      0.3551                        
                       DAY28  1 vs 3     -3.3837      1.2584     401      -2.69      0.0075      0.05     -5.8576     -0.9098                        
                       DAY28  2 vs 3     -3.3458      1.2478     395      -2.68      0.0076      0.05     -5.7990     -0.8927                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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     -3.0776      1.2914     398      -2.38      0.0176      0.05     -5.6164     -0.5389                        
                       DAY35  2 vs 3     -3.5055      1.2831     394      -2.73      0.0066      0.05     -6.0281     -0.9829                        
                       DAY42  1 vs 3     -3.1497      1.3398     400      -2.35      0.0192      0.05     -5.7836     -0.5158                        
                       DAY42  2 vs 3     -2.7448      1.3259     392      -2.07      0.0391      0.05     -5.3516     -0.1379                        
                                                                                                                                                     
                                                                                                                                                     
                                                                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             -5.4832      0.6561     405      -8.36      <.0001      0.05     -6.7731     -4.1934            
          AVISITN*TRTPN     7          2             -4.0531      0.6693     406      -6.06      <.0001      0.05     -5.3688     -2.7374            
          AVISITN*TRTPN     7          3             -4.1783      0.6693     402      -6.24      <.0001      0.05     -5.4940     -2.8626            
          AVISITN*TRTPN    14          1             -7.4261      0.7629     431      -9.73      <.0001      0.05     -8.9256     -5.9266            
          AVISITN*TRTPN    14          2             -6.7156      0.7725     436      -8.69      <.0001      0.05     -8.2339     -5.1972            
          AVISITN*TRTPN    14          3             -6.4613      0.7745     437      -8.34      <.0001      0.05     -7.9835     -4.9392            
          AVISITN*TRTPN    21          1             -8.4638      0.8137     436     -10.40      <.0001      0.05    -10.0631     -6.8645            
          AVISITN*TRTPN    21          2             -8.2891      0.8172     436     -10.14      <.0001      0.05     -9.8952     -6.6829            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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             -6.5166      0.8171     435      -7.98      <.0001      0.05     -8.1225     -4.9107            
          AVISITN*TRTPN    28          1             -9.6450      0.9336     444     -10.33      <.0001      0.05    -11.4799     -7.8102            
          AVISITN*TRTPN    28          2             -9.6071      0.9302     446     -10.33      <.0001      0.05    -11.4353     -7.7790            
          AVISITN*TRTPN    28          3             -6.2613      0.9253     437      -6.77      <.0001      0.05     -8.0799     -4.4427            
          AVISITN*TRTPN    35          1            -10.2665      0.9558     438     -10.74      <.0001      0.05    -12.1451     -8.3880            
          AVISITN*TRTPN    35          2            -10.6944      0.9551     446     -11.20      <.0001      0.05    -12.5714     -8.8175            
          AVISITN*TRTPN    35          3             -7.1889      0.9479     434      -7.58      <.0001      0.05     -9.0520     -5.3258            
          AVISITN*TRTPN    42          1            -10.1321      0.9902     440     -10.23      <.0001      0.05    -12.0783     -8.1860            
          AVISITN*TRTPN    42          2             -9.7272      0.9815     439      -9.91      <.0001      0.05    -11.6561     -7.7983            
          AVISITN*TRTPN    42          3             -6.9824      0.9792     436      -7.13      <.0001      0.05     -8.9069     -5.0579            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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     397       1.71    0.1819                                            
                                          AVISITN*TRTPN    14             2     402       0.48    0.6179                                            
                                          AVISITN*TRTPN    21             2     397       1.97    0.1407                                            
                                          AVISITN*TRTPN    28             2     400       4.83    0.0085                                            
                                          AVISITN*TRTPN    35             2     399       4.44    0.0124                                            
                                          AVISITN*TRTPN    42             2     398       3.31    0.0376                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1ab.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                 
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                              2 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                       40      7613.60524       190.34013       1.72    0.0053                                  
                                                                                                                                                    
                               Error                      397     43878.35138       110.52481                                                       
                                                                                                                                                    
                               Corrected Total            437     51491.95662                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.147860     -115.4357      10.51308     -9.107306                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2      612.642653      306.321327       2.77    0.0638                                  
                               POOLCNTR                    37     5773.449566      156.039177       1.41    0.0603                                  
                               BASE                         1      231.354002      231.354002       2.09    0.1487                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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            147      -9.97278912       11.8933305       39.5986395       6.69354613                                 
                                2            147      -9.85714286       10.3632649       39.5646259       6.81664766                                 
                                3            144      -7.45833333       10.0959557       39.5347222       7.19840036                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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         -10.0466880       0.9524391      <.0001           1                                             
                                          2          -9.5942969       0.9741456      <.0001           2                                             
                                          3          -7.3212133       0.9759953      <.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                      0.7141        0.0284                                                    
                                                      2        0.7141                      0.0674                                                    
                                                      3        0.0284        0.0674                                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                 TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                     
                                                 1          -10.046688      -11.919143    -8.174233                                                  
                                                 2           -9.594297      -11.509426    -7.679168                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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           -7.321213       -9.239979    -5.402448                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for Effect TRTPN                                                         
                                                                                                                                                    
                                                           Difference                                                                               
                                                              Between    95% Confidence Limits for                                                  
                                               i    j           Means       LSMean(i)-LSMean(j)                                                     
                                                                                                                                                    
                                               1    2       -0.452391       -2.877963     1.973180                                                  
                                                1    3       -2.725475       -5.161161    -0.289788                                                  
                                                2    3       -2.273084       -4.709885     0.163718                                                  
                                                                                                                                                     
                                                                                                                                                     
NOTE: To ensure overall protection level, only probabilities associated with pre-planned comparisons should be used.                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                   -2.72547476      1.23893152      -2.20      0.0284                                      
                                   2 vs 3                   -2.27308361      1.23949880      -1.83      0.0674                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1b.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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      1840.15567       613.38522       5.36    0.0012                                  
                                                                                                                                                    
                               Error                      434     49651.80095       114.40507                                                       
                                                                                                                                                    
                               Corrected Total            437     51491.95662                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.035737     -117.4445      10.69603     -9.107306                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2      578.702364      289.351182       2.53    0.0809                                  
                               BASE                         1     1255.840210     1255.840210      10.98    0.0010                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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            147      -9.97278912       11.8933305       39.5986395       6.69354613                                 
                                2            147      -9.85714286       10.3632649       39.5646259       6.81664766                                 
                                3            144      -7.45833333       10.0959557       39.5347222       7.19840036                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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         -9.96480823      0.88219703      <.0001           1                                             
                                          2         -9.85753273      0.88219375      <.0001           2                                             
                                          3         -7.46608250      0.89133895      <.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                      0.9315        0.0469                                                    
                                                      2       0.9315                      0.0572                                                    
                                                      3        0.0469        0.0572                                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                 TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                     
                                                 1           -9.964808      -11.698718    -8.230898                                                  
                                                 2           -9.857533      -11.591436    -8.123629                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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           -7.466082       -9.217960    -5.714205                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                        Least Squares Means for Effect TRTPN                                                         
                                                                                                                                                     
                                                            Difference                                                                               
                                                               Between    95% Confidence Limits for                                                  
                                                i    j           Means       LSMean(i)-LSMean(j)                                                     
                                                                                                                                                     
                                                1    2       -0.107275       -2.559390     2.344839                                                  
                                                1    3       -2.498726       -4.963591    -0.033860                                                  
                                                2    3       -2.391450       -4.856302     0.073402                                                  
                                                                                                                                                     
                                                                                                                                                     
NOTE: To ensure overall protection level, only probabilities associated with pre-planned comparisons should be used.                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                   -2.49872573      1.25410047      -1.99      0.0469                                      
                                   2 vs 3                   -2.39145023      1.25409345      -1.91      0.0572                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1c.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 2
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                      114     17280.04047       151.57930       1.43    0.0080                                  
                                                                                                                                                     
                                Error                      323     34211.91615       105.91925                                                       
                                                                                                                                                     
                                Corrected Total            437     51491.95662                                                                       
                                                                                                                                                     
                                                                                                                                                     
                                                 R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.335587     -113.0050      10.29171     -9.107306                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2      316.610526      158.305263       1.49    0.2259                                  
                               POOLCNTR                    37     5824.724354      157.424983       1.49    0.0390                                  
                               TRTPN*POOLCNTR              74     9666.435233      130.627503       1.23    0.1128                                  
                               BASE                         1      244.872536      244.872536       2.31    0.1294                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMCNTR; TABLE: stat1d.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.4      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 4
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
      
------------------------------------------------------------------------------------------------------------------------------          
     
                    4  -9.58 (5.15)     4  -8.41 (5.15)     3  -11.5 (5.97)  CTN SR 200MG VS. PLACEBO     1.87 (-13.6, 17.36)           
      
                                                                             CTN SR 400MG VS. PLACEBO     3.05 (-12.5, 18.60)           
      
                    4  -9.37 (5.15)     2  -8.00 (7.31)     4  -0.58 (5.15)  CTN SR 200MG VS. PLACEBO    -8.79 (-23.1,  5.54)           
      
                                                                             CTN SR 400MG VS. PLACEBO    -7.42 (-25.0, 10.15)           
      
                    4  -11.1 (5.15)     3  -12.6 (5.95)     3  -0.13 (5.94)  CTN SR 200MG VS. PLACEBO    -11.0 (-26.4,  4.51)           
      
                                                                             CTN SR 400MG VS. PLACEBO    -12.5 (-29.1,  4.01)           
      
                    3  0.78 (5.95)      3  -12.8 (5.99)     3  -2.84 (5.94)  CTN SR 200MG VS. PLACEBO     3.62 (-12.9, 20.16)           
      
                                                                             CTN SR 400MG VS. PLACEBO    -9.99 (-26.6,  6.59)           
      
                    2  -16.7 (7.32)     2  -2.53 (7.40)     1  -0.23 (10.3)  CTN SR 200MG VS. PLACEBO    -16.5 (-41.3,  8.32)           
      
                                                                             CTN SR 400MG VS. PLACEBO    -2.31 (-27.2, 22.60)           
      
                    5  -4.09 (4.61)     6  -14.0 (4.25)     4  -9.65 (5.15)  CTN SR 200MG VS. PLACEBO     5.57 (-8.02, 19.16)           
      
                                                                             CTN SR 400MG VS. PLACEBO    -4.37 (-17.5,  8.75)           
      
                    3  -7.50 (5.97)     2  -8.00 (7.28)     3  -16.5 (5.94)  CTN SR 200MG VS. PLACEBO     8.96 (-7.59, 25.51)           
      
                                                                             CTN SR 400MG VS. PLACEBO     8.46 (-10.0, 26.94)           
      
                    1  2.20 (10.3)      1  -21.1 (10.3)    1  -1.51 (10.3)  CTN SR 200MG VS. PLACEBO     3.71 (-24.9, 32.35)           
      
                                                                             CTN SR 400MG VS. PLACEBO    -19.6 (-48.2,  9.07)           
      
                    2  -7.22 (7.28)     2  -18.1 (7.29)     3  -17.8 (5.94)  CTN SR 200MG VS. PLACEBO    10.62 (-7.87, 29.12)           
      
                                                                             CTN SR 400MG VS. PLACEBO    -0.24 (-18.7, 18.25)           
      
                    2  -29.1 (7.30)     1  0.50 (10.3)      1  -3.51 (10.3)  CTN SR 200MG VS. PLACEBO    -25.6 (-50.5, -0.77)           
      
                                                                             CTN SR 400MG VS. PLACEBO     4.01 (-24.7, 32.67)           
      
                    2  -7.87 (7.28)     1  5.06 (10.3)      2  0.77 (7.28)   CTN SR 200MG VS. PLACEBO    -8.64 (-28.9, 11.60)           
      
                                                                             CTN SR 400MG VS. PLACEBO     4.29 (-20.5, 29.09)           
      
                    2  -0.78 (7.37)     2  -8.14 (7.33)     1  -1.66 (10.3)  CTN SR 200MG VS. PLACEBO     0.88 (-24.1, 25.87)           
      
                                                                             CTN SR 400MG VS. PLACEBO    -6.48 (-31.4, 18.46)           
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 4
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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           
       
------------------------------------------------------------------------------------------------------------------------------          
       
                    2  -20.1 (7.29)     2  -12.2 (7.28)     2  1.85 (7.28)   CTN SR 200MG VS. PLACEBO    -21.9 (-42.2, -1.68)           
       
                                                                             CTN SR 400MG VS. PLACEBO    -14.0 (-34.2,  6.25)           
       
                    7  -14.7 (3.91)     8  -5.20 (3.65)     7  -6.89 (3.90)  CTN SR 200MG VS. PLACEBO    -7.81 (-18.6,  3.01)           
       
                                                                             CTN SR 400MG VS. PLACEBO     1.69 (-8.79, 12.17)           
       
                    3  -19.3 (5.96)     4  -11.7 (5.15)     2  -6.87 (7.28)  CTN SR 200MG VS. PLACEBO    -12.4 (-31.0,  6.09)           
       
                                                                             CTN SR 400MG VS. PLACEBO    -4.85 (-22.4, 12.69)           
       
                    3  -11.0 (5.98)     4  -7.26 (5.15)     3  -15.9 (5.96)  CTN SR 200MG VS. PLACEBO     4.95 (-11.6, 21.49)           
       
                                                                             CTN SR 400MG VS. PLACEBO     8.69 (-6.80, 24.17)           
       
                    1  -15.5 (10.3)     2  -11.0 (7.34)     2  -15.2 (7.32)  CTN SR 200MG VS. PLACEBO    -0.28 (-25.1, 24.54)           
       
                                                                             CTN SR 400MG VS. PLACEBO     4.28 (-16.0, 24.53)           
       
                    9  -26.4 (3.52)    13  -14.5 (2.95)    12  -14.1 (3.10)  CTN SR 200MG VS. PLACEBO    -12.3 (-21.2, -3.37)           
       
                                                                             CTN SR 400MG VS. PLACEBO    -0.42 (-8.53,  7.69)           
       
                    1  -5.95 (10.3)     1  -2.53 (10.3)     1  4.62 (10.3)   CTN SR 200MG VS. PLACEBO    -10.6 (-39.2, 18.07)           
       
                                                                             CTN SR 400MG VS. PLACEBO    -7.14 (-35.8, 21.49)           
       
                    2  -1.93 (7.31)     2  2.70 (7.30)      2  -1.58 (7.28)  CTN SR 200MG VS. PLACEBO    -0.35 (-20.6, 19.91)           
       
                                                                             CTN SR 400MG VS. PLACEBO     4.27 (-16.0, 24.58)           
       
                    1  -10.1 (10.3)     2  -15.2 (7.28)     1  -10.2 (10.3)  CTN SR 200MG VS. PLACEBO     0.16 (-28.5, 28.83)           
       
                                                                             CTN SR 400MG VS. PLACEBO    -4.99 (-29.8, 19.84)           
       
                    2  -21.0 (7.28)     1  -2.64 (10.3)     1  -0.78 (10.3)  CTN SR 200MG VS. PLACEBO    -20.2 (-45.0,  4.59)           
       
                                                                             CTN SR 400MG VS. PLACEBO    -1.86 (-30.5, 26.78)           
       
                    6  -4.42 (4.22)     6  -3.87 (4.20)     6  -8.94 (4.20)  CTN SR 200MG VS. PLACEBO     4.52 (-7.22, 16.25)           
       
                                                                             CTN SR 400MG VS. PLACEBO     5.07 (-6.62, 16.76)           
       
                    7  -2.82 (3.89)     7  -9.31 (3.92)     8  -8.44 (3.66)  CTN SR 200MG VS. PLACEBO     5.63 (-4.86, 16.11)           
       
