Conditions: Schizophrenia
Keywords: aripiprazole ziprasidone lurasidone schizophrenia ASP4345 quetiapine olanzapine brexpiprazole risperidone paliperidone
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 233
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy of ASP4345 on cognitive impairment compared to placebo using change from baseline in MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score (excluding social cognition domain). The primary estimand used a Hypothetical Strategy and compared participants as though the participant had continued on the assigned treatment and to evaluate the safety and tolerability of ASP4345 compared to placebo. This study also evaluated the effects of ASP4345 compared to placebo on functional capacity using the University of California San Diego Performance-based Skills Assessment-2 Extended Range (UPSA-2-ER) total score and evaluated the pharmacokinetic profile of ASP4345.

Detailed description:
Participants received oral doses of ASP4345 or matching placebo QD (once daily) for 12 weeks. All participants were administered the first dose of blinded study drug at the site following randomization and provided with web-based applications that provided supplemental cognitive training and recorded treatment compliance. Participants returned to the clinic weekly for safety, efficacy, and/or pharmacokinetic procedures. Participants continued the participant's antipsychotic treatment for the entire study and were followed for 14 days after the participant's last dose of study drug.

Arms:
arm 1: Participants on stable doses of antipsychotic medication received ASP4345 50 mg, capsules, orally, once daily for 12 weeks. arm 2: Participants on stable doses of antipsychotic medication received ASP4345 150 mg, capsules, orally, once daily for 12 weeks. arm 3: Participants on stable doses of antipsychotic medication received ASP4345 placebo matching capsules, orally, once daily for 12 weeks.

Interventions: intervention 1: ASP4345 intervention 2: placebo intervention 3: risperidone intervention 4: quetiapine intervention 5: olanzapine intervention 6: ziprasidone intervention 7: aripiprazole intervention 8: brexpiprazole intervention 9: paliperidone intervention 10: lurasidone
Intervention descriptions: intervention 1: oral administration intervention 2: oral administration intervention 3: oral or depot administration intervention 4: oral administration intervention 5: Oral or depot administration intervention 6: Oral or depot administration intervention 7: Oral or depot administration intervention 8: Oral administration intervention 9: Oral or depot administration intervention 10: Oral administration

Protocol document:
Prot_000.pdf: 
A Phase 2a, Randomized, Double-Blind, Placebo-
Controlled, Parallel-group Study to Assess the Safety and 
Efficacy of ASP4345 as Add-on Treatment for Cognitive 
Impairment in Subjects with Schizophrenia on Stable 
Doses of Antipsychotic Medication
ISN/Protocol 4345-CL-0015
ClinicalTrials.gov Identifier: NCT03557931
Date of Protocol: 17 Aug 2018
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 4345-CL-0015
- CONFIDENTIAL -
17 Aug 2018
Astellas
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Version 2.0 Incorporating Substantial Amendment 1
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-group Study to Assess the Safety and Efficacy of 
ASP4345 as Add-on Treatment for Cognitive Impairment 
in Subjects with Schizophrenia on Stable Doses 
of Antipsychotic Medication 
ISN/Protocol 4345-CL-0015 
Version 2.0
Incorporating Substantial Amendment 1 [See Attachment 1]
17 August 2018
IND 124721
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 [06 Mar 2018]
Version 1.1 [08 Jun 2018]
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s 
team who agrees to hold this information in confidence. 


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Table of Contents
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························10
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················11
IV.
SYNOPSIS··························································································15
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································24
1
INTRODUCTION·················································································28
1.1
Background ····················································································28
1.2
Nonclinical and Clinical Data ·······························································29
1.3
Summary of Key Safety Information for Study Drugs ···································32
1.4
Risk Benefit Assessment ·····································································33
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································33
2.1
Study Objective(s) ············································································33
2.1.1
Primary Objectives······································································33
2.1.2
Secondary Objectives ···································································33
2.1.3
Exploratory Objectives ·································································34
2.2
Study Design and Dose Rationale···························································34
2.2.1
Study Design·············································································34
2.2.2
Dose Rationale···········································································35
2.3
Endpoints·······················································································36
2.3.1
Primary Endpoints·······································································36
2.3.2
Secondary Endpoints····································································36
2.3.3
Exploratory Endpoints ··································································36
3
STUDY POPULATION··········································································37
3.1
Selection of Study Population ·······························································37
3.2
Inclusion Criteria··············································································37
3.3
Exclusion Criteria ·············································································39
4
TREATMENT ·····················································································41
4.1
Identification of Investigational Product(s) ················································41
4.1.1
Study Drug ···············································································41
4.1.2
Comparative Drug·······································································41
4.2
Packaging and Labeling ······································································41


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4.3
Study Drug Handling ·········································································41
4.4
Blinding ························································································42
4.4.1
Blinding Method·········································································42
4.4.2
Confirmation of the Indistinguishability of the Study Drugs ······················42
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································42
4.4.4
Breaking the Treatment Code for Emergency ·······································43
4.4.5
Breaking the Treatment Code by the Sponsor ·······································43
4.5
Assignment and Allocation ··································································43
5
TREATMENTS AND EVALUATION························································44
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················44
5.1.1
Dose/Dose Regimen and Administration Period ····································44
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································44
5.1.3
Previous and Concomitant Treatment (Medication and NonMedication 
Therapy) ··················································································44
5.1.4
Treatment Compliance··································································46
5.1.5
Restrictions During the Study··························································46
5.2
Demographics and Baseline Characteristics ···············································46
5.2.1
Demographics including Smoking History···········································46
5.2.2
Medical and Psychiatric History·······················································47
5.2.3
Duplicate Subject Database Check····················································47
5.2.4
Diagnosis of the Target Disease, Severity, and Duration of Disease··············47
5.2.5
Mini-International Neuropsychiatric Interview······································48
5.3
Efficacy and Pharmacokinetics Assessments··············································48
5.3.1
Efficacy Assessments ···································································48
5.3.1.1
MATRICS Consensus Cognitive Battery·······································48
5.3.1.2
University of San Diego Performance-based Skills Assessment-2 
Extended Range····································································49
5.3.1.3
Positive and Negative Syndrome Scale ·········································49
5.3.1.4
Negative Symptom Assessment-16··············································50
5.3.1.5
Clinical Global Impression of Severity Scale ··································50
5.3.2
Pharmacokinetics Assessments························································50
5.4
Safety Assessment ············································································51
5.4.1
Vital Signs················································································51
5.4.2
Adverse Events ··········································································51


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5.4.2.1
Adverse Events of Possible Hepatic Origin ····································51
5.4.3
Laboratory Assessments································································52
5.4.4
Physical Examination···································································54
5.4.5
Electrocardiogram·······································································54
5.4.6
Metabolic Parameters ···································································54
5.4.7
Sponsor Consult on Concomitant Medications ······································54
5.4.8
Columbia Suicide Severity Rating Scale ·············································54
5.4.9
Abnormal Involuntary Movement Scale··············································55
5.4.10
Simpson Angus Scale···································································55
5.4.11
Barnes Akathisia Rating Scale·························································55
5.4.12
Safety Narrative Plan ···································································55
5.5
Adverse Events and Other Safety Aspects ·················································56
5.5.1
Definition of Adverse Events ··························································56
5.5.1.1
Abnormal Laboratory Findings ··················································56
5.5.1.2
Potential Cases of Drug-Induced Liver Injury ·································56
5.5.1.3
Disease Progression and Study Endpoints······································56
5.5.2
Definition of Serious Adverse Events·················································57
5.5.3
Criteria for Causal Relationship to Study Drug······································57
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························58
5.5.5
Reporting of Serious Adverse Events·················································59
5.5.6
Follow-up of Adverse Events··························································60
5.5.7
Special Situations········································································60
5.5.7.1
Pregnancy···········································································60
5.5.7.2
Medication Error, Overdose and “Off-Label Use” ····························61
5.5.7.3
Misuse/Abuse ······································································61
5.5.7.4
Occupational Exposure ···························································62
5.5.7.5
Suspected Drug-Drug Interaction················································62
5.5.8
Supply of New Information Affecting the Conduct of the Study··················62
5.6
Test Drug Concentration ·····································································62
5.7
Other Measurements, Assessments or Methods ···········································62
5.7.1
Blood Sample for the Analysis of Antipsychotics···································62
5.7.2
Blood Sample for the Analysis of Genes Related to Pharmacokinetics, 
Efficacy, and Safety (Optional)························································63
5.7.3
Blood Sample for Future Pharmacogenetic Analysis (Retrospective 
Pharmacogenetic Analysis) (Optional) ···············································63
5.7.4
Rater Training and Quality Assurance················································63


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5.7.5
Cognitive Training for the Subject ····················································63
5.7.6
Virtual Monitoring of Study Drug Compliance······································64
5.8
Total Amount of Blood·······································································64
6
DISCONTINUATION············································································64
6.1
Discontinuation of Individual Subject(s)···················································64
6.2
Discontinuation of the Site···································································65
6.3
Discontinuation of the Study·································································65
7
STATISTICAL METHODOLOGY ···························································66
7.1
Sample Size····················································································66
7.2
Analysis Sets···················································································66
7.2.1
Full Analysis Set ········································································66
7.2.2
Intent-to-Treat Set·······································································66
7.2.3
Safety Analysis Set······································································66
7.2.4
Pharmacokinetic Analysis Set ·························································67
7.3
Demographics and Baseline Characteristics ···············································67
7.3.1
Subject Disposition······································································67
7.3.2
Previous and Concomitant Medications ··············································67
7.3.2.1
Analysis of Antipsychotic Trough Levels ······································67
7.3.3
Medical and Psychiatric History·······················································67
7.4
Analysis of Efficacy ··········································································67
7.4.1
Analysis of Primary Endpoint ·························································68
7.4.1.1
Primary Analysis···································································68
7.4.1.2
Sensitivity Analysis ·······························································68
7.4.2
Analysis of Secondary Endpoints ·····················································68
7.4.3
Analysis of Exploratory Endpoints····················································69
7.5
Analysis of Safety·············································································69
7.5.1
Adverse Events ··········································································69
7.5.2
Laboratory Assessments································································69
7.5.3
Vital Signs················································································70
7.5.4
Metabolic Parameters ···································································70
7.5.5
Routine 12-lead Electrocardiograms ··················································70
7.5.6
Columbia-Suicide Severity Rating Scale ·············································70
7.5.7
Movement disorder (Abnormal Involuntary Movement Scale)····················70
7.5.8
Simpson Angus Scale···································································70


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7.5.9
Barnes Akathisia Rating Scale·························································70
7.6
Analysis of Pharmacokinetics ·······························································70
7.6.1
Estimation of Pharmacokinetic Parameters ··········································70
7.7
Major Protocol Deviations and Other Analyses···········································71
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················71
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········71
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················71
8.1
Procedure for Clinical Study Quality Control ·············································71
8.1.1
Data Collection ··········································································71
8.1.2
Specification of Source Documents···················································72
8.1.3
Clinical Study Monitoring······························································73
8.1.4
Direct Access to Source Data/Documents············································73
8.1.5
Data Management ·······································································73
8.1.6
Major Protocol Deviations ·····························································73
8.1.7
End-of-Trial in All Participating Countries ··········································74
8.2
Ethics and Protection of Subject Confidentiality··········································74
8.2.1
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities················································································74
8.2.2
Ethical Conduct of the Study···························································75
8.2.3
Informed Consent of Subjects ·························································75
8.2.3.1
Subject Information and Consent················································75
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························75
8.2.4
Subject Confidentiality and Privacy···················································76
8.3
Administrative Matters ·······································································76
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····76
8.3.2
Documents and Records Related to the Clinical Study ·····························77
8.3.3
Protocol Amendment and/or Revision················································77
8.3.4
Signatory Investigator for Clinical Study Report····································78
9
QUALITY ASSURANCE········································································78
10
STUDY ORGANIZATION······································································78
10.1
Independent Data-Monitoring Committee ·················································78
10.2
Other Study Organization ····································································78
11
REFERENCES ····················································································79


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12
APPENDICES ·····················································································81
12.1
List of Excluded Concomitant Medications················································81
12.2
List of Inducers and Inhibitors of CYP2C19, CYP2D6 and CYP1A2··················82
12.3
Liver Safety Monitoring and Assessment ··················································83
12.4
Common Serious Adverse Events···························································86
12.5
Retrospective Pharmacogenetics Sub-Study···············································87
12.6
Clinical Outcome Assessment Scales·······················································89
12.7
Adverse Events of Interest Related to Abuse ··············································90
12.8
Drug Withdrawal-Related Adverse Events Occurring Following Drug 
Discontinuation (Preferred Terms; MedDRA 18.0)·······································94
13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 1 ·································96
14
SPONSOR’S SIGNATURES·································································· 109


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I.
SIGNATURES
1.  SPONSOR’S SIGNATURES
Required signatures (e.g., Protocol authors and contributors, etc.) are located in [Section 14
Sponsor’s Signatures].


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2.  INVESTIGATOR’S SIGNATURE
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-group 
Study to Assess the Safety and Efficacy of ASP4345 as Add-on Treatment for 
Cognitive Impairment in Subjects with Schizophrenia on Stable Doses of 
Antipsychotic Medication
ISN/Protocol 4345-CL-0015
Version 2.0
Incorporating Substantial Amendment 1
17 Aug 2018
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and applicable local regulations. I will 
also ensure that subinvestigator(s) and other relevant members of my staff have access to copies of 
this protocol and the ICH GCP guidelines to enable them to work in accordance with the provisions of 
these documents.
Principal Investigator:
Signature:   ----------------------------------------------------------------------------------------------
                                                                                                             Date (DD Mmm YYYY)
Printed Name:    -----------------------------------------------------------------------------------------
<Insert name and qualification of the Investigator>
Address:    ---------------------------------------------------------------------------------------------------------
                  ---------------------------------------------------------------------------------------------------------
     




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
anti-HAV
hepatitis A virus antibodies
anti-HCV
hepatitis C virus antibodies
APGD
Astellas Pharma Global Development, Inc.
ASSR
auditory steady-state response
AST
aspartate aminotransferase
ASST
attentional set-shifting task
AUC
area under the concentration-time curve
BARS
Barnes Akathisia Rating Scale
β-HCG
beta human chorionic gonadotropin
BMI
body mass index
CA
Competent Authorities
CGI-S
Clinical Global Impression of Severity Scale
CI
confidence interval
CIAS
cognitive impairment associated with schizophrenia
CIOMS
council for international organizations of medical sciences
Cmax
maximum concentration
CNS
central nervous system
COMT
catechol-O-methyltransferase
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia Suicide Severity Rating Scale
CV
coefficient of variation
CYP1A2
Cytochrome P450 1A2
CYP2C19
Cytochrome P450 2C19
CYP2D6
Cytochrome P450 2D6
D1
dopamine receptor type 1
D2
dopamine receptor type 2
D3
dopamine receptor type 3
DILI
drug-induced liver injury
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
electrocardiogram
eCRF
electronic case report form
ED
extradimensional


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Abbreviations
Description of abbreviations
EEA
European Economic Area
EEG
electroencephalography
EU
European Union
EoT
end-of-treatment
FAS
full analysis set
GCP
good clinical practice
GFR
glomerular filtration rate
GGT
gamma glutamyl transpeptidase
Glu
glutamate
GMP
good manufacturing practices
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HDL
high-density lipoprotein
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
IB
investigator’s brochure
ICD-10
International Statistical Classification of Diseases and Related Health Problem, 
10th revision
ICF
informed consent form
ICH 
international council for harmonisation of technical requirements for registration 
of pharmaceuticals for human use
IDMC
Independent Data Monitoring Committee
IEC
independent ethics committee
IgM
immunoglobulin M
IND
Investigational New Drug
INR
international normalized ratio
IRB
institutional review board
IRT
Interactive Response Technology
ISN
international study number
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine system
LA-CRF
liver abnormality case report form
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LFT
liver function tests
LS
least squares
MAD
multiple ascending dose
MATRICS
Measurement and Treatment Research to Improve Cognition in Schizophrenia
MATRICS-CT
Measurement and Treatment Research to Improve Cognition in Schizophrenia 
Coprimary and Translations


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Abbreviations
Description of abbreviations
MCCB
Measurement and Treatment Research to Improve Cognition in Schizophrenia
Consensus Cognitive Battery
MedDRA
medical dictionary for regulatory activities
MDRD
Modification of Diet in Renal Disease
M.I.N.I. 7.02
M.I.N.I. International Neuropsychiatric Interview, version 7.02
MMRM
Mixed Models Repeated Measures
mPFC
medial prefrontal cortex
NIMH
National Institute of Mental Health
NOAEL
no-observed-adverse-effect-level
NSA-16
Negative Symptom Assessment Scale
NSAIDs
non-steroidal anti-inflammatory drugs
PAM
positive allosteric modulator
PANSS
Positive and Negative Symptom Scale
PCP
1-(1-phenylcyclohexyl) piperidine
PGx
pharmacogenetic
PKAS
pharmacokinetic analysis set
QD
daily
QTcF
QT interval using Fridericia’s formula
SAD
single ascending dose
(S)AE
serious adverse event or adverse event
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SAS
Simpson Angus Scale
SC
study coordinator
SCID-P
Structured Clinical Interview for DSM diagnoses
SE
standard error
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reactions
TBL
total bilirubin
TEAE
treatment emergent adverse events
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UPSA-2-ER
University of California San Diego Performance-based Skills Assessment-2 
Extended Range
VIM
Validation of Intermediate Measures


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Definition of Key Study Terms
Terms
Definition of terms
Baseline
Assessments of subjects as they enter a trial before they receive any treatment. 
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a trial.
Enroll
To register or enter a subject into a clinical trial. NOTE: Once a subject has 
received the study drug or placebo, the clinical trial protocol applies to the 
subject. 
Intervention
The drug, device, therapy or process under investigation in a clinical study that 
is believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics). 
Investigational 
period
Period of time where major interests of protocol objectives  are observed, and 
where the test drug or comparative drug (sometimes without randomization) is 
usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug.
Post investigational 
period
Period of time after the last assessment of the protocol. Follow-up observations 
for sustained adverse events and/or survival are done in this period.
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet 1 or more criteria required for participation 
in a trial.
Screening period
Period of time before entering the investigational period, usually from the time 
when a subject signs the consent until just before the test drug or comparative 
drug (sometimes without randomization) is given to a subject.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis: 
17 Aug 2018/Version 2.0
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
Protocol Number: 
4345-CL-0015
Name of Study Drug: 
ASP4345
Phase of Development:
Phase 2a
Title of Study:
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-group Study to Assess the 
Safety and Efficacy of ASP4345 as Add-on Treatment for Cognitive Impairment in Subjects with 
Schizophrenia on Stable Doses of Antipsychotic Medication
Planned Study Period:
From 3Q2018 to 1Q2020
Study Objective(s):
The objectives of the study, conducted in subjects with cognitive impairment associated with 
schizophrenia, are the following:
Primary Objectives
To evaluate the efficacy of ASP4345 on cognitive impairment compared to placebo using change 
from baseline in MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite 
score (excluding social cognition domain). The primary estimand will use a Hypothetical Strategy 
and compare patients as though they had continued on the assigned treatment.
To evaluate the safety and tolerability of ASP4345 compared to placebo
Secondary Objectives
To evaluate the effects of ASP4345 compared to placebo on functional capacity using the 
University of California San Diego Performance-based Skills Assessment-2 Extended Range 
(UPSA-2-ER) total score.
To evaluate the pharmacokinetic profile of ASP4345 and its metabolites, if necessary
Exploratory Objectives
To evaluate the effects of ASP4345 compared to placebo using:
○the 16-item version of the Negative Symptom Assessment Scale (NSA-16)
○the individual domains of the MCCB 
○the assessment of general clinical symptoms with the Positive and Negative Symptom Scale 
(PANSS)
○the assessment of the Clinical Global Impression of Severity Scale (CGI-S)
To evaluate the relationship between the CGI-S and MCCB neurocognitive composite score
To evaluate the relationship between the number of cognitive training levels, including repeat 
levels, completed (as a measure of compliance with cognitive training) and MCCB neurocognitive 
composite score
To evaluate the pharmacogenetic impact on ASP4345 pharmacodynamic results
Planned Total Number of Study Centers and Location(s):
Up to approximately 25 centers in the United States


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Study Population:
Male and female adult subjects with cognitive impairment associated with schizophrenia on stable 
doses of risperidone, quetiapine, olanzapine, ziprasidone, aripiprazole, brexpiprazole, paliperidone or 
lurasidone for at least 4 weeks prior to screening and 2 months for depot medications.
Number of Subjects to be Enrolled/Randomized:
Approximately 420 subjects are planned to be screened for 210 subjects randomized to receive either 
1 of 2 doses of ASP4345 or placebo in a 3:2:2 ratio (approximately 90 placebo subjects and 
60 subjects each per active study arm). 
Study Design Overview:
This is a randomized, double-blind, placebo-controlled, 3-arm oral dose study to evaluate the safety 
and efficacy of ASP4345 in subjects with cognitive impairment associated with schizophrenia on 
stable doses of risperidone, quetiapine, olanzapine, ziprasidone, aripiprazole, brexpiprazole, 
paliperidone or lurasidone for at least 4 weeks prior to screening for oral medications and 2 months 
for depot medications.  The study will consist of the following periods:
Screening period (up to 28 days)
Double-blind treatment period (12 weeks/84 days)
Follow-up period (14 days post last dose)
Up to 210 subjects will be enrolled in 1 of 3 arms.  Study groups will consist of approximately 
90 placebo subjects and 60 subjects each per active study arm randomized in 3:2:2 ratio to receive 
1 of 2 doses of ASP4345 or matching placebo daily (QD) for 12 weeks. Study treatment assignments 
will be according to the following table:
Group
Dose Regimen
Number
A
50 mg, QD
60
B
150 mg, QD
60
C
Placebo, QD
90
After signing informed consent and during the screening period, study site personnel will check that 
potential subjects have not already been pre-screened, initiated or completed screening, or have been 
randomized into this study or another clinical trial using an independent subject participation 
database.
After completing the screening procedures, subjects will be evaluated for randomization eligibility. 
After randomization on day 1, subjects will receive oral doses of ASP4345 or matching placebo QD 
for 12 weeks. All subjects will be administered the first dose of blinded study drug at the site 
following randomization and provided with mobile applications that provide supplemental cognitive
training and record treatment compliance.  Subjects will return to the clinic weekly for safety, 
efficacy, and/or pharmacokinetic procedures at days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77 and 84.  
Subjects will continue their antipsychotic treatment for the entire study and will be followed for 
14 days after their last dose of study drug.  
Subjects terminating early from the study will be encouraged to complete scheduled visits. All 
subjects are allowed to stop study drug, but continue in the study through day 84 according to the 
current visit schedule unless the participant specifically withdraws consent for any further contact 
with him/her or persons previously authorized by the participant provide this information
Pharmacokinetic trough samples will be collected prior to dosing at days 7, 14 or 21, 42 and 84.  
Additional samples will be collected at approximately 2 hours and 4 hours post dose on day 42.


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To determine changes in cognition with the MCCB instrument, cognitive testing will be performed at 
each screening visit, on days 1 (prior to first dose), 42 and 84.  All MCCB assessments following 
randomization should be performed within a 2-hour window of the baseline test. In order to avoid an 
acute impact of nicotine and caffeine on cognitive testing, smoking and intake of coffee will not be 
allowed approximately 30 minutes before the MCCB assessment.
Inclusion/Exclusion Criteria:
Inclusion Criteria:
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board/Independent Ethics Committee approved written informed consent 
and privacy language as per national regulations (e.g., Health Insurance Portability and 
Accountability Act Authorization for US sites) must be obtained from the subject or legally 
authorized representative prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).
2.
Subject is a male or female subject between 18 to 55 years of age, inclusive, at screening.
3.
Subject has a diagnosis of schizophrenia or schizoaffective disorder according to the Diagnostic 
and Statistical Manual of Mental Disorders, 5th edition criteria and confirmed by the Mini-
International Neuropsychiatric Interview version 7.02.
4.
Subject has a stable clinical course as suggested by the following:
no psychiatric hospitalization within the last 4 months, 
no symptom-related changes in psychotropic medications (as defined in the concomitant 
medication section) within 4 weeks prior to baseline for oral medications and within 
2 months for depot medications, 
and core positive symptoms no worse than moderate in severity and no evidence of a 
current severe major depressive episode (moderately severe depression is allowed).
5.
Subject has a stable living situation.
6.
Subject’s extrapyramidal symptoms are no worse than mild in severity.
7.
Subject must be in ongoing maintenance (i.e., at least 4 weeks prior to day 1 for oral medications 
and 2 months for depot medications) on up to 2 antipsychotic therapies (oral or depot) other than 
clozapine.  
8.
Subject has a body mass index range of 18.5 to 45.0 kg/m2.
9.
Female subject must either:
Be of nonchildbearing potential:
o Postmenopausal (defined as at least 1 year without any menses for which there is no 
other obvious pathological or physiological cause) prior to screening, or 
o Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy)
Or, if of childbearing potential, 
o Agrees not to try to become pregnant during the study and for 28 days after the final 
study drug administration,
o And has a negative blood pregnancy test at screening and a negative urine pregnancy 
test at day 1,
o And if heterosexually active, agrees to consistently use 1 form of highly effective birth 
control* starting at screening and throughout the study period and for 28 days after the 
final study drug administration.


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10. Female subject must agree not to breastfeed starting at screening and throughout the study period, 
and for 28 days after the final study drug administration.
11. Female subject must not donate ova starting at screening and throughout the study period, and for 
28 days after the final study drug administration. 
12. A sexually active male subject with female partner(s) who is of childbearing potential is eligible 
if:
Agrees to use a male condom starting at screening and continue throughout study treatment 
and for 90 days after the final study drug administration. 
13. Male subject must not donate sperm starting at screening and throughout the study period, and for 
90 days after the final study drug administration. 
14. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a 
condom for the duration of the pregnancy or time partner is breastfeeding throughout the study 
period and for 90 days after the final study drug administration.
15. Subject agrees not to participate in another interventional study while participating in the present 
study, defined as signing the informed consent form until completion of the last study visit.
16. Subject has a negative urine drug screen for drugs of abuse at screening and day 1, excluding 
cannabis and documented prescribed benzodiazepines.
*Highly effective forms of birth control include:
Consistent and correct usage of established hormonal contraceptives that inhibit ovulation,
Established intrauterine device (IUD) or intrauterine system (IUS).
Bilateral tubal occlusion
Vasectomy (A vasectomy is a highly effective contraception method provided the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used)
Male is sterile due to a bilateral orchiectomy
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual activity during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant
Waivers to the inclusion criteria will NOT be allowed.
Exclusion Criteria:
Subject will be excluded from participation if any of the following apply:
1.
Subject has a known or suspected hypersensitivity to ASP4345 or any components of the 
formulation.
2.
Subject has had previous exposure with ASP4345.
3.
Subject has a history of suicide attempt or suicidal behavior within 1 year prior to screening or 
has any suicidal ideation that meets criteria at a level of 4 or 5 by using the Columbia Suicide 
Severity Rating Scale (C-SSRS) or who is at significant risk to commit suicide, as assessed by the 
investigator at screening or at day 1.
4.
Subject has any clinically significant liver chemistry test result (aspartate aminotransferase 
[AST], alanine aminotransferase [ALT], total bilirubin [TBL]) or a result > 1.5 times above the 
upper limit of normal (ULN) at screening or repeated within 1 week prior to potential 
randomization (day 1). In such a case, the assessment may be repeated once.


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5.
Subject has any history or evidence of any clinically significant allergic, cardiovascular, 
gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, 
pulmonary, neurologic, dermatologic, history of seizure disorder, renal and/or other major disease 
or malignancy, as determined by the investigator. 
6.
Subject has any clinically significant abnormality following the investigator’s review of the 
physical examination, electrocardiogram (ECG) and protocol-defined clinical laboratory tests at 
screening or at admission to the study (day 1).
7.
Subject has known kidney disease and a glomerular filtration rate (GFR) < 60 mL/min per meter 
squared at screening and subjects will be discontinued from treatment only for decreases in the 
GFR that are clinically relevant.
8.
Subject has a resting systolic blood pressure > 180 mmHg or < 90 mmHg, and a resting diastolic 
blood pressure > 100 mmHg at screening.  These assessments may be repeated once, after a 
reasonable timeperiod, at the investigator’s discretion (but within the screening period).
9.
Subject has a mean corrected QT interval using Fridericia’s formula (QTcF) > 450 msec (for male 
subjects) and > 470 msec (for female subjects) at screening or at randomization. If the mean 
QTcF exceeds the limits above, one additional triplicate ECG can be taken on day 1.
10. Subject has a history in the 6 months prior to screening of consuming more than 14 units of 
alcoholic beverages per week for males and more than 7 units of alcoholic beverages per week for 
females. (Note 1 unit = 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits).  
11. Subject is currently using protocol-specified prohibited medications and is unable to washout, 
including over-the-counter products and agrees not to consume grapefruit and/or grapefruit juice 
(as defined in the concomitant medication section).
12. Subject is currently using clozapine for treatment of schizophrenia.
13. Subject has a positive test for hepatitis B surface antigen (HBsAg), hepatitis A virus antibodies 
(immunoglobulin M) (anti-HAV [IgM]) or hepatitis C virus antibodies (anti-HCV) at Screening 
or has history of a positive test for human immunodeficiency virus type 1(HIV-1) and/or type 2 
(HIV-2).
14. Subject who has had electroconvulsive therapy within the 6 months prior to screening.
15. Subject has a history of head injury with clinically significant sequelae, including loss of 
consciousness for 1 hour or greater. 
16. Subject is an employee of the Astellas Group or Contract Research Organization involved in the 
clinical study.
17. Subject has received investigational study drug within 28 days or 5 half-lives, whichever is 
longer, prior to screening. 
18. Subject has any condition, which, in the investigator’s opinion, makes the subject unsuitable for 
study participation.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product(s):
ASP4345
Strengths: 50 mg capsules 
Dose(s): 
Dose range of 50 mg and 150 mg


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Mode of Administration:
ASP4345 capsules will be administered orally as a single daily dose on days 2 through 84, in the 
morning with or without food (the first dose on day 1 will be taken at the study site). The subject will 
also dose at the study site on the following 4 visits: days 7, 14 or 21, 42 and 84/end-of-treatment 
(EoT).
Comparative Drug(s):
Placebo to match for ASP4345
Doses(s):
Not applicable
Mode of Administration:
Matching placebo capsules will be administered orally as a single daily dose on days 2 through 84, 
in the morning with or without food.  Dosing at the study site will be performed at the designated 
timepoints noted above for the ASP4345 capsules.
Concomitant Medication Restrictions or Requirements:
Permitted Concomitant Antipsychotics:
Subjects are required to be on a stable dose of an antipsychotic or a stable regimen of up to 
2 antipsychotics, for 4 weeks prior to baseline (i.e., day 1) for oral drugs and for 2 months prior to 
baseline for depot treatment and throughout the study. The subject will continue to take their 
prescribed antipsychotic throughout the study at their usual dosing time and interval. Permitted 
antipsychotics include quetiapine, risperidone, olanzapine, ziprasidone, aripiprazole, brexpiprazole, 
paliperidone or lurasidone. 
Prohibited Concomitant Medications:
The following concomitant medications are prohibited:

Use of clozapine for treatment of schizophrenia 

Initiation of medications during the conduct of the study that are inducers and inhibitors (strong 
and moderate) for enzymes cytochrome P450(CYP)2C19, CYP2D6 and CYP1A2 are prohibited 
to avoid potential confounding effects on the study results. See Appendix 12.2 List of Inducers 
and Inhibitors of CYP2C19, CYP2D6 and CYP1A2.

