Clinical trial NCT02287584
Conditions: Schizophrenia
Sponsor: Sumitomo Pharma Co., Ltd.
Start date: 2014-12-01; Completion date: 2018-12-01
Enrollment: 580 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the efficacy of DSP-5423P compared with placebo in patients with schizophrenia.

Detailed description:

Arms: arm 1: Percutaneous DSP-5423P Placebo was applied once daily for 6 weeks during the double-blinded treatment phase. Subjects who completed the double-blind treatment phase were able to entere the open-label treatment phase. The study drug was applied to the back, chest, or abdomen. arm 2: Percutaneous DSP-5423P 40mg was applied once daily for 6 weeks during the double-blinded treatment phase. Subjects who completed the double-blind treatment phase were able to entere the open-label treatment phase. The study drug was applied to the back, chest, or abdomen. arm 3: Percutaneous DSP-5423P 80mg was applied once daily for 6 weeks during the double-blinded treatment phase. Subjects who completed the double-blind treatment phase were able to entere the open-label treatment phase. The study drug was applied to the back, chest, or abdomen. arm 4: Percutaneous Subjects received DSP-5423P Placebo once daily for 6 weeks in the double-blind treatment phase. In the open-label treatment phase, DSP-5423P was applied as flexible dose (40, 60, or 80 mg) once daily for 28 weeks (outside Japan) or 52 weeks (in Japan). The study drug was applied to the back, chest, or abdomen. arm 5: Percutaneous Subjects received DSP-5423P 40mg or 80mg once daily for 6 weeks in the double-blind treatment phase. In the open-label treatment phase, DSP-5423P was applied as flexible dose (40, 60, or 80 mg) once daily for 28 weeks (outside Japan) or 52 weeks (in Japan). The study drug was applied to the back, chest, or abdomen.
Interventions: intervention 1: DSP-5423P Placebo intervention 2: DSP-5423P 40mg intervention 3: DSP-5423P 80mg intervention 4: DSP-5423P Placebo-to-Flex intervention 5: DSP-5423P Active-to-Flex
Intervention descriptions: intervention 1: DSP-5423P Placebo was applied to the subject's back, chest, or abdomen once daily intervention 2: DSP-5423P 40mg was applied to the subject's back, chest, or abdomen once daily intervention 3: DSP-5423P 80mg was applied to the subject's back, chest, or abdomen once daily intervention 4: DSP-5423P Placebo:

DSP-5423P Placebo was applied to the subject's back, chest, or abdomen once daily

DSP-5423P Flex:

DSP-5423P 20mg, 60mg or 80mg was applied to the subject's back, chest, or abdomen once daily intervention 5: DSP-5423P Active:

DSP-5423P 40mg or 80mg was applied to the subject's back, chest, or abdomen once daily

DSP-5423P Flex:

DSP-5423P 20mg, 60mg or 80mg was applied to the subject's back, chest, or abdomen once daily

Protocol documents:
Prot_000.pdf: 
Protocol D4904020, Version 2.04 
DSP-5423P 
Confidential and Proprietary 
 
8 May 2018  
 
 
 
 
 
DSP-5423P 
Blonanserin 
D4904020 
 
 
Confirmatory Study of DSP-5423P in Patients with Schizophrenia 
<Phase 3> 
 
 
 
Version 2.04 
 
8 May 2018 
 
 
 
SUMITOMO DAINIPPON PHARMA CO., LTD. 
1-13-1, Kyobashi, Chuo-ku, Tokyo, Japan 
 


Protocol D4904020, Version 2.04 
DSP-5423P 
Confidential and Proprietary 
 
8 May 2018  
RESTRICTED DISTRIBUTION OF PROTOCOLS 
 
This protocol and the data gathered during the conduct of this protocol contain 
information that is proprietary to Sumitomo Dainippon Pharma Co., Ltd..  This 
information is being provided to you for the purpose of conducting a clinical study for 
Sumitomo Dainippon Pharma Co., Ltd..  You may disclose the contents of this 
protocol to the study personnel under your supervision and to your Institutional 
Review Board or Independent Ethics Committee for the above purpose.  You may not 
disclose the contents of this protocol to any other parties, unless such disclosure is 
required by government regulations or laws, without the prior written permission of 
Sumitomo Dainippon Pharma Co., Ltd.. 
 
Any supplemental information (eg, a protocol amendment) that may be added to this 
document is also proprietary to Sumitomo Dainippon Pharma Co., Ltd., and should be 
handled consistently with that stated above. 
 