                                                                             CTN SR 400MG VS. PLACEBO    -0.87 (-11.4,  9.61)           
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 4
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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           
        
-----------------------------------------------------------------------------------------------------------------------          
       
            2  1.21 (7.28)      1  -14.2 (10.3)     1  -12.9 (10.3)  CTN SR 200MG VS. PLACEBO   14.16 (-10.7, 39.00)           
       
                                                                     CTN SR 400MG VS. PLACEBO    -1.29 (-29.9, 27.35)           
       
            2  -12.5 (7.29)     1  -1.36 (10.3)     1  -10.5 (10.3)  CTN SR 200MG VS. PLACEBO    -2.01 (-26.8, 22.82)           
       
                                                                     CTN SR 400MG VS. PLACEBO     9.14 (-19.5, 37.78)           
       
            1  -23.9 (10.3)     1  -1.23 (10.3)     2  -6.52 (7.31)  CTN SR 200MG VS. PLACEBO    -17.4 (-42.2,  7.37)           
       
                                                                     CTN SR 400MG VS. PLACEBO     5.29 (-19.5, 30.11)           
        
                                                                                                                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.1      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 2
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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      9    -27.56  13    -15.62  12    -15.42             -12.14              -0.20                  
               
               USA      2     -7.50   2    -17.50   3    -17.67              10.17               0.17                  
               
               USA      7    -15.29   8     -5.63   7     -7.29              -8.00               1.66                  
               
               USA     11    -14.18  11     -4.00  10     -6.30              -7.88               2.30                  
               
               USA      2    -30.00   1      0.00   1     -3.00             -27.00               3.00                  
               
               USA      1      3.00   1    -24.00   1    -28.00              31.00               4.00                  
               
               USA      2     -7.50   1      5.00   2      1.00              -8.50               4.00                  
               
               USA      4     -9.75   4     -8.00   3    -12.33               2.58               4.33                  
               
               USA      7     -7.71   8     -1.75   8     -6.13              -1.59               4.38                  
               
               USA      1    -15.00   2     -9.50   2    -14.00             -1.00               4.50                  
               
               USA      1    -23.00   1     -1.00   2     -5.50             -17.50               4.50                  
               
               USA      6     -3.83   6     -4.00   6     -9.17               5.33               5.17                  
               
               USA      2     -3.00   2      3.50   2     -2.00              -1.00               5.50                  
               
               USA      3    -10.00   4     -7.25   3    -15.33               5.33               8.08                  
               
               USA      3     -8.33   2     -8.50   3    -16.67               8.33               8.17                  
               
               USA      2    -12.00   1     -2.00   1    -11.00              -1.00               9.00                  
               
                                                                                                                       
                
                                                                                                                       
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                                   
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/center.sas                                                                  
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.5.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       142       141       1.45    0.0287                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              147     -7.7823      9.5684      0.7892    -41.0000      7.0000                                    
                                   3              144     -6.9167      8.7909      0.7326    -36.0000      8.0000                                    
                                   Diff (1-2)             -0.8656      9.1919      1.0777                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                               -7.7823     -9.3420  -6.2226      9.5684      8.5855  10.8076                             
                          3                               -6.9167     -8.3647  -5.4686      8.7909      7.8794   9.9427                             
                           Diff (1-2)    Pooled            -0.8656     -2.9869   1.2556      9.1919      8.4998  10.0078                             
                           Diff (1-2)    Satterthwaite     -0.8656     -2.9850   1.2537                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -0.80      0.4225                                              
                                            Satterthwaite    Unequal      287.82      -0.80      0.4221                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       146       143       1.18    0.3099                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              147     -8.5714      9.5530      0.7879    -40.0000      7.0000                                    
                                   3              144     -6.9792      8.8929      0.7411    -39.0000      7.0000                                    
                                   Diff (1-2)             -1.5923      9.2323      1.0825                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                               -8.5714    -10.1286  -7.0142      9.5530      8.5717  10.7901                             
                           3                               -6.9792     -8.4440  -5.5143      8.8929      7.9708  10.0581                             
                           Diff (1-2)    Pooled            -1.5923     -3.7228   0.5383      9.2323      8.5371  10.0517                             
                           Diff (1-2)    Satterthwaite     -1.5923     -3.7212   0.5367                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -1.47      0.1424                                              
                                            Satterthwaite    Unequal      288.25      -1.47      0.1421                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       146       143       1.15    0.3909                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              147     -9.5578     11.2318      0.9264    -47.0000      8.0000                                    
                                   3              144     -6.8611      9.5972      0.7998    -50.0000     10.0000                                    
                                   Diff (1-2)             -2.6967     10.4550      1.2258                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                               -9.5578    -11.3887  -7.7270     11.2318     10.0780  12.6863                             
                           3                               -6.8611     -8.4420  -5.2802      9.5972      8.6021  10.8547                             
                           Diff (1-2)    Pooled            -2.6967     -5.1094  -0.2840     10.4550      9.6677  11.3829                             
                           Diff (1-2)    Satterthwaite     -2.6967     -5.1057  -0.2877                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -2.20      0.0286                                              
                                            Satterthwaite    Unequal      283.79      -2.20      0.0284                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       146       143       1.37    0.0599                                                   
                                                                                                                                                     
                                                                                                                                                    
                                                                                                                                                     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              147    -10.0816     11.1358      0.9185    -46.0000      7.0000                                    
                                  3              144     -7.5694     10.1545      0.8462    -41.0000     11.0000                                    
                                   Diff (1-2)             -2.5122     10.6616      1.2501                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                              -10.0816    -11.8968  -8.2664     11.1358      9.9919  12.5779                             
                           3                               -7.5694     -9.2421  -5.8967     10.1545      9.1016  11.4850                             
                           Diff (1-2)    Pooled            -2.5122     -4.9725  -0.0518     10.6616      9.8587  11.6079                             
                           Diff (1-2)    Satterthwaite     -2.5122     -4.9703  -0.0541                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -2.01      0.0454                                              
                                            Satterthwaite    Unequal      287.53      -2.01      0.0452                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       146       143       1.20    0.2691                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              147     -9.9728     11.8933      0.9809    -47.0000      7.0000                                    
                                   3              144     -7.4583     10.0960      0.8413    -50.0000      9.0000                                    
                                   Diff (1-2)             -2.5145     11.0406      1.2945                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                               -9.9728    -11.9115  -8.0341     11.8933     10.6716  13.4335                             
                           3                               -7.4583     -9.1214  -5.7953     10.0960      9.0492  11.4188                             
                          Diff (1-2)    Pooled            -2.5145     -5.0623   0.0334     11.0406     10.2092  12.0205                             
                           Diff (1-2)    Satterthwaite     -2.5145     -5.0582   0.0293                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -1.94      0.0531                                              
                                            Satterthwaite    Unequal      283.29      -1.95      0.0527                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       146       143       1.39    0.0500                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              144     -4.7569      7.1088      0.5924    -29.0000     11.0000                                    
                                   3              142     -4.8169      7.2284      0.6066    -32.0000      7.0000                                    
                                   Diff (1-2)              0.0600      7.1684      0.8478                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                               -4.7569     -5.9279  -3.5860      7.1088      6.3717   8.0402                             
                           3                               -4.8169     -6.0161  -3.6177      7.2284      6.4742   8.1831                             
                           Diff (1-2)    Pooled             0.0600     -1.6088   1.7287      7.1684      6.6243   7.8108                             
                           Diff (1-2)    Satterthwaite      0.0600     -1.6090   1.7289                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           284       0.07      0.9437                                              
                                            Satterthwaite    Unequal      283.73       0.07      0.9437                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       141       143       1.03    0.8423                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               15 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              147     -7.2245      8.6395      0.7126    -42.0000     11.0000                                    
                                   3              144     -6.9167      8.7909      0.7326    -36.0000      8.0000                                    
                                   Diff (1-2)             -0.3078      8.7147      1.0218                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                               -7.2245     -8.6328  -5.8162      8.6395      7.7520   9.7583                             
                           3                               -6.9167     -8.3647  -5.4686      8.7909      7.8794   9.9427                             
                           Diff (1-2)    Pooled            -0.3078     -2.3189   1.7033      8.7147      8.0585   9.4882                             
                           Diff (1-2)    Satterthwaite     -0.3078     -2.3193   1.7036                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -0.30      0.7634                                              
                                            Satterthwaite    Unequal      288.58      -0.30      0.7635                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               16 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       143       146       1.04    0.8344                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               17 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              147     -8.6871      9.4643      0.7806    -41.0000     10.0000                                    
                                   3              144     -6.9792      8.8929      0.7411    -39.0000      7.0000                                    
                                   Diff (1-2)             -1.7079      9.1860      1.0770                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                               -8.6871    -10.2298  -7.1443      9.4643      8.4920  10.6899                             
                           3                               -6.9792     -8.4440  -5.5143      8.8929      7.9708  10.0581                             
                           Diff (1-2)    Pooled            -1.7079     -3.8277   0.4119      9.1860      8.4943  10.0013                             
                           Diff (1-2)    Satterthwaite     -1.7079     -3.8264   0.4106                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -1.59      0.1139                                              
                                            Satterthwaite    Unequal       288.5      -1.59      0.1137                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               18 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       146       143       1.13    0.4555                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               19 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              147     -9.7143     10.6179      0.8757    -41.0000     10.0000                                    
                                   3              144     -6.8611      9.5972      0.7998    -50.0000     10.0000                                    
                                   Diff (1-2)             -2.8532     10.1257      1.1872                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                               -9.7143    -11.4451  -7.9835     10.6179      9.5272  11.9929                             
                           3                               -6.8611     -8.4420  -5.2802      9.5972      8.6021  10.8547                             
                           Diff (1-2)    Pooled            -2.8532     -5.1899  -0.5165     10.1257      9.3632  11.0244                             
                           Diff (1-2)    Satterthwaite     -2.8532     -5.1875  -0.5188                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -2.40      0.0169                                              
                                            Satterthwaite    Unequal      287.16      -2.41      0.0168                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               20 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       146       143       1.22    0.2260                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                              21 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              147    -10.6327     11.0094      0.9080    -43.0000     10.0000                                    
                                  3              144     -7.5694     10.1545      0.8462    -41.0000     11.0000                                    
                                   Diff (1-2)             -3.0632     10.5950      1.2422                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                              -10.6327    -12.4273  -8.8381     11.0094      9.8784  12.4351                             
                           3                               -7.5694     -9.2421  -5.8967     10.1545      9.1016  11.4850                             
                           Diff (1-2)    Pooled            -3.0632     -5.5082  -0.6182     10.5950      9.7972  11.5354                             
                           Diff (1-2)    Satterthwaite     -3.0632     -5.5062  -0.6202                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -2.47      0.0142                                              
                                            Satterthwaite    Unequal      287.96      -2.47      0.0142                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               22 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       146       143       1.18    0.3328                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               23 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              147     -9.8571     10.3633      0.8547    -38.0000     10.0000                                    
                                   3              144     -7.4583     10.0960      0.8413    -50.0000     9.0000                                    
                                   Diff (1-2)             -2.3988     10.2319      1.1997                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                               -9.8571    -11.5464  -8.1679     10.3633      9.2987  11.7053                             
                           3                               -7.4583     -9.1214  -5.7953     10.0960      9.0492  11.4188                             
                           Diff (1-2)    Pooled            -2.3988     -4.7600  -0.0376     10.2319      9.4614  11.1400                             
                           Diff (1-2)    Satterthwaite     -2.3988     -4.7594  -0.0383                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           289      -2.00      0.0465                                              
                                            Satterthwaite    Unequal      288.99      -2.00      0.0464                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               24 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       146       143       1.05    0.7543                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTLOCF; TABLE: stat1h.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.6      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      142       141       1.45    0.0287                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              133     -7.9699      9.5932      0.8318    -41.0000      7.0000                                    
                                   3              136     -7.0588      8.9648      0.7687    -36.0000      8.0000                                    
                                   Diff (1-2)             -0.9111      9.2808      1.1318                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                               -7.9699     -9.6154  -6.3245      9.5932      8.5624  10.9084                             
                           3                               -7.0588     -8.5791  -5.5385      8.9648      8.0111  10.1782                             
                           Diff (1-2)    Pooled            -0.9111     -3.1395   1.3173      9.2808      8.5559  10.1408                             
                           Diff (1-2)    Satterthwaite     -0.9111     -3.1412   1.3190                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           267      -0.81      0.4215                                              
                                            Satterthwaite    Unequal      264.86      -0.80      0.4219                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       132       135       1.15    0.4343                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              124     -8.8871      9.8346      0.8832    -40.0000      4.0000                                    
                                   3              134     -7.2910      9.1255      0.7883    -39.0000      7.0000                                    
                                   Diff (1-2)             -1.5961      9.4728      1.1804                                                            
                                                                                                                                                    