Strong and moderate CYP3A inhibitor use (e.g., but not limited to: boceprevir, clarithromycin, 
conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole)

Any nonprescribed drugs (including natural and herbal remedies [e.g., Valerian]) from 2 weeks 
prior to administration of the study drug


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Allowed Concomitant Medications:
In addition to the antipsychotics listed above, the following concomitant medications at stable doses 
(i.e., 4 weeks prior to day 1) are allowed during the study:

Stable doses of antidepressants (except for fluvoxamine, buproprion, tricyclic antidepressants, 
and monoamine oxidase inhibitors) are permitted

Short-acting hypnotic agents (trazodone or zolpidem or zaleplon or zopiclone or eszopiclone 
(Note: Short-acting hypnotics are not allowed within 12 hours prior to cognitive testing) 

Anticholinergics are permitted (Note: use of anticholinergics is not allowed within 8 hours prior 
to cognitive testing)

Approved use of concomitant medication for the treatment of hypertension, hyperlipidemia or 
diabetes mellitus

Occasional use of non-steroidal anti-inflammatory drugs (NSAIDs) (including acetaminophen 
[up to 2 g/day], ibuprofen and naproxen)

Vitamins and cardiovascular prophylactic aspirin up to 325 mg/day

Any other prescribed medications are allowed during the study only after approval by the 
investigator in consultation with the study medical monitor
Duration of Treatment:
Once daily for 12 weeks (i.e., 84 days)
Formal Stopping Rules:
Individual Subject Stopping Criteria
Dosing of a subject will be discontinued in the event that any of the following criteria are fulfilled.  
The subject will be allowed to continue in the clinical study through day 84 according to the current 
visit schedule unless the participant specifically withdraws consent for any further contact with 
him/her or persons previously authorized by the participant provide this information.
If the following finding occurs in 2 consecutive measures within 24 hours study drug should be 
discontinued:

ALT or AST ≥ 3 x ULN, or ALT or AST ≥ 2 x ULN and ALT or AST ≥ 5 x baseline value, or 
TBL ≥ 2 x ULN.
These findings will be confirmed by repeat measurements within 48 hours. Generally liver 
enzymes will be followed by repeated measurements until they return to baseline or stable values.
If the following findings occur, the study drug should be immediately discontinued:

QTcF ≥ 500 ms (confirmed on immediate repeat measurements).

Serum creatinine increases > 26.52 μmol/L (0.3 mg/dL) in an absolute amount or increases 
> 1.5-fold greater than the baseline value or serum cystatin C > 2-fold greater than the baseline 
value for which there is no alternate clinical explanation.


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Endpoints for Evaluation:
Primary Endpoints:

Change from baseline to week 12/EoT for ASP4345 compared to placebo for the MCCB 
neurocognitive composite score (excluding social cognition domain)

Safety and Tolerability
o Nature, frequency and severity of adverse events (AEs)
o Vital signs (sitting or supine blood pressure, pulse and body temperature)
o Clinical laboratory tests (hematology, biochemistry [including cystatin and serum prolactin] 
and urinalysis)
o Routine 12-lead ECG
o Columbia-Suicide Severity Rating Scale (C-SSRS)
o Changes in individual indices of metabolic syndrome (weight, waist circumference, 
cholesterol, triglycerides, high-density lipoprotein [days 1 and 84/EoT] and fasting glucose), 
and hemoglobin A1c [HbA1c]
o Movement disorder (Abnormal Involuntary Movement Scale [AIMS], Simpson Angus Scale 
[SAS] and Barnes Akathisia Rating Scale [BARS])
Secondary Endpoints:

Change from baseline to week 12/EoT for ASP4345 compared to placebo for the UPSA-2-ER 
instrument.

Pharmacokinetics: 
o ASP4345 and its metabolites, if necessary (plasma) Ctrough   Cmaxss and AUCss for ASP4345 
and its metabolites, if necessary, will be estimated based on population pharmacokinetic 
modeling.
Exploratory Endpoints:

Change from baseline to week 12/EoT for ASP4345 compared to placebo for the NSA-16 only for 
the subjects who have at least 1 negative symptom of moderate severity

Change from baseline to week 12/EoT for ASP4345 compared to placebo for the MCCB 
composite score

Change from baseline to week 12/EoT for ASP4345 compared to placebo for each of the MCCB 
domains

Change from baseline to week 12/EoT for ASP4345 compared to placebo for the PANSS

Change from baseline to week 12/EoT for ASP4345 compared to placebo for the Clinical Global 
Impression of Severity Scale (CGI-S)

Correlation between MCCB and CGI-S scores at each measurement (weeks -4, -3, 0, 6, 12)

Correlation between change from baseline to week 12/EoT in MCCB and change from baseline to 
week 12/EoT in CGI-S scores

To evaluate the relationship between number of cognitive training levels achieved (as a measure 
of compliance with cognitive training) and MCCB

Correlation between the number of cognitive training levels, including repeat levels, completed 
(as a measure of compliance with cognitive training) and MCCB neurocognitive composite score

Pharmacogenetics:
o Catechol-O-methyltransferase (COMT) and dopamine D1 and D3 receptor genotyping


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Statistical Methods:
Sample Size:
A total sample size of 210 subjects will be randomized in 3:2:2 ratio (approximately 90 placebo and 
60 subjects each per active study arm) into 1 of 2 doses of ASP4345 or matching placebo. The sample 
size will provide approximately 82% power for the pairwise comparisons to placebo to detect an 
effect size of at least 0.43, assuming a 1-sided 5% significance level, with statistical significance 
achieved at an effect size of approximately 0.28.  Note that the decision criteria to proceed will be 
based on effect sizes rather than statistical significance.  The number of subjects planned for this 
clinical study are considered sufficient to achieve the clinical study objectives.
Efficacy:
Analysis of the primary efficacy endpoint will be conducted on the full analysis set (FAS) and Intent-
to-Treat (ITT) set. The interpretation of results from statistical tests will be based on the FAS. The 
ITT will be used to assess the robustness of the results from the statistical tests based on the FAS. 
Analysis of the secondary and exploratory efficacy endpoints will be done on the FAS.
A 2-sided significance level of 0.10, unless otherwise specified, will be used for all statistical tests on 
efficacy endpoints without multiplicity adjustment.
Based on the estimand, the primary endpoint will be analyzed using a Mixed Models Repeated 
Measures (MMRM) approach, with the corresponding score at baseline used as the covariate. Other 
continuous endpoints will be analyzed using either a MMRM or Analysis of Covariance (ANCOVA), 
depending on the schedule of events, with the corresponding scores at baseline used as a covariate.  A 
2-sided 90% confidence interval (CI) for the treatment difference in least squares (LS) mean changes 
between ASP4345 and placebo will be provided.
Sensitivity analyses of the primary efficacy endpoint and selected secondary/exploratory endpoints 
will be performed based on duration since the first psychotic break, smoking status, subject age, 
biotype and background antipsychotics. 
Pharmacokinetics:
Population pharmacokinetic model will be developed based on ASP4345 plasma concentration data 
obtained from subjects who have at least 1 pharmacokinetic sample. Population pharmacokinetics 
and/or pharmacokinetic/pharmacodynamics analyses will be performed by modeling and simulation 
scientist. All details of the population pharmacokinetic analysis will be described in a separate 
analysis plan and a separate population pharmacokinetic modeling report will be written.
Pharmacogenetics:
The pharmacogenetic parameters, mentioned under exploratory endpoints, will be analyzed using 
either an MMRM or ANCOVA model, as used for the analysis of the primary and some of the 
secondary and exploratory efficacy endpoints.
Safety:
To characterize the safety profile, descriptive statistics will be provided for AEs, vital signs (body 
temperature, pulse rate and sitting or supine blood pressure), clinical laboratory evaluations 
(hematology and biochemistry [including serum prolactin]), routine 12-lead ECG recordings, 
C-SSRS, indices of metabolic syndrome, movement disorder, for each ASP4345 treatment and pooled 
placebo, where applicable.




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Table 1
Schedule of Assessments
Period
Screening
Treatment and Observation
Follow-
up
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15/
EoT
16
Visit Week
-4 to 
-3
-3 to 
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
Visit Day
-28 to 
-21
-20 to 
-7
1
7
14
21
28
35
42
49
56
63
70
77
84
98/
EoS
Visit Window
-1
day (a)
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 days
(b)
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 days
(b)
±3 
days 
Informed Consent
X
Verify Eligibility Criteria
X
X(a)
Demographics, including Smoking History and use 
of Cannabis (c), Height, BMI
X
Weight and Waist Circumference)
X
X(a)
X
X
Medical and Psychiatric History
X
X(a)
Duplicate Subject Database Check
X
Mini-International Neuropsychiatric Interview
X
Sponsor consult on concomitant medications)
X
X(a)
Vital Signs (d)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 Lead Electrocardiogram (e)
X
X
X
X
Physical Examination
X
X
X
X
Pregnancy Test (f, g)
X (f)
X (g)
X (g)
X (f)
X (f)
Urine Drug and Alcohol Test
X
X
X
Hematology, Biochemistry,Urinalysis
X 
X (h)
X (h)
X (h)
X
Abbreviated Biochemistry 
X
X
X
X
X
X
X
X
X
X
X
Serology for Hepatitis Testing
X
Plasma Adrenocorticotropic Hormone and Prolactin
X
X
MATRICS Consensus Cognitive Battery ( i, j)
X 
X
X (i)
X (i)
X (i)
University of San Diego Performance-based Skills 
Assessment-2 Extended Range (a, b)
X
X
Positive and Negative Syndrome Scale (a, b)
X
X(a)
X
X(b)
X (b)
Negative Symptom Assessment-16 Scale (a, b)
X
X(a)
X(b)
X (b)
Table continued on next page


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Period
Screening
Treatment and Observation
Follow-
up
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15/
EoT
16
Visit Week
-4 to 
-3
-3 to 
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
Visit Day
-28 to 
-21
-20 to 
-7
1
7
14
21
28
35
42
49
56
63
70
77
84
98/
EoS
Visit Window
-1
day (a)
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 days
(b)
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 days
(b)
±3 
days 
Clinical Global Impression of Severity Scale
X
X
X(a)
X(b)
X (b)
Randomization
X(a)
Abnormal Involuntary Movement Scale
X(a)
X(b)
X (b)
Simpson Angus Scale
X(a)
X(b)
X (b)
Barnes Akathisia Rating Scale
X(a)
X(b)
X (b)
Cognitive Training (a) and Study Drug Compliance 
via mobile applications (k)
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration and Review (l) 
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Sampling for ASP4345 Pharmacokinetics (m, 
n)
X
X 
X (n)
X
Blood Sampling for Antipsychotic 
Pharmacokinetics
X
X
X
Pharmacogenetic testing: COMT and dopamine D1
and D3 genotyping (o)
X
Biobanking Sample for Retrospective PGx 
Analysis (o)
X
Columbia-Suicide Severity Rating Scale (p) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking Status
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: BMI: body mass index; C-SSRS: Columbia–Suicide Severity Rating Scale; COMT: catechol-O-methyltransferase; D1: Dopamine Receptor Type 1; D3: Dopamine Receptor Type 
3; ECG: electrocardiogram; EoT: end-of- treatment; EoS: end-of-study; GFR: Glomerular Filtration Rate; ICF: informed consent form; MATRICS: Measurement and Treatment Research to 
Improve Cognition in Schizophrenia; MCCB: Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery; NSA-16: Negative Symptom 
Assessment Scale; PANSS: Positive and Negative Symptom Scale; PGx: pharmacogenetic; QTcF:  QT interval using Fridericia’s formula; UPSA-2-ER: University of California San Diego 
Performance-based Skills Assessment-2 Extended Range
Footnotes continued on next page


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(a) The following assessments can be performed on day -1: Verify Eligibilty Criteria (also day 1), Weight and Waist Circumference, Medical and Psychiatric History 
Review, sponsor consult on concomitant medications (if changes have occurred), Cognitive Training Mobile Application Set-up, Positive and Negative Syndrome 
Scale, Negative Symptom Assessment-16 scale, Clinical Global Impression of Severity Rating Scale, Abnormal Involuntary Movement Scale, Simpson Angus Scale, 
and Barnes Akathisia Rating Scale.  ALL other assessments must be performed as listed on day 1.  
(b) The following clinical assessments can be performed the day prior to days 42 and 84 visits: Positive and Negative Syndrome Scale, Negative Symptom Assessment-16 
Scale, Clinical Global Impression of Severity Scale, Abnormal Involuntary Movement Scale, Simpson Angus Scale and Barnes Akathisia Rating Scale. Performing 
these assessments the day prior to days 42 and/or 84 is optional.  All other assessments must be performed as listed on day 42 and day 84. 
(c) Current and former history of smoking and use of cannabis (via smoking or ingestion) will be collected.
(d) Vital signs include body temperature, pulse and sitting or supine blood pressure.
(e) ECGs should be collected prior to pharmacokinetic sample collection at screening and days 1, 42 and 84/EoT. Prior to performing ECGs, subjects should rest in the 
supine position for at least 5 minutes.  One additional triplicate ECG can be taken on day 1 if the QTcF exceeds the limits in Exclusion Criterion 9.
(f)
Serum pregnancy tests will be performed for women of childbearing potential at the screening visit, and on days 84/EoT and 98/EoS. 
(g) Urine pregnancy tests will be performed for women of childbearing potential only on days 1 and 42.
(h) Blood samples for glucose should be performed fasting at the second screening visit (baseline for this test), and days 35 and 77.
(i)
All MCCB testing following randomization (i.e., days 42 and 84/EoT) should be performed within a 2 hour window of baseline (day 1).
(j)
In order to avoid an acute impact of nicotine and caffeine on cognitive testing, smoking and intake of coffee will not be allowed approximately 
30 minutes before the MCCB assessment.
(k) Cognitive Training will consist of a mobile application provided to the subject with instructions to use 4 times per week from randomization through day 84/EoT. 
The application will be reviewed with the subject at each visit to check compliance.  Study drug compliance will also be recorded using a mobile application.
(l)
Subjects will begin dose on day 1 of the study following all baseline procedures performed and randomization.  At each subsequent weekly visit study drug will be 
counted for compliance and a new packet dispensed except for day 84/EoT.
(m) Pharmacokinetic trough samples will be collected prior to dosing at days 7, 14 or 21, 42 and 84/EoT.
(n) Additional pharmacokinetic samples will be collected at approximately 2 hours and 4 hours post dose on day 42.
(o) The samples for pharmacogenetic testing (COMT and dopamine D1 and D3 receptor genotyping) and biobanking for retrospective pharmacogenetic analysis are 
optional and will be collected at baseline (day 1) prior to dosing. ICFs for substudies may be collected prior to day 1 sample collection.
(p) The version of the C-SSRS to be performed at the first screening visit is the “Lifetime” version and the version of the C-SSRS to be performed on at the second 
screening visits and on days 1 though day 98/EoS is the “Since Last Visit.”


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1
INTRODUCTION
Protocol 4345-CL-0015 is a proof-of-concept study to examine the effects of ASP4345 in 
subjects with cognitive impairment associated with schizophrenia on stable doses of risperidone, 
quetiapine, olanzapine, ziprasidone, aripiprazole, brexpiprazole, paliperidone or lurasidone.
1.1
Background
Schizophrenia is a chronically debilitating syndrome that affects approximately 1% of the 
global population and is accompanied by extraordinary high medical and economic burden 
[Awad & Voruganti, 2008].  The 3 primary clinical symptom domains of schizophrenia 
include positive symptoms (delusions and hallucinations), negative symptoms (apathy, 
blunted affect, anhedonia, avolition, alogia, social and emotional withdrawal) and a wide 
range of cognitive symptoms, in addition to a general disorganization of thinking and 
behavior [Tandon et al, 2009]. Cognitive impairment associated with schizophrenia (CIAS) 
includes significant deficits (approximately 1 standard deviation [SD] below performance of 
healthy control subjects) in attention/vigilance, processing speed, working memory, 
reasoning, problem solving, verbal memory, visual memory and social cognition that are
present both in patients on antipsychotics, as well as drug-naïve patients [Fatouros-Bergman 
et al, 2014; Schaefer et al, 2013]. These impairments have been shown to be associated with 
several key functional outcomes [Shamsi et al, 2011; Green et al, 2000].
Dopamine is a neurotransmitter playing a key role in the central nervous system (CNS) 
[Snyder et al, 1970].  The physiological actions of dopamine are mediated by dopamine
receptors, which belong to the G protein-coupled receptor superfamily. On the basis of their 
structural, pharmacological and biochemical properties, dopamine receptors are classified 
into either the D1-class (dopamine receptor type 1 [D1] and dopamine receptor type 5 
receptors) or the D2-class (dopamine receptor type 2, dopamine receptor type 3 and dopamine
receptor type 4 receptors). Among them, D1 receptors are expressed at a high level of density 
in the dopamine rich area of the forebrain and play a crucial role in a variety of cognitive 
functions [Zhang et al, 2009]. It is reported that abnormal neurotransmission, especially the 
dopamine and glutamate (Glu) system, plays a critical role in the pathophysiology of 
schizophrenia. One of the therapeutic targets for CIAS is the activation of D1 receptors 
[Tamminga, 2006; Goldman-Rakic et al, 2004].  The hyperactivity of dopamine in 
subcortical structures is thought to be associated with positive symptoms; whereas, D1
receptor hypoactivity in the frontal cortical area has been suggested to be associated with 
negative symptoms and impaired cognitive function [Laruelle, 2014]. Indeed, D1 receptors in 
the frontal cortex are reported to be involved in working memory expression [Arnsten et al, 
1994].  These findings indicate that the stimulation of the D1 receptor is a promising target 
for improving CIAS; however, no D1 receptor agonist has been identified as a drug candidate 
for CIAS because of their powerful hypotensive effect [Blanchet et al, 1998; Duncker et al, 
1997].
Increased activation of D1 receptors remains a compelling mechanism of action to treat 
CIAS, as identified by a consensus of academic and industry experts during the Measurement 
and Treatment Research to Improve Cognition in Schizophrenia initiative [Buchanan et al, 


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2007; Tamminga, 2006].  However, this mechanism has not been adequately tested in the 
clinic due to limitations of available D1 receptor agonists. Positive allosteric modulators 
(PAMs) are an alternative option for stimulating receptor function.  They positively modulate 
the effect of the agonist, which binds to the orthosteric site, without directly stimulating the 
receptor [May et al, 2004] and are therefore expected to exert agonist-like activity with a 
lower incidence of undesirable side effects.  ASP4345 is an orally available, small-molecule 
and selective D1 receptor PAM discovered by Astellas Pharma Inc.  ASP4345 is expected to 
effectively ameliorate CIAS without side effects such as hypotension.
1.2
Nonclinical and Clinical Data
The PAM effect of ASP4345 on the human D1 receptor was investigated using in vitro 
studies.  In a cyclic adenosine monophosphate assay using human D1 receptor-expressing 
cells, ASP4345 enhanced the potency of dopamine in a concentration-related manner. In a
binding study, dopamine hydrochloride concentration-relatedly inhibited binding of 
[3H]SCH23390, a D1 receptor antagonist radioligand, to D1 receptors.  ASP4345 (10 μmol/L) 
positively modulated the dopamine -induced inhibitory activity. This result suggests that 
ASP4345 enhances the binding activity of orthosteric D1 receptor ligands. ASP4345 at a 
concentration of 10 μmol/L had no appreciable affinity (less than 50% inhibition 
displacement of specific binding) to the D1 receptor orthosteric site or 53 other receptors, ion 
channels and transporters.
At an in vivo level, the potentiating effect of ASP4345 on c-fos expression stimulated by a D1
agonist at the medial prefrontal cortex (mPFC) was assessed in neonatally 1-(1-phenylcyclohexyl) 
piperidine (PCP)-treated mice. Oral treatment with 1 mg/kg ASP4345 enhanced the c-fos 
expression in (±)-SKF38393 hydrochloride (1 mg/kg)-treated mice.
It is widely accepted that cognitive deficits, including cognitive inflexibility are a core feature 
of schizophrenia.  Cognitive flexibility may be assessed in rodents using the attentional 
set-shifting task (ASST).  The effect on extradimensional (ED) shift deficits using the ASST 
was evaluated in subchronic PCP-treated rats.  ASP4345 significantly ameliorated ED shift 
deficits at doses of 0.3 and 1 mg/kg. 
The effect of ASP4345 on the release of neurotransmitters at the mPFC was assessed in 
subchronic PCP-treated rats using an in vivo microdialysis technique. Treatment of ASP4345 
increased the γ-aminobutyric acid level at 1 and 30 mg/kg doses and dopamine efflux at the 
1 mg/kg dose.  Oral treatment of ASP4345 did not affect glutamate efflux at any dose.
In summary, results of both the in vitro and in vivo studies indicate that ASP4345 is an orally 
active D1 receptor PAM and a promising candidate for use in treating CIAS.
The preclinical toxicology studies are reviewed in detail in the ASP4345 Investigator’s 
Brochure.  ASP4345 is considered a PAM with important findings noted below, including 
1 rat death associated with renal toxicity at the highest dose in a toxicological study and 
while the reversibility of the renal toxicity was noted in survival animals.  In dogs, vomiting, 
salivation, blood pH/electrolyte changes were observed but the histological changes in the 
kidney observed during the 1-week study were not replicated in the 4-week or 13-week 


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studies. Overall, the available toxicology data indicate that the target organs are the liver, 
kidneys, adrenal glands, ovary, gastrointestinal (vomiting and salivation) and possible 
embryo-fetal toxicity.
Safety, tolerability, and pharmacokinetics of ASP4345 have been evaluated in healthy male 
and female subjects in a single ascending oral dose escalation study (SAD; 4345-CL-0001)
and further, in male and female subjects with schizophrenia in a multiple ascending oral dose 
escalation study (MAD; 4345-CL-0002) in phase 1.  The mean exposure limit (AUC24 no 
greater than 14597 h•ng/mL) for the SAD and MAD studies were based on the no-observed-
adverse-effect-levels (NOAELs) from the preclinical toxicology studies.  A total of 
92 subjects were treated with ASP4345 up to 900 mg single doses and 150 mg repeated doses 
during the phase 1 studies of 4345-CL-0001 and 4345-CL-0002.
ASP4345 was well-tolerated in the SAD study, consistent with the failure to identify a 
maximum tolerated dose and any clinically significant adverse reactions with single doses up 
to 900 mg (Study 4345-CL-0001).  There were no deaths, serious adverse events (SAEs) or 
study discontinuations, and there were relatively few treatment-emergent or dose-related 
adverse events (AEs).  Furthermore, there were not any apparent dose-related effect on the 
incidence of total or any specific AEs, laboratory results, electrocardiograms (ECGs) or vital 
signs.
ASP4345 was well-tolerated in the MAD study, also consistent with the failure to identify a 
maximum tolerated dose with multiple doses up to 150 mg/day over 14 days.  In the MAD 
study (4345-CL-0002), mean steady-state conditions were reached by approximately day 5 of 
dosing across ASP4345 treatment groups, although 1 to 2 patients in each treatment group 
had more variability due to the length of time it took for these patients to reach steady-state. 
Mean steady-state AUCtau did not exceed the mean exposure limit (AUC24, day14 no greater 
than 14597 h•ng/mL) for any ASP4345 treatment group, including the 150 mg ASP4345 
treatment group. However, median steady-state AUCtau exceeded the exposure limit for the 
150 mg treatment group.
The mean t½ ranged from 11.1 to 26.8 hours, with the highest mean value observed in the 
50 mg ASP4345 treatment group. Rac (AUC) was similar across ASP4345 treatment groups 
and was approximately 1- to 2-fold at steady-state. There was no dose-dependency observed 
for rate of absorption (tmax), lag time (tlag) or half-life (t½). There was no evidence of time 
variant pharmacokinetics (e.g., auto-induction or -inhibition).
Based on the results of the slope estimates for the dose range tested (3 to 150 mg ASP4345), 
both Cmax and AUCtau failed to achieve dose proportionality at steady-state due to an 
unknown pharmacokinetic variable. The amount of ASP4345 excreted in urine was small 
with < 1% of the dose excreted unchanged.
Phamacodynamic effects of ASP4345 were also explored in the MAD trial by applying 
cognitive testing as well as EEG testing. The following tests were selected to cover a broad
spectrum of cognitive domains thought to be modulated by dopamine to assess for any subtle 
changes in cognition as part of the specific CogState panel for schizophrenia: Detection 


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Tasks (psychomotor function and information processing), Identification Task (visual 
attention) and One Back Task (attention and working memory).
While the study was not powered to see significant differences (including the 90% confidence 
interval [CI]), the direction and magnitude of effect sizes for cognitive testing suggests that 
treatment with ASP4345 was associated with a benefit of psychomotor function, information 
processing and visual attention. For all doses of ASP4345, performance on the Detection Task 
was numerically superior to baseline and placebo on day 14 with effect sizes ranging from 
0.577 to 0.993. Once treatment “stopped” these positive effects remained although they were 
reduced in magnitude. For all doses of ASP4345, performance on the Identification Task was 
numerically superior to placebo on day 14. There was no trend as compared to placebo for the 
One Back Task.
Neurophysiological EEG testing in this study included the Auditory Steady-state Response 
(ASSR), Mismatch Negativity (MMN) and P300 assessments (P3a-FZ, P3b-CZ, P3b-PZ) that 
were performed over a 2-hour period. Regarding the EEG results, ASSR showed a positive 
response as compared to placebo on day 14 for the 150 mg treatment group, while MMN 
shows trends for benefits over placebo across treatment groups, except the 50 mg ASP4345 
treatment group.
There were no patient deaths, study drug-related SAEs or TEAEs leading to withdrawal of
treatment. There was 1 SAE of small intestinal obstruction in a patient who received 50 mg 
ASP4345 on days 19 through 23 that was considered severe in nature. The last dose day for 
this patient was day 14, 5 days prior to the start of the SAE. The SAE was considered by the 
investigator to be not related to study drug and attributable to past medical history.
In multiple ascending dose study (4345-CL-0002), the more common TEAEs occurring in 
> 10% of patients in either the respective placebo group vs the ASP4345 group were 
headache (33.3%, 4/12 vs 25.0%, 9/36), somnolence (8.3%, 1/12 vs 19.4%, 7/36), dizziness 
(16.7%, 2/12 vs 5.6%, 2/36), insomnia (25.0%, 3/12 vs 8.3%, 3/36), back pain (none vs 
11.1%, 4/36), abdominal pain (16.7%, 2/12 vs none) and constipation (none vs 13.9%, 5/36). 
Therefore, with respect to TEAEs there was no clear pattern of tolerability issues for 
ASP4345 compared with placebo in this study with a limited sample size and duration of 
treatment.
Given nonclinical evidence of potential renal toxicity, laboratory tests directly assessing renal 
function were evaluated. Cystatin C values were monitored for changes in kidney function
throughout and after the end-of-treatment (EoT). In multiple ascending dose study (4345-CL-
0002), no patients in any ASP4345 dose group had changes from baseline to day 14 in 
cystatin C values > 30% compared to baseline.  There were no apparent dose-related effects 
on cystatin C values.
There were no clinically significant changes in hematology or other chemistry laboratory
analytes. This included an absence of patients with a potentially clinically significant value
for liver enzymes or total bilirubin. With respect to vital sign findings, there were no time- or 
dose-dependent changes apparent for pulse rates, systolic blood pressure or diastolic blood 


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pressure. The incidence of positive orthostatic challenge test results was low and there was 
no consistent pattern that would indicate a dose-related effect. There were also no study drug-
related changes in weight, waist circumference or body mass index (BMI).
During study 4345-CL-0002, from a cardiac standpoint, no patient had a clinically 
significantly abnormal ECG result at baseline or any postbaseline time point through day 18 
(96 hours after the last dose). No patient had a QT interval using Fridericia’s formula (QTcF)
value > 480 msec through day 14 or a > 30 msec change from baseline in QTcF.
No patient showed evidence of suicidal ideation based on C-SSRS results.
In summary, ASP4345 appeared safe and well-tolerated with respect to a 14-day treatment
duration with daily doses up to 150 mg.
Please refer to the Investigator’s Brochure for detailed information from nonclinical and 
clinical studies.
1.3
Summary of Key Safety Information for Study Drugs
Given the early stage of development, there are currently no expected AEs for ASP4345.
ASP4345 is considered a PAM with a relatively tolerable safety profile but with important 
preclinical toxicology findings noted below, including 1 rat death associated with renal toxcity 
at the highest dose in a toxicological study and while the reversibility of the renal toxicity was 
noted in survival animals.  In dogs, vomiting, salivation, blood pH/electrolyte changes were 
observed but the histological changes in the kidney observed during the 1-week study were not 
replicated in the 4-week or 13-week studies.  Overall, the available toxicology data indicate 
that the target organs are the liver, kidneys, adrenal glands, ovary, gastrointestinal (vomiting 
and salivation) and possible embryo-fetal toxicity.
ASP4345 may be associated with Treatment Emergent Adverse Events (TEAEs) based on the 
clinical studies. The following were key clinical observations: headache, somnolence, 
dizziness, insomnia, back pain, abdominal pain, and constipation. 
A maximum tolerated dose was not identified in either the SAD study (4345-CL-0001) or the 
MAD study in subjects with schizophrenia (4345-CL-0002) using dosing up to 900 mg single 
doses and 150 mg daily doses that did not exceed the mean exposure limit (AUC24 no greater 
than 14597 h•ng/mL) that was based on the NOAEL from the preclinical toxicology studies.
Further information can be found in the Investigator’s Brochure.


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1.4
Risk Benefit Assessment
No clinical efficacy studies have been conducted to date with ASP4345 for the treatment of
cognitive impairment associated with schizophrenia (CIAS).  Therefore, the actual benefit of 
ASP4345 in the treatment of CIAS is unknown. There are no known risks unambiguously
identified with this mechanism of action, as ASP4345 is a first-in-class compound for the 
proposed indication. Based on the safety profile from the phase 1 clinical studies and 
especially with subjects with schizophrenia, proceeding to phase 2 trials appear to be justified 
from a risk benefit assessment. 
An overview of the risk benefit of ASP4345 can be found in the Investigator’s Brochure, 
including monitoring and mitigation steps taken to maintain safety of the subjects while on 
study treatment. Routine risk minimization procedures are planned in this study along with 
weekly visits, including laboratory assessments, so that increases in cystatin C suggesting renal 
toxicity can be detected if a longer duration of treatment is related to the risks. Due to the 
known effects of the antipsychotic therapies used in this study and a potential interaction with 
ASP4345, prolactin will also be monitored. Other risks are monitorable and reversible (liver 
toxicity by LFTs; adrenal gland vacuolation by adrenocorticotropic hormone).  Additional 
potential risks are reversible (vomiting and salivation), therefore, no additional safety 
monitoring is required. Other potential risks such as changes in blood pH/blood chloride were 
likely due to the salt load for the administered dose and are unlikely to be of relevance for 
human studies associated with lower drug exposures. Changes in blood pH/blood chloride 
were not observed during phase 1 studies.  Therefore, only chloride will be monitored in this 
study but for general monitoring of renal function as described above.  
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objective(s)
The objectives of the study, conducted in subjects with cognitive impairment associated with 
schizophrenia, are the following:
2.1.1
Primary Objectives
●
To evaluate the efficacy of ASP4345 on cognitive impairment compared to placebo 
using change from baseline in MATRICS Consensus Cognitive Battery (MCCB) 
neurocognitive composite score (excluding social cognition domain). The primary 
estimand will use a Hypothetical Strategy and compare patients as though they had 
continued on the assigned treatment.
●
To evaluate the safety and tolerability of ASP4345 compared to placebo
2.1.2
Secondary Objectives
●
To evaluate the effects of ASP4345 compared to placebo on functional capacity using 
the University of California San Diego Performance-based Skills Assessment-2 
Extended Range (UPSA-2-ER) total score.
●
To evaluate the pharmacokinetic profile of ASP4345 and its metabolites, if necessary


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2.1.3
Exploratory Objectives
●
To evaluate the effects of ASP4345 compared to placebo using:
o
the 16-item version of the Negative Symptom Assessment Scale (NSA-16)
o
the individual domains of the MCCB 
o
the assessment of general clinical symptoms with the Positive and Negative 
Symptom Scale (PANSS)
o
the assessment of the Clinical Global Impression of Severity Scale (CGI-S)
●
To evaluate the relationship between the CGI-S and MCCB neurocognitive composite 
score
●
To evaluate the relationship between number of cognitive training levels, including 
repeat levels, completed (as a measure of compliance with cognitive training) and 
MCCB neurocognitive composite score To evaluate the pharmacogenetic impact on 
ASP4345 pharmacodynamic results
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a randomized, double-blind, placebo-controlled, 3-arm oral dose study to evaluate the 
safety and efficacy of ASP4345 in subjects with cognitive impairment associated with 
schizophrenia on stable doses of risperidone, quetiapine, olanzapine, ziprasidone, 
aripiprazole, brexpiprazole, paliperidone or lurasidone for at least 4 weeks prior to screening 
for oral medications and 2 months for depot medications.  The study will consist of the 
following periods:
●
Screening period (up to 28 days)
●
Double-blind treatment period (12 weeks/84 days)
●
Follow-up period (14 days post last dose)
Approximately 420 subjects are planned to be screened with up to 210 subjects enrolled in 
1 of 3 arms.  Study groups will consist of approximately 90 placebo subjects and 60 subjects 
each per active study arm randomized in 3:2:2 ratio to receive 1 of 2 doses of ASP4345 or 
matching placebo daily (QD) for 12 weeks. Study treatment assignments will be according to 
the following table:
Group
Dose Regimen
Number
A
50 mg, QD
60
B
150 mg, QD
60
C
Placebo, QD
90
After signing informed consent and during the screening period, study site personnel will 
check that potential subjects have not already been pre-screened, initiated or completed 
screening or have been randomized into this study, or another clinical trial, using an 
independent subject participation database.


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After completing the screening procedures, subjects will be evaluated for randomization 
eligibility. After randomization on day 1, subjects will receive oral doses of ASP4345 or 
matching placebo QD for 12 weeks. All subjects will be administered the first dose of blinded 
study drug at the site following randomization and provided with mobile applications that 
provide supplemental cognitive training and record treatment compliance.  Subjects will return 
to the clinic weekly for safety, efficacy, and/or pharmacokinetic procedures at days 7, 14, 21, 
28, 35, 42, 49, 56, 63, 70, 77 and 84.  Subjects will continue their antipsychotic treatment for 
the entire study and will be followed for 14 days after their last dose of study drug. 
Subjects terminating early from the study treatment will be encouraged to complete scheduled 
visits.  All subjects are allowed to stop study drug, but continue in the study through day 84 
according to the current visit schedule unless the participant specifically withdraws consent for 
any further contact with him/her or persons previously authorized by the participant provide 
this information.
Pharmacokinetic trough samples will be collected prior to dosing at days 7, 14 or 21, 42 and 
84.  Additional samples will be collected at approximately 2 hours and 4 hours post dose on 
day 42.
To determine changes in cognition with the MCCB instrument, cognitive testing will be 
performed at each screening visit, on days 1 (prior to first dose), 42, and 84.  All MCCB 
assessments following randomization should be performed within a 2-hour window of the 
baseline test. In order to avoid an acute impact of nicotine and caffeine on cognitive testing, 
smoking and intake of coffee will not be allowed approximately 30 minutes before the MCCB
assessment.
Study day 84/EoT visit completes the treatment period for the subject. Subjects will return to 
the clinic for a follow-up visit on day 98 to complete the final assessments.  Individual subject 
discontinuation of study drug treatment or study is addressed in Section 6 Discontinuation. 
Once the subject has completed or discontinued the study, no further treatment with ASP4345 
for cognitive impairment is planned to be offered.  
2.2.2
Dose Rationale
Astellas is proposing to conduct this PoC trial with separate 50 and 150 mg ASP4345 dose 
groups. This decision is based on the pharmacokinetic data and positive results for the 
a priori chosen electroencephalogram (EEG) evoked response and improvements in cognition 
(based on a specific CogState panel for schizophrenia) that were obtained for the ASP4345 
50 and 150 mg dose groups as compared with placebo in 4345-CL-0002. An additional 
reason is not having observed safety or adverse events of concern in the of the multiple 
ascending oral dose study (4345-CL-0002). Further reasoning behind these dose choices 
follows.
ASP4345 is a D1 receptor PAM and it is standard to evaluate 2 doses for a PAM or agonist, 
especially for a target where there is nonclinical data for both nonhuman primates and rodents 
suggesting potential inverted U dose (exposure)-response relationships. Both doses are within 
the presumptive nonclinical efficacious exposure range and evidence has been observed for 


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doses ranging from 3 to 150 mg. The 50 mg dose is the next highest dose to the 150 mg dose 
and data from the 50 mg dose will be valuable if safety data with the 150 mg dose are found 
to be inadequate.
Since the mean half-life of ASP4345 is approximately 10 to 20 h and patients achieved 
steady-state in the ongoing study by day 14, the pharmacokinetic parameters in a 12-week 
study are expected to be similar to the pharmacokinetic parameters observed on day 14 in 
Study 4345-CL-0002.
The ability of ASP4345 to improve cognitive impairment in subjects with schizophrenia will 
be assessed at doses of 50 mg and 150 mg QD over a period of 12 weeks. 
2.3
Endpoints 
2.3.1
Primary Endpoints
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the MCCB 
neurocognitive composite score (excluding social cognition domain).
●
Safety and Tolerability:
o
Nature, frequency and severity of AEs.
o
Vital signs (sitting or supine blood pressure, pulse and body temperature)
o
Clinical laboratory tests (hematology, biochemistry [including cystatin, serum 
prolactin, and ACTH] and urinalysis)
o
Routine 12-lead ECG
o
Columbia-Suicide Severity Rating Scale (C-SSRS)
o
Changes in individual indices of metabolic syndrome (weight, waist 
circumference, cholesterol, triglycerides, high-density lipoprotein [HDL; the 
second screening visit and day 77), and hemoglobin A1c [HbA1c]
o
Movement disorder (Abnormal Involuntary Movement Scale [AIMS], Simpson 
Angus Scale [SAS] and Barnes Akathisia Rating Scale [BARS])
2.3.2
Secondary Endpoints 
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the 
UPSA-2-ER instrument
●
Pharmacokinetics: 
o
ASP4345 and its metabolites, if necessary (plasma) Ctrough. Cmaxss and AUCss for 
ASP4345 and its metabolites, if necessary, will be estimated based on population 
pharmacokinetic modeling
2.3.3
Exploratory Endpoints
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the NSA-16 
only for the subjects who have at least 1 negative symptom of moderate severity
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the MCCB 
composite score.
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for each of the 
MCCB domains.


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●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the PANSS
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the CGI-S
●
Correlation between MCCB and CGI-S scores at each measurement (weeks -4, -3, 0, 6, 12)
●
Correlation between change from baseline to week 12/EoT in MCCB and change from 
baseline to week 12/EoT in CGI-S scores
●
Correlation between the number of cognitive training levels, including repeat levels, 
completed (as a measure of compliance with cognitive training) and MCCB 
neurocognitive composite score
●
Pharmacogenetics:
o
Catechol-O-methyltransferase (COMT) and dopamine D1 and D3 receptor 
genotyping
3
STUDY POPULATION
3.1
Selection of Study Population 
Male and female adult subjects with cognitive impairment associated with schizophrenia on 
stable doses of risperidone, quetiapine, olanzapine, ziprasidone, aripiprazole, brexpiprazole, 
paliperidone or lurasidone for at least 4 weeks prior to screening and 2 months for depot 
medications.
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1. Institutional Review Board/Independent Ethics Committee approved written informed 
consent and privacy language as per national regulations (e.g., Health Insurance 
Portability and Accountability Act Authorization for US sites) must be obtained from the 
subject or legally authorized representative prior to any study-related procedures 
(including withdrawal of prohibited medication, if applicable).
2. Subject is a male or female subject between 18 to 55 years of age, inclusive, at screening.
3. Subject has a diagnosis of schizophrenia or schizoaffective disorder according to the 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria and confirmed 
by the Mini-International Neuropsychiatric Interview version 7.02.
4. Subject has a stable clinical course as suggested by the following:
●no psychiatric hospitalization within the last 4 months, 
●no symptom-related changes in psychotropic medications (as defined in the 
concomitant medication section) within 4 weeks prior to baseline for oral 
medications and within 2 months for depot medications, 
●and core positive symptoms no worse than moderate in severity and no evidence of a 
current severe major depressive episode (moderately severe depression is allowed).
5. Subject has a stable living situation.
6. Subject’s extrapyramidal symptoms are no worse than mild in severity.


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7. Subject must be in ongoing maintenance (i.e., at least 4 weeks prior to day 1 for oral 
medications and within 2 months for depot medications) on up to 2 antipsychotic 
therapies (oral or depot) other than clozapine.  
8. Subject has a body mass index range of 18.5 to 45.0 kg/m2.
9. Female subject must either:
●Be of nonchildbearing potential:

Postmenopausal (defined as at least 1 year without any menses for which there 
is no other obvious pathological or physiological cause) prior to screening, or 

Documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy)
●Or, if of childbearing potential, 

Agrees not to try to become pregnant during the study and for 28 days after 
the final study drug administration,

And has a negative blood pregnancy test at screening and a negative urine 
pregnancy test at day 1,

And if heterosexually active, agrees to consistently use 1 form of highly 
effective birth control* starting at screening and throughout the study period 
and for 28 days after the final study drug administration.
10. Female subject must agree not to breastfeed starting at screening and throughout the 
study period, and for 28 days after the final study drug administration.
11. Female subject must not donate ova starting at screening and throughout the study period, 
and for 28 days after the final study drug administration. 
12. A sexually active male subject with female partner(s) who is of childbearing potential is 
eligible if:
●Agrees to use a male condom starting at screening and continue throughout study 
treatment and for 90 days after the final study drug administration. 
13. Male subject must not donate sperm starting at screening and throughout the study 
period, and for 90 days after the final study drug administration. 
14. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent 
or use a condom for the duration of the pregnancy or time partner is breastfeeding 
throughout the study period and for 90 days after the final study drug administration.
15. Subject agrees not to participate in another interventional study while participating in the 
present study, defined as signing the informed consent form until completion of the last 
study visit.
16. Subject has a negative urine drug screen for drugs of abuse at screening and day 1, 
excluding cannabis and documented prescribed benzodiazepines.


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*Highly effective forms of birth control include:
●Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation,
●Established intrauterine device (IUD) or intrauterine system (IUS).
●Bilateral tubal occlusion
●Vasectomy (A vasectomy is a highly effective contraception method provided the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used)
●Male is sterile due to a bilateral orchiectomy
●Sexual Abstinence is considered a highly effective method only if defined as 
refraining from heterosexual activity during the entire period of risk associated with 
the study drug. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant.
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1. Subject has a known or suspected hypersensitivity to ASP4345 or any components of the 
formulation.
2. Subject has had previous exposure with ASP4345.
3. Subject has a history of suicide attempt or suicidal behavior within 1 year prior to 
screening or has any suicidal ideation that meets criteria at a level of 4 or 5 by using the 
Columbia Suicide Severity Rating Scale (C-SSRS) or who is at significant risk to commit 
suicide, as assessed by the investigator at screening or at day 1.
4. Subject has any clinically significant liver chemistry test result (aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) or a 
result > 1.5 times above the upper limit of normal (ULN) at screening or repeated within 
1 week prior to potential randomization (day 1). In such a case, the assessment may be
repeated once.
5. Subject has any history or evidence of any clinically significant allergic, cardiovascular, 
gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, 
pulmonary, neurologic, dermatologic, history of seizure disorder, renal and/or other major 
disease or malignancy, as determined by the investigator. 
6. Subject has any clinically significant abnormality following the investigator’s review of 
the physical examination, electrocardiogram (ECG) and protocol-defined clinical 
laboratory tests at screening or at admission to the study (day 1).
7. Subject has known kidney disease and a glomerular filtration rate (GFR) < 60 mL/min 
per meter squared at screening and subjects will be discontinued from treatment only for 
decreases in the GFR that are clinically relevant.


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8.
Subject has a resting systolic blood pressure > 180 mmHg or < 90 mmHg, and a resting 
diastolic blood pressure > 100 mmHg at screening.  These assessments may be repeated 
once, after a reasonable time period, at the investigator’s discretion (but within the 
screening period).
9. Subject has a mean corrected QTcF > 450 msec (for male subjects) and > 470 msec (for 
female subjects) at screening or at randomization. If the mean QTcF exceeds the limits 
above, one additional triplicate ECG can be taken on day 1.
10. Subject has a history in the 6 months prior to screening of consuming more than 14 units 
of alcoholic beverages per week for males and more than 7 units of alcoholic beverages 
per week for females. (Note 1 unit = 12 ounces of beer, 4 ounces of wine, or 1 ounce of 
spirits).  
11. Subject is currently using protocol-specified prohibited medications and is unable to 
washout, including over-the-counter products and agrees not to consume grapefruit 
and/or grapefruit juice (as defined in the concomitant medication section).
12. Subject is currently using clozapine for treatment of schizophrenia.
13. Subject has a positive test for hepatitis B surface antigen (HBsAg), hepatitis A virus 
antibodies (immunoglobulin M) (anti-HAV [IgM]) or hepatitis C virus antibodies 
(anti-HCV) at Screening or has history of a positive test for human immunodeficiency 
virus type 1(HIV-1) and/or type 2 (HIV-2).
14. Subject who has had electroconvulsive therapy within the 6 months prior to screening.
15. Subject has a history of head injury with clinically significant sequelae, including loss of 
consciousness for 1 hour or greater. 
16. Subject is an employee of the Astellas Group or Contract Research Organization involved 
in the clinical study.
17. Subject has received investigational study drug within 28 days or 5 half-lives, whichever 
is longer, prior to screening. 
18. Subject has any condition, which, in the investigator’s opinion, makes the subject 
unsuitable for study participation.
Waivers to the exclusion criteria will NOT be allowed.


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4
TREATMENT
4.1
Identification of Investigational Product(s)
4.1.1
Study Drug
ASP4345 will be supplied as 50 mg capsules for oral administration in hard gelatin capsules 
with a yellow cap and Swedish orange body.
The capsules are packaged in aluminum/aluminum blister strips, which are contained in a 
tri-fold dosing card.  ASP4345 capsules are stored at ambient room temperature 20° - 25° C 
(68° - 77° F). Excursions are permitted between 15° and 30° C (59°and 86° F).
ASP4345 capsules are released in accordance with Good Manufacturing Practice (GMP) by 
Astellas.
4.1.2
Comparative Drug 
Matching placebo will be supplied in the same packaging configuration as ASP4345 and has 
the same storage requirements.
4.2
Packaging and Labeling
All study drug(s) used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at APGD or sponsor’s designee in accordance with APGD or 
sponsor’s designee Standard Operating Procedures (SOPs), GMP guidelines, International 
Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals 
for Human Use (ICH) Good Clinical Practice (GCP) guidelines, and applicable local 
laws/regulations.
Each dosing card will bear a label conforming to regulatory guidelines, GMP and local laws 
and regulations that identifies the contents as investigational drug.
4.3
Study Drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by the investigator/or designee and that:
●
Such deliveries are recorded,
●
Study drug is handled and stored according to labeled storage conditions,
●
Only study drug with appropriate expiry/retest is dispensed to study subjects in 
accordance with the protocol, and
●
Any unused study drug is returned to the sponsor.
Study drug inventory and accountability records will be kept by the investigator or designee.
Study drug accountability throughout the study must be documented and reconciled. The 
following guidelines are therefore pertinent:
●
The investigator or designee (i.e., study drug manager) agrees not to supply study drugs 
to any persons except the eligible subjects in this study in accordance with the protocol.


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●
The investigator or designee (i.e., study drug manager) will keep the study drugs in a 
pharmacy or other locked and secure storage facility under controlled storage conditions, 
accessible only to those authorized by the investigator to dispense these study drugs.
●
A study drug inventory will be maintained by the investigator or designee (i.e., study 
drug manager).  The inventory will include details of material received and a clear record 
of when they were dispensed and to which subject.
●
At the conclusion or termination of this study, the investigator or designee (i.e., study 
drug manager) agrees to conduct a final drug supply inventory and to record the results 
of this inventory on the Drug Accountability Record. It must be possible to reconcile 
delivery records with those of used and/or returned study drug. Any discrepancies must 
be accounted for and documented. Appropriate forms of deliveries and returns must be 
signed by the site staff delegated this responsibility.
●
The site staff must return study drug to the sponsor or designee at the end of the study or 
upon expiration unless otherwise approved by the sponsor.
4.4
Blinding
This is a double blind study. Subjects will be randomized to receive ASP4345 or placebo in a 
blinded fashion such that the investigator, sponsor’s study management team, clinical staff, 
nor the subject will know which agent is being administered. The randomization number will 
be assigned based on information obtained from the Interactive Response Technology (IRT).
4.4.1
Blinding Method 
This is a double blind study. Subjects will be randomized to receive 1 of 2 doses of ASP4345
or placebo in a blinded fashion such that neither the investigator, Sponsor’s study 
management team, clinical staff, nor the subject will know which agent is being administered. 
The randomization number will be assigned based on information obtained from the IRT.
The randomization list will be provided to Global Pharmacovigilance of Astellas, who will 
break the codes for all Suspected Unexpected Serious Adverse Reaction (SUSAR) cases for 
reporting purposes only. They are also capable of breaking the code in emergency situations.
The randomization list is also provided to BioAnalysis Scientist for the purposes of 
pharmacokinetic analysis prior to unblinding.  The pharmacokinetic analysis results will not 
be shared prior to unblinding at database lock.
4.4.2
Confirmation of the Indistinguishability of the Study Drugs
The appearance and the form of both the drug and packaging of the ASP4345 50 mg capsules
are identical to those of the matching placebo.
4.4.3
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking 
The randomization list and study medication blind will be maintained by the IRT system.


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4.4.4
Breaking the Treatment Code for Emergency 
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject.  The time, 
date, subject number and reason for obtaining any of these codes, and therefore breaking the 
blind, must be documented in the study file.  The treatment code must only be requested by 
the investigator or other persons designated as sub-investigators.  No subjects or other study 
personnel will be made aware of the treatment given to any subject unless a medical 
emergency necessitates such disclosure.  
Unblinding of the study drug should only be considered for subject safety or when critical 
therapeutic decisions are contingent upon knowing the blinded study drug assignment.  Any 
unblinding by the investigational staff must be reported immediately to the Sponsor and must 
include an explanation of why the study drug was unblinded.  If possible, the Sponsor should 
be contacted prior to unblinding of the study drug.
4.4.5
Breaking the Treatment Code by the Sponsor
The sponsor may break the treatment code for subjects who experience a SUSAR, in order to 
determine if the individual case or a group of cases requires expedited regulatory reporting. 
Individual Emergency Codes will be provided to the limited staff who are responsible to 
break the codes for all SUSAR cases for reporting purposes.
4.5
Assignment and Allocation
Subjects will be randomized in a 3:2:2 ratio to a treatment arm (placebo to active) according 
to the randomization schedules through IRT. All subjects who meet the eligibility criteria will 
be randomized. The site personal will dispense the treatment according to the IRT system’s 
assignment. Specific procedures for randomization through the IRT are contained in the 
study procedures manual.
If a subject is assigned a randomization number, but does not receive study drug, the 
randomization number will not be used again.  The randomization schedules that determine 
subject treatment will be computer-generated by IRT before the beginning of the study.  
Specific procedures for randomization through the IRT are contained in the study-specific 
IRT manual.
All subject numbers will be assigned using the IRT starting at screening. All subjects will 
have a unique, 10-digit subject number.  The first 5 digits of this number will be the 
investigator’s site number.  The second 5 digits will be represent the subject’s accession 
number.  This will be the number that identifies a subject during the course of the study.


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5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other 
Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
Subjects randomized to either of the ASP4345 groups will receive ASP4345 50 mg 
(1 capsule of 50 mg and 2 capsules of placebo) or ASP4345 150 mg (3 capsules of 50 mg and 
no placebo) QD for the duration of 12 weeks. Subjects randomized to the placebo group will 
receive placebo to match ASP4345 (3 capsules) QD for the duration of 12 weeks. 
ASP4345 capsules will be administered orally as a single daily dose on days 2 through 84, in 
the morning with or without food (the first dose on day 1 will be taken at the study site). The 
subject will also dose at the study site on the following 4 visits: days 7, 14 or 21, 42 and 
84/EoT.
Doses should be taken in the morning with or without food. If a subject forgets a dose, the 
dose should be taken as soon as they remember but prior to bedtime that day. The next day's 
dose should still be taken as planned. Two doses should not be taken in the same day.
At randomization and weekly thereafter, subjects will receive the assigned treatment 
sufficient for a period of 1 week with a 2-day window (including morning dose on the day of 
the next visit). 
Pharmacokinetic samples will be taken pre-dose on day 7, 14 or 21, 42 and 84; post-dose at 
approximately 2 and 4 hours on day 42 (Week 6).  There are no fasting requirements for the 
pharmacokinetic samples but date and time of the dose taken prior to collecting the 
pharmacokinetic sample will be captured in the electronic case report form (eCRF).
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
The doses of 50 and 150 mg QD of ASP4345 were tested in the phase 1 multiple dose study. 
These doses were well tolerated and no maximum tolerated dose was determined. Stopping 
criteria are presented in Section 6.1 Discontinuation of Individual Subject(s). Study 
4345-CL-0015 is a fixed dose, proof-of-concept study. In order to adequately evaluate the 
hypothesis, it is important to assess efficacy and safety across a common dose, therefore, 
dose increases and decreases are not allowed. 
5.1.3
Previous and Concomitant Treatment (Medication and NonMedication 
Therapy)
Medications taken for treatment of schizophrenia during the 12 months prior to screening and 
other medication taken 28 days prior to the screening visit and up to the first dose of study 
medication (treatment period) will be documented in the appropriate case report form as prior 
schizophrenia medications or other prior medication, respectively. Subjects taking prohibited 
medications who are willing to discontinue these medications, as clinically indicated and
based upon the investigator’s recommendation, may washout over a period of 5 half-lives on 
a schedule determined by the investigator in consultation with the study medical monitor. 


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Medications taken after the first dose of study medication and up to EoS will be documented 
on the appropriate case report form as concomitant medication. 
During screening and prior to randomization, the investigator or designee will submit the 
subject’s list of medications to the study medical monitor for review and approval.  Subjects 
are instructed not to take any concomitant medication without first consulting the Investigator 
or study coordinator (SC) throughout the duration of the study.
Permitted Concomitant Antipsychotics:
Subjects are required to be on a stable dose of an antipsychotic, or a stable regimen of up to 
2 antipsychotics, for 4 weeks prior to baseline (i.e., day 1) for oral drugs and for 2 months 
prior to baseline for depot treatment and throughout the study. The subject will continue to 
take their prescribed antipsychotic throughout the study at their usual dosing time and 
interval. Permitted antipsychotics include quetiapine, risperidone, olanzapine, ziprasidone, 
aripiprazole, brexpiprazole, paliperidone or lurasidone. 
Prohibited Concomitant Medications:
The following concomitant medications are prohibited:
●
Use of clozapine for treatment of schizophrenia.
●
Strong and moderate CYP3A inhibitor use (e.g., but not limited to: boceprevir, 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole).
●
Initiation of medications during the conduct of the study that are inducers and inhibitors 
(strong and moderate) for enzymes cytochrome P450(CYP)2C19, CYP2D6 and 
CYP1A2 are prohibited to avoid potential confounding effects on the study results.  See 
Appendix 12.2 List of Inducers and Inhibitors of CYP2C19, CYP2D6 and CYP1A2. 
●
Any nonprescribed drugs (including natural and herbal remedies [e.g., Valerian]) from 
2 weeks prior to administration of the study drug.
●
For a list of prohibited concomitant medications see Appendix 12.1 List of Excluded 
Concomitant Medications.
Allowed Concomitant Medications:
In addition to the antipsychotics listed above, the following concomitant medications at 
stable doses (i.e., 4 weeks prior to day 1) are allowed during the study:
●
Stable doses of antidepressants (except for fluvoxamine, buproprion, tricyclic 
antidepressants, and monoamine oxidase inhibitors) are permitted
●
Short-acting hypnotic agents (trazodone or zolpidem or zaleplon or zopiclone or 
eszopiclone (Note: Short-acting hypnotics are not allowed within 12 hours prior to 
cognitive testing) 
●
Anticholinergics are permitted (Note: use of anticholinergics is not allowed within 8 
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●
Approved use of concomitant medication for the treatment of hypertension, 
hyperlipidemia or diabetes mellitus
●
Occasional use of non-steroidal anti-inflammatory drugs (NSAIDs) (including 
acetaminophen [up to 2 g/day], ibuprofen and naproxen)
●
Vitamins and cardiovascular prophylactic aspirin up to 325 mg/day
●
Oral contraceptive use is permitted as long as the subject is on a stable dose prior to 
screening.
●
Any other prescribed medications are allowed during the study only after approval by the 
investigator in consultation with the study medical monitor.
5.1.4
Treatment Compliance
Study subjects should be counseled on the need to meet 100% compliance with study drug.  
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period.  Compliance will be verified by the accounting of study drug at each monthly visit 
after day 1. When study drug is administered at the research facility, it will be administered 
under the supervision of study personnel.
Compliance of the study drug will be monitored by the accounting of unused medication 
returned by the subject at visits. Additionally, study drug compliance will also be 
documented by the use of a clinically-validated artificial intelligence technology application.
Subjects who are less than 85% compliant and more than 100% compliant with the dosage 
regimen for greater than 2 consecutive visit periods during the study should be counseled 
regarding steps to improve compliance. Subject use of the cognitive training application 
should also be assessed as outlined in Section 5.7.5 at the same time as compliance with 
study drug treatment.
Treatment compliance should be monitored closely and deviation in compliance should be 
reported to the sponsor.
5.1.5
Restrictions During the Study 
Subjects are requested not to eat grapefruit and/or drink grapefruit juice (see exclusion 
criterion 11).  Subject smoking is not restricted.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics including Smoking History
Date of birth, sex, race, ethnicity, height, weight, and BMI will be recorded at screening. 
Height will be measured at screening only. Weight and waist circumference will also be 
collected prior to randomization and on days 1, 42 and 84 as part of the assessment for 
metabolic syndrome described in Section 5.4.6 Metabolic Parameters.
Smoking history will be recorded at screening, including use of cannabis.