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                               -8.8871    -10.6353  -7.1389      9.8346      8.7442  11.2381                             
                           3                               -7.2910     -8.8503  -5.7318      9.1255      8.1483  10.3713                             
                           Diff (1-2)    Pooled            -1.5961     -3.9206   0.7285      9.4728      8.7186  10.3711                             
                           Diff (1-2)    Satterthwaite     -1.5961     -3.9276   0.7355                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           256      -1.35      0.1775                                              
                                            Satterthwaite    Unequal       250.2      -1.35      0.1788                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       123       133       1.16    0.3970                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              117    -10.4444     11.9391      1.1038    -47.0000      8.0000                                    
                                   3              129     -7.2093     10.0122      0.8815    -50.0000     10.0000                                    
                                   Diff (1-2)             -3.2351     10.9706      1.4006                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                              -10.4444    -12.6306  -8.2583     11.9391     10.5806  13.7010                             
                           3                               -7.2093     -8.9536  -5.4650     10.0122      8.9216  11.4091                             
                           Diff (1-2)    Pooled            -3.2351     -5.9939  -0.4764     10.9706     10.0776  12.0386                             
                           Diff (1-2)    Satterthwaite     -3.2351     -6.0186  -0.4517                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           244      -2.31      0.0217                                              
                                            Satterthwaite    Unequal      227.35      -2.29      0.0229                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       116       128       1.42    0.0522                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              113    -10.8761     11.7975      1.1098    -46.0000      6.0000                                    
                                  3              122     -8.1721     10.4405      0.9452    -41.0000     11.0000                                    
                                   Diff (1-2)             -2.7040     11.1135      1.4510                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                              -10.8761    -13.0751  -8.6771     11.7975     10.4342  13.5739                             
                           3                               -8.1721    -10.0435  -6.3008     10.4405      9.2744  11.9445                             
                           Diff (1-2)    Pooled            -2.7040     -5.5627   0.1548     11.1135     10.1895  12.2231                             
                           Diff (1-2)    Satterthwaite     -2.7040     -5.5767   0.1688                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           233      -1.86      0.0636                                              
                                            Satterthwaite    Unequal      224.22      -1.85      0.0649                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       112       121       1.28    0.1875                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              109    -10.8349     12.9332      1.2388    -47.0000      7.0000                                    
                                   3              119     -7.7815     10.5358      0.9658    -50.0000      9.0000                                    
                                   Diff (1-2)             -3.0533     11.7427      1.5569                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           1                              -10.8349    -13.2903  -8.3794     12.9332     11.4145  14.9218                             
                           3                               -7.7815     -9.6941  -5.8689     10.5358      9.3460  12.0755                             
                           Diff (1-2)    Pooled            -3.0533     -6.1212   0.0145     11.7427     10.7527  12.9350                             
                           Diff (1-2)    Satterthwaite     -3.0533     -6.1500   0.0433                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           226      -1.96      0.0511                                              
                                            Satterthwaite    Unequal      208.64      -1.94      0.0533                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       108       118       1.51    0.0297                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              144     -4.7569      7.1088      0.5924    -29.0000     11.0000                                    
                                   3              142     -4.8169      7.2284      0.6066    -32.0000      7.0000                                    
                                   Diff (1-2)              0.0600      7.1684      0.8478                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                               -4.7569     -5.9279  -3.5860      7.1088      6.3717   8.0402                             
                           3                               -4.8169     -6.0161  -3.6177      7.2284      6.4742   8.1831                             
                           Diff (1-2)    Pooled             0.0600     -1.6088   1.7287      7.1684      6.6243   7.8108                             
                           Diff (1-2)    Satterthwaite      0.0600     -1.6090   1.7289                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           284       0.07      0.9437                                              
                                            Satterthwaite    Unequal      283.73       0.07      0.9437                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       141       143       1.03    0.8423                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               15 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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              137     -7.5985      8.7737      0.7496    -42.0000     11.0000                                    
                                   3              136     -7.0588      8.9648      0.7687    -36.0000      8.0000                                    
                                   Diff (1-2)             -0.5397      8.8694      1.0736                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                               -7.5985     -9.0809  -6.1162      8.7737      7.8434   9.9563                             
                           3                               -7.0588     -8.5791  -5.5385      8.9648      8.0111  10.1782                             
                           Diff (1-2)    Pooled            -0.5397     -2.6534   1.5740      8.8694      8.1814   9.6847                             
                           Diff (1-2)    Satterthwaite     -0.5397     -2.6536   1.5741                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           271      -0.50      0.6156                                              
                                            Satterthwaite    Unequal      270.77      -0.50      0.6156                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               16 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       135       136       1.04    0.8022                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                    
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               17 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              133     -9.0902      9.5691      0.8297    -41.0000     10.0000                                    
                                   3              134     -7.2910      9.1255      0.7883    -39.0000      7.0000                                    
                                   Diff (1-2)             -1.7992      9.3491      1.1443                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                               -9.0902    -10.7315  -7.4489      9.5691      8.5409  10.8810                             
                           3                               -7.2910     -8.8503  -5.7318      9.1255      8.1483  10.3713                             
                           Diff (1-2)    Pooled            -1.7992     -4.0523   0.4539      9.3491      8.6164  10.2191                             
                           Diff (1-2)    Satterthwaite     -1.7992     -4.0527   0.4544                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           265      -1.57      0.1171                                              
                                            Satterthwaite    Unequal       264.2      -1.57      0.1171                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               18 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       132       133       1.10    0.5855                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               19 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              124    -10.6452     10.9092      0.9797    -41.0000     10.0000                                    
                                  3              129     -7.2093     10.0122      0.8815    -50.0000     10.0000                                    
                                   Diff (1-2)             -3.4359     10.4614      1.3157                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                              -10.6452    -12.5844  -8.7059     10.9092      9.6997  12.4662                             
                           3                               -7.2093     -8.9536  -5.4650     10.0122      8.9216  11.4091                             
                           Diff (1-2)    Pooled            -3.4359     -6.0270  -0.8447     10.4614      9.6208  11.4642                             
                           Diff (1-2)    Satterthwaite     -3.4359     -6.0316  -0.8401                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           251      -2.61      0.0096                                              
                                            Satterthwaite    Unequal      247.13      -2.61      0.0097                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               20 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       123       128       1.19    0.3369                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               21 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              114    -12.0263     11.1993      1.0489    -43.0000     10.0000                                    
                                  3              122     -8.1721     10.4405      0.9452    -41.0000     11.0000                                    
                                   Diff (1-2)             -3.8542     10.8136      1.4086                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                              -12.0263    -14.1044  -9.9482     11.1993      9.9101  12.8770                             
                           3                               -8.1721    -10.0435  -6.3008     10.4405      9.2744  11.9445                             
                           Diff (1-2)    Pooled            -3.8542     -6.6294  -1.0790     10.8136      9.9163  11.8907                             
                           Diff (1-2)    Satterthwaite     -3.8542     -6.6363  -1.0721                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           234      -2.74      0.0067                                              
                                            Satterthwaite    Unequal      229.63      -2.73      0.0068                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               22 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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       113       121       1.15    0.4477                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               23 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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              119    -10.8908     10.6276      0.9742    -38.0000     10.0000                                    
                                  3              119     -7.7815     10.5358      0.9658    -50.0000      9.0000                                    
                                   Diff (1-2)             -3.1092     10.5818      1.3718                                                            
                                                                                                                                                     
                           TRTPN         Method               Mean       95% CL Mean        Std Dev      95% CL Std Dev                              
                                                                                                                                                     
                           2                              -10.8908    -12.8200  -8.9615     10.6276      9.4274  12.1807                             
                           3                               -7.7815     -9.6941  -5.8689     10.5358      9.3460  12.0755                             
                           Diff (1-2)    Pooled            -3.1092     -5.8118  -0.4066     10.5818      9.7072  11.6310                             
                           Diff (1-2)    Satterthwaite     -3.1092     -5.8118  -0.4066                                                              
                                                                                                                                                     
                                            Method           Variances        DF    t Value    Pr > |t|                                              
                                                                                                                                                     
                                            Pooled           Equal           236      -2.27      0.0243                                              
                                            Satterthwaite    Unequal      235.98      -2.27      0.0243                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               24 OF 24
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       118       118       1.02    0.9251                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: TTESTOC; TABLE: stat1i.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.7      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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      0.7626    0.3825                                            
                                             2        Row Mean Scores Differ     2      1.6961    0.4283                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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      1.0930   0.2958                                            
                                             2        Row Mean Scores Differ     2      1.6783    0.4321                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      3.4385    0.0637                                            
                                              2        Row Mean Scores Differ     2      5.1565    0.0759                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                     
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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      3.8708    0.0491                                            
                                             2        Row Mean Scores Differ     2      6.2158    0.0447                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                    
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      3.0224    0.0821                                            
                                              2        Row Mean Scores Differ     2      3.9747    0.1371                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
¹ WILCOXON TEST STRATIFIED BY (POOLED) CENTER.                                                                                                       
                                                                                                                                                     
SOURCE: NPAR; TABLE: stat1j.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                     
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.8      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 9
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                                                                    
                                                                                                                                                     
                                                             Tests for Location: Mu0=0                                                               
                                                                                                                                                     
                                                  Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                     
                                                  Student's t    t  -0.62601    Pr > |t|    0.5317                                                   
                                                  Sign           M      28.5    Pr >= |M|   0.0026                                                   
                                                  Signed Rank    S      1596    Pr >= |S|   0.3942                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                              Quantiles (Definition 5)                                                               
                                                                                                                                                     
                                                              Level          Quantile                                                                
                                                                                                                                                     
                                                              100% Max       19.94892                                                                
                                                              99%            17.59826                                                                
                                                              95%            13.42180                                                                
                                                              90%            11.14587                                                                
                                                              75% Q3          7.91676                                                                
                                                              50% Median      1.86002                                                                
                                                              25% Q1         -6.96455                                                                
                                                              10%           -15.95262                                                                
                                                              5%            -21.57855                                                                
                                                              1%            -31.78702                                                                
                                                              0% Min        -33.88736                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 9
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                                      
                                                                                                                                                    
                                                    -33.8874     1677         16.6970      714                                                      
                                                    -33.3787     1554         17.5983     1295                                                      
                                                    -33.1571      411         18.8332     2204                                                      
                                                    -31.7870     1798         19.4803     2243                                                      
                                                     -28.1267     1406         19.9489     1355                                                      
                                                                                                                                                     
                                                                                                                                                     
                       Histogram                     #             Boxplot                                   Normal Probability Plot                 
     17.5+*****                                      9                |                   17.5+                                        ++++ ******   
         .***********************                   45                |                       |                                   **********         
         .**************************************    76             +-----+                    |                            ********                  
         .************************************      72             *-----*                    |                       ******+                        
         .***********************                   46             |  +  |                    |                   *****++                            
     -7.5+***************                           30             +-----+                -7.5+                 ***+                                 
         .***************                           29                |                       |            +****                                     
         .*********                                 18                |                       |       +++****                                        
         .******                                    12                |                       |   +++*****                                           
         .***                                        6                |                       |+++****                                               
    -32.5+**                                         4                0                  -32.5+***                                                   
          ----+----+----+----+----+----+----+---                                               +----+----+----+----+----+----+----+----+----+----+   
          * may represent up to 2 counts                                                           -2        -1         0        +1        +2        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 9
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                         347    Sum Weights                347                                            
                                         Mean               -0.0353861    Sum Observations    -12.278976                                            
                                         Std Deviation      1.02339086    Variance            1.04732886                                            
                                         Skewness           -0.8014075    Kurtosis            0.14366209                                            
                                          Uncorrected SS     362.810289    Corrected SS        362.375784                                            
                                          Coeff Variation    -2892.0705    Std Error Mean       0.0549385                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.03539     Std Deviation            1.02339                                                
                                               Median    0.17390     Variance                 1.04733                                                
                                               Mode      0.05664     Range                    5.12952                                                
                                                                     Interquartile Range      1.41016                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 4 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 9
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                                                    
                                                                                                                                                    
                                                            Tests for Location: Mu0=0                                                               
                                                                                                                                                    
                                                 Test           -Statistic-    -----p Value------                                                   
                                                                                                                                                    
                                                 Student's t    t   -0.6441    Pr > |t|    0.5199                                                   
                                                 Sign           M      28.5    Pr >= |M|   0.0026                                                   
                                                 Signed Rank    S      1567    Pr >= |S|   0.4028                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                             Quantiles (Definition 5)                                                               
                                                                                                                                                    
                                                             Level          Quantile                                                                
                                                                                                                                                    
                                                             100% Max       1.902521                                                                
                                                             99%            1.671961                                                                
                                                             95%            1.269575                                                                
                                                             90%            1.049981                                                                
                                                             75% Q3         0.749161                                                                
                                                             50% Median     0.173896                                                                
                                                             25% Q1        -0.660998                                                                
                                                             10%           -1.496158                                                                
                                                              5%            -2.066916                                                                
                                                              1%            -2.976287                                                                
                                                              0% Min        -3.227003                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 9
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                                                      
                                                                                                                                                     
                                                     -3.22700     1677         1.65677     1295                                                      
                                                     -3.14078     1554         1.67196      714                                                      
                                                     -3.10521      411         1.76566     2204                                                      
                                                     -2.97629     1798         1.82508     2243                                                      
                                                     -2.70089     1406         1.90252     1355                                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 9
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                 
      18 30                                         2                |                    1.9+                                           ++     *   
      16 677                                        3                |                       |                                         ++    ***    
      14 5711                                       4                |                       |                                        +    **       
      12 16777700777                               11                |                       |                                      ++ ****         
      10 00011123555667711666789                   23                |                       |                                    +*****            
       8 000012566777889000112344555555666778      36                |                       |                                 *****                
       6 00011222333445566778899112222355556788    38             +-----+                    |                             *****                    
       4 111122344588889111466899                  24             |     |                    |                           ***++                      
       2 0134556677888999044555666788888           31             |    |                    |                         ***++                        
       0 111223345666677900122445556779            30             *-----*                    |                       ***++                          
      -0 9753329887665443322                       19             |  +  |                    |                      **++                            
      -2 977654111998877631                        18             |     |                    |                    **++                             
      -4 99855427665543000                         17             |     |                    |                   **+                                
      -6 88652998765321                            14             +-----+                -0.7+                 ***                                  
      -8 86541766431                               11                |                       |                **                                    
     -10 8755332865333                             13                |                       |              +**                                     
     -12 76407765541                               11                |                       |            +***                                      
     -14 3007666310                                10                |                       |          ++**                                        
     -16 985100642                                  9                |                       |        ++***                                         
     -18 977                                        3                |                       |      ++ **                                           
     -20 4418720                                    7                |                       |    ++ ***                                            
     -22 7865                                       4                |                       |  ++  **                                              
     -24 105                                        3                |                       |++  **                                                
     -26 03                                         2                |                       |   **                                                 
     -28 8                                          1                0                       |  *                                                   
     -30 41                                         2                0                       |**                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 9
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                                                                    
                                                                                                                                                     
      -32 3                                          1                0                   -3.3+*                                                     
          ----+----+----+----+----+----+----+---                                               +----+----+----+----+----+----+----+----+----+----+   
      Multiply Stem.Leaf by 10**-1                                                                 -2        -1         0        +1        +2        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 9
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                                                                                         
     20 +      AA             A                 A A    A AAA B                                                                                      
  R     |  B  A  A        A AB D AB    A    A  A   CCAA A   AB   AA A    A     A    AA   A A A                                                      
 e     |        A A     A  BBAAD   CAAA          CDBA  B BABBADCHAHDIHDFCFDDDEDH BBCFD BACBCD A CBA   A  A  AA AA         A                        
  s     |     AAA A          AAAA ABA D BA  A   A ABD A  BBCCCBDBCAHDHFHGILLOKFGNLGLQQOHLLGGEFEEEDACFD BBBB E A  A   A               A              
  i     |  A     A          A AAB A A A           AB  A BBCBBG BCCDDAHGIEDLIKGHKHHJIHPRQMOJPOQLOKRKNOJHGGIBIGEF AA BAAA                             
  d   0 +  A   A B           BABAA  AAA      A     C B  A BAA BBBCCBDDEDDCDAEEGPIGFMGKIJILJFMIFLHKPOIHGCDJJKMCDBB BB AEAA  B   B  AA                
  u     |    AA  AA A A      AA A AC BB A          A BBAB BAA  ABBCCBABBCCFFFJDHDBHJECICBEFHECMEIDFEECACCEGGCAAA BA BAB   A       A                 
  a     |                     A   AA        A     BAB      B  A BBCBABDFBEACCDF DGECBIEJEDCECBCDHEDEDCC BBCBEAA   A   B                             
  l     |      AAA  AAA   A   B B A  AAAA AA A A  B  A A  A  AB BAAACCEADCDDAFECCACHDDCFCABFBDBBDACC  AA A A  AA     A                             
        |   A AACAAAB        A     A   A    B      A     B   B AAABDAABDBBBC BCCACA DBCCCCCE    BB   A A                                            
    -20 +  A   A BAAA       AB A   A A A        AA A            ABAAA CCBAEAABBA A  BBABA  A A     B              A                                 
        |                   A   AAA   A      A   A  A            A     BB A BAB AAA  AA D AA   A   A        A                                       
        |                                        A          A  AAA         A A  AAB    AA              A                                            
        |                     B                       AAA               A   A    A B       A                                                        
        |                                                                                                                                           
    -40 +                                                                                                                                           
        |                                                                                                                                           
        ---+---------+---------+---------+---------+---------+---------+---------+---------+---------+---------+---------+---------+---------+--    
           -22       -20       -18       -16       -14       -12       -10       -8        -6        -4        -2         0         2         4      
                                                                                                                                                     
                                                                         Predicted                                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX1; TABLE: stat1k.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.9      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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         438  
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                    
                                               
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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                     72                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        438                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2292                                                      
                                                   Number of Observations Used            2292                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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     16529.25629156                                                              
                                                    1              2     14188.42661779      0.00057908                                              
                                                    2              1     14185.23002848      0.00001628                                              
                                                    3              1     14185.14601175      0.00000002                                              
                                                   4              1     14185.14589278      0.00000000                                              
                                                                                                                                                     
                                                                                                                                                    
                                                            Convergence criteria met.                                                               
                                                                                                                                                    
                                                                                    
                                                     
                                                      Estimated R Matrix for SUBJID
                                                    
                                                                                                                                                    
                                    Row        Col1        Col2        Col3        Col4        Col5        Col6                                     
                                                                                                                                                    
                                      1     46.0381     41.1715     36.7487     32.9053     36.5459     38.5770                                     
                                      2     41.1715     72.3189     63.2366     57.9165     61.0600     61.5916                                     
                                      3     36.7487     63.2366     85.0775     79.2283     82.7270     77.0389                                     
                                      4     32.9053     57.9165     79.2283      109.98     96.5075     92.0782                                     
                                      5     36.5459     61.0600     82.7270     96.5075      108.06     90.3451                                     
                                      6     38.5770     61.5916     77.0389     92.0782     90.3451      107.13                                     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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        Col5        Col6                                     
                                                                                                                                                    
                                      1      1.0000      0.7135      0.5872      0.4624      0.5182      0.5493                                     
                                      2      0.7135      1.0000      0.8062      0.6494      0.6907      0.6997                                     
                                      3      0.5872      0.8062      1.0000      0.8191      0.8628      0.8069                                     
                                      4      0.4624      0.6494      0.8191      1.0000      0.8853      0.8483                                     
                                      5      0.5182      0.6907      0.8628      0.8853      1.0000      0.8397                                     
                                      6      0.5493      0.6997      0.8069      0.8483      0.8397      1.0000                                     
                                                                                                                                                    
                                                                                                                                                    
                                                      Estimated R Matrix for SUBJID
                                                      
                                                                                    
                                                       
                                    Row        Col1        Col2        Col3        Col4        Col5        Col6                                     
                                                                                                                                                    
                                      1     65.6662     44.0115     46.3127     47.7634     47.6829     43.0330                                     
                                      2     44.0115     78.8090     65.0532     70.3450     71.8874     74.0759                                     
                                      3     46.3127     65.0532     84.1997     82.8999     84.5571     87.9428                                     
                                      4     47.7634     70.3450     82.8999      117.91      107.76      115.71                                     
                                      5     47.6829     71.8874     84.5571      107.76      118.69      119.10                                     
                                      6     43.0330     74.0759     87.9428      115.71      119.10      146.06                                     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                                     
                                                                                                                                                     
                                       1     46.3693     34.8314     31.0449     30.9025     30.4290     32.7595                                     
                                       2     34.8314     65.0980     57.0928     58.3247     56.0968     55.8943                                     
                                       3     31.0449     57.0928     73.8230     68.5633     73.5792     69.9148                                     
                                       4     30.9025     58.3247     68.5633     88.3257     83.0181     81.2208                                     
                                       5     30.4290     56.0968     73.5792     83.0181      104.07     88.0138                                     
                                       6     32.7595     55.8943     69.9148     81.2208     88.0138     99.0964                                     
                                                                                                                                                     
                                                                                                                                                     
                                                           Covariance Parameter Estimates                                                            
                                                                                                                                                     
                                                     Cov Parm    Subject    Group      Estimate                                                      
                                                                                                                                                     
                                                     UN(1,1)     SUBJID     TRTPN 1     65.6662                                                      
                                                     UN(2,1)     SUBJID     TRTPN 1     44.0115                                                      
                                                     UN(2,2)     SUBJID     TRTPN 1     78.8090                                                      
                                                     UN(3,1)     SUBJID     TRTPN 1     46.3127                                                      
                                                     UN(3,2)     SUBJID     TRTPN 1     65.0532                                                      
                                                     UN(3,3)     SUBJID     TRTPN 1     84.1997                                                      
                                                     UN(4,1)     SUBJID     TRTPN 1     47.7634                                                      
                                                     UN(4,2)     SUBJID     TRTPN 1     70.3450                                                      
                                                     UN(4,3)     SUBJID     TRTPN 1     82.8999                                                      
                                                     UN(4,4)     SUBJID     TRTPN 1      117.91                                                      
                                                     UN(5,1)     SUBJID     TRTPN 1     47.6829                                                      
                                                     UN(5,2)     SUBJID     TRTPN 1     71.8874                                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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(5,3)     SUBJID     TRTPN 1     84.5571                                                      
                                                     UN(5,4)     SUBJID     TRTPN 1      107.76                                                      
                                                     UN(5,5)     SUBJID     TRTPN 1      118.69                                                      
                                                     UN(6,1)     SUBJID     TRTPN 1     43.0330                                                      
                                                     UN(6,2)     SUBJID     TRTPN 1     74.0759                                                      
                                                     UN(6,3)     SUBJID     TRTPN 1     87.9428                                                      
                                                     UN(6,4)     SUBJID     TRTPN 1      115.71                                                      
                                                     UN(6,5)     SUBJID     TRTPN 1      119.10                                                      
                                                    UN(6,6)     SUBJID     TRTPN 1      146.06                                                      
                                                     UN(1,1)     SUBJID     TRTPN 2     46.0381                                                      
                                                     UN(2,1)     SUBJID     TRTPN 2     41.1715                                                      
                                                     UN(2,2)     SUBJID     TRTPN 2     72.3189                                                      
                                                     UN(3,1)     SUBJID     TRTPN 2     36.7487                                                      
                                                     UN(3,2)     SUBJID     TRTPN 2     63.2366                                                      
                                                     UN(3,3)     SUBJID     TRTPN 2     85.0775                                                      
                                                     UN(4,1)     SUBJID     TRTPN 2     32.9053                                                      
                                                     UN(4,2)     SUBJID     TRTPN 2     57.9165                                                      
                                                     UN(4,3)     SUBJID     TRTPN 2     79.2283                                                      
                                                     UN(4,4)     SUBJID     TRTPN 2      109.98                                                      
                                                     UN(5,1)     SUBJID     TRTPN 2     36.5459                                                      
                                                     UN(5,2)     SUBJID     TRTPN 2     61.0600                                                      
                                                     UN(5,3)     SUBJID     TRTPN 2     82.7270                                                      
                                                     UN(5,4)     SUBJID     TRTPN 2     96.5075                                                      
                                                     UN(5,5)     SUBJID     TRTPN 2      108.06                                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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(6,1)     SUBJID     TRTPN 2     38.5770                                                      
                                                    UN(6,2)     SUBJID     TRTPN 2     61.5916                                                      
                                                    UN(6,3)     SUBJID     TRTPN 2     77.0389                                                      
                                                    UN(6,4)     SUBJID     TRTPN 2     92.0782                                                      
                                                    UN(6,5)     SUBJID     TRTPN 2     90.3451                                                      
                                                    UN(6,6)     SUBJID     TRTPN 2      107.13                                                      
                                                    UN(1,1)     SUBJID     TRTPN 3     46.3693                                                      
                                                    UN(2,1)     SUBJID     TRTPN 3     34.8314                                                      
                                                    UN(2,2)     SUBJID     TRTPN 3     65.0980                                                      
                                                    UN(3,1)     SUBJID     TRTPN 3     31.0449                                                      
                                                    UN(3,2)     SUBJID     TRTPN 3     57.0928                                                      
                                                    UN(3,3)     SUBJID     TRTPN 3     73.8230                                                      
                                                    UN(4,1)     SUBJID     TRTPN 3     30.9025                                                      
                                                    UN(4,2)     SUBJID     TRTPN 3     58.3247                                                      
                                                    UN(4,3)     SUBJID     TRTPN 3     68.5633                                                      
                                                    UN(4,4)     SUBJID     TRTPN 3     88.3257                                                      
                                                    UN(5,1)     SUBJID     TRTPN 3     30.4290                                                      
                                                    UN(5,2)     SUBJID     TRTPN 3     56.0968                                                      
                                                    UN(5,3)     SUBJID     TRTPN 3     73.5792                                                      
                                                    UN(5,4)     SUBJID     TRTPN 3     83.0181                                                      
                                                    UN(5,5)     SUBJID     TRTPN 3      104.07                                                      
                                                    UN(6,1)     SUBJID     TRTPN 3     32.7595                                                      
                                                    UN(6,2)     SUBJID     TRTPN 3     55.8943                                                      
                                                    UN(6,3)     SUBJID     TRTPN 3     69.9148                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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(6,4)     SUBJID     TRTPN 3     81.2208                                                      
                                                     UN(6,5)     SUBJID     TRTPN 3     88.0138                                                      
                                                     UN(6,6)     SUBJID     TRTPN 3     99.0964                                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                  Fit Statistics                                                                     
                                                                                                                                                     
                                                       -2 Res Log Likelihood         14185.1                                                         
                                                       AIC (Smaller is Better)       14311.1                                                         
                                                       AICC (Smaller is Better)      14314.9                                                         
                                                       BIC (Smaller is Better)       14568.3                                                         
                                                                                                                                                     
                                                                                                                                                     
                                                          Null Model Likelihood Ratio Test                                                           
                                                                                                                                                     
                                                            DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                     
                                                            62       2344.11          <.0001                                                         
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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                                             0.4124      4.8142     479       0.09      0.9318                        
                      AVISITN                     7                        -0.8831      2.8978     372      -0.30      0.7607                        
                      AVISITN                    14                        -0.7454      2.4446     354      -0.30      0.7606                        
                      AVISITN                    21                        -2.9398      2.0177     326      -1.46      0.1461                        
                      AVISITN                    28                         2.5080      1.7494     323       1.43      0.1526                        
                      AVISITN                    35                         0.3320      1.7659     337       0.19      0.8510                        
                      AVISITN                    42                              0                                                                   
                      TRTPN                                  1             -3.0330      1.3769     249      -2.20      0.0285                        
                      TRTPN                                  2             -2.7565      1.2456     260      -2.21      0.0278                        
                      TRTPN                                  3                   0                                                                   
                      AVISITN*TRTPN               7          1              1.7304      1.2761     241       1.36      0.1764                        
                      AVISITN*TRTPN               7          2              2.8863      1.0986     274       2.63      0.0091                        
                      AVISITN*TRTPN               7          3                   0                                                                   
                      AVISITN*TRTPN              14          1              2.0397      1.0425     235       1.96      0.0516                        
                      AVISITN*TRTPN              14          2              2.4871      0.9315     261       2.67      0.0081                        
                      AVISITN*TRTPN              14          3                   0                                                                   
                      AVISITN*TRTPN              21          1              1.0810      0.8683     218       1.24      0.2145                        
                      AVISITN*TRTPN              21          2              0.9914      0.7662     241       1.29      0.1969                        
                      AVISITN*TRTPN              21          3                   0                                                                   
                      AVISITN*TRTPN              28          1             -0.3136      0.7115     221      -0.44      0.6598                        
                      AVISITN*TRTPN              28          2             -0.5811      0.6981     233      -0.83      0.4061                        
                      AVISITN*TRTPN              28          3                   0                                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               15 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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            -0.02212      0.6892     228      -0.03      0.9744                        
                     AVISITN*TRTPN              35          2             -0.7416      0.7276     234      -1.02      0.3091                        
                     AVISITN*TRTPN              35          3                   0                                                                   
                     AVISITN*TRTPN              42          1                   0                                                                   
                     AVISITN*TRTPN              42          2                   0                                                                   
                     AVISITN*TRTPN   
      42          3                  0                                                                   
                     POOLCNTR       
                                -1.3093      3.9540     335      -0.33      0.7408                        
                     POOLCNTR       
                                -0.7279      3.8546     333      -0.19      0.8503                        
                     POOLCNTR       
                                -1.6459      3.9898     337      -0.41      0.6802                        
                     POOLCNTR       
                                -1.6408      3.7641     330      -0.44      0.6632                        
                     POOLCNTR       
                                -1.6465      3.8229    333      -0.43      0.6670                        
                     POOLCNTR       
                                -2.4145      4.3086     350      -0.56      0.5756                        
                     POOLCNTR       
                                -6.6124      4.3891     343      -1.51      0.1328                        
                     POOLCNTR       
                                -7.0649      5.4521     366      -1.30      0.1959                        
                     POOLCNTR       
                                -5.7267      3.9888     333      -1.44      0.1520                        
                     POOLCNTR       
                                -2.2694      4.8320     342      -0.47      0.6389                        
                     POOLCNTR       
                                -3.1596      3.7355     330      -0.85      0.3983                        
                     POOLCNTR       
                                -6.0142      4.1721     353      -1.44      0.1503                        
                     POOLCNTR       
                                 0.8807      4.2539     340       0.21      0.8361                        
                     POOLCNTR       
                                -3.8300      4.2304     355      -0.91      0.3659                        
                     POOLCNTR       
                                -2.5117      4.3115     345      -0.58      0.5606                        
                     POOLCNTR       
                                -2.7422      4.8000     380      -0.57      0.5681                        
                                     
                                                                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               16 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       
                                -2.6550      3.9942     344      -0.66      0.5067                        
                     POOLCNTR       
                                -5.0193      4.3859     342      -1.14      0.2533                        
                     POOLCNTR       
                                0.07424      5.4356     368       0.01      0.9891                        
                     POOLCNTR       
                                -2.1018      4.4549     338      -0.47      0.6374                        
                     POOLCNTR       
                                -4.1304      5.1284     376      -0.81      0.4211                        
                      POOLCNTR       
                                 0.3290      4.7835     343       0.07      0.9452                        
                      POOLCNTR       
                                -1.2695      4.8590     375      -0.26      0.7940                        
                      POOLCNTR       
                                -3.0686      4.5967     355      -0.67      0.5048                        
                      POOLCNTR       
                                -2.1150      3.8922     338      -0.54      0.5872                        
                      POOLCNTR       
                                -4.1346      4.2846     359      -0.96      0.3352                        
                      POOLCNTR       
                                -4.7395      4.1998     347      -1.13      0.2599                        
                      POOLCNTR       
                                -4.0008      4.7432     345      -0.84      0.3995                        
                      POOLCNTR       
                               -11.9023      3.8364     333      -3.10      0.0021                        
                      POOLCNTR       
                                 2.1419      5.4591     363       0.39      0.6950                        
                      POOLCNTR       
                                 3.1038      4.6133     353       0.67      0.5015                        
                      POOLCNTR       
                                -2.8280      5.0206     357      -0.56      0.5736                        
                      POOLCNTR       
                                -2.0196      5.1661     388      -0.39      0.6961                        
                      POOLCNTR       
                                -1.0234      3.9312     338      -0.26      0.7948                        
                      POOLCNTR       
                                -5.1194      3.8469     331      -1.33      0.1842                        
                      POOLCNTR       
                                -1.7274      5.0914     377      -0.34      0.7346                        
                      POOLCNTR       
                                -1.2967      5.0881     378      -0.25      0.7990                        
                      POOLCNTR       
                                      0                                                                   
                                      
                                                                                                          
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               17 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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|                        
                                                                                                                                                     
                      BASE*AVISITN                7                       -0.02539     0.06167     394      -0.41      0.6808                        
                      BASE*AVISITN               14                       -0.08601     0.07029     442      -1.22      0.2217                        
                      BASE*AVISITN               21                       -0.03257     0.07393     445      -0.44      0.6597                        
                      BASE*AVISITN               28                        -0.1639     0.08209    447      -2.00      0.0465                        
                      BASE*AVISITN               35                        -0.1325     0.08419     458      -1.57      0.1163                        
                      BASE*AVISITN               42                        -0.1191     0.08648     447      -1.38      0.1690                        
                                                                                                                                                     
                                                                                                                                                     
                                                           Type 3 Tests of Fixed Effects                                                             
                                                                                                                                                     
                                                                   Num     Den                                                                       
                                                 Effect             DF      DF    F Value    Pr > F                                                  
                                                                                                                                                     