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5.2.2
Medical and Psychiatric History
A detailed medical history for each subject will be obtained at screening, including a history 
of prior head trauma and treatment. A detailed psychiatric history will also be obtained at 
screening, including all treatments and therapies used. All relevant past and present 
conditions, as well as prior surgical procedures will be recorded.  
5.2.3
Duplicate Subject Database Check
After signing informed consent and during the screening period, study site personnel will 
check that potential subjects have not already been pre-screened, initiated or completed 
screening, or have been randomized into this study or another clinical trial using an 
independent subject participation database.  Independent subject participation databases seek 
to reduce duplicate enrollment by identifying duplicates before they randomize into the study, 
and this measure is consistent with exclusion requirement of not participating in another 
interventional clinical trial during the conduct of the study (inclusion criterion 15).  In order 
to complete this check and per the informed consent, study personnel will request that the 
subject present a valid picture identification (e.g., driver’s license, passport, state issued ID 
card, etc.) and study personnel may be required to provide certain authorized information that 
could potentially be used to identify study subjects identifiers (e.g., date of birth, initials, etc.) 
so that the match algorithms can be run. 
Subjects that meet the inclusion criteria, none of the exclusion criteria, and are not identified 
as a duplicate subject (e.g., certainly, possible, probably), will be enrolled into the study. 
Appropriate documentation reflecting the subject’s eligibility according to these criteria will 
be reflective in the subject’s source documents.
5.2.4
Diagnosis of the Target Disease, Severity, and Duration of Disease 
The diagnosis of schizophrenia or schizoaffective disorder must be confirmed by the 
investigator and documented in the subject’s medical notes as meeting the Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition criteria and the criteria from the Mini-
International Neuropsychiatric Interview version 7.02 at screening. Duration of 
schizophrenia or schizoaffective disorder, date of the first psychotic break and associated 
symptoms (agitation, delusions, hallucinations, and thought disorder) and date of the most 
recent psychotic break and associated symptoms (agitation, delusions, hallucinations, and 
thought disorder) will be recorded in the eCRF. 
The subject’s medical notes at screening must also confirm no psychiatric hospitalization 
within the last 4 months, no symptom-related changes in psychotropic medications (as 
defined in the concomitant medications section), core positive symptoms no worse than 
moderate in severity, and no evidence of a current severe major depressive episode. The 
subject must also have a stable living situation documented in the medical notes at screening.


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5.2.5
Mini-International Neuropsychiatric Interview
The M.I.N.I. International Neuropsychiatric Interview (M.I.N.I. 7.02) is a short, structured 
diagnostic interview administered by trained personnel. The instrument captures the major 
Axis I psychiatric disorders in Diagnostic and Statistical Manual of Mental Disorders, 5th 
edition (DSM-V) and ICD-10, and has demonstrated equivalent reliability, validity, and 
decreased interview time when compared to the Structured Clinical Interview for DSM-V
diagnoses (SCID-P). Each module begins with screening questions that are answered yes or 
no. A negative response in the screening algorithm advances the interview to the next 
module, whereas a positive response will prompt additional questions that ask patients to 
characterize behavior with “yes” or “no” responses. Some questions contain a recall period 
(e.g., “Past Two Weeks,” “Past Episode” and “Current Episode”). After completion of the 
additional questions, the clinician indicates whether or not the diagnostic criteria have been 
met, based on the instrument scoring criteria [Amorim et al, 1998; Sheehan et al, 1998; 
Lecrubier et al, 1997; Sheehan et al, 1997].
The M.I.N.I. 7.02 will be completed at screening on paper by trained site personnel, in 
accordance with the structured interview requirements.
5.3
Efficacy and Pharmacokinetics Assessments
5.3.1
Efficacy Assessments
The principal investigator or qualified delegate will complete the MCCB and UPSA-2-ER 
using a paper copy of the licensed instrument and the results will be recorded in a central 
database by the vendor following scoring of the scales. The data will be transferred 
electronically to the Sponsor. 
For the NSA-16, PANSS, and CGI-S a tablet will be used by the principal investigator or 
qualified delegate to assess the subject during clinic visits. Site personnel will receive 
training on how to complete the assessments on the tablet.  Data will be automatically 
transmitted to a central database from the tablet.
When possible continuity of raters should be maintained across scales for each patient. See 
[Appendix 12.6 Clinical Outcome Assessment Scales] for information on all COAs used in 
the study.
5.3.1.1 MATRICS Consensus Cognitive Battery
The MCCB was developed as a standard battery for clinical trials of cognition-enhancing 
interventions for schizophrenia.  The instrument measures seven separate but intercorrelated 
cognitive domains: working memory, attention/vigilance, verbal learning and memory, visual 
learning and memory, reasoning/problem solving, speed of processing and social cognition. 
These domains were the consensus of the National Institute of Mental Health (NIMH) 
Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) 
initiative.  The output of this process (test-retest reliability, utility as a repeated measure, 
relationship to functional outcome, potential sensitivity to pharmacological treatment and 


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practicality/tolerability from 5 clinical sites) was published as the 7-domain MCCB 
[Nuechterlein et al, 2008].
The MCCB should be completed by the principal investigator or qualified delegate twice 
during the 28-day screening period, and on days 1, 42 and 84/EoT.  The data will be 
completed on paper by the principal investigator or qualified delegate.
5.3.1.2 University of San Diego Performance-based Skills Assessment-2 Extended Range
The UPSA-2 was developed to assess the functional abilities of the subject with schizophrenia in 
6 domains: household management, communication, financial skills, transportation, 
comprehension/planning and medication management.  The assessment is performed as a role-
play with the rater in which participants are asked to utilize props to demonstrate how well they 
perform every day activities.  The UPSA-2-ER contains additional questions to increase the level 
of difficulty for each subscale.
As part of the MATRICS Coprimary and Translations (MATRICS-CT) initiative, the Validation 
of Intermediate Measures (VIM) study established that the UPSA-2 demonstrated good test-
retest reliability, was not burdensome to patients and was adequate for repeated measurements.  
The VIM study also demonstrated that performance-based measures were strongly correlated to 
cognition interview-based measures.  Based on the available evidence, the MATRICS-CT 
initiative concluded that the UPSA-2 was suitable as a coprimary measure [Green et al, 2011].  
Additional evidence has demonstrated correlation with the MCCB battery [Keefe et al, 2011].  In 
a study reported by Patterson and colleagues [2001], the UPSA-2 performance correlated 
significantly with the severity of negative symptoms and symptoms of cognitive impairment.  As 
described above, the UPSA-2-ER contains additional questions to increase the level of difficulty 
for each subscale and has been used in previous CIAS trials.
The UPSA-2-ER scoring will be completed by the principal investigator or qualified delegate 
on paper on days 1 and 84/EoT.
5.3.1.3 Positive and Negative Syndrome Scale
The PANSS was developed based on patient interviews [Kay et al, 1987] and has been 
widely used in schizophrenia trials. The validity and reliability of the PANSS has been 
extensively studied and established [Lindenmayer et al, 1995], including its ability to assess 
positive and negative symptoms in subjects with recent onset of schizophrenia [Emsley et al, 
2003].  The PANSS contains 30-items rated on 7-point Likert scales and is scored to assess 
3 subscales:  positive symptoms, negative symptoms and psychopathological symptoms.  A 
5-factor structure has also been identified to explore changes in the traditional subscales, and 
also those that may align with disorganized (or cognitive) factors, as well as excited and 
depression/anxiety factors [Lindenmayer et al, 1995].
Data from the PANSS is enhanced when subjects identify a person who can serve as an 
informant for its completion.  Although not required for inclusion, sites and subjects are 
highly encouraged to identify a reliable subject (e.g., family member, social worker or case 
manager) who spends sufficient time with them to be able to provide information to PANSS 
raters and who has interacted with the subject during the past seven days.


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The informant needs to be able and willing to attend clinic visits or to provide input via 
telephone.  The same informant should be used throughout the study whenever possible. The 
informant must be considered to be reliable by the site. 
The PANSS will be completed by the principal investigator or qualified delegate on the tablet 
at screening and days 1, 14, 42 and 84/EoT.
5.3.1.4 Negative Symptom Assessment-16
The NSA-16 [Axelrod et al, 1993] is a semi-structured interview conducted by the principal 
investigator or qualified delegate to determine the severity of the subject’s negative 
symptoms in the areas of problems in communication, emotion and/or affect, motivation, and 
sociality. Based on a 7-point scale (0-6) for each of the 16 items, a total negative symptom 
score is calculated by adding the items; a higher score indicates more severe symptoms. The 
negative symptom burden will be further assessed using NSA-16 for patients who have at 
least 1 negative symptom of moderate severity.  While some overlap between concepts on the 
PANSS negative symptom subscale and the NSA-16 exist, the NSA-16 assesses additional 
concepts covering verbal skills and activities of daily living, both of which may change if 
improved cognition is observed.
The NSA-16 will be completed by the principal investigator or qualified delegate on the 
tablet at screening and days 1, 42 and 84/EoT.
5.3.1.5 Clinical Global Impression of Severity Scale
The CGI-S [Schneider et al., 1997] is used to measure severity, treatment response and the 
efficacy of treatment in studies of patients with mental disorders.  The CGI-S is a 7-point 
scale that requires the clinician to rate the severity of the patients illness. 
The CGI-S will be completed by the principal investigator or qualified delegate on the tablet 
at days 1, 42 and 84/EoT.
5.3.2
Pharmacokinetics Assessments
Pharmacokinetic trough samples will be collected at/on 4 visits: prior to dosing at days 7, 14 or 
21, 42 and 84.  Additional samples will be collected at approximately 2 hours and 4 hours post 
dose on day 42. Subjects should be reminded not to dose at home prior to their clinic visit.  
Details on sample collection, processing, labeling, storage, and shipment procedures are 
provided in the laboratory manual. Analysis of ASP4345 and any metabolites (if applicable) 
will be performed using a validated method at a bioanalytical laboratory specified by the 
Sponsor.


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5.4
Safety Assessment
Safety will be assessed through AEs, safety laboratory tests (chemistry, hematology and 
urinalysis), physical examination, vital signs, 12-lead ECGs, metabolic syndrome assessment 
(weight, waist circumference, cholesterol, triglycerides, HDL [the second screening visit and 
day 77] and fasting glucose), HbA1c and the C-SSRS. Unscheduled assessments will be 
performed if clinically warranted. The ARCI and Bond Lader instruments did not reveal any 
effects of ASP4345 during phase 1. Therefore, they are not included in the safety assessments.  
Phase 1 testing with ASP4345 has not revealed a clinically significant effect with orthostatic 
vital signs and these measures are not included in this trial.
ASP4345 penetrates the CNS in humans; therefore, a prospective assessment of suicidality 
will be performed using the C-SSRS.
5.4.1
Vital Signs
Vital signs consist of body temperature, pulse and sitting or supine blood pressure.  Single 
measures of vital signs will be obtained during the screening visit, and at each weekly visit
through day 84/EoT.  Vital signs should be obtained prior to scheduled blood draws.
5.4.2
Adverse Events
See [Section 5.5 Adverse Events and Other Safety Aspects] for information regarding AE 
collection and data handling. 
5.4.2.1 Adverse Events of Possible Hepatic Origin
See [Appendix 12.3 Liver Safety Monitoring and Assessment] for detailed information on 
liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study 
and receiving study drug is accompanied by increases in Liver Function Tests value ([LFT], 
e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, etc.) or is 
suspected to be due to hepatic dysfunction.
Subjects with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored.


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5.4.3
Laboratory Assessments
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
See Table 1 Schedule of Assessments for study visit collection dates. 
Panel
Visits
Parameters to be analyzed
Hematology and 
Coagulation
Screening visits and days 35, 
77 and 98/EoS
Hemoglobin
Hematocrit
Erythrocytes (red blood cell)
Leukocytes (white blood cell)
Differential white blood cell
Platelets
Prothrombin time (PT) and International normalized 
ratio (INR) 
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH)
Reticulocytes 
Abbreviated 
Biochemistry 
Weekly starting at 
randomization except for days 
35, 77 and 98/EoS
Chloride
Creatinine
Cystatin-C
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Blood Urea Nitrogen (BUN)
Glomerular Filtration Rate (GFR) calculated using 
Modification of Diet in Renal Disease (MDRD)
Biochemistry
Screening visits, and days 35, 
77 and 98/EoS – Fasting at all 
visits except for the first 
screening visit and day 98/EoS
Sodium
Potassium
Calcium
Chloride
Magnesium
Glucose – fasting at screening, randomization and days 
42 and 84/EoT
Creatine Kinase
Creatinine
Cystatin-C
Alkaline Phosphatase
Lactate dehydrogenase (LDH)
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Gamma glutamyl transpeptidase (GGT)
Total bilirubin (direct and indirect)
Total protein
Table continued on next page


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Panel
Visits
Parameters to be analyzed
Biochemistry
(continued)
Screening visits, and days 35, 
77 and 98/EoS – Fasting at all 
visits except for the first 
screening visit and day 98/EoS
Albumin
Total cholesterol
HDL (only at the second screening and day 77)
Triglycerides
Uric Acid
Blood Urea Nitrogen (BUN)
Inorganic phosphate
Glomerular Filtration Rate (GFR) calculated using 
Modification of Diet in Renal Disease (MDRD)
HbA1c
Hormones
Randomization and day 
84/EoT 
Plasma Adrenocorticotropic Hormone (ACTH)
Prolactin
Thyroid-stimulating hormone (TSH; only at Screening 
and EoT)
Serology
Screening
Hepatitis B surface antigen (HBsAg)
Hepatitis A virus antibodies
(immunoglobulin M) (anti-HAV [IgM])
Hepatitis C (HCV) Antibody
Urinalysis
Screening visits and days 35, 
77 and 98/EoS  
Leucocytes
Nitrite
Protein
Glucose
pH
Blood
Urobilinogen
Bilirubin
Ketones
Potassium
Drug Screen 
(urine 
collection/urine 
dip stick)
Screening, randomization and 
day 84/EoT
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids
Cocaine
Opioids
Alcohol screen 
(urine)
Screening, randomization and 
day 84/EoT
Alcohol
Serum Pregnancy 
test (for females 
of child-bearing 
potential only)
Screening visit and days 
84/EoT and 98/EoS
Serum beta human chorionic gonadotropin (β-HCG)
Urine Pregnancy 
test (for females 
of child-bearing 
potential only)
Randomization and day 42
Urine beta human chorionic gonadotropin (β-HCG)
EoS: end-of-study; EoT: end-of-treatment
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/sub-investigator who is a qualified physician.  Unscheduled tests or a 
repeat of abnormal laboratory test(s) may be performed if clinically indicated and to follow-up 
on suspected AEs.


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The analyses on hematology and coagulation, biochemistry, serology and urinalysis samples 
will be performed by a central laboratory.  Kits from the central laboratory will be provided 
to the sites to perform urine pregnancy tests on females of child-bearing potential.  Results 
will be noted in the subject’s chart.  
5.4.4
Physical Examination 
The subject will be examined by a principal investigator or qualified delegate at screening, 
randomization (predose), and days 42 and 84/EoT. Physical examination may also be 
performed at unscheduled visits if necessary. It includes examination of main body systems, 
such as abdomen, central nervous system and musculoskeletal system.  
The principal investigator or qualified delegate will conduct the exam, determine findings 
and assess any abnormalities as to clinical significance and whether any exclusion criteria 
have been met. After study drug administration, new abnormal findings or a worsening of an 
ongoing abnormal condition must be recorded as an AE.
5.4.5
Electrocardiogram 
A 12-lead ECG will be performed at screening, randomization, and day 42 and 84/EoT visits. 
All ECGs should be taken before any scheduled blood draws. ECGs will be recorded with the 
subject in the supine position, after the subject has been lying down for approximately 
5 minutes. There should be at least 5 minutes between ECG measurements in case a repeat is 
needed. Any clinically significant adverse changes on the ECG will be reported as AEs. 
Printouts of all ECGs, marked with the subject number and initials, visit date and visit 
number should be stored in the subject’s source data.
5.4.6
Metabolic Parameters
Metabolic parameters (waist circumference, cholesterol, triglycerides, HDL [the second 
screening visit and day 77], fasting glucose and weight) and HbA1c will be measured at both 
screening visits, and at days 35 and 77 visits.  
5.4.7
Sponsor Consult on Concomitant Medications
The principal investigator or qualified delegate or allied health professional will consult with 
the Astellas medical monitor or designee at screening on the concomitant medication history 
for the subject to confirm no excluded medications are listed.  If any changes were made to 
medications between the screening and randomization visits, the site will contact the medical 
monitor for a second consult.  The consultation will be documented by worksheet.
5.4.8
Columbia Suicide Severity Rating Scale
The C-SSRS [Posner et al, 2009] was developed as a screening tool to identify suicide risk. 
The interview asks subjects detailed questions regarding suicidal ideation, behaviors, 
intensity of ideation, and attempts. Response options and recall periods vary in accordance 
with the nature of the question.
The C-SSRS will be performed by trained site staff via interview at screening, randomization, 
at all subsequent study visits. At the first screening, the “Lifetime” version is to be used to 


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determine eligibility. During all subsequent visits, including the second screening visit, the 
“since last visit” version is used to monitor on-study suicidal ideation and behavior after the 
initial assessment. Responses will be reported on the tablet. When possible continuity of raters 
should be maintained across scales for each patient.
Subjects who have a history of suicide attempt or suicidal behavior within the last 12 months, 
or has suicidal ideation within the last 12 months (a response of “yes” to questions 4 or 5 on
the suicidal ideation domain), will be excluded.
5.4.9
Abnormal Involuntary Movement Scale 
The AIMS [Rush, 2000] aids in the early detection of tardive dyskinesia, as well as providing a 
method for on-going surveillance. The AIMS is a checklist and uses a 5-point rating scale for
recording scores for 7 body areas: face, lips, jaw, tongue, upper extremities, lower extremities 
and trunk. The assessments will be performed by the principal investigator or qualified 
delegate on the tablet at randomization and day 42 and 84/EoT visits. When possible continuity 
of raters should be maintained across scales for each patient.
5.4.10
Simpson Angus Scale
The SAS [Simpson & Angus, 1970] is a 10-item scale used to rate adverse neurological effects 
of antipsychotic medications more broadly. It involves direct observation and a brief
neurological examination. Rating requires the investigator to observe the patient’s gait and check 
for tremor, excessive salivation and rigidity in the arms, shoulder and neck. Each item is rated 
from 0 to 4 and a total score can be obtained. Assessments will be performed by the principal 
investigator or qualified delegate on the tablet at randomization and day 42 and 84/EoT visits.
When possible continuity of raters should be maintained across scales for each patient.
5.4.11
Barnes Akathisia Rating Scale
The BARS [Barnes, 1989] is a rating scale that is used to assess the severity of drug-induced
akathisia. The assessments will be performed by the principal investigator or qualified delegate 
on the tablet at randomization and day 42 and 84/EoT visits. When possible continuity of raters 
should be maintained across scales for each patient.
5.4.12
Safety Narrative Plan
In addition to typical narratives regarding SAEs and study discontinuation due to TEAEs, 
subject narratives will describe potential signs of abuse. For more details, refer to 
Appendices 12.7 and 12.8  Please pay attention to the first page of Appendix 12.7, which 
includes many of the more specific terms with a higher probability of being related to 
potential signals of abuse. The remainder of Appendix 12.7 deals with less specific terms 
that also increase the sensitivity of picking up potential signs of abuse.


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5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events
An AE is any untoward medical occurrence in a subject, temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product.
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drug treatment. AE collection begins after the signing of the informed consent 
and will be collected until 28 days after the last dose of study drug.
5.5.1.1 Abnormal Laboratory Findings
Any abnormal laboratory test result (e.g., hematology, clinical chemistry, or urinalysis) or 
other safety assessment (e.g., ECGs, radiolographic scans, vital signs measurements, physical 
examination), including those that worsen from baseline, which is considered to be clinically 
significant in the medical and scientific judgment of the investigator and not related to 
underlying disease, is to be reported as a serious adverse event or an adverse event ([S]AE).
Any clinically significant abnormal laboratory finding or other abnormal safety assessment 
which is associated with the underlying disease does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition.
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE.  Any abnormal test result that is determined to be 
an error does not require reporting as an AE.
5.5.1.2 Potential Cases of Drug-Induced Liver Injury
Refer to [Appendix 12.3 Liver Safety Monitoring and Assessment] for detailed instructions on 
Drug Induced Liver Injury (DILI). Abnormal values in AST and/or ALT concurrent or with 
abnormal elevations in total bilirubin that meet the criteria outlined in [Appendix 12.3 Liver 
Safety Monitoring and Assessment], in the absence of other causes of liver injury, are 
considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and are
always to be considered important medical events and reported per [Section 5.5.5 Reporting of 
Serious Adverse Events].
5.5.1.3 Disease Progression and Study Endpoints
Under this protocol, the following event(s) will not be considered as an (S)AE:
●
Pre-planned and elective hospitalizations or procedures for diagnostic, therapeutic, or 
surgical procedures for a pre-existing condition that did not worsen during the course of 
the clinical trial. These procedures are collected per the eCRFs Completion Guidelines.


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5.5.2
Definition of Serious Adverse Events
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:
●
Results in death
●
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
●
Results in congenital anomaly, or birth defect
●
Requires inpatient hospitalization (except for planned procedures as allowed per study) or 
leads to prolongation of hospitalization (except if prolongation of planned hospitalization 
is not caused by an AE). Hospitalization for treatment/observation/examination caused by 
AE is to be considered as serious.) 
●
Other medically important events (defined in paragraph below)
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above. These events, including those that may result in disability/incapacity, usually are
considered serious. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.
The sponsor has a list of events that they classify as “always serious” events.  If an AE is 
reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.  
5.5.3
Criteria for Causal Relationship to Study Drug
The investigator is obligated to assess the relationship between the study drug and the
occurrence of each (S)AE. The investigator will use clinical judgment to determine the 
relationship. The investigator should also use the Investigator’s Brochure (IB). The 
investigator is requested to provide an explanation for the causality assessment for each SAE 
and must document this on the SAE worksheet. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. The investigator may revise
his/her assessment of causality in light of new information regarding the SAE and shall send 
an SAE follow-up report and update the eCRF with the new information and updated 
causality assessment.
Following a review of the relevant data, the causal relationship between the study drug and 
each (S)AE will be assessed by answering ‘yes’ or ‘no’ to the question “Do you consider 


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that there is a reasonable possibility that the event may have been caused by the study 
drug”.
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a ‘reasonable possibility’ 
that an (S)AE may have been caused by the study drug (rather than a relationship cannot be 
ruled out) or if there is evidence to reasonably deny a causal relationship:
●
Plausible temporal relationship between exposure to the study drug and (S)AE onset 
and/or resolution. Has the subject actually received the study drug? Did the (S)AE occur 
in a reasonable temporal relationship to the administration of the study drug? 
●
Plausibility; i.e., could the event been caused by the study drug? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and clinical study data, etc.
●
Dechallenge/Dose reduction/Rechallenge:
○Did the (S)AE resolve or improve after stopping or reducing the dose of the suspect 
drug? Also consider the impact of treatment for the event when evaluating a 
dechallenge experience. 
○Did the (S)AE reoccur if the suspected drug was reintroduced after having been 
stopped?  
●
Laboratory or other test results; a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the study drug (e.g., based on values pre-, during 
and post-treatment)
●
Available alternative explanations independent of study drug exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc. and strength of the alternative 
explanation
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the sponsor. With limited or insufficient information about 
the event to make an informed judgment and in absence of any indication or evidence to 
establish a causal relationship, a causality assessment of ‘no’ is to be considered. In such 
instance, the investigator is expected to obtain additional information regarding the event as 
soon as possible and to re-evaluate the causality upon receipt of additional information. 
5.5.4
Criteria for Defining the Severity of an Adverse Event
The investigator will use the following definitions to rate the severity of each AE:
●
Mild: 
No disruption of normal daily activities
●
Moderate:Affect normal daily activities
●
Severe: 
Inability to perform daily activities


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5.5.5
Reporting of Serious Adverse Events
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
informed consent and will continue to 28 days after the last dose of study drug.
In the case of a SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness).
The investigator must complete and submit a SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by email or fax immediately 
(within 24 hours of awareness).
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE/Special Situations Worksheet to:
Astellas Pharma Global Development – United States
Pharmacovigilance
Fax number 888-396-3750
Alternative Fax 847-317-1241
Email: safety.us@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor's Medical Monitor/Study Physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel]. 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification).
Full details of the SAE should be recorded on the medical records, SAE/Special Situation 
Worksheet and on the (e)CRF.
The following minimum information is required:
●
International Study Number (ISN)/Study number, 
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness criteria), 
●
Causal relationship to the study drug (including reason), and
●
The drug provided (if any) 
The sponsor or sponsor's designee will submit expedited safety reports (e.g., Investigational 
New Drug [IND] Safety Reports, CIOMS-I) to Competent Authorities (CA) and concerned 
Ethics Committee per current local regulations, and will inform the investigators of such 
regulatory reports as required. Investigators must submit safety reports as required by their 
Institutional Review Board (IRB)/local Independent Ethics Committee (IEC) within timelines 
set by regional regulations (e.g., European Union [EU], electronic Common Technical 
Document, FDA) where required. Documentation of the submission to and receipt by the 
IRB/local IEC of expedited safety reports should be retained by the site.


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The sponsor will notify all investigators responsible for ongoing clinical studies with the 
study drug of all SUSARs which require submission per local requirements of the IRB.
The investigators should provide written documentation of IRB notification for each report to 
the sponsor.
The investigator may contact the sponsor's Medical Monitor/Study Physician for any other 
problem related to the safety, welfare, or rights of the subject.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator. 
If after the protocol defined AE collection period [see Section 5.5.1 Definition of Adverse 
Event], an AE progresses to a SAE, or the investigator learns of any (S)AE including death,
where he/she considers there is reasonable possibility it is related to the study drug treatment 
or study participation, the investigator must promptly notify the sponsor.
5.5.7
Special Situations 
Certain Special Situations observed in association with the study drug(s), such as incorrect 
administration (e.g., wrong dose of study drug, comparator, or background therapy) are 
collected in the eCRF, as Protocol Deviation per [Section 8.1.6 Protocol Deviations] or may 
require special reporting, as described below. These Special Situations are not considered 
AEs, but do require to be communicated to Astellas as per the timelines defined below.
If a Special Situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the Special Situation and captured as an AE in the eCRF. If the AE meets the 
definition of a SAE, the SAE is to be reported as described in [Section 5.5.5 Reporting of 
Serious Adverse Events] and the details of the associated Special Situation are to be included 
in the clinical description on the SAE worksheet.
The Special Situations are:
●
Pregnancy
●
Medication Error, Overdose and “Off label use”
●
Misuse/abuse
●
Occupational exposure
●
Suspected Drug-Drug interaction
5.5.7.1 Pregnancy
If a female subject becomes pregnant during the study dosing period or within 28 days from 
the discontinuation of dosing, the investigator is to report the information to the sponsor
according to the timelines in [Section 5.5.5 Reporting of Serious Adverse Events] using the 
Pregnancy Reporting Form and in the eCRF.
The investigator will attempt to collect pregnancy information on any female partner of a male 
subject who becomes pregnant during the study dosing period or within 90 days from the


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discontinuation of dosing and report the information to the sponsor according to the timelines 
in Section 5.5.5 Reporting of Serious Adverse Events using the Pregnancy Reporting Form. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
study subject as an AE in the eCRF or SAE per Section 5.5.5 Reporting of Serious Adverse 
Events. For (S)AEs experienced by a female partner of a male subject, (S)AEs are to be 
reported via the Pregnancy Reporting Form.
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below:
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion.
●
Death of a newborn or infant within 1 month after birth is to be reported as an SAE
regardless of its relationship with the study drug.
●
If an infant dies more than 1 month after the birth, is to be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator.
●
Congenital anomaly (including anomaly in miscarried fetus)
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination. (S)AEs 
experienced by the newborn/infant should be reported via the Pregnancy Reporting Form. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.
5.5.7.2 Medication Error, Overdose and “Off-Label Use”
If a Medication Error, Overdose or “Off label Use” (i.e., use outside of what is stated in the 
protocol) is suspected, refer to Section 8.1.6 Protocol Deviations. Any associated (S)AEs are 
to be reported in the eCRF. If the AE meets the definition of a SAE, the SAE is also to be 
reported as described in Section 5.5.5 Reporting of Serious Adverse Events together with the 
details of the medication error, overdose or “Off-Label Use.”
In the event of suspected ASP4345 overdose, the subject should receive supportive care and 
monitoring. The Medical Monitor should be contacted as applicable.
5.5.7.3 Misuse/Abuse
If misuse or abuse of the study drug(s) is suspected, the investigator must forward the Special 
Situation worksheet to the sponsor by fax or email immediately (within 24 hours of 
awareness). Any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of a SAE, the SAE is also to be reported as described in Section 5.5.5 Reporting of 
Serious Adverse Events together with details of the misuse or abuse of the study drug(s).