                                                 AVISITN             5     369       1.80    0.1124                                                  
                                                 TRTPN               2     259       3.15    0.0444                                                  
                                                 AVISITN*TRTPN      10     316       1.70    0.0795                                                  
                                                 POOLCNTR           37     387       2.00    0.0007                                                  
                                                 BASE*AVISITN        6     392       1.99    0.0662                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               18 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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             -5.4621      0.7260     152      -7.52      <.0001      0.05     -6.8964     -4.0278            
          AVISITN*TRTPN     7          2             -4.0298      0.6402     174      -6.29      <.0001      0.05     -5.2934     -2.7661            
          AVISITN*TRTPN     7          3             -4.1595      0.6417     166      -6.48      <.0001      0.05     -5.4263     -2.8926            
          AVISITN*TRTPN    14          1             -7.4177      0.7968     154      -9.31      <.0001      0.05     -8.9917     -5.8437            
          AVISITN*TRTPN    14          2             -6.6938      0.7750     166      -8.64      <.0001      0.05     -8.2239     -5.1637            
          AVISITN*TRTPN    14          3             -6.4243      0.7445     165      -8.63      <.0001      0.05     -7.8943     -4.9544            
          AVISITN*TRTPN    21          1             -8.4528      0.8292     144     -10.19      <.0001      0.05    -10.0918     -6.8137            
          AVISITN*TRTPN    21          2             -8.2660      0.8380     158      -9.86      <.0001      0.05     -9.9212     -6.6108            
          AVISITN*TRTPN    21          3             -6.5008      0.7887     165      -8.24      <.0001      0.05     -8.0580     -4.9436            
          AVISITN*TRTPN    28          1             -9.6039      0.9837     145      -9.76      <.0001      0.05    -11.5482     -7.6596            
          AVISITN*TRTPN    28          2             -9.5949      0.9555     153     -10.04      <.0001      0.05    -11.4827     -7.7071            
          AVISITN*TRTPN    28          3             -6.2572      0.8577     160      -7.30      <.0001      0.05     -7.9511     -4.5634            
          AVISITN*TRTPN    35          1            -10.2433      0.9879     145     -10.37      <.0001      0.05    -12.1959     -8.2908            
          AVISITN*TRTPN    35          2            -10.6864      0.9502     152     -11.25      <.0001      0.05    -12.5638     -8.8090            
          AVISITN*TRTPN    35          3             -7.1882      0.9300     159      -7.73      <.0001      0.05     -9.0250     -5.3515            
          AVISITN*TRTPN    42          1            -10.0246      1.1034     141      -9.09      <.0001      0.05    -12.2058     -7.8433            
          AVISITN*TRTPN    42          2             -9.7481      0.9464     155     -10.30      <.0001      0.05    -11.6176     -7.8787            
          AVISITN*TRTPN    42          3             -6.9916      0.9122     159      -7.66      <.0001      0.05     -8.7932     -5.1899            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               19 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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            -1.4324     0.8834    249     -1.62     0.1062     0.05    -3.1723     0.3075     
   AVISITN*TRTPN    7         1            7         3            -1.3027     0.8872    253     -1.47     0.1433     0.05    -3.0499     0.4446     
   AVISITN*TRTPN    7         1           14         1             1.9555     0.6484    129      3.02     0.0031     0.05     0.6726     3.2385     
   AVISITN*TRTPN    7         1           14         2             1.2316     0.9852    263      1.25     0.2124     0.05    -0.7083     3.1716     
   AVISITN*TRTPN    7         1           14         3             0.9622     0.9628    263      1.00     0.3186     0.05    -0.9337     2.8580     
   AVISITN*TRTPN    7         1           21         1             2.9906     0.6630    136      4.51     <.0001     0.05     1.6796     4.3017     
   AVISITN*TRTPN    7         1           21         2             2.8038     1.0353    258      2.71     0.0072     0.05     0.7650     4.8426     
   AVISITN*TRTPN    7         1           21         3             1.0387     0.9969    266      1.04     0.2984     0.05    -0.9242     3.0015     
   AVISITN*TRTPN    7         1           28         1             4.1417     0.8366    125      4.95     <.0001     0.05     2.4860     5.7975     
   AVISITN*TRTPN    7         1           28         2             4.1328     1.1322    242      3.65     0.0003     0.05     1.9026     6.3630     
   AVISITN*TRTPN    7         1           28         3             0.7951     1.0524    262      0.76     0.4506     0.05    -1.2771     2.8673     
   AVISITN*TRTPN    7         1           35         1             4.7812     0.8422    126      5.68     <.0001     0.05     3.1144     6.4480     
   AVISITN*TRTPN    7         1           35         2             5.2243     1.1280    240      4.63     <.0001     0.05     3.0022     7.4463     
   AVISITN*TRTPN    7         1           35         3             1.7261     1.1120    255      1.55    0.1219     0.05    -0.4638     3.9160     
   AVISITN*TRTPN    7         1           42         1             4.5625     1.0080    124      4.53     <.0001     0.05     2.5674     6.5575     
   AVISITN*TRTPN    7         1           42         2             4.2860     1.1248    243      3.81     0.0002     0.05     2.0703     6.5017     
   AVISITN*TRTPN    7         1           42         3             1.5294     1.0974    255      1.39     0.1646     0.05    -0.6317     3.6905     
   AVISITN*TRTPN    7         2            7         3             0.1297     0.8064    260      0.16     0.8723     0.05    -1.4582     1.7177     
   AVISITN*TRTPN    7         2           14         1             3.3879     0.9433    247      3.59     0.0004     0.05     1.5300     5.2459     
   AVISITN*TRTPN    7         2           14         2             2.6640     0.5142    139      5.18     <.0001     0.05     1.6473     3.6807     
   AVISITN*TRTPN    7         2           14         3             2.3946     0.8886    255      2.69     0.0075     0.05     0.6447     4.1445     
   AVISITN*TRTPN    7         2           21         1             4.4230     0.9707    233      4.56     <.0001     0.05     2.5105     6.3355     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               20 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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             4.2362     0.6527    138      6.49     <.0001     0.05     2.9457     5.5267     
   AVISITN*TRTPN    7         2           21         3             2.4711     0.9253    248      2.67     0.0081     0.05     0.6486     4.2936     
   AVISITN*TRTPN    7         2           28         1             5.5741     1.1055    214      5.04     <.0001     0.05     3.3950     7.7532     
   AVISITN*TRTPN    7         2           28         2             5.5651     0.8296    133      6.71     <.0001     0.05     3.9243     7.2060     
   AVISITN*TRTPN    7         2           28         3             2.2275     0.9848    232      2.26     0.0246     0.05     0.2872     4.1678     
   AVISITN*TRTPN    7         2           35         1             6.2136     1.1092    214      5.60     <.0001     0.05     4.0273     8.3998     
   AVISITN*TRTPN    7         2           35         2             6.6566     0.7932    130      8.39     <.0001     0.05     5.0873     8.2260     
   AVISITN*TRTPN    7         2           35         3             3.1585     1.0483    227      3.01     0.0029     0.05     1.0928     5.2241     
   AVISITN*TRTPN    7         2           42         1             5.9948     1.2133    198      4.94     <.0001     0.05     3.6023     8.3874     
   AVISITN*TRTPN    7         2           42         2             5.7184     0.7711    134      7.42     <.0001     0.05     4.1932     7.2435     
   AVISITN*TRTPN    7         2           42         3             2.9618     1.0328    226      2.87     0.0045     0.05     0.9267     4.9970     
   AVISITN*TRTPN    7         3           14         1             3.2582     0.9468    250      3.44     0.0007     0.05     1.3935     5.1229     
   AVISITN*TRTPN    7         3           14         2             2.5343     0.9168    245      2.76     0.0061     0.05     0.7286     4.3400     
   AVISITN*TRTPN    7         3           14         3             2.2649     0.5534    139      4.09     <.0001     0.05     1.1708     3.3589     
   AVISITN*TRTPN    7         3           21         1             4.2933     0.9741    231      4.41     <.0001     0.05     2.3741     6.2125     
   AVISITN*TRTPN    7         3           21         2             4.1065     0.9705    231      4.23     <.0001     0.05     2.1944     6.0186     
   AVISITN*TRTPN    7         3           21         3             2.3413     0.6524    140      3.59     0.0005     0.05     1.0515     3.6311     
   AVISITN*TRTPN    7         3           28         1             5.4444     1.1085    215      4.91     <.0001     0.05     3.2595     7.6293     
   AVISITN*TRTPN    7         3           28         2             5.4354     1.0732    214      5.06     <.0001     0.05     3.3200     7.5508     
   AVISITN*TRTPN    7         3           28         3             2.0978     0.7357    142      2.85     0.0050     0.05     0.6435     3.5521     
   AVISITN*TRTPN    7         3           35         1             6.0839     1.1121    215      5.47     <.0001     0.05     3.8918     8.2760     
   AVISITN*TRTPN    7         3           35         2             6.5269     1.0688    214      6.11     <.0001     0.05     4.4202     8.6336     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                              21 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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             3.0287     0.8227    140      3.68     0.0003     0.05     1.4022     4.6552     
   AVISITN*TRTPN    7         3           42         1             5.8651     1.2160    198      4.82    <.0001     0.05     3.4673     8.2630     
   AVISITN*TRTPN    7         3           42         2             5.5886     1.0654    221      5.25     <.0001     0.05     3.4889     7.6884     
   AVISITN*TRTPN    7         3           42         3             2.8321     0.7825    140      3.62     0.0004     0.05     1.2850     4.3792     
   AVISITN*TRTPN   14         1           14         2            -0.7239     1.0393    273     -0.70     0.4867     0.05    -2.7701     1.3222     
   AVISITN*TRTPN   14         1           14         3            -0.9933     1.0181    261     -0.98     0.3301     0.05    -2.9980     1.0113     
   AVISITN*TRTPN   14         1           21         1             1.0351     0.5228    121      1.98    0.0500     0.05   0.000165     2.0701     
   AVISITN*TRTPN   14         1           21         2             0.8483     1.0869    271      0.78     0.4358     0.05    -1.2916     2.9882     
   AVISITN*TRTPN   14         1           21         3            -0.9169     1.0504    265     -0.87     0.3835     0.05    -2.9850     1.1513     
   AVISITN*TRTPN   14         1           28         1             2.1862     0.6913    123      3.16     0.0020     0.05     0.8179     3.5545     
   AVISITN*TRTPN   14         1           28         2             2.1772     1.1796    259      1.85     0.0661     0.05    -0.1455     4.5000     
   AVISITN*TRTPN   14         1           28         3            -1.1604     1.1031    267     -1.05     0.2938     0.05    -3.3324     1.0115     
   AVISITN*TRTPN   14         1           35         1             2.8257     0.6812    124      4.15     <.0001     0.05     1.4775     4.1738     
   AVISITN*TRTPN   14         1           35         2             3.2687     1.1755    256      2.78     0.0058     0.05     0.9538     5.5837     
   AVISITN*TRTPN   14         1           35         3            -0.2295     1.1602    265     -0.20     0.8434     0.05    -2.5137     2.0548     
   AVISITN*TRTPN   14         1           42         1             2.6069     0.8200    121      3.18     0.0019     0.05     0.9836     4.2302     
   AVISITN*TRTPN   14         1           42         2             2.3305     1.1725    260      1.99     0.0479     0.05    0.02168     4.6392     
   AVISITN*TRTPN   14         1           42         3            -0.4261     1.1462    266     -0.37     0.7104     0.05    -2.6828     1.8306     
   AVISITN*TRTPN   14         2           14         3            -0.2694     0.9898    261     -0.27     0.7857     0.05    -2.2183     1.6795     
   AVISITN*TRTPN   14         2           21         1             1.7590     1.0642    265      1.65     0.0995     0.05    -0.3364     3.8545     
   AVISITN*TRTPN   14         2           21         2             1.5722     0.4849    133      3.24     0.0015     0.05     0.6131     2.5313     
   AVISITN*TRTPN   14         2           21         3            -0.1929     1.0229    262     -0.19     0.8505     0.05    -2.2071     1.8212     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               22 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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             2.9101     1.1885    251      2.45     0.0150     0.05     0.5695     5.2508     
    AVISITN*TRTPN   14         2           28         2             2.9011     0.7202    131      4.03     <.0001     0.05     1.4764     4.3259     
    AVISITN*TRTPN   14         2           28         3            -0.4365     1.0770    256     -0.41     0.6856     0.05    -2.5574     1.6844     
    AVISITN*TRTPN   14         2           35         1             3.5496     1.1919    249      2.98     0.0032     0.05     1.2022     5.8970     
    AVISITN*TRTPN   14         2           35         2             3.9926     0.6830    132      5.85     <.0001     0.05     2.6415     5.3438     
    AVISITN*TRTPN   14         2           35         3             0.4945     1.1353    251      0.44     0.6636     0.05    -1.7415     2.7304     
    AVISITN*TRTPN   14         2           42         1             3.3308     1.2893    232      2.58     0.0104     0.05     0.7906     5.8711     
    AVISITN*TRTPN   14         2           42         2             3.0544     0.6732    131      4.54     <.0001     0.05     1.7227     4.3861     
    AVISITN*TRTPN   14         2           42         3             0.2978     1.1211    251      0.27     0.7907     0.05    -1.9101     2.5057     
    AVISITN*TRTPN   14         3           21         1             2.0285     1.0435    246      1.94     0.0530     0.05   -0.02684     4.0838     
    AVISITN*TRTPN   14         3           21         2             1.8416     1.0397    252      1.77     0.0777     0.05    -0.2060     3.8892     
    AVISITN*TRTPN   14         3           21         3            0.07648     0.4315    135      0.18     0.8596     0.05    -0.7769     0.9299     
    AVISITN*TRTPN   14         3           28         1             3.1795     1.1699    236      2.72     0.0071     0.05     0.8747     5.4844     
    AVISITN*TRTPN   14         3           28         2             3.1706     1.1362    239      2.79     0.0057     0.05     0.9323     5.4088     
    AVISITN*TRTPN   14         3           28         3            -0.1671     0.5311    135     -0.31     0.7536     0.05    -1.2175     0.8833     
    AVISITN*TRTPN   14         3           35         1             3.8190     1.1734    236      3.25     0.0013     0.05     1.5074     6.1306     
    AVISITN*TRTPN   14         3           35         2             4.2621     1.1320    238      3.76     0.0002     0.05     2.0320     6.4921     
    AVISITN*TRTPN   14         3           35         3             0.7639     0.6655    135      1.15    0.2530     0.05    -0.5522     2.0799     
    AVISITN*TRTPN   14         3           42         1             3.6003     1.2722    219      2.83     0.0051     0.05     1.0929     6.1076     
    AVISITN*TRTPN   14         3           42         2             3.3238     1.1289    246      2.94     0.0035     0.05     1.1003     5.5473     
    AVISITN*TRTPN   14         3           42         3             0.5672     0.6438    130      0.88     0.3799     0.05    -0.7064     1.8409     
    AVISITN*TRTPN   21         1           21         2            -0.1868     1.1108    266     -0.17     0.8666     0.05    -2.3740     2.0003     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               23 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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            -1.9520     1.0750    255     -1.82     0.0706     0.05    -4.0690     0.1651     
   AVISITN*TRTPN   21         1           28         1             1.1511     0.5594    117      2.06     0.0418     0.05    0.04332     2.2589     
   AVISITN*TRTPN   21         1           28         2             1.1421     1.2016    261      0.95     0.3427     0.05    -1.2240     3.5082     
   AVISITN*TRTPN   21         1           28         3            -2.1955     1.1266    259     -1.95     0.0524     0.05    -4.4141    0.02302     
   AVISITN*TRTPN   21         1           35         1             1.7906     0.5443    116      3.29     0.0013     0.05     0.7125     2.8687     
   AVISITN*TRTPN   21         1           35         2             2.2336     1.1977    257      1.86     0.0633     0.05    -0.1249     4.5921     
   AVISITN*TRTPN   21         1           35         3            -1.2646     1.1825    260     -1.07     0.2859     0.05    -3.5931     1.0640     
   AVISITN*TRTPN   21         1           42         1             1.5718     0.6948    117      2.26     0.0255     0.05     0.1959     2.9478     
   AVISITN*TRTPN   21         1           42         2             1.2953     1.1947    261      1.08     0.2792     0.05    -1.0571     3.6478     
   AVISITN*TRTPN   21         1           42         3            -1.4612     1.1688    259     -1.25     0.2124     0.05    -3.7628     0.8404     
   AVISITN*TRTPN   21         2           21         3            -1.7652     1.0712    256     -1.65     0.1006     0.05    -3.8748     0.3444     
   AVISITN*TRTPN   21         2           28         1             1.3379     1.2304    259      1.09     0.2779     0.05    -1.0849     3.7607     
   AVISITN*TRTPN   21         2           28         2             1.3289     0.5423    125      2.45     0.0156     0.05     0.2557     2.4021     
   AVISITN*TRTPN   21         2           28         3            -2.0087     1.1231    257     -1.79     0.0749     0.05    -4.2203     0.2029     
   AVISITN*TRTPN   21         2           35         1             1.9774     1.2336    257      1.60     0.1102     0.05    -0.4519     4.4067     
   AVISITN*TRTPN   21         2           35         2             2.4204     0.4860    122      4.98     <.0001     0.05     1.4583     3.3826     
   AVISITN*TRTPN   21         2           35         3            -1.0778     1.1791    254     -0.91     0.3616     0.05    -3.3998     1.2443     
   AVISITN*TRTPN   21         2           42         1             1.7586     1.3280    243      1.32     0.1867     0.05    -0.8572     4.3745     
   AVISITN*TRTPN   21         2           42         2             1.4822     0.5617    123      2.64     0.0094     0.05     0.3702     2.5941     
   AVISITN*TRTPN   21         2           42         3            -1.2744     1.1654    254     -1.09     0.2752     0.05    -3.5694     1.0206     
   AVISITN*TRTPN   21         3           28         1             3.1031     1.1982    247      2.59     0.0102     0.05     0.7431     5.4630     
   AVISITN*TRTPN   21         3           28         2             3.0941     1.1652    246      2.66     0.0084     0.05     0.7991     5.3891     
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               24 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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            -0.2436     0.4409   129     -0.55     0.5816     0.05    -1.1158     0.6287     
    AVISITN*TRTPN   21         3           35         1             3.7425     1.2015    247      3.11     0.0021     0.05     1.3760     6.1091     
    AVISITN*TRTPN   21         3           35         2             4.1856     1.1611    246      3.60     0.0004     0.05     1.8987     6.4725     
    AVISITN*TRTPN   21         3           35         3             0.6874     0.4989    125      1.38     0.1707     0.05    -0.2999     1.6747     
    AVISITN*TRTPN   21         3           42         1             3.5238     1.2982    229      2.71     0.0071     0.05     0.9658     6.0817     
    AVISITN*TRTPN   21         3           42         2             3.2473     1.1580    252      2.80    0.0054     0.05     0.9667     5.5279     
    AVISITN*TRTPN   21         3           42         3             0.4908     0.5209    118      0.94     0.3481     0.05    -0.5408     1.5223     
    AVISITN*TRTPN   28         1           28         2           -0.00898     1.3130    269     -0.01     0.9945     0.05    -2.5940     2.5760     
    AVISITN*TRTPN   28         1           28         3            -3.3466     1.2447    256     -2.69     0.0076     0.05    -5.7977    -0.8955     
    AVISITN*TRTPN   28         1           35         1             0.6395     0.4336    113      1.47     0.1430     0.05    -0.2195     1.4985     
    AVISITN*TRTPN   28         1           35         2             1.0825     1.3093    266      0.83    0.4091     0.05    -1.4955     3.6605     
    AVISITN*TRTPN   28         1           35         3            -2.4157     1.2955    265     -1.86     0.0633     0.05    -4.9664     0.1351     
    AVISITN*TRTPN   28         1           42         1             0.4207     0.5447    112      0.77     0.4416     0.05    -0.6586     1.5001     
    AVISITN*TRTPN   28         1           42         2             0.1442     1.3066    267      0.11     0.9122     0.05    -2.4283     2.7168     
    AVISITN*TRTPN   28         1           42         3            -2.6123     1.2830    261     -2.04     0.0427     0.05    -5.1386   -0.08601     
    AVISITN*TRTPN   28         2           28         3            -3.3376     1.2130    252     -2.75     0.0064     0.05    -5.7265    -0.9488     
    AVISITN*TRTPN   28         2           35         1             0.6485     1.3160    268      0.49     0.6226     0.05    -1.9426     3.2395     
    AVISITN*TRTPN   28         2           35         2             1.0915     0.4672    117      2.34     0.0212     0.05     0.1662     2.0168     
    AVISITN*TRTPN   28         2           35         3            -2.4067     1.2650    256     -1.90     0.0582     0.05    -4.8978    0.08446     
    AVISITN*TRTPN   28         2           42         1             0.4297     1.4049    260      0.31     0.7600     0.05    -2.3367     3.1961     
    AVISITN*TRTPN   28         2           42         2             0.1532     0.5269    120      0.29     0.7717     0.05    -0.8901     1.1966     
    AVISITN*TRTPN   28         2           42         3            -2.6033     1.2522    255     -2.08     0.0386     0.05    -5.0693    -0.1373     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               25 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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             3.9861     1.2479    256      3.19     0.0016     0.05     1.5286     6.4436     
    AVISITN*TRTPN   28         3           35         2             4.4291     1.2091    256      3.66     0.0003     0.05     2.0482     6.8101     
    AVISITN*TRTPN   28         3           35         3             0.9310     0.4637    127      2.01     0.0468     0.05    0.01342     1.8485     
    AVISITN*TRTPN   28         3           42         1             3.7673     1.3413    241      2.81     0.0054     0.05     1.1252     6.4095     
    AVISITN*TRTPN   28         3           42         2             3.4909     1.2061    259      2.89     0.0041     0.05     1.1159     5.8659     
    AVISITN*TRTPN   28         3           42         3             0.7343     0.4577    117      1.60     0.1113     0.05    -0.1721     1.6408     
    AVISITN*TRTPN   35         1           35         2             0.4430     1.3124    264      0.34     0.7359     0.05    -2.1410     3.0271     
    AVISITN*TRTPN   35         1           35         3            -3.0551     1.2986    265     -2.35     0.0194     0.05    -5.6120    -0.4983     
    AVISITN*TRTPN   35         1           42         1            -0.2188     0.4942    109     -0.44     0.6589     0.05    -1.1982     0.7607     
    AVISITN*TRTPN   35         1           42         2            -0.4952     1.3097    266     -0.38     0.7056     0.05    -3.0739     2.0834     
    AVISITN*TRTPN   35         1           42         3            -3.2518     1.2861    261     -2.53     0.0121     0.05    -5.7843    -0.7193     
    AVISITN*TRTPN   35         2           35         3            -3.4982     1.2613    258     -2.77     0.0059     0.05    -5.9819    -1.0145     
    AVISITN*TRTPN   35         2           42         1            -0.6618     1.4015    256     -0.47     0.6372     0.05    -3.4217     2.0981     
    AVISITN*TRTPN   35         2           42         2            -0.9383     0.5462    119     -1.72     0.0884     0.05    -2.0198     0.1432     
    AVISITN*TRTPN   35         2           42         3            -3.6948     1.2485    258     -2.96     0.0034     0.05    -6.1533    -1.2363     
    AVISITN*TRTPN   35         3           42         1             2.8364     1.3886    253      2.04     0.0421     0.05     0.1018     5.5710     
    AVISITN*TRTPN   35         3           42         2             2.5599     1.2584    261      2.03     0.0429     0.05    0.08197     5.0379     
    AVISITN*TRTPN   35         3           42         3            -0.1966     0.4806    120     -0.41     0.6832     0.05    -1.1482     0.7549     
    AVISITN*TRTPN   42         1           42         2            -0.2765     1.3989    258     -0.20     0.8435     0.05    -3.0313     2.4783     
    AVISITN*TRTPN   42         1           42         3            -3.0330     1.3769    249     -2.20     0.0285     0.05    -5.7448    -0.3212     
    AVISITN*TRTPN   42         2           42         3            -2.7565     1.2456    260     -2.21     0.0278     0.05    -5.2094    -0.3037     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               26 OF 26
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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     257       1.52    0.2216                                            
                                           AVISITN*TRTPN    14             2     265       0.50    0.6098                                            
                                           AVISITN*TRTPN    21             2     259       2.06    0.1301                                            
                                           AVISITN*TRTPN    28             2     261       5.16    0.0063                                            
                                           AVISITN*TRTPN    35             2     262       4.53    0.0117                                            
                                           AVISITN*TRTPN    42             2     260       3.39    0.0352                                            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMDX2; TABLE: stat1l.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                                  
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-4.10      FINAL                                                             
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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         437   
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                     
                                               