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5.5.7.4 Occupational Exposure
If occupational exposure (e.g., inadvertent exposure to the study drug(s) of site staff whilst 
preparing it for administration to the patient) to the study drug(s) occurs, the investigator 
must forward the Special Situation worksheet to the sponsor by fax or email immediately
(within 24 hours of awareness).  Any associated (S)AEs occurring to the individual
associated with or resulting from the Special Situation are to be reported on the Special
Situations worksheet.
5.5.7.5 Suspected Drug-Drug Interaction
If a suspected drug-drug interaction associated with the study drug(s) is suspected, the 
investigator must forward the Special Situation worksheet to the sponsor by fax or email 
immediately (within 24 hours of awareness). Any associated (S)AEs are to be reported in the 
eCRF. If the AE meets the definition of a SAE, the SAE is also to be reported as described in 
Section 5.5.5 Reporting of Serious Adverse Events together with details of the suspected 
drug-drug interaction.
5.5.8
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed. 
The investigator will also inform the subjects, who will be required to sign an updated 
informed consent form in order to continue in the clinical study.
5.6
Test Drug Concentration
Pharmacokinetic trough samples will be collected at 4 visits: prior to dosing at days 7, 14 or 
21, 42 and 84.  Additional samples will be collected at approximately 2 hours and 4 hours post 
dose on day 42. Subjects should be reminded not to dose at home prior to their clinic visit.  
Details on sample collection, processing, labeling, storage, and shipment procedures are 
provided in the laboratory manual. Analysis will be performed using a validated liquid
chromatography with tandem mass spectrometry method at a bioanalytical laboratory specified 
by the Sponsor. The remainder of the pharmacokinetic samples might be used in the future to 
explore the absorption, distribution, metabolism and excretion profile, mode of action and/or 
safety signals of ASP4345. The samples will be destroyed maximally 5 years after clinical 
study completion.
5.7
Other Measurements, Assessments or Methods
5.7.1
Blood Sample for the Analysis of Antipsychotics
Pharmacokinetic trough samples will be collected at 3 visits: prior to dosing at days 1, 42 and 84. 
Subjects should be reminded not to dose at home prior to their clinic visit for days 42 and 84.  


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Details on sample collection, processing, labeling, storage, and shipment procedures will be 
provided in the laboratory manual. 
5.7.2
Blood Sample for the Analysis of Genes Related to Pharmacokinetics, Efficacy, 
and Safety (Optional)
Knowledge of polymorphisms of genes COMT, and dopamine D1 and D3 receptors may help 
understand and/or explain observed differences in pharmacokinetic profiles, efficacy and 
safety of ASP4345. After randomization (see schedule of assessments), a 2 mL whole blood 
sample for the analysis of these genes will be collected. For detailed sample collection, 
sample labeling and sample shipment procedures refer to the laboratory manual.
5.7.3
Blood Sample for Future Pharmacogenetic Analysis (Retrospective 
Pharmacogenetic Analysis) (Optional)
A pharmacogenetic (PGx) research may be conducted in the future to analyze or determine
genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues. After 
randomization (see schedule of assessments), a 4 mL sample of whole blood for possible 
retrospective PGx analysis will be collected. Samples will be shipped to a sponsor designated 
banking clinical research organization (CRO).
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual.
See [Appendix 12.5, Retrospective PGx Sub-study] for further details on the banking 
procedures.
5.7.4
Rater Training and Quality Assurance
A centralized rater training and certification program will be used to ensure consistency with 
the study conventions for the scales.  Video and/ or audio monitoring will be conducted to 
review inter-rater and intra-rater reliability.
5.7.5
Cognitive Training for the Subject
During the randomization visit the subject will be given access to a mobile application 
designed to provide cognitive training through pre-determined exercises.  The application 
will be uploaded onto the subject’s phone once internet and/or cellular service is confirmed.  
If these capabilities are not available on the subject’s phone or they do not own a phone, a 
hand-held device will be supplied.  
This cognitive training is being used in an attempt to provide a standardized background of 
cognitive engagement for all the subjects.  Multi-center trials for this type of cognitive 
training have revealed minimal if any effect of the cognitive training by itself.  Given that 
ASP4345 is a dopamine D1 receptor PAM, the expectation is that the cognitive training may 
interaction with pharmacological allosteric modulation of the dopamine D1 receptor.
The subject will be instructed to access the system 4 times per week (each session will have 
12 levels to complete and will take approximately 25-45 minutes) throughout the study. The 
site will familiarize the subject on accessing and using the application.  Compliance will be 


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monitored by the site at each weekly visit as well as between the visits as needed. The subject 
should be reminded to continue use of the application during weekly visits; however, lack of 
compliance with these instructions will not be considered a protocol deviation.  If the subject 
has not been compliant it is recommended that the subject complete cognitive training prior to 
leaving the site.  An interim follow up phone call to remind those subjects not compliant with 
training is also recommended prior to the next visit.  Data are automatically transmitted to a 
central database.  Training task performance will be assessed prior to the start of cognitive 
training and again after the last cognitive training with a standardized task assessment to 
evaluate improvement.
5.7.6
Virtual Monitoring of Study Drug Compliance
Subjects will be trained during the randomization visit on use of the mobile application for 
virtual monitoring of study drug compliance.  The application will be uploaded onto the 
subject’s phone once internet and/or cellular service is confirmed.  If these capabilities are 
not available on the subject’s phone or they do not own a phone, a hand-held device will be 
supplied. The site will provide training on use of the application, which includes taking a 
video of themselves dosing the study drug.  Subject’s will be counseled that accurate and 
consistent use of the application is an essential part of their participation in the study. Data 
are automatically transmitted to a central database.
5.8
Total Amount of Blood
Total amount of blood collected per subject for laboratory specimens is approximately 
145.5 mL over a 12-week period.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation from treatment is a subject who enrolled in the study and for whom study 
treatment is permanently discontinued for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to discontinue the subject from study treatment or to terminate a 
subject's involvement in the study at any time if the subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
Discontinuation Criteria from Study Drug Treatment for Individual Subjects:
●
Subject develops unacceptable toxicity
●
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject
●
Subject withdraws consent for further treatment


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●
Subject remains non-compliant with the protocol based on the investigator’s or sponsor’s 
assessment
●
Female subject becomes pregnant 
Additionally, dosing of a subject will be discontinued in the event that any of the following 
criteria are fulfilled. The subject will be encouraged to continue in the clinical study through 
day 84 according to the current visit schedule unless the participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by the 
participant provide this information.
If the following finding occurs in 2 consecutive measures within 24 hours study drug should 
be discontinued:
●
ALT or AST ≥ 3 x ULN, or ALT or AST ≥ 2 x ULN and ALT or AST ≥ 5 x baseline 
value, or total bilirubin (TBL) ≥ 2 x ULN.
These findings will be confirmed by repeat measurements within 48 hours. Generally liver 
enzymes will be followed by repeated measurements until they return to baseline or stable 
values.
If any of the following findings occur, the study drug should be immediately discontinued:
●
QTcF ≥ 500 ms (confirmed on immediate repeat measurements).
●
Serum creatinine increases > 26.52 μmol/L (0.3 mg/dL) in an absolute amount or 
increases > 1.5-fold greater than the baseline value or serum cystatin C > 2-fold greater 
than the baseline value for which there is no alternate clinical explanation. 
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor.
6.3
Discontinuation of the Study
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.


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7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD-US. A 
statistical analysis plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the database soft lock at the latest. Any changes from the analyses planned in the SAP will be 
justified in the CSR. 
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
SD, minimum, median and maximum) for continuous endpoints, and frequency and 
percentage for categorical endpoints.
7.1
Sample Size
A total sample size of 210 subjects will be randomized in 3:2:2 ratio (approximately 
90 placebo and 60 subjects each per active study arm) into 1 of 2 doses of ASP4345 or 
matching placebo. The sample size will provide approximately 82% power for the pairwise 
comparisons to placebo to detect an effect size of at least 0.43 in the primary outcome 
measure, assuming a 1-sided 5% significance level, with statistical significance achieved at 
an effect size of approximately 0.28.  Note that the decision criteria to proceed with the 
development of the compound will be based on effect sizes rather than statistical 
significance.  The number of subjects planned for this clinical study are considered sufficient 
to achieve the clinical study objectives.
7.2
Analysis Sets
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock. 
For each treatment group, the number and percentage of subjects will be characterized for all 
randomized subjects and by each analysis set.
7.2.1
Full Analysis Set
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least one dose of study drug and have at least one post baseline MCCB measurement. This 
will be the primary analysis set for efficacy analyses.
7.2.2
Intent-to-Treat Set
The Intent-to-Treat analysis set (ITT) will consist of all subjects who are randomized into the 
study. The ITT will be used to assess the robustness of the results of the primary efficacy 
endpoint from the statistical tests based on the FAS. Select demographic and baseline 
characteristics may also be summarized for the ITT.
7.2.3
Safety Analysis Set
The Safety Analysis Set (SAF) consists of all subjects who took at least 1 dose of study drug, 
and will be used for safety analyses.
For the statistical summary of the safety data, the SAF will be used.


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7.2.4
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set (PKAS) consists of all subjects who took at least 1 dose of 
study drug and who have at least 1 plasma concentration.
The PKAS will be used for all summaries and analyses of the pharmacokinetic data.
7.3
Demographics and Baseline Characteristics 
Demographics and baseline characteristics (age, sex, race, ethnicity, weight, height and BMI)
will be summarized by treatment group and overall for the FAS, ITT and SAF. Descriptive 
statistics will be presented with the number of subjects, mean, standard deviation, minimum, 
median and maximum for continuous variables and frequency and percentage for categorical 
variables.
7.3.1
Subject Disposition 
The number and percentage of subjects who completed and discontinued treatment and
reasons for treatment discontinuation will be presented for all randomized subjects and for 
subjects in the SAF by treatment group and overall. Similar tables for screening disposition, 
investigational period disposition and follow-up disposition will also be presented for all 
randomized subjects by treatment group and overall. All disposition details and dates of first 
and last evaluations for each subject will be listed.
7.3.2
Previous and Concomitant Medications 
All previous and concomitant medications will be presented in a listing.
7.3.2.1 Analysis of Antipsychotic Trough Levels
Antipsychotic trough levels on days 1, 42 and 84 will be provided in a listing. Additional data 
presentations or listings may be specified in the SAP. 
7.3.3
Medical and Psychiatric History 
Medical and psychiatric history for each subject will be presented in a listing.
7.4
Analysis of Efficacy 
Analysis of the primary efficacy endpoint will be conducted on the FAS and ITT. The 
interpretation of results from statistical tests will be based on the FAS. The ITT will be used 
to assess the robustness of the results from the statistical tests based on the FAS.  Analysis of 
the secondary and exploratory efficacy endpoints will be done on the FAS only. 
A 2-sided significance level of 0.10, unless otherwise specified, will be used for all statistical 
tests on efficacy endpoints without multiplicity adjustment.
Primary and secondary efficacy endpoints will be summarized at each visit by treatment 
group.


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7.4.1
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis
Consistent with the Hypothetical Strategy used for the estimand which is to compare patients 
as though they had continued on the assigned treatment, MMRM will use all available on-
treatment data to inform end of treatment mean treatment effect estimates without requiring 
explicit imputation for missing data (i.e., for discontinued subjects). The primary endpoint of 
change from baseline in MCCB neurocognitive composite score will be analyzed using a 
Mixed Models Repeated Measures (MMRM) approach. The model will contain terms for 
treatment group, pooled site, visit, and treatment by visit, with the MCCB score at baseline 
used as a covariate. Least squares (LS) means (± standard error [SE]) and 2-sided 90% CIs 
for the LS mean treatment differences between each dose of ASP4345 and placebo will be 
presented for the primary endpoint. There will be no adjustment made for multiple 
comparisons. The primary analysis will use the FAS.
There will be two hypotheses tested. Hypothesis 1 is given as follows:
H0A: The LS mean change from baseline at week 12 for Group A (50 mg ASP4345)
and Group C (placebo) are the same
H1A: The LS mean change from baseline at week 12 for Group A (50 mg ASP4345)
and Group C (placebo) are not the same
Hypothesis 2 is given as follows:
H0B: The LS mean change from baseline at week 12 for Group B (150 mg ASP4345)
and Group C (placebo) are the same
H1B: The LS mean change from baseline at week 12 for Group B (150 mg ASP4345)
and Group C (placebo) are not the same
7.4.1.2 Sensitivity Analysis
Sensitivity analyses of the primary efficacy endpoint and selected secondary/exploratory 
endpoints will be performed based on duration since the first psychotic break, smoking status, 
treatment compliance, and sex. Planned sensitivity analyses will be described in detail in the 
statistical analysis plan. 
7.4.2
Analysis of Secondary Endpoints 
The secondary efficacy endpoint of change from baseline to week 12/EoT in the UPSA-2 
Extended Range instrument will be analyzed using ANCOVA. The model will contain terms 
for treatment group and pooled site, with the corresponding score at baseline used as a 
covariate.  LS means (± SE) and 2-sided 90% CIs for the LS mean treatment differences 
between each dose of ASP4345 and placebo will be presented for the primary endpoint. 
There will be no adjustment made for multiple comparisons.
See Section 7.6 Analysis of Pharmacokinetics for description of analysis of pharmacokinetic 
secondary endpoints. 


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7.4.3
Analysis of Exploratory Endpoints 
Exploratory endpoints listed below will be analyzed using the same MMRM model as the 
primary efficacy analysis. 
●
Change from baseline to week 12/EoT for NSA-16 only for the subjects who have at 
least 1 negative symptom of moderate severity
●
Change from baseline to week 12/EoT for the MCCB composite score
●
Change from baseline to week 12/EoT for each of the MCCB domains
●
Change from baseline to week 12/EoT for the PANSS
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the CGI-S
●
The pharmacogenetics test listed below will be measured at baseline only and summary 
statistics will be provided, by treatment group and overall as specified in the statistical 
analysis plan.
●
COMT and dopamine D1 and D3 receptor genotyping
The relationship between MCCB and CGI-S will be examined as follows: 
●
Correlation between MCCB and CGI-S scores at each measurement (weeks -4, -3, 0, 6, 12)
●
Correlation between change from baseline to week 12/EoT in MCCB and change from 
baseline to week 12/EoT in CGI-S scores
The relationship between the number of cognitive training levels, including repeat levels 
completed, (as a measure of compliance with cognitive training) and MCCB neurocognitive 
composite scores will be evaluated using correlations overall and by treatment group.
7.5
Analysis of Safety
7.5.1
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment Emergent Adverse Event (TEAE) is defined as an AE observed after starting 
administration of the study drug and 28 days after the last dose of study drug.
The number and percentage of subjects with treatment-emergent AEs, SAEs, AEs leading to 
withdrawal of treatment, and AEs related to study drug will be summarized by system organ 
class, preferred term and treatment group. The number and percentage of AEs by severity 
will also be summarized. All AEs will be listed.
A study drug-related TEAE is defined as any TEAE with at least possible relationship to 
study treatment as assessed by the investigator or with missing assessment of the causal 
relationship.
7.5.2
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline for subjects in the SAF by treatment group and time point. 
Shifts relative to normal ranges from baseline to each time point during treatment period in 
lab tests will also be tabulated.  Laboratory data will be displayed in listings.


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7.5.3
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and visit. 
7.5.4
Metabolic Parameters
Descriptive statistics will be used to summarize individual indices of metabolic syndrome
results (weight, waist circumference, cholesterol, triglycerides, HDL [the second screening 
visit and day 77], and fasting glucose), and hemoglobin A1c [HbA1c] and changes from 
baseline by treatment group and time point. 
7.5.5
Routine 12-lead Electrocardiograms
Descriptive statistics will be used to summarize the ECG parameter results and changes from 
baseline by treatment group and time point.
7.5.6
Columbia-Suicide Severity Rating Scale
Number and percentage of subjects in each of the categories of C-SSRS, as well as changes 
from baseline, will be summarized by treatment group and visit.
7.5.7
Movement disorder (Abnormal Involuntary Movement Scale)
Number and percentage of subjects in each rating category, as well as changes from baseline,
will be summarized for each of the items of the AIMS by treatment group and visit.
7.5.8
Simpson Angus Scale
Number and percentage of subjects in each rating category, as well as changes from baseline,
will be summarized for each of the items of the SAS by treatment group and visit.
7.5.9
Barnes Akathisia Rating Scale
Number and percentage of subjects in each of the categories of BARS, as well as changes 
from baseline, will be summarized by treatment group and visit.
7.6
Analysis of Pharmacokinetics
Descriptive statistics (e.g., N, mean, standard deviation, minimum, median, maximum, 
coefficient of variation [CV], geometric mean, and geometric CV) will be provided for 
plasma concentrations of ASP4345 and possible metabolite(s) by time point.  
7.6.1
Estimation of Pharmacokinetic Parameters 
Population pharmacokinetic model will be developed based on ASP4345 plasma concentration 
data obtained from subjects who have at least 1 pharmacokinetic sample. Population 
pharmacokinetics and/or pharmacokinetic/pharmacodynamics analyses will be performed by 
modeling and simulation scientist. All details of the population pharmacokinetic analysis will 
be described in a separate analysis plan and a separate population pharmacokinetic modeling 
report will be written.


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7.7
Major Protocol Deviations and Other Analyses
Major protocol deviations as defined in [Section 8.1.6 Major Protocol Deviations] will be 
summarized for all randomized subjects by treatment group and total as well as by site. A 
data listing will be provided by site and subject.
The major protocol deviation criteria will be uniquely identified in the summary table and 
listing. The unique identifiers will be as follows. The major protocol deviation criteria will be 
uniquely identified as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
This section is not applicable for this study.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data will be done. Exceptions are the start and 
stop dates of AEs and concomitant medication. The imputed dates will be used to allocate the 
concomitant medication and AEs to a treatment group, in addition to determining whether an 
AE is/is not treatment emergent. Listings of the AEs and concomitant medications will present 
the actual partial dates; imputed dates will not be shown.
Subjects who do not receive the study drug to which they have been randomized will be 
analyzed as treated.
See the SAP for details of the definition for windows to be used for analyses by visit.
Sites that do not enroll a sufficient number of subjects will be pooled for analyses by site. The 
pooling decisions will be made and documented prior to study hard-lock.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected using an Electronic Data Capture 
system. In the interest of collecting data in the most efficient manner, the investigator or site 
designee should record data (including laboratory values, if applicable) in the eCRF within 
5 days after the subject visit.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site.


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The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Laboratory tests are performed at a central laboratory. Central laboratory data will be 
transferred electronically to the sponsor or designee at predefined intervals during the study. 
The Central laboratory will provide the sponsor or designee with a complete and clean copy 
of the data. 
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.
All procedures conducted under the protocol must be documented. For screen failures, the 
minimum demographic data (sex, birth date, race and informed consent date), outcome of 
eligibility assessment (inclusion and exclusion criteria), reason for screen failure and AEs 
details must be documented.
The investigator or designee will be responsible for eCRF completion and that all data and 
queries are accurate, complete and are verifiable with the source. The source should be 
appropriately maintained by the clinical unit.
Electronic data sources and any supporting documents should be available for review/retrieval 
by the sponsor/designee at any given time.
Clinical Outcome Assessments and Electronic Clinical Outcome Assessments:
Subject clinical outcome assessments for the MCCB and UPSA-2-ER will be completed on a 
paper copy of the licensed instrument at the site by the principal investigator or qualified 
delegate.  Data will be entered into a database by the vendor following scoring and 
transmitted to the sponsor. 
Subject electronic clinical outcome assessments for the PANSS, NSA-16, C-SSRS, AIMS, 
SAS, BARS and CGI-S will also be completed by the principal investigator or qualified 
delegate on an electronic tablet.  The completed information will be automatically uploaded 
into a central website. 
All COA data will be transferred electronically to the sponsor at predefined intervals during 
the study.  The vendor will provide the sponsor with a complete and clean copy of the data.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  
The following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated informed consent forms 
●
Visit dates


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●
Medical history and physical examination details
●
Key efficacy and safety data as specified in the protocol
●
AEs and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts (if applicable)
●
Details of dispensing and return of study drug 
●
Reason for premature discontinuation (if applicable)
●
Randomization number (if applicable)
●
Pharmacokinetic sample processing and storage history, including date/time each sample 
is transferred to the freezer, freezer identification and the temperature log for the freezer
(if applicable)
8.1.3
Clinical Study Monitoring
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
[refer to Section 8.1.2 Specification of Source Documents] when they are requested by the 
sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Data Science department of the sponsor in 
accordance with the SOPs for data management. All study-specific processes and definitions 
will be documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA 
and World Health Organization Drug Dictionary, respectively.
8.1.6
Major Protocol Deviations
A major protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study subjects.  


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A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
The major protocol deviation criteria are as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment.
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified. The sponsor will follow-up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety 
and/or efficacy of the subject to determine subject continuation in the study. 
If a major deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately.
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the trial master file.  
8.1.7
End-of-Trial in All Participating Countries
The end of the study is defined as the last visit or follow-up contact of the last subject in the 
study. 
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities
GCP requires that the clinical protocol, any protocol amendments, the Investigator’s 
Brochure, the informed consent and all other forms of subject information related to the study 
(e.g., advertisements used to recruit subjects) and any other necessary documents be 
reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific and medical 
appropriateness of the study before it is conducted.  IEC/IRB approval of the protocol, 
informed consent and subject information and/or advertising, as relevant, will be obtained 
prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible ethics committees and regulatory agencies, as required. During the conduct 
of the study, the investigator should promptly provide written reports (e.g., ICH Expedited 
Reports, and any additional reports required by local regulations) to the IEC/IRB of any 


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changes that affect the conduct of the study and/or increase the risk to subjects. Written 
documentation of the submission to the IEC/IRB should also be provided to sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies, or for Astellas Pharma Europe 
B.V./Astellas Pharma Europe Ltd-sponsored studies within 1 year after last subject out or 
termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject or his/her guardian or  
legal representative, the person who administered the informed consent and any other 
signatories according to local requirements. A copy of the signed informed consent form will 
be given to the subject and the original will be placed in the subject’s medical record. An 
entry must also be made in the subject’s dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a 
signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and whether the subject is willing to remain 
in the study or not must be confirmed and documented.
2.
The investigator must update their informed consent form (ICF) and submit it for 
approval to the IRB/IEC. The investigator or his/her representative must obtain written 
informed consent from the subject on all updated ICFs throughout their participation in 
the study. The investigator or his/her designee must reconsent subjects with the updated 


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ICF even if relevant information was provided orally. The investigator or his/her 
representative who obtained the written informed consent and the subject should sign 
and date the informed consent form. A copy of the signed informed consent form will be 
given to the subject and the original will be placed in the subject’s medical record. An 
entry must be made in the subject’s records documenting the re-consent process.
8.2.4
Subject Confidentiality and Privacy
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties. 
The sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
sponsor. However, the sponsor requires the investigator to permit the sponsor, sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and Privacy laws in the US.  If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then sponsor shall serve as the controller of such 
data, as defined by the European Union (EU) Data Protection Directive, and Investigator 
and/or third party  shall act only under the instructions of the sponsor in regard to personal 
data   If sponsor is not based in the EEA, sponsor must appoint a third party to act as its local 
data protection representative or arrange for a co-controller established in the EU for data 
protection purposes in order to comply with the Directive.
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical investigators or to regulatory 


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agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the clinical study agreement.
8.3.2
Documents and Records Related to the Clinical Study
The sponsor will provide the investigator and/or institution with the following:
●
Study protocol (and amendments, where applicable)
●
Investigator’s Brochure (and amendments, where applicable)
●
eCRFs 
●
Study drug with all necessary documentation
●
Study contract
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the sponsor: 
●
Financial disclosure in compliance with federal regulation 21CFR Part 54
●
Signed and dated FDA form 1572
●
Signed Investigator's Statement in this protocol and eCRF
●
Current Curricula Vitae of all investigators
●
List of sub-investigators and collaborators 
●
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY)
●
Study contract
●
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee)
The investigator will archive all study data (e.g., subject identification code list, source data, 
CRFs and investigator's file) and relevant correspondence.  These documents are to be kept 
on file for the appropriate term determined by local regulation (for US sites, 2 years after 
approval of the NDA or discontinuation of the IND). The sponsor will notify the 
site/investigator if the NDA is approved or if the IND is discontinued.  The investigator 
agrees to obtain the sponsor's agreement prior to disposal, moving, or transferring of any 
study-related records. The sponsor will archive and retain all documents pertaining to the 
study according to local regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes.
All data will be entered on the CRFs supplied for each subject.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
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or notification may be required. The changes will become effective only after the approval of 
the sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).
Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the informed consent, written verification of IRB/IEC approval must 
be forwarded to the sponsor.  An approved copy of the new informed consent must also be 
forwarded to the sponsor. 
8.3.4
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock.
9
QUALITY ASSURANCE
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied.
The sponsor or sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee 
This section is not applicable for this study.
10.2
Other Study Organization
This section is not applicable for this study.


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11
REFERENCES 
Amorim P, Lecrubier Y, Weiller E, Hergueta T, Sheehan D: DSM-III-R Psychotic Disorders: procedural 
validity of the M.I.N.I. International Neuropsychiatric Interview (M.I.N.I.). Concordance and 
causes for discordance with the CIDI. European Psychiatry. 1998; 13:26-34.
Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS. Dopamine D1 receptor mechanisms in the 
cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl). 
1994;116:143-51.
Awad AG, Voruganti LN. The burden of schizophrenia on caregivers: a review. Pharmacoeconomics. 
2008;26:149-62.
Axelrod BN, Goldman RS, Alphs LD. Validation of the 16-item Negative Symptom Assessment. J 
Psychiatr Res. 1993 Jul-Sep;27(3):253-8.
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989 May;154:672-6.
Blanchet PJ, Fang J, Gillespie M, Sabounjian L, Locke KW, Gammans R, et al. Effects of the full 
dopamine D1 receptor agonist dihydrexidine in Parkinson's disease. Clin Neuropharmacol. 
1998;21:339-43.
Buchanan RW, Freedman R, Javitt DC, Abi-Dargham A, Lieberman JA. Recent advances in the 
development of novel pharmacological agents for the treatment of cognitive impairments in 
schizophrenia. Schizophr Bull. 2007;33:1120-30.
Duncker DJ, Haitsma DB, van der Geest IE, Stubenitsky R, van Meegen JR, Man in't Veld AJ, et al. 
Systemic, pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist 
in awake pigs at rest and during treadmill exercise Z1046. Br J Pharmacol. 1997;120:1101-13.
Emsley R, Rabinowitz J, Torreman M, RIS-INT-35 Psychosis Global Working Group. The factor 
structure for the Positive and Negative Syndrome Scale (PANSS) in a recent-onset psychosis. 
Schizophr Res. 2003;61:47-57.
Fatouros-Bergman H, Cervenka S, Flyckt L, Edman G, Farde L. Meta-analysis of cognitive performance
in drug-naïve patients with schizophrenia. Schizophrenia Res. 2014;158:156-62.
Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV. Targeting the dopamine D1 
receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl). 
2004;174:3-16.
Green MF, Schooler NR, Kern RS, Frese FJ, Granberry W, Harvey PD, et al. Evaluation of functionally 
meaningful measures for clinical trials of cognition enhancement in schizophrenia. Am J Psychiatry. 
2011;168:400–7. 
Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: 
are we measuring the "right stuff"? Schizophr Bull. 2000;26:119-36.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. 
Schizophr Bull. 1987;13:261-76
Keefe RS, Fox KH, Harvey PD, Cucchiaro J, Siu C, Loebel A. Characteristics of the MATRICS 
Consensus Cognitive Battery in a 29-site antipsychotic schizophrenia clinical trial. Schizophr Res. 
2011;125:161–8
Laruelle M. Schizophrenia: from dopaminergic to glutamatergic interventions. Curr Opin Pharmacol. 
2014;14:97-102.