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               7 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                              8 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                     72                                                          
                                                       Columns in Z                      0                                                          
                                                       Subjects                        437                                                          
                                                       Max Obs per Subject               6                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                             Number of Observations                                                                 
                                                                                                                                                    
                                                   Number of Observations Read            2288                                                      
                                                   Number of Observations Used            2288                                                      
                                                   Number of Observations Not Used           0                                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                Iteration History                                                                   
                                                                                                                                                    
                                           Iteration    Evaluations    -2 Res Log Like       Criterion                                              
                                                                                                                                                    
                                                   0              1      5394.49812760                                                              
                                                   1              2      3445.02451748      0.00188171                                              
                                                   2              1      3444.38818261      0.00001015                                              
                                                   3              1      3444.38487436      0.00000000                                              
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       0.3229                                                            
                                                         UN(2,1)     SUBJID       0.2034                                                            
                                                         UN(2,2)     SUBJID       0.4814                                                            
                                                         UN(3,1)     SUBJID       0.1871                                                            
                                                         UN(3,2)     SUBJID       0.4119                                                            
                                                         UN(3,3)     SUBJID       0.6159                                                            
                                                         UN(4,1)     SUBJID       0.1907                                                            
                                                         UN(4,2)     SUBJID       0.3954                                                            
                                                         UN(4,3)     SUBJID       0.5303                                                            
                                                         UN(4,4)     SUBJID       0.6979                                                            
                                                         UN(5,1)     SUBJID       0.1737                                                            
                                                         UN(5,2)     SUBJID       0.4163                                                            
                                                         UN(5,3)     SUBJID       0.5399                                                            
                                                         UN(5,4)     SUBJID       0.5865                                                            
                                                         UN(5,5)     SUBJID       0.7044                                                            
                                                         UN(6,1)     SUBJID       0.2284                                                            
                                                         UN(6,2)     SUBJID       0.4456                                                            
                                                         UN(6,3)     SUBJID       0.5853                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       0.6539                                                            
                                                         UN(6,5)     SUBJID       0.6649                                                            
                                                         UN(6,6)     SUBJID       0.8820                                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                 Fit Statistics                                                                     
                                                                                                                                                    
                                                      -2 Res Log Likelihood          3444.4                                                         
                                                      AIC (Smaller is Better)        3486.4                                                         
                                                      AICC (Smaller is Better)       3486.8                                                         
                                                      BIC (Smaller is Better)        3572.1                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                         Null Model Likelihood Ratio Test                                                           
                                                                                                                                                    
                                                           DF    Chi-Square      Pr > ChiSq                                                         
                                                                                                                                                    
                                                           20       1950.11          <.0001                                                         
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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     380       2.29    0.0451                                                  
                                                 TRTPN               2     400       2.66    0.0710                                                  
                                                 AVISITN*TRTPN      10     562       1.94    0.0377                                                  
                                                 POOLCNTR           37     395       1.39    0.0694                                                  
                                                 BASE*AVISITN        6     423       4.40    0.0003                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                     Estimates                                                                       
                                                                                                                                                     
                                                    Standard                                                                                         
                       Label            Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper                       
                                                                                                                                                     
                       DAY7  1 vs 3     -0.07467     0.06756     397      -1.11      0.2697      0.05     -0.2075     0.05815                        
                       DAY7  2 vs 3     -0.01014     0.06743     397      -0.15      0.8805      0.05     -0.1427      0.1224                        
                       DAY14  1 vs 3    -0.04254     0.08369     401      -0.51      0.6115      0.05     -0.2071      0.1220                        
                       DAY14  2 vs 3    -0.04226     0.08328     398      -0.51      0.6121      0.05     -0.2060      0.1215                        
                       DAY21  1 vs 3     -0.1321     0.09557     392      -1.38      0.1678      0.05     -0.3200     0.05583                        
                       DAY21  2 vs 3     -0.1574     0.09468     385      -1.66      0.0971      0.05     -0.3436     0.02870                        
                       DAY28  1 vs 3     -0.1752      0.1030     403      -1.70      0.0898      0.05     -0.3778     0.02735                        
                       DAY28  2 vs 3     -0.2175      0.1019     396      -2.13      0.0334      0.05     -0.4178    -0.01719                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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     -0.1864      0.1039     401      -1.79      0.0736      0.05     -0.3907     0.01789                        
                      DAY35  2 vs 3     -0.3316      0.1032     398      -3.21      0.0014      0.05     -0.5345     -0.1288                        
                       DAY42  1 vs 3     -0.2664      0.1169     407      -2.28      0.0232      0.05     -0.4963    -0.03659                        
                       DAY42  2 vs 3     -0.2789      0.1155     399      -2.42      0.0162      0.05     -0.5059    -0.05194                        
                                                                                                                                                     
                                                                                                                                                     
                                                                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             -0.3156     0.05150     409      -6.13      <.0001      0.05     -0.4169     -0.2144            
          AVISITN*TRTPN     7          2             -0.2511     0.05228     413      -4.80      <.0001      0.05     -0.3539     -0.1483            
          AVISITN*TRTPN     7          3             -0.2410     0.05226     411      -4.61      <.0001      0.05     -0.3437     -0.1383            
          AVISITN*TRTPN    14          1             -0.4574     0.06241     434      -7.33      <.0001      0.05     -0.5801     -0.3348            
          AVISITN*TRTPN    14          2             -0.4571     0.06273     440      -7.29      <.0001      0.05     -0.5804     -0.3339            
          AVISITN*TRTPN    14          3             -0.4149     0.06281     439      -6.61      <.0001      0.05     -0.5383     -0.2914            
          AVISITN*TRTPN    21          1             -0.5918     0.07085     432      -8.35      <.0001      0.05     -0.7311     -0.4526            
          AVISITN*TRTPN    21          2             -0.6172     0.07042     432      -8.76      <.0001      0.05     -0.7556     -0.4788            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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             -0.4598     0.07038     430      -6.53      <.0001      0.05     -0.5981     -0.3214            
          AVISITN*TRTPN    28          1             -0.6662     0.07633     445      -8.73      <.0001      0.05     -0.8162     -0.5162            
          AVISITN*TRTPN    28          2             -0.7085     0.07549     445      -9.38      <.0001      0.05     -0.8569     -0.5601            
          AVISITN*TRTPN    28          3             -0.4910     0.07503     437      -6.54      <.0001      0.05     -0.6385     -0.3435            
          AVISITN*TRTPN    35          1             -0.6877     0.07674     439      -8.96      <.0001      0.05     -0.8385     -0.5369            
          AVISITN*TRTPN    35          2             -0.8330     0.07652     449     -10.89      <.0001      0.05     -0.9833     -0.6826            
          AVISITN*TRTPN    35          3             -0.5013     0.07580     435      -6.61      <.0001      0.05     -0.6503     -0.3523            
          AVISITN*TRTPN    42          1             -0.7818     0.08592     443      -9.10      <.0001      0.05     -0.9507     -0.6130            
          AVISITN*TRTPN    42          2             -0.7943     0.08453     440      -9.40      <.0001      0.05     -0.9605     -0.6282            
          AVISITN*TRTPN    42          3             -0.5154     0.08437     438      -6.11      <.0001      0.05     -0.6812     -0.3496            
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 14
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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     397       0.72    0.4872                                            
                                          AVISITN*TRTPN    14             2     400       0.17    0.8421                                            
                                          AVISITN*TRTPN    21             2     390       1.59    0.2056                                            
                                          AVISITN*TRTPN    28             2     402       2.56    0.0788                                            
                                          AVISITN*TRTPN    35             2     402       5.19    0.0059                                            
                                          AVISITN*TRTPN    42             2     405       3.70    0.0257                                            
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: MMRMOUT; TABLE: stat1cgisa.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                              
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.1      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                       40      46.6607952       1.1665199       1.38    0.0659                                  
                                                                                                                                                    