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Lecrubier Y, Sheehan D, Weiller E, Amorim P, Bonora I, Sheehan K, Janavs J, Dunbar G. The M.I.N.I. 
International Neuropsychiatric Interview (M.I.N.I.) A Short Diagnostic Structured Interview: 
Reliability and Validity According to the CIDI. European Psychiatry. 1997; 12: 224-231.
Lindenmayer JP, Bernstein-Hyman B, Grochowski S, Bark N. Psychopathology of schizophrenia: initial 
validation of a 5-factor model. Psychopathology. 1995;28:22-31.
May LT, Avlani VA, Sexton PM, Christopoulos A. Allosteric modulation of G protein-coupled receptors. 
Curr Pharm Des. 2004;10:2003-13.
Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. The MATRICS 
Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 
2008;165:203-13.
Patterson TL, Goldman S, McKibbin CL, Hughs T, Jeste DV. UCSD performance-based skills 
assessment: development of a new measure of everyday functioning for severely mentally ill adults. 
Schizophr Bull. 2001;27:235–45. 
Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, et al. Columbia Suicide-Severity Rating 
Scale: Baseline/Screening Version and Since Last Visit.  New York, NY: The Research Foundation 
for Mental Hygiene: 2009.
Rush JA jr, Handbook of Psychiatric Measures, American Psychiatric Association. 2000;166-168.
Schaefer J, Giangrande E, Weinberger DR, Dickinson D. The global cognitive impairment in 
schizophrenia: consistent over decades and around the world. Schizophr Res. 2013;150:42-50.
Schneider L, Olin J, Doddy R, Clark C, Morris J, Reisberg B, Schmitt F, Grundman M, Thomas R, Ferris 
S, and the ADCS. “Validity and Reliability of the Alzheimer’s Disease Cooperative Study –
Clinical Global Impression of Change.” Alzheimer’s Disease and Associated Disorders. 
1997;Vol11(2):S22-S32
Shamsi S, Lau A, Lencz T, Burdick KE, DeRosse P, Brenner R, et al. Cognitive and symptomatic 
predictors of functional disability in schizophrenia. Schizophr Res. 2011;126:257-64.
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Janavs J, Weiller E, Bonara LI, Keskiner A, Schinka J, 
Knapp E, Sheehan MF, Dunbar GC. Reliability and Validity of the M.I.N.I. International 
Neuropsychiatric Interview (M.I.N.I.): According to the SCID-P. European Psychiatry. 1997; 
12:232-241.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International 
Neuropsychiatirc Interview (M.I.N.I.):  the development and validation of a structured diagnostic 
psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22-33.
Simpson GM & Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 
1970;212:11-9.
Snyder SH, Taylor KM, Coyle JT, Meyerhoff JL. The role of brain dopamine in behavioral regulation and 
the actions of psychotropic drugs. Am J Psychiatry. 1970;127:199-207.
Tamminga CA. The neurobiology of cognition in schizophrenia. J Clin Psychiatry. 2006;67(suppl 9):9-13.
Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, "just the facts" 4. Clinical features and 
conceptualization. Schizophr Res. 2009;110:1-23.
Zhang J, Xiong B, Zhen X, Zhang A. Dopamine D1 receptor ligands: where are we now and where are 
we going. Med Res Rev. 2009;29:272-94.


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
These lists are not exhaustive. Medications should be considered excluded if taken alone or 
as part of a combination product. If in doubt, please contact the Medical Monitor.
Strong CYP3A inhibitors (> 5-fold increase in AUC)
indinavir/RIT
Ketoconazole
tipranavir/RIT
Itraconazole
Ritonavir
Voriconazole
cobicistat (GS-9350)
Posaconazole
Indinavir
Telithromycin
Nelfinavir
Troleandomycin
Saquinavir
Clarithromycin
elvitegravir/RIT
Conivaptan
saquinavir/RIT
Nefazodone
lopinavir/RIT
Mibefradil
Boceprevir
grapefruit juice DS
Telaprevir
Idelasib
danoprevir/RIT
LCL161
Moderate CYP3A inhibitors (> 2-fold increase in AUC)
atazanavir/RIT
Diltiazem
Darunavir
Dronedarone
darunavir/RIT
Aprepitant
Atazanavir
Casopitant
Amprenavir
Netupitant
Cyclosporine
Cimetidine
Ledipasvir
Tofisopam
Fluconazole
grapefruit juice
Ciprofloxacin
schisandra sphenanthera 
Erythromycin
Lomitapide
Imatinib
ACT-178882
Crizotinib
FK1706
Verapamil
Potent CYP3A inducers (> 80% )
Rifampin
Simvastatin
Rifabutin
Atorvastatin
Mitotane
Fluvastatin
Enzalutamide
Rosuvastatin
Phenytoin
Pitavastatin
Carbamazepine
Pravastatin
Avasimibe
Lovastatin
St John's Wort
AUC: area under the curve; CYP3A: cytochrome P450 3A; DS = double strength; RIT = Ritonavir (it is a 
combination drug)


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12.2
List of Inducers and Inhibitors of CYP2C19, CYP2D6 and CYP1A2
Below is a list of strong and moderate inhibitors and inducers of CYP1A2, CYP2C19 and 
CYP2D6. These lists are not exhaustive. These medications can be continued if the subject is 
on a stable dose prior to screening, but cannot be initiated during the study.  Medications 
should be considered excluded if taken alone or as part of a combination product. If in 
doubt, please contact the Medical Monitor.
Enzyme
Inhibitor (Strong and Moderate)
Inducer (Strong and Moderate)
CYP1A2
Enoxacin, Zafirlukast, 
Methoxsalen, Mexiletine, Oral 
contraceptives*
Teriflunomide
CYP2C19
Fluoxetine,  Ticlopidine
Efavirenz
CYP2D6
Fluoxetine, Paroxetine, Quinidine, 
Trebinafine, Cinacalcet, 
Duloxetine, Mirabegron
*Oral contraceptives are allowed if the subject is on a stable dose prior to screening [refer to Section 5.1.3
Previous and Concomitant Treatment (Medication and NonMedication Therapy)].


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12.3
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN or bilirubin > 2 × ULN should undergo detailed 
testing for liver enzymes (including at least ALT, AST, alkaline phosphatase [ALP], and 
TBL). Testing should be repeated within 72 hours of notification of the test results. For 
studies for which a central laboratory is used, alerts will be generated by the central 
laboratory regarding moderate and severe liver abnormality to inform the investigator, study 
monitor and study team. Subjects should be asked if they have any symptoms suggestive of 
hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 × ULN 
or
> 2 × ULN
Severe
> 3 × ULN
and
> 2 × ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN.
●
ALT or AST > 5 × ULN for more than 2 weeks.  
●
ALT or AST > 3 × ULN and International Normalized Ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site should complete the liver abnormality 
case report form (LA-CRF) that has been developed globally and can be activated for any 
study or an appropriate document. Subjects with confirmed abnormal liver function testing 
should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE.  The 


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sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases.  Symptoms 
and new-onset diseases is to be recorded as “AEs” within the (e)CRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic and/or diabetic patients, and may be associated with 
fluctuating AT levels.  The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function. 
●
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets.  Medications, is to be entered in the (e)CRF.  Information on alcohol, other 
substance use and diet should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history,  other testing may be appropriate including: 
○Acute viral hepatitis (A, B, C, D, E or other infectious agents),
○Ultrasound or other imaging to assess biliary tract disease,
○Other laboratory tests including INR, direct bilirubin.
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, preexisting or 
acute liver disease, or exposure to other agents associated with liver injury, the subject may 
be discontinued from the study. The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment. Discontinuation of treatment should be considered 
if:
●
ALT or AST > 8 × ULN.
●
ALT or AST > 5 × ULN for more than 2 weeks.
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5) (If INR testing is 
applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.
*Hy’s Law Definition: Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10 to 50% mortality 
(or transplant). The 2 “requirements” for Hy’s Law are: 1) Evidence that a drug can cause 


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hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 × ULN (“2 × ULN elevations are too common in treated and untreated patients to be 
discriminating”). 2) Cases of increased bilirubin (at least 2 × ULN) with concurrent 
transaminase elevations at least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin 
obstruction (elevated ALP) or Gilbert’s syndrome [Temple, 2006].
References
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3.
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.  


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12.4
Common Serious Adverse Events
The following is a list of SAEs that the sponsor considers to be associated with the disease 
state being studied. The list does NOT change your reporting obligations or prevent the need 
to report an AE meeting the definition of an SAE as detailed in [Section 5.5.2 Definition of 
Serious Adverse Events]. The purpose of this list is to alert the investigator that some events 
reported as SAEs may not require expedited reporting to the regulatory authorities based on 
the classification of “common SAEs.” The investigator is required to follow the 
requirements detailed in [Section 5.5.5 Reporting of Serious Adverse Events].
Serious Adverse Events Associated with Schizophrenia:
●
Neuroleptic malignant syndrome 
●
Worsening of psychosis requiring hospitalization 
●
Worsening of suicidal ideation


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12.5
Retrospective Pharmacogenetics Sub-Study
INTRODUCTION
Pharmacogenetics (PGx) research aims to provide information regarding how naturally 
occurring changes in a subject’s gene and/or expression based on genetic variation may 
impact what treatment options are best suited for the subject. Through investigation of PGx 
by technologies such as genotyping, gene sequencing, statistical genetics and Genome-Wide 
Association Studies, the relationship between gene profiles and a drug’s kinetics, efficacy or 
toxicity may be better understood. As many diseases may be influenced by 1 or more genetic 
variations, PGx research may identify which genes are involved in determining the way a 
subject may or may not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study may participate in this PGx sub-
study. As part of this sub-study, subjects must provide written consent prior to providing any 
blood samples that may be used at a later time for genetic analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this sub-study will provide one 4 mL tube of whole 
blood per Astellas’ instructions. Each sample will be identified by the unique subject number 
(first code). Samples will be shipped frozen to a designated banking CRO either directly from 
site or via a central laboratory as directed by Astellas.
PHARMACOGENETICS ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s 
kinetics, efficacy and/or safety. 
DISPOSAL OF PHARMACOGENETICS SAMPLES/DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely.


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INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas. 


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12.6
Clinical Outcome Assessment Scales
4345-CL-0015 Clinical Outcomes Assessment Scales
Efficacy Scales
MATRICS Cognitive Consensus Battery (MCCB)
Primary Endpoint
Paper-based test 
University of San Diego Performance-based Skills 
Assessment-2 Extended Range Scale (UPSA-2ER)
Secondary Endpoint
Paper-based test
Positive and Negative Symptom Scale (PANSS)
Exploratory Endpoint
Tablet-based test
Negative Symptom Assessment-16 Scale (NSA-16)
Exploratory Endpoint
Tablet-based test
Clinical Global Impression of Severity Scale (CGI-S)
Exploratory Endpoint
Tablet-based test
Safety Scales
Columbia Suicide Severity Rating Scale (C-SSRS)
Safety Endpoint
Tablet-based test
Abnormal  Involuntary Movement Scale (AIMS)
Safety Endpoint
Tablet-based test
Simpson Angus Scale (SAS)
Safety Endpoint
Tablet-based test
Barnes Akathisia Rating Scale (BARS)
Safety Endpoint
Tablet-based test


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12.7
Adverse Events of Interest Related to Abuse
Euphoria-related Terms
Preferred term
Lowest level term
Euphoric mood
Feeling high
Elevated mood
Feeling abnormal
Feeling drunk
Feeling of relaxation
Thinking abnormal
Hallucination, mixed
Inappropriate affect
Dizziness and giddiness
Dissociative/Psychotic Terms
Preferred term
Lowest level term
Psychosis acute
Psychosis
Aggression
Confusion and disorientation
Terms Indicative of Impaired Attention, Cognition, Mood, and Psychomotor Events
Preferred term
Lowest level term
Somnolence
Psychomotor hyperactivity/decreased activity
Hyperactivity/hypoactivity
Mood disorders and disturbances
Mental impairment disorders
Drug tolerance, habituation, drug withdrawal 
syndrome, substance-related disorders
Inappropriate Affect
Preferred term
Lowest level term
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Inappropriate mood elevation
Product tampering
Medication tampering


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Complete Abuse Screening Terms
System Organ 
Class
Higher Level 
GT
Higher Level 
Term
Preferred 
term
Lower Level Term
Psychiatric 
disorders
Mood disorders 
and disturbances 
NEC
Emotional and 
mood 
disturbances 
NEC
Euphoric Mood
Euphoria
Euphoric
Euphoric mood
Exaggerated well-being
Feeling high
Felt high
High
High feeling
Laughter
Mood altered
Affect alteration
Affect altered
Altered mood
Bad mood
Mood alteration NOS
Mood altered
Mood change
Elevated mood
Elevated mood
Mood elevated
Affect 
alterations
Inappropriate 
affect
Elation inappropriate
Exhilaration 
inappropriate
Exhiliration 
inappropriate
Feeling happy 
inappropriately
Inappropriate affect
Inappropriate crying
Inappropriate elation
Inappropriate 
exhilaration
Inappropriate laughter
Inappropriate mood 
elevation
Mood elevation 
inappropriate
Disturbances in 
thinking and 
perception
Perception 
disturbances
Hallucination
Drug-induced 
hallucinosis
Hallucinating
Hallucination
Hallucination NOS


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System Organ 
Class
Higher Level 
GT
Higher Level 
Term
Preferred 
term
Lower Level Term
Hallucinations
Hallucinations 
aggravated
Kinesthetic hallucination
Organic hallucinosis 
syndrome
Pseudohallucination
Sensory hallucinations
Stump hallucination
Hallucination, 
auditory
Auditory hallucinations
Hallucination auditory
Hallucination, auditory
Verbal hallucinations
Hallucination, 
visual
Hallucination visual
Hallucination with color
Hallucination with 
colour
Hallucination, visual
Visual hallucinations
General disorders 
and administration 
site conditions
General system 
disorders NEC
Feelings and 
sensations 
NEC
Feeling drunk
Drunk-like effect
Drunkenness feeling of
Feeling drunk
Feeling 
abnormal
Cotton wool in head
Feeling abnormal
Feeling bad
Feeling dazed
Feeling floating
Feeling lifeless
Feeling miserable
Feeling stoned
Feeling strange
Feeling weightless
Feels awful
Feels bad
Feels poorly
Felt like a zombie
Floating feeling
Foggy feeling head
Funny episode
Fuzzy
Fuzzy head


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System Organ 
Class
Higher Level 
GT
Higher Level 
Term
Preferred 
term
Lower Level Term
Muzzy head
Neck strange feeling of
Soft feeling
Spaced out
Thick head
Unstable feeling 
Weird feeling
NEC: not elsewhere classified; NOS: not otherwise specified


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12.8
Drug Withdrawal-Related Adverse Events Occurring Following 
Drug Discontinuation (Preferred Terms; MedDRA 18.0)
Higher Level GT
Higher Level Term
Preferred Term
Psychiatric disorders
Anxiety disorders and 
symptoms
Anxiety symptoms
Agitation
Nervous system 
disorders
Neurological disorders 
NEC
Neurological signs and 
symptoms NEC
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations with 
depressive symptoms
Anhedonia
Psychiatric disorders
Anxiety disorders and 
symptoms
Anxiety symptoms
Anxiety
Musculoskeletal and 
connective tissue 
disorders
Muscle disorders
Muscle related signs 
and symptoms NEC
Chills
Musculoskeletal and 
connective tissue 
disorders
Muscle disorders
Feelings and sensations 
NEC
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations with 
depressive symptoms
Depressed mood
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Depressive disorders
Depression
Gastrointestinal 
disorders
Gastrointestinal 
motility and 
defaecation conditions
Diarrhoea (excl 
infective)
Diarrhoea
Psychiatric disorders
Mood disorders and 
disturbances
Emotional and mood 
disturbances NEC
Dysphoria
Nervous system 
disorders
Sleep disturbances (incl 
subtypes)
Sleep disturbances 
NEC
Dyssomnia
Psychiatric disorders
Sleep disorders and 
disturbances 
Dyssomnias
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Depressive disorders
Dysthymic disorder
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations with 
depressive symptoms
Feeling of despair
Nervous system 
disorders
Headaches
Headaches NEC
Headache
Skin and subcutaneous 
tissue disorders 
Skin appendage 
conditions
Apocrine and eccrine 
gland disorders
Hyperhidrosis
General disorders and 
administration site 
conditions
General system 
disorders NEC
General signs and 
symptoms NEC


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Higher Level GT
Higher Level Term
Preferred Term
Psychiatric disorders
Sleep disorders and 
disturbances 
Disturbances in 
initiating and 
maintaining sleep
Insomnia
Nervous system
disorders
Sleep disturbances
Disturbances in 
initiating and 
maintaining sleep
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations with 
depressive symptoms
Morose
Gastrointestinal 
disorders
Gastrointestinal signs 
and symptoms
Nausea and vomiting 
symptoms
Nausea
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations with 
depressive symptoms
Negative thoughts
Psychiatric disorders
Anxiety disorders and 
symptoms
Anxiety symptoms
Nervousness
Psychiatric disorders
Anxiety disorders and 
symptoms
Obsessive-compulsive 
disorders and 
symptoms
Obsessive thoughts
General disorders and 
administration site 
conditions
General system 
disorders NEC
Pain and discomfort 
NEC
Pain
Nervous system 
disorders
Sleep disturbances (incl 
subtypes)
Sleep disturbances 
NEC
Poor quality sleep
Psychiatric disorders
Sleep disorders and 
disturbances 
Dyssomnias
Cardiac disorders
Cardiac disorder signs 
and symptoms
Cardiac signs and 
symptoms NEC
Syncope
Vascular disorders
Decreased and 
nonspecific blood 
pressure disorders and 
shock
Circulatory collapse 
and shock
Nervous system 
disorders
Neurological disorders 
NEC
Disturbances in 
consciousness NEC
Psychiatric disorders
Sleep disorders and 
disturbances 
Disturbances in 
initiating and 
maintaining sleep
Terminal insomnia 
(lower level term of 
interest:  early 
morning awakening)
Nervous system 
disorders
Sleep disturbances
Disturbances in 
initiating and 
maintaining sleep
Nervous system 
disorders
Movement disorders 
(incl parkinsonism)
Tremor (excl 
congenital)
Tremor
Gastrointestinal 
disorders
Gastrointestinal signs 
and symptoms
Nausea and vomiting 
symptoms
Vomiting


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13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 1
I.  The purpose of this amendment is:
Substantial Changes
1.
Update Amount of Blood Collected
DESCRIPTION OF CHANGE: 
The total amount of blood collected is increased to 145.5 mL.
RATIONALE:
Total amount of blood collected increased due to adding the analysis of antipsychotic trough 
levels.
2.
Update Schedule of Assessments
DESCRIPTION OF CHANGE: 
Revise screening visit 2 to day -20 to -7. 
Clarify a visit window of -1 day at visit 3.  
Add row for blood sampling for antipsychotic pharmacokinetics at visits 3, 9 and 15/EOT. 
Add footnotes to list the procedures that are required on days -1, 42 and 84. 
RATIONALE:
Screening visit 2 is revised to ensure there is a week in between MCCB assessment 
performed at second screening visit and Randomization.  
Added window for visits Day 1, 42 and 84 to allow some assessments to be performed the 
day prior to alleviate subject burden. 
3.
Add Blood Samples for Analysis of Antipsychotics
DESCRIPTION OF CHANGE: 
Add new section (5.7.1) to the protocol for the collection of blood samples for analysis of 
antipsychotics.
RATIONALE:
Added blood sample collection for analysis of antipsychotics to measure if subjects are 
taking their prescribed antipsychotics.
4.
Add Analysis of Antipsychotic Trough Levels
DESCRIPTION OF CHANGE: 
Add new section (7.3.2.1) to the protocol for the analysis of antipsychotic trough levels.
RATIONALE:
To provide the details on how the antipsychotic analysis will be presented.


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Nonsubstantial Changes
1.
Update Key Sponsor’s Contact Details
DESCRIPTION OF CHANGE: 
Replace one of two Medical Monitors/Study Physicians and remove a clinical research 
contact.
RATIONALE:
This change is made because of a change in study personnel.
2.
Revise Preparation for Cognitive and Functional Tests
DESCRIPTION OF CHANGE:
Remove University of California San Diego Performance-based Skills Assessment-2 
Extended Range (UPSA-2-ER), Positive and Negative Symptom Scale (PANSS), Negative 
Symptom Assessment Scale (NSA16) and Clinical Global Impression of Severity Scale 
(CGI-S) from the list of assessments that must not be performed within 30 minutes of 
smoking and/or drinking coffee.
RATIONALE:
Smoking and/or drinking coffee do not have an acute impact on these functional assessments, 
so restricting use is not necessary.
3.
Add Clarification for Oral Contraceptives.
DESCRIPTION OF CHANGE:
Add a bullet to clarify that oral contraceptive use is permitted as long as the subject is on a 
stable dose prior to screening.
RATIONALE:
Clarifying oral contraceptive use is permitted as long as subject is already using the 
medication prior to study start.
4.
Update Demographics
DESCRIPTION OF CHANGE:
Remove highest level of education and handedness from demographics.
RATIONALE:
Removed from protocol since this information will not be collected.


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5.
Update Procedure for Positive and Negative Syndrome Scale
DESCRIPTION OF CHANGE:
Remove the requirement that states the informant who completes the positive and negative 
syndrome scale must consent to participate.
RATIONALE:
Minor clarification to the protocol. Informant is provided an information sheet that does not 
require a signature.
6.
Clarify Reporting of Serious Adverse Events
DESCRIPTION OF CHANGE:
Add text to clarify that the collection and reporting of serious adverse events will continue 
until 28 days after the last dose of study drug.
RATIONALE:
Added text for consistency throughout protocol.
7.
Update the List of Inducers and Inhibitors of CYP2C19, CYP2D6 and CYP1A2
DESCRIPTION OF CHANGE:
Modify the list of inhibitors and inducers and note that these medications may be continued if 
the subject is taking these medications prior to study start.
RATIONALE:
Clarified usage of medications and removed the medications that were also listed in 
Appendix 12.1 since these medications are excluded and cannot be continued even if already 
taking them at the beginning of the study. 
8.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes (e.g., typos, format, numbering, consistency 
throughout the protocol).  
RATIONALE:
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures.


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Version 2.0 Incorporating Substantial Amendment 1
II.  Amendment Summary of Changes:
IIA.  Substantial Changes
5 Treatments and Evaluation
5.8 Total Amount of Blood
WAS:
Total amount of blood collected per subject for laboratory specimens is approximately 109.5 
mL over a 12-week period.
IS AMENDED TO:
Total amount of blood collected per subject for laboratory specimens is approximately 
145.5109.5 mL over a 12-week period.


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V Flow Chart and Schedule of Assessments
Table 1 Schedule of Assessments
WAS:
Period
Screening
Treatment and Observation
Follow-
up
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15/
EoT
16
Visit Week
-4 to 
-3
-3 to 
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
Visit Day
-28 to -
21
-20 to -
1
1
7
14
21
28
35
42
49
56
63
70
77
84
98/
EoS
Visit Window
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 days
±3 
days 
Informed Consent
X
Verify Eligibility Criteria
X
X
Demographics, including Smoking History and 
use of Cannabis (a), Height, BMI
X
Weight and Waist Circumference 
X
X
X
X
Medical and Psychiatric History
X
X
Duplicate Subject Database Check
X
Mini-International Neuropsychiatric Interview
X
Sponsor consult on concomitant medications
X
X
Vital Signs (b)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 Lead Electrocardiogram (c)
X
X
X
X
Physical Examination
X
X
X
X
Pregnancy Test (d, e)
X (d)
X (e)
X (e)
X (d)
X (d)
Urine Drug and Alcohol Test
X
X
X
Hematology, Biochemistry,Urinalysis
X 
X (f)
X (f)
X (f)
X
Abbreviated Biochemistry 
X
X
X
X
X
X
X
X
X
X
X
Serology for Hepatitis Testing
X
Plasma Adrenocorticotropic Hormone and 
Prolactin
X
X
MATRICS Consensus Cognitive Battery ( g, h)
X 
X
X (g)
X (g)
X (g)
University of San Diego Performance-based 
Skills Assessment-2 Extended Range (h)
X
X


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Positive and Negative Syndrome Scale (h)
X
X
X
X
X
Negative Symptom Assessment-16 Scale (h)
X
X
X
X
Clinical Global Impression of Severity Scale
X
X
X
X
X
Randomization
X
Abnormal Involuntary Movement Scale
X
X
X
Simpson Angus Scale
X
X
X
Barnes Akathisia Rating Scale
X
X
X
Cognitive Training and Study Drug 
Compliance via mobile applications (j)
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration and Review (j) 
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Sampling for ASP4345 
Pharmacokinetics (k, l)
X
X 
X (k, l)
X
Pharmacogenetic testing: COMT and 
dopamine D1 and D3 genotyping (m)
X
Biobanking Sample for Retrospective PGx 
Analysis (m)
X
Columbia-Suicide Severity Rating Scale (n) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking Status
X
X
X
X
X
X
X
X
X
X
X
X
X
(a)
Current and former history of smoking and use of cannabis (via smoking or ingestion) will be collected.
(b)
Vital signs include body temperature, pulse and sitting or supine blood pressure.
(c)
Electrocardiograms should be collected prior to pharmacokinetic sample collection at screening and days 1, 42 and 84/EoT. Prior to performing ECGs, subjects should rest 
in the supine position for at least 5 minutes.  One additional triplicate ECG can be taken on day 1 if the QTcF exceeds the limits in Exclusion Criterion 9.
(d)
Serum pregnancy tests will be performed for women of childbearing potential at the screening visit, and on days 84/EoT and 98/EoS. 
(e)
Urine pregnancy tests will be performed for women of childbearing potential only on days 1, and 42.
(f)
Blood samples for glucose should be performed fasting at the second screening visit (baseline for this test), and days 35 and 77.
(g)
All MCCB testing following randomization (i.e., days 42 and 84/EoT) should be performed within a 2 hour window of baseline (day 1).
(h)
In order to avoid an acute impact of nicotine and caffeine on cognitive and functional testing, smoking and intake of coffee will not be allowed approximately 30 minutes
before the MCCB, UPSA-2-ER, PANSS, NSA-16 and CGI-S assessments.
(i)
Cognitive Training will consist of a mobile application provided to the subject with instructions to use 4 times per week from randomization through day 84/EoT. The 
application will be reviewed with the subject at each visit to check compliance.  Study drug compliance will also be recorded using a mobile application.
(j)
Subjects will begin dose on day 1 of the study following all baseline procedures performed and randomization.  At each subsequent weekly visit study drug will be counted 
for compliance and a new packet dispensed except for day 84/EoT.


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(k)
Pharmacokinetic trough samples will be collected prior to dosing at days 7, 14 or 21, 42 and 84/EoT.
(l)
Additional pharmacokinetic samples will be collected at approximately 2 hours and 4 hours post dose on day 42.
(m)
The samples for pharmacogenetic testing (COMT and dopamine D1 and D3 receptor genotyping) and biobanking for retrospective pharmacogenetic analysis are optional 
and will be collected at baseline (day 1) prior to dosing.
(n)
The version of the C-SSRS to be performed at the first screening visit is the “Lifetime” version and the version of the C-SSRS to be performed on at the second screening 
visits and on days 1 though day 98/EoS is the “Since Last Visit.”
IS AMENDED TO:
Period
Screening
Treatment and Observation
Follow-
up
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15/
EoT
16
Visit Week
-4 to 
-3
-3 to 
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
14
Visit Day
-28 to -
21
-20 to -
71
1
7
14
21
28
35
42
49
56
63
70
77
84
98/
EoS
Visit Window
-1 
days 
(a)
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
(b)
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 days
(b)
±3 
days 
Informed Consent
X
Verify Eligibility Criteria
X
X (a)
Demographics, including Smoking History and 
use of Cannabis (ca), Height, BMI
X
Weight and Waist Circumference
X
X (a)
X
X
Medical and Psychiatric History
X
X (a)
Duplicate Subject Database Check
X
Mini-International Neuropsychiatric Interview
X
Sponsor consult on concomitant medications
X
X (a)
Vital Signs (db)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 Lead Electrocardiogram (ec)
X
X
X
X
Physical Examination
X
X
X
X
Pregnancy Test (d, ef, g)
X (fd)
X 
(ge)
X (ge)
X (fd)
X (fd)
Urine Drug and Alcohol Test
X
X
X
Hematology, Biochemistry,Urinalysis
X 
X (hf)
X 
X 
X


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(hf)
(hf)
Abbreviated Biochemistry 
X
X
X
X
X
X
X
X
X
X
X
Serology for Hepatitis Testing
X
Plasma Adrenocorticotropic Hormone and 
Prolactin
X
X
MATRICS Consensus Cognitive Battery ( g, h
i, j)
X 
X
X (g)
X (ig)
X (ig)
University of San Diego Performance-based 
Skills Assessment-2 Extended Range (h)
X
X
Positive and Negative Syndrome Scale (ah)
X
X (a)
X
X (b)
X
Negative Symptom Assessment-16 Scale (ah)
X
X (a)
X (b)
X
Clinical Global Impression of Severity Scale
X
X
X (a)
X
X
Randomization
X (a)
Abnormal Involuntary Movement Scale
X (a)
X
X
Simpson Angus Scale
X (a)
X
X
Barnes Akathisia Rating Scale
X (a)
X
X
Cognitive Training and Study Drug 
Compliance via mobile applications (j, k)
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration and Review (lj) 
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Sampling for ASP4345 
Pharmacokinetics (k, lm, n)
X
X 
X (nk, l)
X
Blood Sampling for Antipsychotic 
Pharmacokinetics
X
X
X
Pharmacogenetic testing: COMT and 
dopamine D1 and D3 genotyping (om)
X
Biobanking Sample for Retrospective PGx 
Analysis (om)
X
Columbia-Suicide Severity Rating Scale (pn) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking Status
X
X
X
X
X
X
X
X
X
X
X
X
X
(a)      The following assessments can be performed on day 1: Verify Eligibilty Criteria (also day 1), Weight and Waist Circumference, Medical and Psychiatric 
History Review, sponsor consult on concomitant medications (if changes have occurred), Cognitive Training Mobile Application Set-up, Positive and 
Negative Syndrome Scale, Negative Symptom Assessment-16 scale, Clinical Global Impression of Severity Rating Scale, Abnormal Involuntary Movement 
Scale, Simpson Angus Scale, and Barnes Akathisia Rating Scale.  ALL other assessments must be performed as listed on day 1.  
(b)
The following clinical assessments can be performed the day prior to days 42 and 84 visits: Positive and Negative Syndrome Scale, Negative Symptom 


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Assessment-16 Scale, Clinical Global Impression of Severity Scale, Abnormal Involuntary Movement Scale, Simpson Angus Scale and Barnes Akathisia 
Rating Scale. Performing these assessments the day prior to days 42 and/or 84 is optional.  All other assessments must be performed as listed on day 42 and 
day 84.
(c)      Current and former history of smoking and use of cannabis (via smoking or ingestion) will be collected.
(bd)
Vital signs include body temperature, pulse and sitting or supine blood pressure.
(ce)
Electrocardiograms ECGs should be collected prior to pharmacokinetic sample collection at screening and days 1, 42 and 84/EoT. Prior to performing ECGs, subjects 
should rest in the supine position for at least 5 minutes.  One additional triplicate ECG can be taken on day 1 if the QTcF exceeds the limits in Exclusion Criterion 9.
(df)
Serum pregnancy tests will be performed for women of childbearing potential at the screening visit, and on days 84/EoT and 98/EoS. 
(eg)
Urine pregnancy tests will be performed for women of childbearing potential only on days 1, and 42.
(fh)
Blood samples for glucose should be performed fasting at the second screening visit (baseline for this test), and days 35 and 77.
(gi)
All MCCB testing following randomization (i.e., days 42 and 84/EoT) should be performed within a 2 hour window of baseline (day 1).
(hj)
In order to avoid an acute impact of nicotine and caffeine on cognitive and functional testing, smoking and intake of coffee will not be allowed approximately 
30 minutes before the MCCB, UPSA 2 ER, PANSS, NSA 16 and CGI S assessments.
(ik)
Cognitive Training will consist of a mobile application provided to the subject with instructions to use 4 times per week from randomization through day 84/EoT. 
The application will be reviewed with the subject at each visit to check compliance.  Study drug compliance will also be recorded using a mobile application.
(jl)
Subjects will begin dose on day 1 of the study following all baseline procedures performed and randomization.  At each subsequent weekly visit study drug will be 
counted for compliance and a new packet dispensed except for day 84/EoT.
(km) Pharmacokinetic trough samples will be collected prior to dosing at days 7, 14 or 21, 42 and 84/EoT.
(ln)
Additional pharmacokinetic samples will be collected at approximately 2 hours and 4 hours post dose on day 42.
(mo) The samples for pharmacogenetic testing (COMT and dopamine D1 and D3 receptor genotyping) and biobanking for retrospective pharmacogenetic analysis are 
optional and will be collected at baseline (day 1) prior to dosing. ICFs for substudies may be collected prior to day 1 sample collection.
(np)
The version of the C-SSRS to be performed at the first screening visit is the “Lifetime” version and the version of the C-SSRS to be performed on at the second 
screening visits and on days 1 though day 98/EoS is the “Since Last Visit.”






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Version 2.0 Incorporating Substantial Amendment 1
The subject’s highest level of education (in years) and handedness will be recorded.  In 
addition, the highest level of education (in years) for the subject’s mother and father will also 
be recorded.
5 Treatments and Evaluation
5.3.1.3 Positive and Negative Syndrome Scale
DELETED:
The informant must consent to participate.
5 Treatments and Evaluation
5.5.5 Reporting of Serious Adverse Events
WAS:
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
informed consent and will continue to 28 days.
IS AMENDED TO:
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
informed consent and will continue to 28 days after the last dose of study drug.
12 Appendices
12.2 List of Inducers and Inhibitors of CYP2C19, CYP2D6 and CYP1A2
WAS:
Below is a list of strong and moderate inhibitors and inducers of CYP1A2, CYP2C19 and 
CYP2D6. These lists are not exhaustive. Medications should be considered excluded if taken 
alone or as part of a combination product. If in doubt, please contact the Medical Monitor.
Enzyme
Inhibitor (Strong and Moderate)
Inducer (Strong and Moderate)
CYP1A2
Ciprofloxacin, Enoxacin,  
Zafirlukast, Methoxsalen, 
Mexiletine, Oral contraceptives
Phenytoin, Rifampin, Ritonavir, 
Teriflunomide
CYP2C19
Fluconazole, Fluoxetine,  
Ticlopidine
Rifampin, Ritonavir, Efavirenz, 
Enzalutamide, Phenytoin
CYP2D6
Bupropion, Fluoxetine, 
Paroxetine, Quinidine, 
Trebinafine, Cimetidine, 
Cinacalcet, Duloxetine, 
Mirabegron
IS AMENDED TO:
Below is a list of strong and moderate inhibitors and inducers of CYP1A2, CYP2C19 and 
CYP2D6. These lists are not exhaustive. These medications can be continued if the subject 
is on a stable dose prior to screening, but cannot be initiated during the study.  


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Version 2.0 Incorporating Substantial Amendment 1
Medications should be considered excluded if taken alone or as part of a combination 
product. If in doubt, please contact the Mmedical Mmonitor.
Enzyme
Inhibitor (Strong and Moderate)
Inducer (Strong and Moderate)
CYP1A2
Ciprofloxacin, Enoxacin,  
Zafirlukast, Methoxsalen, 
Mexiletine, Oral contraceptives*
Phenytoin, Rifampin, Ritonavir,
Teriflunomide
CYP2C19
Fluconazole, Fluoxetine,  
Ticlopidine
Rifampin, Ritonavir, Efavirenz, 
Enzalutamide, Phenytoin
CYP2D6
Bupropion, Fluoxetine, 
Paroxetine, Quinidine, 
Trebinafine, Cimetidine,
Cinacalcet, Duloxetine, 
Mirabegron
*Oral contraceptives are allowed if the subject is on a stable dose prior to screening [refer to Section 5.1.3 
Previous and Concomitant Treatment (Medication and NonMedication Therapy].


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Version 2.0 Incorporating Substantial Amendment 1
14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
A Phase 2a, Randomized, Double-Blind, Placebo-
Controlled, Parallel-group Study to Assess the Safety and 
Efficacy of ASP4345 as Add-on Treatment for Cognitive 
Impairment in Subjects with Schizophrenia on Stable 
Doses of Antipsychotic Medication
ISN/Protocol 4345-CL-0015
ClinicalTrials.gov Identifier: NCT03557931
Date of Statistical Analysis Plan: 22 Aug 2019
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: Astellas Pharma Global Development, Inc. (APGD)
SAP Final Version 2.0
ISN/Protocol 4345-CL-0015
22-August-2019
Astellas
Page 1 of 34
STATISTICAL ANALYSIS PLAN
Final Version 2.0 dated 22-August-2019
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-group Study to Assess 
the Safety and Efficacy of ASP4345 as Add-on Treatment for Cognitive Impairment 
in Subjects with Schizophrenia on Stable Doses 
of Antipsychotic Medication
ISN: 4345-CL-0015
Astellas Pharma Global Development, Inc. (APGD)
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Sponsor: Astellas Pharma Global Development, Inc. (APGD)
SAP Final Version 2.0
ISN/Protocol 4345-CL-0015
22-August-2019
Astellas
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Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 7
2
STUDY OBJECTIVE(S) AND DESIGN······················································· 7
2.1
Study Objective(s) ············································································· 7
2.1.1
Primary Objectives······································································· 7
2.1.2
Secondary Objectives···································································· 7
2.1.3
Exploratory Objectives ·································································· 7
2.2
Study Design···················································································· 8
2.3
Randomization·················································································· 8
3
SAMPLE SIZE ····················································································· 9
4
ANALYSIS SETS ·················································································· 9
4.1
Full Analysis Set ··············································································· 9
4.1.1
Modified Full Analysis Set 1 ··························································· 9
4.1.2
Modified Full Analysis Set 2 ··························································· 9
4.2
Intent-to-Treat Set·············································································· 9
4.3
Safety Analysis Set ···········································································10
4.4
Pharmacokinetics Analysis Set······························································10
5
EFFICACY ENDPOINTS ·······································································10
5.1
Primary Efficacy Endpoint(s)································································10
5.2
Secondary Efficacy Endpoints·······························································10
5.3
Exploratory Efficacy Endpoints·····························································10
6
STATISTICAL METHODOLOGY ···························································11
6.1
General Considerations·······································································11
6.2
Study Population ··············································································11
6.2.1
Disposition of Subjects ·································································11
6.2.2
Protocol Deviations ·····································································12
6.2.3
Demographic and Other Baseline Characteristics ···································12
6.2.4
Previous and Concomitant Medications ··············································12
6.3
Study Drugs Exposure and Compliance····················································12
6.4
Analysis of Efficacy ··········································································13
6.4.1
Analysis of Primary Efficacy Endpoint(s)············································13


Sponsor: Astellas Pharma Global Development, Inc. (APGD)
SAP Final Version 2.0
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Page 3 of 34
6.4.2
Analysis of Secondary Efficacy Endpoints···········································15
6.4.3
Analysis of Exploratory Endpoints····················································16
6.5
Analysis of Safety·············································································18
6.5.1
Adverse Events ··········································································18
6.5.2
Clinical Laboratory Evaluation ························································19
6.5.3
Vital Signs················································································20
6.5.4
Electrocardiograms······································································21
6.5.5
Metabolic Parameters···································································21
6.5.6
Columbia-Suicide Severity Rating Scale·············································21
6.5.7
Movement Disorder (Abnormal Involuntary Movement Scale) ···················21
6.5.8
Simpson Angus Scale···································································22
6.5.9
Barnes Akathisia Rating Scale·························································22
6.6
Analysis of Pharmacokinetic ································································22
6.6.1
Estimation of Pharmacokinetic Parameters ··········································22
6.7
Interim Analysis (and Early Discontinuation of the Clinical Study)····················22
6.8
Additional Conventions ······································································23
6.8.1
Analysis Windows ······································································23
6.8.2
Imputation Rules for Incomplete Dates···············································25
7
REVISION AND RATIONALE································································26
8
REFERENCES ····················································································26
9
APPENDICES ·····················································································27
9.1
Appendix 1: Author and Approver Signatures ············································27
9.2
Appendix 2: Adverse Events of Special Interest (Preferred Terms; MedDRA 
18.0) ····························································································28
9.2.1
Adverse Events of Interest Related to Abuse requiring narratives ················28
9.2.2
Drug Abuse – Related Adverse Events ···············································29
9.2.3
Drug Withdrawal – Related Adverse Events·········································32


Sponsor: Astellas Pharma Global Development, Inc. (APGD)
SAP Final Version 2.0
ISN/Protocol 4345-CL-0015
22-August-2019
Astellas
Page 4 of 34
I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
Analysis of Covariance
APGD
Astellas Pharma Global Development, Inc.
ASSR
auditory steady-state response
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BARS
Barnes Akathisia Rating Scale
BMI
body mass index
CGI-S
Clinical Global Impression of Severity Scale
CI
confidence interval
CIAS
cognitive impairment associated with schizophrenia
Cmax
maximum concentration
COMT
catechol-o-methyltransferase
C-SSRS
Columbia Suicide Severity Rating Scale
CV
coefficient of variation
ECG
electrocardiogram
eCRF
electronic case report form
EoT
end-of-treatment
ET
early termination
FAS
full analysis set
HDL
high-density lipoprotein
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LDL
Low-density lipoprotein
LS
least squares
MATRICS
Measurement and Treatment Research to Improve Cognition in Schizophrenia
MATRICS-CT
Measurement and Treatment Research to Improve Cognition in Schizophrenia 
Coprimary and Translations
MCCB
Measurement and Treatment Research to Improve Cognition in Schizophrenia
Consensus Cognitive Battery
MedDRA
medical dictionary for regulatory activities
MMRM
Mixed Models Repeated Measures
NSA-16
Negative Symptom Assessment Scale
NSAIDs
non-steroidal anti-inflammatory drugs
PANSS
Positive and Negative Symptom Scale


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Abbreviations
Description of abbreviations
PGx
pharmacogenetic
PKAS
pharmacokinetic analysis set
QD
daily
QTcF
QT interval using Fridericia’s formula
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SAS
Simpson Angus Scale
SE
standard error
TEAE
treatment emergent adverse events
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UPSA-2-ER
University of California San Diego Performance-based Skills Assessment-2 
Extended Range


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List of Key Terms
Terms
Definition of terms
Baseline
The last measurement/evaluation on or prior to the first dose of randomized 
therapy is considered the baseline measure/evaluation.
Endpoint 
Variable that pertains to the efficacy or safety evaluations of a trial.
Enroll
To register or enter a subject into a clinical trial. NOTE: Once a subject has 
received the study drug or placebo, the clinical trial protocol applies to the 
subject.
Intervention
The drug, device, therapy or process under investigation in a clinical study that 
is believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics).
Investigational 
period
Period of time where major interests of protocol objectives  are observed, and 
where the test drug or comparative drug (sometimes without randomization) is 
usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug.
Post investigational 
period
Period of time after the last assessment of the protocol. Follow-up
observations for sustained adverse events and/or survival are done in this 
period.
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet 1 or more criteria required for participation 
in a trial.
Screening period
Period of time before entering the investigational period, usually from the time 
when a subject signs the consent until just before the test drug or comparative 
drug (sometimes without randomization) is given to a subject.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes procedures for 
executing the statistical analysis to fulfil the objectives of the study.
The final SAP will be approved prior to database hardlock and unblinding the subject 
treatment assignment.
Critical changes that affected the statistical analyses from the analyses planned in the SAP 
will be documented in the Clinical Study Report (CSR).
2
STUDY OBJECTIVE(S) AND DESIGN
2.1
Study Objective(s)
The objectives of the study, conducted in subjects with cognitive impairment associated with 
schizophrenia, are the following:
2.1.1
Primary Objectives
●
To evaluate the efficacy of ASP4345 on cognitive impairment compared to placebo 
using change from baseline in MATRICS Consensus Cognitive Battery (MCCB) 
neurocognitive composite score (excluding social cognition domain). The primary 
estimand will use a Hypothetical Strategy and compare patients as though they had 
continued on the assigned treatment.
●
To evaluate the safety and tolerability of ASP4345 compared to placebo
2.1.2
Secondary Objectives
●
To evaluate the effects of ASP4345 compared to placebo on functional capacity using 
the University of California San Diego Performance-based Skills Assessment-2 
Extended Range (UPSA-2-ER) total score.
●
To evaluate the pharmacokinetic profile of ASP4345 and its metabolites, if necessary 
2.1.3
Exploratory Objectives
●
To evaluate the effects of ASP4345 compared to placebo using:
o
the 16-item version of the Negative Symptom Assessment Scale (NSA-16)
o
the individual domains of the MCCB 
o
the assessment of general clinical symptoms with the Positive and Negative 
Symptom Scale (PANSS)
o
the assessment of the Clinical Global Impression of Severity Scale (CGI-S)
●
To evaluate the relationship between the CGI-S and MCCB neurocognitive composite 
score
●
To evaluate the relationship between number of cognitive training levels, including 
repeat levels, completed (as a measure of compliance with cognitive training) and 
MCCB neurocognitive composite score

To evaluate the pharmacogenetic impact on ASP4345 pharmacodynamic results


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2.2
Study Design
This is a randomized, double-blind, placebo-controlled, 3-arm oral dose study to evaluate the 
safety and efficacy of ASP4345 in subjects with cognitive impairment associated with 
schizophrenia on stable doses of risperidone, quetiapine, olanzapine, ziprasidone, 
aripiprazole, brexpiprazole, paliperidone or lurasidone for at least 4 weeks prior to screening 
for oral medications and 2 months for depot medications.  The study will consist of the 
following periods:
●
Screening period (up to 28 days)
●
Double-blind treatment period (12 weeks/84 days)
●
Follow-up period (14 days post last dose)
Approximately 420 subjects are planned to be screened with up to 210 subjects enrolled in 1 
of 3 arms.  Study groups will consist of approximately 90 placebo subjects and 60 subjects 
each per active study arm randomized in 3:2:2 ratio to receive 1 of 2 doses of ASP4345 or 
matching placebo daily (QD) for 12 weeks. Study treatment assignments will be according to 
the following table:
Group
Dose Regimen
Number
A
50 mg, QD
60
B
150 mg, QD
60
C
Placebo, QD
90
All subjects will be administered the first dose of blinded study drug at the site following 
randomization and provided with mobile applications that provide supplemental cognitive 
training and record treatment compliance.  Subjects will return to the clinic weekly for safety, 
efficacy, and/or pharmacokinetic procedures at days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77 
and 84.  Subjects will continue their antipsychotic treatment for the entire study and will be 
followed for 14 days after their last dose of study drug. 
Subjects terminating early from the study treatment will be encouraged to complete 
scheduled visits.  All subjects are allowed to stop study drug, but continue in the study 
through day 84 according to the current visit schedule unless the participant specifically 
withdraws consent for any further contact with him/her or persons previously authorized by 
the participant provide this information.
2.3
Randomization
Subjects will be randomized in a 3:2:2 ratio to a treatment arm (placebo to active) according 
to the randomization schedules through IRT. All subjects who meet the eligibility criteria 
will be randomized. The site personal will dispense the treatment according to the IRT 
system’s assignment. Randomization will occur by site (stratified by site). In order to reduce 
the impact of incomplete blocks at any given site, a Latin square design will be used to 
generate the randomization list such that blocks are balanced both in regard to the number of 
treatment assignments but also to the order in which treatments are assigned. Blocks will be 


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dynamically assigned by the IRT system to sites once they request a randomization number, 
so that all blocks in a Latin square will be assigned before moving on to the next Latin square. 
3
SAMPLE SIZE
A total sample size of 210 subjects will be randomized in 3:2:2 ratio (approximately 
90 placebo and 60 subjects each per active study arm) into 1 of 2 doses of ASP4345 or 
matching placebo. The sample size will provide approximately 82% power for the pairwise 
comparisons to placebo to detect an effect size of at least 0.43 in the primary outcome 
measure, assuming a 1 sided 5% significance level, with statistical significance achieved at 
an effect size of approximately 0.28.  Note that the decision criteria to proceed with the 
development of the compound will be based on effect sizes rather than statistical significance.  
The number of subjects planned for this clinical study are considered sufficient to achieve the 
clinical study objectives.
4
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
The determination of whether subjects are included or excluded from the safety and efficacy 
analysis sets will be made prior to database hard-lock. All classifications can be made
programmatically and so a Classificiation meeting may not be held. 
4.1
Full Analysis Set 
The full analysis set (FAS) will consist of all subjects who are randomized and receive at 
least one dose of study drug and have at least one post baseline MCCB measurement. This 
will be the primary analysis set for efficacy analyses.
4.1.1
Modified Full Analysis Set 1
A modified full analysis set 1 (mFAS1) will be a subset of the FAS, with the exclusion of 
subjects whose study coordinator may have become unblinded during the study due to an 
error in the drug accountability system, and where the subejct’s rater is the same person as 
the study coordinator.
4.1.2
Modified Full Analysis Set 2
A modified full analysis set 2 (mFAS2) will be a subset of the FAS, with the exclusion of 
subjects whose study coordinator may have become unblinded during the study due to an 
error in the drug accountability system. 
4.2
Intent-to-Treat Set
The Intent-to-Treat analysis set (ITT) will consist of all subjects who are randomized into the 
study. The ITT will be used to assess the robustness of the results of the primary efficacy 
endpoint from the statistical tests based on the FAS. Select demographic and baseline 
characteristics may also be summarized for the ITT.


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4.3
Safety Analysis Set
The Safety Analysis Set (SAF) consists of all subjects who took at least 1 dose of study drug, 
and will be used for safety analyses.
For the statistical summary of the safety data, the SAF will be used.
4.4
Pharmacokinetics Analysis Set 
The pharmacokinetic analysis set (PKAS) consists of all subjects who took at least 1 dose of 
study drug and who have at least 1 plasma concentration. 
The PKAS will be used for all summaries and analyses of the pharmacokinetic data.
5
EFFICACY ENDPOINTS 
5.1
Primary Efficacy Endpoint(s)
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the MCCB 
neurocognitive composite score (excluding social cognition domain).
●
Safety and Tolerability:
o
Nature, frequency and severity of AEs.
o
Vital signs (sitting or supine blood pressure, pulse and body temperature)
o
Clinical laboratory tests (hematology, biochemistry [including cystatin C, serum 
prolactin, and ACTH] and urinalysis)
o
Routine 12-lead ECG
o
Columbia-Suicide Severity Rating Scale (C-SSRS)
o
Changes in individual indices of metabolic syndrome (weight, waist circumference, 
cholesterol, triglycerides, high-density lipoprotein [HDL; the second screening visit 
and day 77), and hemoglobin A1c [HbA1c]
o
Movement disorder (Abnormal Involuntary Movement Scale [AIMS], Simpson 
Angus Scale [SAS] and Barnes Akathisia Rating Scale [BARS])
5.2
Secondary Efficacy Endpoints
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the UPSA 
2 ER instrument total score
●
Pharmacokinetics: 
o
ASP4345 and its metabolites, if necessary (plasma): Ctrough. 
5.3
Exploratory Efficacy Endpoints
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the NSA-16 
only for the subjects who have at least 1 negative symptom of at least moderate severity
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the MCCB 
composite score.
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for each of the 
MCCB domains.
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the PANSS
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the CGI-S


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●
Correlation between MCCB and CGI-S scores at each measurement (weeks -4, -3, 0, 6, 12)
●
Correlation between change from baseline to week 12/EoT in MCCB and change from 
baseline to week 12/EoT in CGI-S scores
●
Correlation between the number of cognitive training levels, including repeat levels, 
completed (as a measure of compliance with cognitive training) and MCCB 
neurocognitive composite score
●
Pharmacogenetics:
○
Catechol-o-methyltransferase (COMT) and dopamine D1 and D3 receptor 
genotyping
6
STATISTICAL METHODOLOGY
6.1
General Considerations
Continuous data will be summarized descriptively including the number of subjects (n), 
mean, standard deviation (SD), median, minimum and maximum.  Categorical data will be 
summarized by frequencies and percentages. Percentages by categories will be based on the 
number of subjects with no missing data, i.e. the percentages for the non-missing categories 
will add up to 100%.
A 2-sided significance level of 0.10, unless otherwise specified, will be used for all statistical 
tests on efficacy endpoints without multiplicity adjustment.
All data summarization and analyses will be performed using SAS® Version 9.3 or higher 
on Unix. Specifications for table, figures, and data listing formats can be found in the TLF 
specifications.
6.2
Study Population
Analysis of the primary efficacy endpoint will be conducted on the FAS and ITT. The 
interpretation of results from statistical tests will be based on the FAS. The ITT will be used 
to assess the robustness of the results from the statistical tests based on the FAS.  Analysis of 
the secondary and exploratory efficacy endpoints will be done on the FAS only. 
Data such as patient disposition, demographics and baseline characteristics will be 
summarized for FAS in the event that the definition of FAS is identical to SAF (i.e., if no 
patients were given wrong study drug and all have a post-baseline MCCB neurocognitive 
composite score). If FAS is not identical to SAF then data will be summarized for both FAS 
and SAF as specified in the relevant sections.
6.2.1
Disposition of Subjects
Disposition of subjects will be summarized for the FAS by treatment group and overall. 
Number of subjects who complete or prematurely discontinue from the treatment or study (ie, 
follow up period) will be summarized by treatment group and overall. For the discontinuation, 
the primary reason reported by the investigator will be summarized.
Number and percentage of subjects for each analysis set will be summarized by treatment 
group and overall. 


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6.2.2
Protocol Deviations
The number and percentage of subjects with the following protocol deviation criteria will be 
summarized for each criterion and overall, by treatment group and  total as well as by 
investigative site. Subjects deviating from a criterion more than once will be counted once for 
the corresponding criterion.
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment.
6.2.3
Demographic and Other Baseline Characteristics
Demographic, age, sex, race, ethnicity, weight, height, BMI, and smoking status, and other 
baseline characteristics will be summarized descriptively by treatment group and overall for 
the FAS, ITT and SAF. 
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT), by treatment group and overall for the SAF.
Medical and psychiatric history for each subject will be presented in a listing.
6.2.4
Previous and Concomitant Medications
Previous and concomitant medications will be summarized by therapeutic subgroup (ATC 
2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name by treatment 
group for the FAS. Subjects taking the same medication multiple times will be counted once 
per medication and investigational period. A medication which can be classified into several 
chemical and/or therapeutic subgroups is presented in all chemical and therapeutic subgroups.
Medications taken for treatment of schizophrenia during the 12 months prior to screening and 
other medication taken 28 days prior to the screening visit and up to the first dose of study 
medication (treatment period) will be defined as prior schizophrenia medications or other 
prior medication, respectively. Concomitant medications are defined as any medications that 
patients took after the first dose of study medication and through last dose of study drug. 
Medications that started prior to first administration of study drug and continued while study 
drug was given will be counted in both previous and concomitant medications.
6.3
Study Drugs Exposure and Compliance
Duration and compliance  of study drug will be summarized for FAS, ITT, and SAF by 
treatment group and overall. 
Number and percentages of subjects with the following categories of study drug duration will
be summarized: >0 to ≤ 2 days, >2 to ≤ 7 days, >7 to ≤ 14 days, >14 to ≤ 21 days, >21 to 
≤42 days, >42 to ≤ 56 days, >56 to ≤ 84 days.  


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Number and percentages of subjects with the following cumulative categories of study drug 
duration will be summarized: ≥ 1 day, ≥ 7 days, ≥ 14 days, ≥ 21 days, ≥ 28 days, ≥ 42 days, 
and ≥ 56 days. 
Study drug compliance will be summarized and listed both for product accountability from 
an IRT system as well as from daily virtual monitoring by use of a mobile application. 
Product accountability will be the primary source of compliance, and % compliance will be 
calculated at each visit and overall as ([the number of pills dispensed] – [the number of pills 
returned]) / [the number of pills expected consumed] * 100, where the number of pills 
expected consumed is the duration in days. 
6.4
Analysis of Efficacy 
6.4.1
Analysis of Primary Efficacy Endpoint(s)
No multiplicity adjustment will be necessary in this study.
6.4.1.1 Primary Analysis for Primary Efficacy Endpoint(s) 
Consistent with the Hypothetical Strategy used for the estimand which is to compare patients 
as though they had continued on the assigned treatment, MMRM will use all available on-
treatment data to inform end of treatment mean treatment effect estimates without requiring 
explicit imputation for missing data (i.e., for discontinued subjects). There will be no 
adjustment made for multiple comparisons. The primary analysis will use the FAS.
The MCCB neurocognitive composite score is a standardized mean of the six domain scores 
(excluding social cognition). Raw scores are converted to age and sex adjusted t-scores 
which are standardized to normative data, and have a mean of 50 and standard deviation of 
10 in the general healthy population. A higher score indicates less impairment.
The primary endpoint of change from baseline in MCCB neurocognitive composite T score 
will be analyzed using a Mixed Models Repeated Measures (MMRM) approach. The model 
will contain fixed effect terms for treatment group, pooled site, visit (the repeated term), 
treatment by visit, and visit by baseline, with the MCCB neurocognitive composite score at 
baseline used as a covariate. Pooled centers will be generated and documented prior to 
database lock. If the inclusion of pooled centers creates modeling problems, then dropping 
that factor will be considered. Subject will be identified as subject in the repeated statement. 
Residuals from the model will be tested for normality using the Shapiro-Wilk test; if the
normality assumption is rejected then data transformations will be explored. If necessary, the 
model may be run on ranked values as a non-parametric alternative. An unstructrured 
covariance structure will be used initially, if the model fails to converge other covariance 
structures will be explored. The Kenward-Roger method of estimation of degrees of freedom 
and the restricted maximum likelihood (REML) method will be used. 
Least squares (LS) means (± standard error [SE]) and 2-sided 90% CIs and p-values for the 
LS mean treatment differences between each dose of ASP4345 and placebo will be presented 
for the primary endpoint. Effect size (Cohen’s d) will also be shown, as:


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where t is the t-value for the least squares mean pairwise difference of ASP4345 vs placebo 
from the MMRM model. 
There will be two hypotheses tested. Hypothesis 1 is given as follows:
H0A: The LS mean change from baseline at week 12 for Group A (50 mg ASP4345) and 
Group C (placebo) are the same
H1A: The LS mean change from baseline at week 12 for Group A (50 mg ASP4345) and 
Group C (placebo) are not the same
Hypothesis 2 is given as follows:
H0B: The LS mean change from baseline at week 12 for Group B (150 mg ASP4345)
and Group C (placebo) are the same
H1B: The LS mean change from baseline at week 12 for Group B (150 mg ASP4345)
and Group C (placebo) are not the same
6.4.1.2 Sensitivity Analysis for Primary Efficacy Endpoint(s) 
The relationship between the number of cognitive training levels, including repeat levels 
completed at week 12, (as a measure of compliance with cognitive training) and MCCB 
neurocognitive composite end of treatment scores will be evaluated using correlations overall 
and by treatment group. 
Additionally, the primary efficacy analysis as defined in section 6.4.1.1 will be conducted 
using mFAS1 and mFAS2.
6.4.1.2.1
Cognitive Training 
The number of training levels completed as well as the percentage of the number expected 
completed will be summarized. The percent of the number of training levels completed out of 
the number expected completed will be calculated as: [number of levels played / expected 
number of levels] * 100, where the expected number of training levels will increase in a step 
fashion, by 48 on day 1, day 7, day 14 and so on (as shown in the table below). In between 
'steps', i.e. from day 1 until day 7, regardless of whether a subject completes the entire week 
the expected number of training levels will be constant. Additionally, training task 
performance will be assessed prior to the start of cognitive training (pre assessment) and 
again after the last cognitive training (post assessment) with a standardized task assessment 
(Sound Sweeps) to evaluate improvement. Pre, post and change pre to post values will be 
summarized.