                               Error                      396     333.8884039       0.8431525                                                       
                                                                                                                                                    
                               Corrected Total            436     380.5491991                                                                       
                                                                                                                                                    
                                                                                                                                                    
                                                R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                    
                                                0.122614     -136.9515      0.918233     -0.670481                                                  
                                                                                                                                                    
                                                                                                                                                    
                               Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                    
                               TRTPN                        2      4.37202022      2.18601011       2.59    0.0761                                  
                               POOLCNTR                    37     31.85599793      0.86097292       1.02    0.4390                                  
                               BASE                         1      9.96617520      9.96617520      11.82    0.0006                                  
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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            146      -0.71917808       1.02212187       4.47945205       0.60136830                                 
                               2            147      -0.76190476       0.94603233       4.53061224       0.60029813                                 
                               3            144      -0.52777778       0.81028739       4.51388889       0.55452507                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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         -0.71916295      0.08370474      <.0001           1                                             
                                           2         -0.72793134      0.08502853      <.0001           2                                             
                                           3         -0.50965777      0.08513983      <.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                      0.9353        0.0543                                                    
                                                      2        0.9353                      0.0445                                                    
                                                      3        0.0543        0.0445                                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                 TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                     
                                                 1           -0.719163       -0.883724    -0.554602                                                  
                                                 2           -0.727931       -0.895095    -0.560768                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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           -0.509658       -0.677040    -0.342275                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for Effect TRTPN                                                         
                                                                                                                                                    
                                                           Difference                                                                               
                                                              Between    95% Confidence Limits for                                                  
                                               i    j           Means       LSMean(i)-LSMean(j)                                                     
                                                                                                                                                    
                                               1    2        0.008768       -0.203504     0.221040                                                  
                                               1    3       -0.209505       -0.422864     0.003854                                                  
                                               2    3       -0.218274       -0.431132    -0.005415                                                  
                                                                                                                                                     
                                                                                                                                                     
NOTE: To ensure overall protection level, only probabilities associated with pre-planned comparisons should be used.                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                   -0.20950519      0.10852592      -1.93      0.0543                                      
                                    2 vs 3                   -0.21827357      0.10827131      -2.02      0.0445                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1cgisb.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.2      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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      14.8047973       4.9349324       5.84    0.0006                                  
                                                                                                                                                     
                                Error                      433     365.7444018       0.8446753                                                       
                                                                                                                                                     
                                Corrected Total            436     380.5491991                                                                       
                                                                                                                                                     
                                                                                                                                                     
                                                 R-Square     Coeff Var      Root MSE      CHG Mean                                                  
                                                                                                                                                     
                                                 0.038904     -137.0751      0.919062     -0.670481                                                  
                                                                                                                                                     
                                                                                                                                                     
                                Source                      DF     Type III SS     Mean Square    F Value    Pr > F                                  
                                                                                                                                                     
                                TRTPN                        2      4.53162949      2.26581475       2.68    0.0695                                  
                                BASE                         1     10.29745513     10.29745513      12.19    0.0005                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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            146      -0.71917808       1.02212187       4.47945205       0.60136830                                 
                               2            147      -0.76190476       0.94603233       4.53061224       0.60029813                                 
                               3            144      -0.52777778       0.81028739       4.51388889       0.55452507                                 
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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         -0.72668484      0.07609251      <.0001           1                                             
                                           2         -0.75596312      0.07582207      <.0001           2                                             
                                           3         -0.52623218      0.07658979      <.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                      0.7854        0.0641                                                    
                                                      2        0.7854                      0.0336                                                    
                                                      3       0.0641        0.0336                                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                 TRTPN      CHG LSMEAN      95% Confidence Limits                                                    
                                                                                                                                                     
                                                 1           -0.726685       -0.876241    -0.577128                                                  
                                                 2           -0.755963       -0.904988    -0.606938                                                  
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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           -0.526232       -0.676766    -0.375698                                                  
                                                                                                                                                    
                                                                                                                                                    
                                                       Least Squares Means for Effect TRTPN                                                         
                                                                                                                                                    
                                                           Difference                                                                               
                                                              Between    95% Confidence Limits for                                                  
                                               i    j           Means       LSMean(i)-LSMean(j)                                                     
                                                                                                                                                    
                                               1    2        0.029278       -0.181918     0.240475                                                  
                                               1    3       -0.200453       -0.412667     0.011762                                                  
                                               2    3       -0.229731       -0.441540    -0.017922                                                  
                                                                                                                                                     
                                                                                                                                                     
NOTE: To ensure overall protection level, only probabilities associated with pre-planned comparisons should be used.                                 
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 6
PROTOCOL 405-201-00013                                                                                                                               
                                                                      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                   -0.20045266      0.10797208      -1.86      0.0641                                      
                                    2 vs 3                   -0.22973094      0.10776584      -2.13      0.0336                                      
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
SOURCE: GLMOUT; TABLE: stat1cgisc.lis; RUN: 18JUN2020 10:00; ANALYSIS DATASET CREATED: 11JUN2020 07:28                                               
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/stat1.sas                                                                   
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-5.3      FINAL                                                              
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               2 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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  -0.10717    Pr > |t|    0.9147                                                   
                                                 Sign           M      30.5    Pr >= |M|   0.0037                                                   
                                                 Signed Rank    S    4507.5    Pr >= |S|   0.0794                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.950477    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.096707    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  1.114552    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq   6.25502    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               3 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       18.12976                                                                
                                                              99%            14.28640                                                                
                                                              95%             9.63500                                                                
                                                              90%             7.03550                                                                
                                                              75% Q3          4.19872                                                                
                                                              50% Median      1.02764                                                                
                                                              25% Q1         -3.24896                                                                
                                                              10%            -9.50864                                                                
                                                              5%            -13.14533                                                                
                                                              1%            -22.53575                                                                
                                                              0% Min        -26.41979                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               4 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                    
         -26.4198   40520100013-
                         31         14.2864   40520100013-
                        253           
         -25.0595   40520100013-
                        241         14.5137   40520100013-
                        127           
         -24.7070   40520100013-
                        345         15.9196   40520100013-
                        344           
         -23.8012   40520100013-
                        126         17.4347   40520100013-
                        336           
         -22.5358   40520100013-
                        215         18.1298   40520100013-
                        348           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               5 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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                         429    Sum Weights                429                                            
                                         Mean               -0.0055696    Sum Observations    -2.3893447                                            
                                         Std Deviation      0.99907873    Variance            0.99815832                                            
                                         Skewness           -0.8889627    Kurtosis            1.51349761                                            
                                          Uncorrected SS     427.225068    Corrected SS         427.21176                                            
                                          Coeff Variation    -17938.172    Std Error Mean      0.04823598                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.00557     Std Deviation            0.99908                                                
                                              Median    0.14511     Variance                 0.99816                                                
                                               Mode     -0.84411     Range                    6.28819                                                
                                                                     Interquartile Range      1.08259                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 2 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               6 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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  -0.11547    Pr > |t|    0.9081                                                   
                                                  Sign           M      30.5    Pr >= |M|   0.0037                                                   
                                                  Signed Rank    S    4427.5    Pr >= |S|   0.0849                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                Tests for Normality                                                                  
                                                                                                                                                     
                                             Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                     
                                             Shapiro-Wilk          W     0.951168    Pr < W     <0.0001                                              
                                             Kolmogorov-Smirnov    D     0.096496    Pr > D     <0.0100                                              
                                             Cramer-von Mises      W-Sq  1.109796    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  6.205792    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                              7 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       2.547354                                                                
                                                             99%            2.106636                                                                
                                                             95%            1.406654                                                                
                                                             90%            1.041059                                                                
                                                             75% Q3         0.623263                                                                
                                                             50% Median     0.145113                                                                
                                                             25% Q1        -0.459331                                                                
                                                             10%           -1.394934                                                                
                                                              5%            -1.925385                                                                
                                                              1%            -3.293143                                                                
                                                              0% Min        -3.740832                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               8 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                    
         -3.74083   40520100013-
                         31         2.10664   40520100013-
                        253           
         -3.59734   40520100013-
                        241         2.14602   40520100013-
                        127           
         -3.51327   40520100013-
                        126         2.23609   40520100013-
                        344           
         -3.47412   40520100013-
                        345         2.45134   40520100013-
                        336           
         -3.29314   40520100013-
                        215         2.54735   40520100013-
                        348           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               9 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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                         406    Sum Weights                406                                            
                                         Mean               -0.0512213    Sum Observations    -20.795843                                            
                                          Std Deviation      8.29126377    Variance             68.745055                                            
                                          Skewness            -0.918599    Kurtosis            0.87158088                                            
                                          Uncorrected SS     27842.8125    Corrected SS        27841.7473                                            
                                          Coeff Variation    -16187.144    Std Error Mean      0.41148851                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.05122     Std Deviation            8.29126                                                
                                               Median    1.44518     Variance                68.74505                                                
                                               Mode     -4.28518     Range                   45.92221                                                
                                                                     Interquartile Range     10.09103                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 4 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               10 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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  -0.12448    Pr > |t|    0.9010                                                   
                                                  Sign           M        33    Pr >= |M|   0.0012                                                   
                                                  Signed Rank    S    4233.5    Pr >= |S|   0.0735                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                Tests for Normality                                                                  
                                                                                                                                                     
                                             Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                     
                                             Shapiro-Wilk          W     0.946146    Pr < W     <0.0001                                              
                                             Kolmogorov-Smirnov    D     0.091654    Pr > D     <0.0100                                              
                                             Cramer-von Mises      W-Sq  1.123579    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  6.515695    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               11 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       18.12438                                                                
                                                              99%            15.31626                                                                
                                                              95%            10.82306                                                                
                                                              90%             8.96116                                                                
                                                              75% Q3          5.77732                                                                
                                                              50% Median      1.44518                                                                
                                                              25% Q1         -4.31372                                                                
                                                              10%           -11.65152                                                                
                                                              5%            -16.87371                                                                
                                                              1%            -25.37928                                                                
                                                              0% Min        -27.79784                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               12 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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           
                                                                                                                                                     
          -27.7978   40520100013-
                       729         15.3163   40520100013-
                        630           
          -26.3480   40520100013-
                       701         15.4412   40520100013-
                        549           
          -26.1345   40520100013-
                       586         15.9561   40520100013-
                        747           
          -25.7353   40520100013-
                       459         17.3297   40520100013-
                        748           
          -25.3793   40520100013-
                       664         18.1244   40520100013-
                        746           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               13 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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                         406    Sum Weights                406                                            
                                         Mean               -0.0056236    Sum Observations     -2.283187                                            
                                         Std Deviation       1.0070444    Variance            1.01413842                                            
                                         Skewness           -0.9021239    Kurtosis            0.83485956                                            
                                          Uncorrected SS     410.738899    Corrected SS        410.726059                                            
                                          Coeff Variation    -17907.426    Std Error Mean      0.04997877                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.00562     Std Deviation            1.00704                                                
                                               Median    0.17363     Variance                 1.01414                                                
                                              Mode     -0.51324     Range                    5.55938                                                
                                                                     Interquartile Range      1.22582                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 4 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               14 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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  -0.11252    Pr > |t|    0.9105                                                   
                                                  Sign           M        33    Pr >= |M|   0.0012                                                   
                                                  Signed Rank    S    4183.5    Pr >= |S|   0.0770                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                Tests for Normality                                                                  
                                                                                                                                                     
                                             Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                     
                                             Shapiro-Wilk          W     0.947415    Pr < W     <0.0001                                              
                                             Kolmogorov-Smirnov    D     0.091557    Pr > D     <0.0100                                              
                                             Cramer-von Mises      W-Sq  1.124298    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  6.464081    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               15 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       2.162711                                                                
                                                             99%            1.902737                                                                
                                                             95%            1.310225                                                                
                                                             90%            1.083757                                                                
                                                             75% Q3         0.706394                                                                
                                                             50% Median     0.173632                                                                
                                                             25% Q1        -0.519422                                                                
                                                             10%           -1.416902                                                                
                                                              5%            -2.033019                                                                
                                                              1%            -3.115779                                                                
                                                              0% Min        -3.396667                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               16 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                    
         -3.39667   40520100013-
                        729         1.90274   40520100013-
                        747           
         -3.16989   40520100013-
                        701         1.90542   40520100013-
                        549           
         -3.12956   40520100013-
                        664         2.01127   40520100013-
                        554           
         -3.11745   40520100013-
                        547         2.06617   40520100013-
                        748           
         -3.11578   40520100013-
                        586         2.16271   40520100013-
                        746           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               17 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                         391    Sum Weights                391                                            
                                          Mean               -0.1603789    Sum Observations    -62.708169                                            
                                          Std Deviation      8.75757561    Variance            76.6951306                                            
                                          Skewness           -0.7967468    Kurtosis            0.37509191                                            
                                          Uncorrected SS      29921.158    Corrected SS         29911.101                                            
                                          Coeff Variation    -5460.5518    Std Error Mean      0.44288964                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.16038     Std Deviation            8.75758                                                
                                               Median    1.40218     Variance                76.69513                                                
                                               Mode     -4.23564     Range                   49.66442                                                
                                                                     Interquartile Range     11.21801                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 3 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               18 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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  -0.36212    Pr > |t|    0.7175                                                   
                                                 Sign           M      24.5    Pr >= |M|   0.0151                                                   
                                                 Signed Rank    S      2593    Pr >= |S|   0.2467                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W      0.95566    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.082594    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.827025    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  5.002996    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               19 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       17.73069                                                                
                                                              99%            14.32811                                                                
                                                              95%            11.25169                                                                
                                                              90%             9.52209                                                                
                                                              75% Q3          6.20743                                                                
                                                              50% Median      1.40218                                                                
                                                              25% Q1         -5.01058                                                                
                                                              10%           -12.76245                                                                
                                                              5%            -17.32377                                                                
                                                              1%            -23.46337                                                                
                                                              0% Min        -31.93373                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               20 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                     
          -31.9337   40520100013
                       988         14.1209   40520100013-
                      1020           
         -30.9690   40520100013
                      1101         14.3281   40520100013-
                      1146           
         -24.7107   40520100013
                      1129         14.3988   40520100013-
                      1192           
         -23.4634   40520100013
                       865         15.9977   40520100013-
                       958           
         -22.6585   40520100013
                       952         17.7307   40520100013-
                       955           
                                
                                                          
                                      