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Week
Interval
Increase in Expected 
Number of Training 
Levels at Start of 
Interval
Cumulative Expected Number of 
Training Levels
1
Day 1 to <7
48
48
2
Day 7 to <14
48
96
3
Day 14 to <21
48
144
4
Day 21 to <28
48
192
5
Day 28 to <35
48
240
6
Day 35 to <42
48
288
7
Day 42 to <49
48
336
8
Day 49 to <56
48
384
9
Day 56 to <63
48
432
10
Day 63 to <70
48
480
11
Day 70 to <77
48
528
12
Day 77 to <=84
48
576
An additional interval may be added for subjects with extended treatment periods. 
Incomplete intervals will be normalized to the expected interval. 
6.4.1.3 Subgroup Analysis for Primary Efficacy Endpoint(s)  
The primary outcome of neurocognitive MCCB score will be summarized by subgroups. The 
subgroups (categories) will be:
●
Duration of diagnosis (>10 years, ≤10 years)
●
Type of diagnosis (schizophrenia, schizoaffective)
●
Smoking status (current, non-smoker ([including former])
●
Sex (male, female)
●
Cannabis use (3 groups based on laboratory results: Never positive, positive pre-dose or 
week 12, positive predose and week 12; where positive pre-dose is positive week 0 
and/or screening) 
●
Compliance based on electronic mobile application (<85% compliance, ≥85% 
compliance)
6.4.2
Analysis of Secondary Efficacy Endpoints 
The secondary efficacy endpoint of change from baseline to week 12/EoT in the UPSA-2 
Extended Range instrument will be analyzed using ANCOVA, in each of the six domains and 
a total score. The model will contain terms for treatment group and pooled site, with the 
corresponding score at baseline used as a covariate.  
LS means (± SE) and 2-sided 90% CIs for the LS mean treatment differences between each 
dose of ASP4345 and placebo will be presented as for the primary endpoint. There will be no 
adjustment made for multiple comparisons.


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The sensitivity analysis described in 6.4.1.2 and the subgroups described in section 6.4.1.3
will also be completed for the secondary efficacy endpoint. 
6.4.3
Analysis of Exploratory Endpoints 
Exploratory endpoints listed below will be analyzed using the same MMRM model as the 
primary efficacy analysis. 
●
Change from baseline to week 12/EoT for NSA-16 total negative score, only for the 
subjects who have at least 1 negative symptom of moderate severity at baseline (a score 
≥3 or ≤6 for one of the 16 symptoms assessed)
●
Change from baseline to week 12/EoT for NSA-16 global negative symptoms rating
●
Change from baseline to week 12/EoT for the MCCB composite T score
●
Change from baseline to week 12/EoT for each of the seven MCCB domain T scores
●
Change from baseline to week 12/EoT for the PANSS total score
●
Change from baseline to week 12/EoT for ASP4345 compared to placebo for the CGI-S
●
The pharmacogenetics test listed below will be measured at baseline only. Genotyping 
data will be analyzed and reported separatelyfrom the rest of the study data.
o
Catechol-o-methyltransferase (COMT) and dopamine D1 and D3 receptor 
genotyping
The NSA-16 consists of 16 negative symptoms with scores of 0-6 for each item. Scores of 9 
(not able to rate) will not be included in any continuous summary statistics. Scores for five 
factors (Communication, Emotion/Affect, Social Involvement, Motivation and Retardation) 
will be calculated. If all item have scores ≥0 and ≤ 6, each factor score is the sum of all the 
items in that factor. If there are missing items (including ratings of 9) within a factor, 
provided the number missing is ≤ 34% the factor score will be calculated as the sum of all 
items within the factor, with the missing item imputed as the average score of the observed 
items. 
A factor score will not be calculated if the number missing is greater than 34%, and if any 
factor score is not calculated the total score will be not be calculated. Provided all factor 
scores are calculated, the total negative score will be the sum of all factor scores.. 
●
Communication [4 items; minimum number of items to calculate factor score is 3]
o
Q1, Prolonged time to respond
o
Q2, Restricted speech quantity
o
Q3, Impoverished speech content
o
Q4, Inarticulate speech
●
Emotion/Affect [3 items; minimum number of items to calculate factor score is 2]
o
Q5, Reduced range
o
Q6, Reduced modulation of intensity
o
Q7, Reduced display on demand
●
Social Involvement [3 items; minimum number of items to calculate factor score is 2]
o
Q8, Reduced social drive
o
Q9, Poor rapport with interviewer


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o
Q10, Interest in Emotional and Physical Intimacy
●
Motivation [4 items; minimum number of items to calculate factor score is 3]
o
Q11, Poor grooming and hygiene
o
Q12, Reduced sense of purpose
o
Q13, Reduced interests
o
Q14, Reduced daily activity
●
Retardation [2 items; minimum number of items to calculate factor score is 2]
o
Q15, Reduced expressive gestures
o
Q16, Slowed movements
A higher score indicates more severe symptoms. A global negative symptoms rating (a scale 
ranging from ‘1=No evidence of negative symptoms’ to ‘7=Extremely severe negative 
symptoms (incapacitating)’ is also assessed. 
For patients who have at least one negative symptom of at least moderate severity (a score 
≥3 or ≤6 for one of the 16 symptom assessments), the negative symptom burden will be 
further assessed with the total negative score, as calculated above. Continuous descriptive 
statistics for each factor score, the total negative symptom score and the global negative 
symptoms rating will be shown, along with the number and percentage in each category for 
the individual 16 symptom scores, by treatment and week.
PANSS total score is the summation of ratings across all 30 items. Traditional PANSS 
subscores are calculated as follows:
●
Positive score: summation of ratings across 7 positive items (P1 to P7)
●
Negative score: summation of ratings across 7 negative items (N1 to N7)
●
General psychopathology score: summation of ratings across 16 general 
psychopathology items (G1 to G16).
●
Composite score: positive score – negative score
In addition, five factors are calculated as follows:
●
Anergia: summation of N1, N2, G7 and G10
●
Thought Disturbance: summation of P2, P3, P5 and G9
●
Activation: summation of P4, G4 and G5
●
Paranoid / Belligerence: summation of P6, P7 and G8
●
Depression: summation of G1, G2, G3 and G6
PANSS total score, sub-scores, five factors and associated changes from baseline will be  
listed and summarized by treatment and visit. The PANSS individual item ratings will be 
listed.
The Clinical Global Impression of Severity Scale (CGI-S) is a 7-point scale rating the 
severity of a patient’s illness. Continuous descriptive statistics as well as the number and 
percentage in each category will be shown by treatment and week. The relationship between 
MCCB and CGI-S will be examined as follows: 


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●
Correlation between MCCB and CGI-S scores at each measurement (weeks -4, -3, 0, 
6, 12)
●
Correlation between change from baseline to week 12/EoT in MCCB and change 
from baseline to week 12/EoT in CGI-S scores
6.5
Analysis of Safety
6.5.1
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment Emergent Adverse Event (TEAE) is defined as an AE observed after starting 
administration of the study drug and 28 days after the last dose of study drug. A study drug-
related TEAE is defined as any TEAE with at least possible relationship to study treatment as 
assessed by the investigator or with missing assessment of the causal relationship. There are 
two types of adverse events of special interest: TEAEs related to abuse, and TAEAs related 
to drug withdrawal. See appendix 2 for a complete list of the MedDRA preferred AE terms to 
be included in each AE of special interest type.
An overview table will include the following:
●
Number of TEAEs
●
Number and percentage of subjects with TEAEs
●
Number of drug related TEAEs
●
Number and percentage of subjects with causally drug related TEAEs
●
Number of serious TEAEs
●
Number and percentage of subjects with serious TEAEs
●
Number of serious drug related TEAEs
●
Number and percentage of subjects with serious drug related TEAEs
●
Number of TEAEs leading to withdrawal of treatment
●
Number and percentage of subjects with TEAEs leading to withdrawal of treatment, and
●
Number of deaths
●
Number of TEAEs leading to death
●
Number and percentage of subjects with TEAEs leading to death
●
Number of drug related TEAEs leading to death
●
Number and percentage of subjects with drug related TEAEs leading to death
●
Number of TEAEs of special interest related to abuse during the treatment period
●
Number of TEAEs of special interest related to abuse during the follow up period
●
Number of TEAEs of special interest related to drug withdrawal during the treatment 
period
●
Number of TEAEs of special interest related to drug withdrawal during the follow up 
period
The number and percentage of subjects with TEAEs, as classified by SOC, and PT will be 
summarized for each treatment group. Summaries will be provided for the following:
●
TEAEs
●
drug related TEAEs


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●
drug related TEAEs by severity
●
drug related TEAEs leading to death
●
serious TEAEs
●
drug related serious TEAEs
●
TEAEs by severity
●
TEAEs leading to death
●
TEAEs leading to withdrawal of treatment
●
drug related TEAEs leading to withdrawal of treatment
●
Common (>=5% in Any Treatment Group) TEAEs excluding serious adverse events
●
TEAEs of special interest related to abuse during the treatment period
●
TEAEs of special interest related to abuse during the follow up period
●
TEAEs of special interest related to drug withdrawal during the treatment period 
●
TEAEs of special interest related to drug withdrawal during the follow up period
The number of TEAEs and the number and percentage of subjects with TEAEs, as classified 
by SOC and PT will be summarized by severity and by relationship to study drug. In the 
subject count, if a subject has multiple TEAEs with the same SOC or PT, but with differing 
severity or relationship, then the subject will be counted once with the worst severity and 
highest degree of relationship. If any of the severity or relationship values are missing then 
the subject will be counted only once with missing severity or relationship.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized for each treatment group by time interval. For each adverse event in a particular 
interval, a subject will be counted if there is an onset of a treatment-emergent adverse event 
regardless of onset in other intervals.
Time intervals will be categorized according to the following categories:
○
less than 7 days
○
at least 7 days, less than 14 days
○
at least 14 days, less than 28 days
○
at least 28 days, less than 42 days
○
42 days or more
Following data will be presented graphically by treatment group:
●
Overview of TEAEs using dot-and-forest plot
●
TEAEs by SOC using dot-and-forest plot
6.5.2
Clinical Laboratory Evaluation
The baseline value will be the last non-missing value taken on or prior to day of first dose of 
study drug.  Quantitative values evaluated by the central laboratory including hematology, 
biochemistry, and urinalysis will be summarized using mean, standard deviation, minimum, 
maximum and median by treatment group at each analysis visit. Additionally, a within-
subject change will be calculated as the post-baseline measurement minus the baseline 
measurement and summarized in the same way. Each laboratory result will be classified as 
low (L), normal (N), or high (H) at each visit according to the laboratory supplied reference 


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ranges. The number and percentage of subjects below and above reference range will be 
summarized for each treatment group at each visit. 
For hematology and biochemistry, a summary of shifts of reference range changes from 
baseline to worst finding during the treatment period will be presented for each treatment 
group.
The following data will be presented graphically by treatment group: 
●
Change from baseline in laboratory test results using box plot
6.5.2.1 Liver Safety Assessment
The liver safety assessments will be summarized by the following categories below based on 
the measurements from  Alkaline Phosphatase (ALP), Alanine Transaminase (ALT), total 
bilirubin, Aspartate Transaminase (AST) and their combination are defined. These 
parameters will be measured from a central laboratory.
The subject’s highest value during the investigational period (day of first dose and through 
1 day of the last dose of study drug) will be used.
●
ALT > 3xULN, > 5xULN, > 10xULN, >20xULN
●
AST > 3xULN, > 5xULN, > 10xULN, >20xULN
●
ALT or AST > 3xULN, > 5xULN, > 10xULN, >20xULN
●
ALP > 1.5xULN
●
Total Bilirubin >2xULN
●
(ALT or AST > 3xULN) and Total Bilirubin > 2xULN
●
(ALT or AST > 3xULN) and ALP< 2xULN and Total Bilirubin > 2xULN
The last 2 criteria where 2 or more parameters are evaluated will be with the measurements 
on the same day or up to a maximum of 1 day apart.
The denominator for each criterion will be the number of subjects who have at least one 
value during the investigational period. The number and percentage of subjects meeting the 
criteria during the investigational period will be summarized by treatment group. 
6.5.3
Vital Signs
The baseline value will be the last non-missing value taken on or prior to day of first dose of 
study drug.  
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized by treatment group and visit. Additionally, a within-subject change will be 
calculated at each visit as the post-baseline measurement minus the baseline measurement 
and summarized by treatment group and visit. Analysis visits are defined in the Analysis 
Windows section 6.8.1


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6.5.4
Electrocardiograms
ECG variables will be summarized using mean, standard deviation, minimum, maximum and 
median for each treatment group at each treatment visit and time point, including changes 
from baseline.
Number and percent of subjects with normal, not clinically significant abnormal, and 
clinically significant abnormal results as assessed by investigator for the 12 lead ECG will be 
tabulated by treatment group at each treatment visit and time point. 
The QTcF interval will be summarized using frequency tables for each treatment visit and 
time point for values of clinical importance using the range criteria below.
QTcF Interval Criteria Value (msec)
Normal
Borderline
Prolonged
Clinically significant
≤ 450 males; ≤ 470 females
> 450 males; > 470 females
> 480 males; > 490 females
> 500 males; > 500 females
The QTcF interval will also be summarized by the frequencies of subjects with a change 
from baseline of clinical importance using the criteria identified below. These summaries will 
be provided for each treatment visit and time point. 
Variable
Change from Baseline
QTcF Interval (msec)
> 30 
> 60
Differences between treatments in the frequency of changes greater than 30, and greater than 
60, will be evaluated with the Chi-square test at each treatment visit.
6.5.5
Metabolic Parameters
Descriptive statistics will be used to summarize individual indices of metabolic syndrome
results (weight, waist circumference, cholesterol, triglycerides, HDL [the second screening 
visit and day 77], and fasting glucose), and hemoglobin A1c [HbA1c] and changes from 
baseline by treatment group and time point. Differences between treatments in change from 
baseline will be assessed with same MMRM model as the primary efficacy analysis, with the 
exception of HDL which will be analyzed using the same ANCOVA model as the secondary 
analysis. 
6.5.6
Columbia-Suicide Severity Rating Scale
Number and percentage of subjects in each of the categories of C-SSRS, as well as changes 
from baseline, will be summarized by treatment group and visit.
6.5.7
Movement Disorder (Abnormal Involuntary Movement Scale)
Number and percentage of subjects in each rating category will be summarized for each of 
the items of the AIMS by treatment group and visit. A total score will be calculated as the 
sum of items 1 through 7 and descriptive statistics will be used to summarize the total score 


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at each visit as well as changes from baseline. Differences between treatments in the total 
score will be evaluated with the same MMRM model as the primary efficacy analysis.
6.5.8
Simpson Angus Scale
Number and percentage of subjects in each rating category will be summarized for each of
the items of the SAS by treatment group and visit. Total scores will be calculated as the sum 
of each item, and categorized as [<3 (normal); 3-5 (minimal); 6-11 (clinically significant); 
12-17 (severe); ≥18 (extreme)]. Descriptive statistics will be used to summarize the total 
score (sum) and total score (categorical) at each visit as well as changes from baseline.
Differences between treatments in categorical total scores  will be evaluated with a general 
estimating equations (GEE) model. The model will contain terms for treatment group, pooled 
site, visit (the repeated term), and treatment by visit, with the categorical score at baseline 
used as a covariate. Odds ratios comparing each active treatment and control will be assessed
at week 6 and week 12. 
6.5.9
Barnes Akathisia Rating Scale
Number and percentage of subjects in each of the categories of BARS will be summarized by 
treatment group and visit. Differences between treatments in the Global Clinical Assessment 
of Akathisia, scored from 0 (absent) to 5 (severe akathisia), will be evaluated with a general 
estimating equations (GEE) model. The model will contain terms for treatment group, pooled 
site, visit (the repeated term), and treatment by visit, with the Global Clinical Assessment of 
Akathisia score at baseline used as a covariate. Odds ratios comparing each active treatment 
and control will be assessed at week 6 and week 12. 
6.6
Analysis of Pharmacokinetic 
Descriptive statistics (e.g., N, mean, standard deviation, minimum, median, maximum, 
coefficient of variation [CV], geometric mean, and geometric CV) will be provided for 
plasma concentrations of ASP4345 and possible metabolite(s) by time point.
6.6.1
Estimation of Pharmacokinetic Parameters
Population pharmacokinetic model will be developed based on ASP4345 plasma 
concentration data obtained from subjects who have at least 1 pharmacokinetic sample.
Population pharmacokinetics and/or pharmacokinetic/pharmacodynamics analyses will be 
performed by modeling and simulation scientist. All details of the population 
pharmacokinetic analysis will be described in a separate analysis plan and a separate 
population pharmacokinetic modeling report will be written.
6.7
Interim Analysis (and Early Discontinuation of the Clinical Study)
There will be no interim analysis. 


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6.8
Additional Conventions
6.8.1
Analysis Windows
The data summary by visits will be done following the analysis windows specified in the 
tables below:
MCCB, NSA-16, ECG, Weight & Waist, Global Impression of Severity Scale, AIMS, 
BARS, and SAS Analysis Windows:
Analysis Visits
Scheduled Day in Protocol
Analysis Windows (day)
Baseline (Week 0)
Day 1 
Last non-missing value between -28 and 1 
(inclusive)
Week 6
Day 42
35 to 49
Week 12
Day 84
77 to 91
Week 12/ET
Day 84
≥ 2
UPSA-2-ER Analysis Windows:
Analysis Visits
Scheduled Day in Protocol
Analysis Windows (day)
Baseline (Week 0)
Day 1 
Last non-missing value between -28 and 1 
(inclusive)
Week 12
Day 84
77 to 91
Week 12/ET
Day 84
≥ 2
Vital Signs Analysis Windows:
Analysis Visits
Scheduled Day in Protocol
Analysis Windows (day)
Baseline (Week 0)
Day 1 
Last non-missing value between -28 and 1 
(inclusive)
Week 1
Day 7
2 to 10
Week 2
Day 14
11 to 17
Week 3
Day 21
18 to 24
Week 4
Day 28 
25 to 31
Week 5
Day 35
32 to 38
Week 6
Day 42
39 to 45
Week 7
Day 49
46 to 52
Week 8
Day 56
53 to 59
Week 9
Day 63
60 to 66
Week 10
Day 70
67 to 73
Week 11
Day 77
74 to 80
Week 12
Day 84
81 to 112
Week 12/ET
Day 84
≥ 2


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Columbia-Suicide Severity Rating Scale Analysis Windows:
Analysis Visits
Scheduled Day in Protocol
Analysis Windows (day)
Baseline (Week 0)
Day 1 
Last non-missing value between -28 and 1 
(inclusive)
Week 1
Day 7
2 to 10
Week 2
Day 14
11 to 17
Week 3
Day 21
18 to 24
Week 4
Day 28 
25 to 31
Week 5
Day 35
32 to 38
Week 6
Day 42
39 to 45
Week 7
Day 49
46 to 52
Week 8
Day 56
53 to 59
Week 9
Day 63
60 to 66
Week 10
Day 70
67 to 73
Week 11
Day 77
74 to 80
Week 12
Day 84
81 to 112
Week 12/ET
Day 84
≥ 2
Week 14
Day 98
91 to 105
Positive and Negative Symptom Scale Analysis Windows:
Analysis Visits
Scheduled Day in Protocol
Analysis Windows (day)
Baseline (Week 0)
Day 1 
Last non-missing value between -28 and 1 
(inclusive)
Week 2
Day 14
7 to 21
Week 6
Day 42
35 to 49
Week 12
Day 84
77 to 91
Week 12/ET
Day 84
≥ 2
Laboratory (Hematology, Full Biochemistry, and Urinalysis) Analysis Windows:
Analysis Visits
Scheduled Day in Protocol
Analysis Windows (day)
Baseline (Week 0)
Day -1 
Last non-missing value between -28 and 1 
(inclusive)
Week 5
Day 35
28 to 42
Week 11
Day 77
70 to 84
Week 11/ET
Day 77
≥ 2
Week 14
Day 98
91 to 105


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Laboratory (Abbreviated Biochemistry) Analysis Windows:
Analysis Visits
Scheduled Day in Protocol
Analysis Windows (day)
Baseline (Week 0)
Day 1 
Last non-missing value between -28 and 1 
(inclusive)
Week 1
Day 7
2 to 10
Week 2
Day 14
11 to 17
Week 3
Day 21
18 to 24
Week 4
Day 28
25 to 35
Week 6
Day 42
36 to 45
Week 7
Day 49
46 to 52
Week 8
Day 56
53 to 59
Week 9
Day 63
60 to 66
Week 10
Day 70
67 to 73
Week 10/ET
Day 70
≥ 2
If more than one observation exists within the analysis window, the observation closest to the 
scheduled visit day will be selected for that visit. If there are two observations that have the 
same distance from the scheduled day, the value that is after the scheduled day will be 
selected in the analysis. If more than one observation is made on the same day, an average 
value if continuous or the worst value if categorical will be included in the analysis. 
The Follow Up visit will include all data collected beyond 10 days after the last dose of study 
drug.  If there are more than one value, then the value that is closest to day 28 from the last 
dose of study drug will be selected for the analysis.  The same logic will be applied as in 
above for more than one value.
6.8.2
Imputation Rules for Incomplete Dates
In case of missing partial start and stop dates for concomitant medications, the following 
rules will be used:
If the start date is missing or partial:
●
if the month is missing, use January 
●
if the day is missing, use the first day of the month under consideration
●
if the year is missing, use year of the informed consent date 
●
if the entire date is missing, use informed consent date 
If the stop date is missing or partial:
●
if the month is missing, use December 
●
if the day is missing, use the last day of the month under consideration
●
if the year or the entire date is missing, set the stop date to December 31st, 2099
If the imputed start date is after the stop date, then the imputed start date will be 1 day prior 
to the stop date.
For AEs, a missing or incomplete onset date will be imputed according to the following 
conventions. 


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If an onset date is missing or only the year is known, the imputed onset date will be the date 
of first dose of study drug.
If only the year is known for the AE onset date, the imputed onset date will be the latest of 
the following non-missing dates:
●
Date of first dose of study drug 
●
January 1 of the year of AE onset date 
If only the month and year is known for the onset date, set the surrogate onset date to the first 
day of that month and then apply the following rules. 
●
If the month and year of the onset date is prior to the month and year of the first dose of 
study drug, then the surrogate onset date will be the imputed onset date.
●
If the month and year of the onset date is on or after the month and year of the first dose 
of study drug, then the imputed onset date will be the latest of the following non-missing 
dates:
○
Date of first dose of study drug 
○
Surrogate onset date
If the imputed onset date is after the adverse event end date, the imputed onset date will be 
the same as the adverse event end date.
7
REVISION AND RATIONALE
8
REFERENCES
Calulating and reporting effect sizes to facitiltate cumulative science: a practical primer for t-tests and 
ANOVAs. Lakens, Daniel,  Frontiers in Psychology November 2013 Vol 4 Article 863.


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9
APPENDICES
9.1
Appendix 1: Author and Approver Signatures
Prepared by:
Date:
Date (DD Mmm YYYY)
Approved by:
Date:
Date (DD Mmm YYYY)
Approved by:
Date:
 
Date (DD Mmm YYYY)
PPD
PPD
PPD


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9.2
Appendix 2: Adverse Events of Special Interest (Preferred Terms; 
MedDRA 18.0)
9.2.1
Adverse Events of Interest Related to Abuse requiring narratives 
Euphoria-related Terms
Preferred term
Lowest level term
Euphoric mood
Feeling high
Elevated mood
Feeling abnormal
Feeling drunk
Feeling of relaxation
Thinking abnormal
Hallucination, mixed
Inappropriate affect
Dizziness and giddiness
Dissociative/Psychotic Terms
Preferred term
Lowest level term
Psychosis acute
Psychosis
Aggression
Confusion and disorientation
Terms Indicative of Impaired Attention, Cognition, Mood, and Psychomotor Events
Preferred term
Lowest level term
Somnolence
Psychomotor hyperactivity/decreased activity
Hyperactivity/hypoactivity
Mood disorders and disturbances
Mental impairment disorders
Drug tolerance, habituation, drug withdrawal 
syndrome, substance-related disorders
Inappropriate Affect
Preferred term
Lowest level term
Inappropriate affect
Elation inappropriate
Exhilaration inappropriate
Inappropriate mood elevation
Product tampering
Medication tampering


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9.2.2
Drug Abuse – Related Adverse Events 
System Organ 
Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lower Level Term
Psychiatric disorders
Mood 
disorders and 
disturbances 
NEC
Emotional 
and mood 
disturbances 
NEC
Euphoric 
Mood
Euphoria
Euphoric
Euphoric mood
Exaggerated well-
being
Feeling high
Felt high
High
High feeling
Laughter
Mood altered
Affect alteration
Affect altered
Altered mood
Bad mood
Mood alteration 
NOS
Mood altered
Mood change
Elevated 
mood
Elevated mood
Mood elevated
Affect 
alterations
Inappropriate 
affect
Elation 
inappropriate
Exhilaration 
inappropriate
Exhiliration 
inappropriate
Feeling happy 
inappropriately
Inappropriate affect
Inappropriate crying
Inappropriate 
elation
Inappropriate 
exhilaration
Inappropriate 
laughter
Inappropriate mood 
elevation
Mood elevation 
inappropriate
Disturbances 
in thinking 
Perception 
disturbances
Hallucination
Drug-induced 
hallucinosis


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System Organ 
Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lower Level Term
and 
perception
Hallucinating
Hallucination
Hallucination NOS
Hallucinations
Hallucinations 
aggravated
Kinesthetic 
hallucination
Organic hallucinosis 
syndrome
Pseudohallucination
Sensory 
hallucinations
Stump hallucination
Hallucination, 
auditory
Auditory 
hallucinations
Hallucination 
auditory
Hallucination, 
auditory
Verbal 
hallucinations
Hallucination, 
visual
Hallucination visual
Hallucination with 
color
Hallucination with 
colour
Hallucination, visual
Visual 
hallucinations
General disorders 
and administration 
site conditions
General 
system 
disorders 
NEC
Feelings and 
sensations 
NEC
Feeling drunk
Drunk-like effect
Drunkenness feeling 
of
Feeling drunk
Feeling 
abnormal
Cotton wool in head
Feeling abnormal
Feeling bad
Feeling dazed
Feeling floating
Feeling lifeless
Feeling miserable
Feeling stoned
Feeling strange


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System Organ 
Class
Higher Level 
GT
Higher 
Level Term
Preferred 
term
Lower Level Term
Feeling weightless
Feels awful
Feels bad
Feels poorly
Felt like a zombie
Floating feeling
Foggy feeling head
Funny episode
Fuzzy
Fuzzy head
Muzzy head
Neck strange feeling 
of
Soft feeling
Spaced out
Thick head
Unstable feeling 
Weird feeling


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9.2.3
Drug Withdrawal – Related Adverse Events 
Higher Level GT
Higher Level Term
Preferred Term
Psychiatric disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Agitation
Nervous system 
disorders
Neurological 
disorders NEC
Neurological signs 
and symptoms NEC
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Anhedonia
Psychiatric disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Anxiety
Musculoskeletal and 
connective tissue 
disorders
Muscle disorders
Muscle related signs 
and symptoms NEC
Chills
Musculoskeletal and 
connective tissue 
disorders
Muscle disorders
Feelings and 
sensations NEC
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Depressed mood
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Depressive disorders
Depression
Gastrointestinal 
disorders
Gastrointestinal 
motility and 
defaecation 
conditions
Diarrhoea (excl 
infective)
Diarrhoea
Psychiatric disorders
Mood disorders and 
disturbances
Emotional and mood 
disturbances NEC
Dysphoria
Nervous system 
disorders
Sleep disturbances 
(incl subtypes)
Sleep disturbances 
NEC
Dyssomnia
Psychiatric disorders
Sleep disorders and 
disturbances 
Dyssomnias
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Depressive disorders
Dysthymic disorder
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Feeling of despair
Nervous system 
disorders
Headaches
Headaches NEC
Headache
Skin and 
subcutaneous tissue 
disorders 
Skin appendage 
conditions
Apocrine and eccrine 
gland disorders
Hyperhidrosis
General disorders 
and administration 
General system 
disorders NEC
General signs and 
symptoms NEC


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Higher Level GT
Higher Level Term
Preferred Term
site conditions
Psychiatric disorders
Sleep disorders and 
disturbances 
Disturbances in 
initiating and 
maintaining sleep
Insomnia
Nervous system 
disorders
Sleep disturbances
Disturbances in 
initiating and 
maintaining sleep
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Morose
Gastrointestinal 
disorders
Gastrointestinal signs 
and symptoms
Nausea and vomiting 
symptoms
Nausea
Psychiatric disorders
Depressed mood 
disorders and 
disturbances
Mood alterations 
with depressive 
symptoms
Negative thoughts
Psychiatric disorders
Anxiety disorders 
and symptoms
Anxiety symptoms
Nervousness
Psychiatric disorders
Anxiety disorders 
and symptoms
Obsessive-
compulsive disorders 
and symptoms
Obsessive thoughts
General disorders 
and administration 
site conditions
General system 
disorders NEC
Pain and discomfort 
NEC
Pain
Nervous system 
disorders
Sleep disturbances 
(incl subtypes)
Sleep disturbances 
NEC
Poor quality sleep
Psychiatric disorders
Sleep disorders and 
disturbances 
Dyssomnias
Cardiac disorders
Cardiac disorder 
signs and symptoms
Cardiac signs and 
symptoms NEC
Syncope
Vascular disorders
Decreased and 
nonspecific blood 
pressure disorders 
and shock
Circulatory collapse 
and shock
Nervous system 
disorders
Neurological 
disorders NEC
Disturbances in 
consciousness NEC
Psychiatric disorders
Sleep disorders and 
disturbances 
Disturbances in 
initiating and 
maintaining sleep
Terminal insomnia 
(lower level term of 
interest:  early 
morning awakening)
Nervous system 
disorders
Sleep disturbances
Disturbances in 
initiating and 
maintaining sleep
Nervous system 
disorders
Movement disorders 
(incl parkinsonism)
Tremor (excl 
congenital)
Tremor
Gastrointestinal 
disorders
Gastrointestinal signs 
and symptoms
Nausea and vomiting 
symptoms
Vomiting


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