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               21 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                         391    Sum Weights                391                                            
                                          Mean               -0.0173302    Sum Observations    -6.7761143                                            
                                          Std Deviation       1.0026023    Variance            1.00521137                                            
                                          Skewness           -0.7767798    Kurtosis            0.33565986                                            
                                          Uncorrected SS     392.149864    Corrected SS        392.032433                                            
                                          Coeff Variation    -5785.2846    Std Error Mean      0.05070378                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.01733     Std Deviation            1.00260                                                
                                               Median    0.15766     Variance                 1.00521                                                
                                               Mode     -0.47523     Range                    5.64738                                                
                                                                     Interquartile Range      1.29404                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 3 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               22 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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  -0.34179    Pr > |t|    0.7327                                                   
                                                 Sign           M      24.5    Pr >= |M|   0.0151                                                   
                                                 Signed Rank    S      2567    Pr >= |S|   0.2515                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.957454    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.082316    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.809936    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  4.874627    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               23 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       2.056753                                                                
                                                              99%            1.617161                                                                
                                                              95%            1.320311                                                                
                                                              90%            1.079049                                                                
                                                              75% Q3         0.709824                                                                
                                                              50% Median     0.157662                                                                
                                                              25% Q1        -0.584218                                                                
                                                              10%           -1.446331                                                                
                                                              5%            -2.015562                                                                
                                                              1%            -2.649605                                                                
                                                              0% Min        -3.590625                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               24 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                    
         -3.59062   40520100013-
                        988         1.61159   40520100013-
                      1146           
         -3.51155   40520100013-
                       1101         1.61716   40520100013-
                      1020           
         -2.83912   40520100013-
                       1129         1.63078   40520100013-
                      1192           
         -2.64961   40520100013-
                        865         1.99613   40520100013-
                       958           
         -2.63088   40520100013-
                        952         2.05675   40520100013-
                       955           
                                
                                                                                                          
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               25 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                         370    Sum Weights                370                                            
                                          Mean               -0.4073769    Sum Observations    -150.72947                                            
                                          Std Deviation      10.1669831    Variance            103.367545                                            
                                          Skewness           -0.7010249    Kurtosis            0.12558616                                            
                                          Uncorrected SS     38204.0278    Corrected SS        38142.6241                                            
                                          Coeff Variation    -2495.7189    Std Error Mean      0.52855628                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.40738     Std Deviation           10.16698                                                
                                               Median    1.71750     Variance               103.36754                                                
                                               Mode      7.54797     Range                   54.45127                                                
                                                                     Interquartile Range     14.48720                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 2 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               26 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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  -0.77074    Pr > |t|    0.4414                                                   
                                                  Sign           M        25    Pr >= |M|   0.0108                                                   
                                                  Signed Rank    S    1007.5    Pr >= |S|   0.6252                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                Tests for Normality                                                                  
                                                                                                                                                     
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                     
                                             Shapiro-Wilk          W     0.959992    Pr < W     <0.0001                                              
                                             Kolmogorov-Smirnov    D     0.090634    Pr > D     <0.0100                                              
                                             Cramer-von Mises      W-Sq  0.856785    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  4.871079    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               27 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       20.54164                                                                
                                                             99%            18.23384                                                                
                                                             95%            12.28388                                                                
                                                             90%            10.47477                                                                
                                                             75% Q3          7.54797                                                                
                                                             50% Median      1.71750                                                                
                                                             25% Q1         -6.93923                                                                
                                                             10%           -14.81352                                                                
                                                             5%            -20.55486                                                                
                                                              1%            -29.58661                                                                
                                                              0% Min        -33.90962                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               28 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                     
          -33.9096   40520100013-
                       1498         18.2304   40520100013-
                       1344           
          -31.7656   40520100013-
                       1517         18.2338   40520100013-
                       1519           
          -31.3573   40520100013-
                       1478         19.0985   40520100013-
                       1518           
          -29.5866   40520100013-
                       1372         20.0136   40520100013-
                       1589           
          -28.0541   40520100013-
                       1504         20.5416   40520100013-
                       1341           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               29 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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                         370    Sum Weights                370                                            
                                          Mean                -0.040986    Sum Observations    -15.164837                                            
                                          Std Deviation      1.01442638    Variance            1.02906089                                            
                                          Skewness           -0.6955724    Kurtosis            0.11422617                                            
                                          Uncorrected SS     380.345015    Corrected SS        379.723468                                            
                                          Coeff Variation     -2475.053    Std Error Mean      0.05273752                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.04099     Std Deviation            1.01443                                                
                                               Median    0.16987     Variance                 1.02906                                                
                                               Mode      0.74219     Range                    5.47903                                                
                                                                     Interquartile Range      1.45931                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 2 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               30 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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  -0.77717    Pr > |t|    0.4376                                                   
                                                 Sign           M        25    Pr >= |M|   0.0108                                                   
                                                 Signed Rank    S     976.5    Pr >= |S|   0.6359                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                                Tests for Normality                                                                  
                                                                                                                                                     
                                             Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                     
                                             Shapiro-Wilk          W      0.96038    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D      0.09143    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.859455    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq     4.871    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               31 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       2.070287                                                                
                                                             99%            1.881686                                                                
                                                             95%            1.228575                                                                
                                                             90%            1.053543                                                                
                                                             75% Q3         0.747789                                                                
                                                             50% Median     0.169875                                                                
                                                             25% Q1        -0.711522                                                                
                                                             10%           -1.471843                                                                
                                                              5%            -2.092184                                                                
                                                              1%            -2.912932                                                                
                                                              0% Min        -3.408746                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               32 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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           
                                                                                                     
                                      
          -3.40875   40520100013-
                       1498         1.79657   40520100013-
                       1519           
          -3.13286   40520100013-
                       1517         1.88169   40520100013-
                       1518           
          -3.10958   40520100013-
                       1478         1.93934   40520100013-
                       1344           
          -2.91293   40520100013-
                       1372         1.97622   40520100013-
                       1589           
          -2.80668   40520100013-
                       1504         2.07029   40520100013-
                       1341           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               33 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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                         349    Sum Weights                349                                            
                                         Mean               -0.4303981    Sum Observations    -150.20894                                            
                                         Std Deviation      10.4068682    Variance            108.302907                                            
                                         Skewness           -0.5781918    Kurtosis             -0.263225                                            
                                          Uncorrected SS     37754.0612    Corrected SS        37689.4115                                            
                                          Coeff Variation    -2417.9632    Std Error Mean      0.55706689                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.43040     Std Deviation           10.40687                                                
                                               Median    1.66772     Variance               108.30291                                                
                                               Mode     -6.91304     Range                   55.34813                                                
                                                                     Interquartile Range     14.82125                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 5 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               34 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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  -0.77261    Pr > |t|    0.4403                                                   
                                                 Sign           M      15.5    Pr >= |M|   0.1082                                                   
                                                 Signed Rank    S     345.5    Pr >= |S|   0.8550                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.964262    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.092832    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq   0.74979    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  4.328771    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               35 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       22.75938                                                                
                                                             99%            17.91271                                                                
                                                             95%            12.68687                                                                
                                                             90%            10.84392                                                                
                                                             75% Q3          7.40753                                                                
                                                             50% Median      1.66772                                                                
                                                             25% Q1         -7.41372                                                                
                                                             10%           -15.22456                                                                
                                                             5%            -20.06777                                                                
                                                              1%            -26.48683                                                                
                                                              0% Min        -32.58874                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                              36 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                    
         -32.5887   40520100013-
                       1852         17.4072   40520100013-
                       1877           
         -31.9099   40520100013-
                       1833         17.9127   40520100013-
                       1872           
         -26.7640   40520100013-
                       1731         17.9954   40520100013-
                       1891           
         -26.4868   40520100013-
                       1694         18.6219   40520100013-
                       1938           
         -26.1038   40520100013-
                       1857         22.7594   40520100013-
                       1702           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               37 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                         349    Sum Weights                349                                            
                                          Mean               -0.0428873    Sum Observations    -14.967661                                            
                                          Std Deviation       1.0147428    Variance            1.02970295                                            
                                          Skewness           -0.5766127    Kurtosis            -0.2605306                                            
                                          Uncorrected SS     358.978549    Corrected SS        358.336627                                            
                                          Coeff Variation    -2366.0694    Std Error Mean      0.05431794                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.04289     Std Deviation            1.01474                                                
                                               Median    0.16924     Variance                 1.02970                                                
                                               Mode     -0.67533     Range                    5.44081                                                
                                                                     Interquartile Range      1.43320                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 5 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               38 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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  -0.78956    Pr > |t|    0.4303                                                   
                                                 Sign           M      15.5    Pr >= |M|   0.1082                                                   
                                                 Signed Rank    S     313.5    Pr >= |S|   0.8683                                                   
                                                                                                                                                    
                                                                                                                                                    
                                                               Tests for Normality                                                                  
                                                                                                                                                    
                                            Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                    
                                            Shapiro-Wilk          W     0.964473    Pr < W     <0.0001                                              
                                            Kolmogorov-Smirnov    D     0.092875    Pr > D     <0.0100                                              
                                            Cramer-von Mises      W-Sq  0.750058    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  4.316386    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               39 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       2.240482                                                                
                                                              99%            1.731891                                                                
                                                              95%            1.229753                                                                
                                                              90%            1.062172                                                                
                                                              75% Q3         0.718334                                                                
                                                              50% Median     0.169236                                                                
                                                              25% Q1        -0.714868                                                                
                                                              10%           -1.501925                                                                
                                                              5%            -1.944037                                                                
                                                              1%            -2.576562                                                                
                                                              0% Min        -3.200330                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               40 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                     
          -3.20033   40520100013-
                       1852         1.72589   40520100013
                       1872           
          -3.09371   40520100013-
                       1833         1.73189   40520100013
                       1891           
          -2.60303   40520100013-
                       1694         1.74498   40520100013
                       1705           
          -2.57656   40520100013-
                       1731         1.79761   40520100013
                       1938           
          -2.55159   40520100013-
                       1857         2.24048   40520100013
                       1702           
                                 
                                                                                                           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               41 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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                         347    Sum Weights                347                                            
                                          Mean               -0.3635827    Sum Observations    -126.16319                                            
                                          Std Deviation      10.8189753    Variance            117.050226                                            
                                          Skewness           -0.8029258    Kurtosis            0.15184193                                            
                                          Uncorrected SS     40545.2491    Corrected SS        40499.3783                                            
                                          Coeff Variation    -2975.6575    Std Error Mean      0.58079302                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.36358     Std Deviation           10.81898                                                
                                               Median    1.86002     Variance               117.05023                                                
                                               Mode      0.60473     Range                   53.83629                                                
                                                                     Interquartile Range     14.88131                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 4 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               42 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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  -0.62601    Pr > |t|    0.5317                                                   
                                                 Sign           M      28.5    Pr >= |M|   0.0026                                                   
                                                 Signed Rank    S      1596    Pr >= |S|   0.3942                                                   
                                                                                                                                                    
                                                                                                                                                     
                                                                Tests for Normality                                                                  
                                                                                                                                                     
                                             Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                     
                                             Shapiro-Wilk          W     0.946801    Pr < W     <0.0001                                              
                                             Kolmogorov-Smirnov    D     0.099018    Pr > D     <0.0100                                              
                                             Cramer-von Mises      W-Sq  1.011224    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  5.883925    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               43 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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       19.94892                                                                
                                                              99%            17.59826                                                                
                                                              95%            13.42180                                                                
                                                              90%            11.14587                                                                
                                                              75% Q3          7.91676                                                                
                                                              50% Median      1.86002                                                                
                                                              25% Q1         -6.96455                                                                
                                                              10%           -15.95262                                                                
                                                              5%            -21.57855                                                                
                                                              1%            -31.78702                                                                
                                                              0% Min        -33.88736                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               44 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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           
                                                                                                                                                    
         -33.8874   40520100013
                       2201         16.6970   40520100013-
                       2053           
         -33.3787   40520100013
                       2183         17.5983   40520100013-
                       2144           
         -33.1571   40520100013
                       2007         18.8332   40520100013-
                       2278           
         -31.7870   40520100013
                       2218         19.4803   40520100013-
                       2284           
         -28.1267   40520100013
                       2160         19.9489   40520100013-
                       2153           
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
                                                                                                                                                    
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               45 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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                         347    Sum Weights                347                                            
                                         Mean               -0.0353861    Sum Observations    -12.278976                                            
                                         Std Deviation      1.02339086    Variance            1.04732886                                            
                                         Skewness           -0.8014075    Kurtosis            0.14366209                                            
                                          Uncorrected SS     362.810289    Corrected SS        362.375784                                            
                                          Coeff Variation    -2892.0705    Std Error Mean       0.0549385                                            
                                                                                                                                                     
                                                                                                                                                     
                                                             Basic Statistical Measures                                                              
                                                                                                                                                     
                                                   Location                    Variability                                                           
                                                                                                                                                     
                                               Mean     -0.03539     Std Deviation            1.02339                                                
                                               Median    0.17390     Variance                 1.04733                                                
                                               Mode      0.05664     Range                    5.12952                                                
                                                                     Interquartile Range      1.41016                                                
                                                                                                                                                     
                                       Note: The mode displayed is the smallest of 4 modes with a count of 2.                                        
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               46 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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   -0.6441    Pr > |t|    0.5199                                                   
                                                  Sign           M      28.5    Pr >= |M|   0.0026                                                   
                                                  Signed Rank    S      1567    Pr >= |S|   0.4028                                                   
                                                                                                                                                     
                                                                                                                                                     
                                                                Tests for Normality                                                                  
                                                                                                                                                     
                                             Test                  --Statistic---    -----p Value------                                              
                                                                                                                                                     
                                             Shapiro-Wilk          W     0.946825    Pr < W     <0.0001                                              
                                             Kolmogorov-Smirnov    D     0.099802    Pr > D     <0.0100                                              
                                             Cramer-von Mises      W-Sq  1.019493    Pr > W-Sq  <0.0050                                              
                                             Anderson-Darling      A-Sq  5.928715    Pr > A-Sq  <0.0050                                              
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               47 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                    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       1.902521                                                                
                                                             99%            1.671961                                                                
                                                             95%            1.269575                                                                
                                                             90%            1.049981                                                                
                                                             75% Q3         0.749161                                                                
                                                             50% Median     0.173896                                                                
                                                             25% Q1        -0.660998                                                                
                                                             10%           -1.496158                                                                
                                                              5%            -2.066916                                                                
                                                              1%            -2.976287                                                                
                                                              0% Min        -3.227003                                                                
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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                                                                                                               48 OF 48
PROTOCOL 405-201-00013                                                                                                                               
                                                                     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           
                                                                                                                                                     
          -3.22700   40520100013
                      2201         1.65677   40520100013-
                       2144           
          -3.14078   40520100013
                      2183         1.67196   40520100013-
                       2053           
          -3.10521   40520100013
                      2007         1.76566   40520100013-
                       2278           
          -2.97629   40520100013
                      2218         1.82508   40520100013-
                       2284           
          -2.70089   40520100013
                      2160         1.90252   40520100013-
                       2153           
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
----------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
                                                                                                                                                     
FILE: normalitybc.lis, RUN: 18JUN2020 10:00                                                                                                          
PROGRAM: /opt/sas/Data/DAP/EB1020/P40520100013/STAT/Program.dev/DOC_STAT/normality.sas                                                               
OPDC, NEW DRUG APPLICATION, IND # 119,361   CENTANAFADINE           STAT-6.1.2      FINAL                                                            
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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


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Document Name: P40520100013_DOC_STAT
Document Number: 1000084975
Document Version: 2.0
Signed by
Meaning of Signature
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(dd-MMM-
yyyy hh:min) -
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Safety Approval
04-Aug-2020
14:03:59
Biostatistics Approval
28-Jul-2020
15:44:56
Clinical Programming
Approval
28-Jul-2020
14:13:56
Clinical Approval
03-Aug-2020
18:34:55
Clinical Study Report 405-201-00013
16.1.9 Documentation of Statistical Methods
Until the information herein is released by Otsuka to the public 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