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1. SYNOPSIS 
Name of Sponsor: 
Sumitomo Dainippon Pharma. Co., Ltd. 
Name of Investigational Product:
DSP-5423P (transdermal patches) 
Name of Active Ingredient:  
Blonanserin 
Title of Study:  
Confirmatory Study of DSP-5423P in Patients with Schizophrenia <Phase 3> 
Proposed Indication: 
Schizophrenia 
Phase of Development:  
Phase 3 
Study period (planned): 
August 2014 ~ December 2018 
Study Objectives:  
Primary:  
The primary objective of the study is to evaluate the efficacy of DSP-5423P (40 and 80 
mg/day) compared with placebo in patients with schizophrenia by assessing the mean 
change in Positive and Negative Syndrome Scale (PANSS) total score from baseline at 
Week 6. 
 
Secondary:  
The secondary objectives are to evaluate the safety of DSP-5423P compared with 
placebo for 6-week treatment, the long-term safety and efficacy of DSP-5423P, and the 
pharmacokinetics of DSP-5423P in patients with schizophrenia. 


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Study Design: 
Double-blind treatment phase 
Multicenter, randomized, double-blind, placebo-controlled, parallel-group 
Open-label treatment phase 
Multicenter, open-label, flexible dose 
 
The unblinded interim analysis for futility will be performed after 50% of target number 
of subjects complete or prematurely discontinue the double-blind treatment phase.   
 
Study schematic 
 
 
 
 
 
Placebo group 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSP-5423P 40 mg group 
outside
DSP-5423P 
 40～80 mg/day 
28 weeks 
 
 
 
 
Japan
 
 
 
 
Placebo 
 
DSP-5423P 40 mg/ day
 
 
 
Follow-up 
observation 
 
  
 
 
 
 
 
 
 
  
 
 
DSP-5423P 80 mg group 
Japan
DSP-5423P 
 40～80 mg/day 
52 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
DSP-5423P 80 mg/day
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
Washout phase 
(single-blind)
Double-blind treatment phase
（6 weeks） 
Open-label treatment phase 
Follow-up 
phase 
 
 
 
1 week 
(At least 3 
days) 
2 weeks 
4 weeks 
28 weeks (outside Japan) 
 or 52 weeks (in Japan) 
1 to 2 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient mandatory 
Inpatient or  
outpatient 
Inpatient or outpatient 
 
 
 
Number of Subjects (planned): 
501 subjects will be randomized to 3 treatment groups (167 subjects in each treatment 
group) in double-blind treatment phase.  Only subjects who have completed the 
6-week double-blind treatment phase without any safety concerns can enter the 
open-label treatment phase. 
Diagnosis: 
Schizophrenia 
Informed Consent 
Screening 


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Criteria for Subject Inclusion at screening:  
＜The procedure in Japan is described in the Japan Appendix.> 
Patients who meet all the following criteria at screening will be included in the study: 
1. 
Patients who have schizophrenia diagnosed by Diagnostic and Statistical Manual of 
Mental Disorders, fifth edition (DSM-5), diagnostic criteria 
2. 
Patients who have psychiatric symptoms (eg, aggravated delusions) with 
schizophrenia showing exacerbation within 2 months (60 days) before screening 
3. 
Patients with a PANSS score of 4 (moderate) or higher for 2 or more of the 
following 5 items: delusions (P1), conceptual disorganization (P2), hallucinations 
(P3), suspiciousness (P6), and unusual thought content (G9) 
4. 
Patients with a total PANSS score of 80 or higher 
5. 
Patients who can be hospitalized from screening until the scheduled date of Visit 4 
6. 
Patients who are aged 18 years or older at informed consent 
7. 
Patients who are fully informed of and understand the objectives, procedures, and 
possible benefits and risks of the study and who voluntarily provide written consent 
to participate in the study.  If the patient is a minor at informed consent, written 
consent will be obtained from a legally acceptable representativeNote in addition to 
that obtained from the patient. 
Note: A legally acceptable representative is defined as a person within the second degree of kinship, in 
principle, who can act in the patient’s best interest in the context of daily lifestyle and the existing 
mental relationship between the two parties. 
 
8. 
Female patients, who are premenopausal and of childbearing potential, with 
negative pregnancy test (urine) results at screening  
9. 
Patients who agree to practice appropriate contraception, when the patients or their 
partners are of childbearing potential 
 
Criteria for Subject Exclusion at screening: 
Patients who meet any of the following criteria will be excluded from the study. 
1. 
Patients in a coma 
2. 
Patients under the strong influence of central nervous system depressants such as 
barbituric acid derivatives 
3. 
Patients receiving treatment with adrenaline, azole antifungals (excluding drugs for 
external use), or human immunodeficiency virus (HIV) protease inhibitors 
4. 
Patients with a history of or current neuroleptic malignant syndrome, tardive 
dyskinesia, or water intoxication 
5. 
Patients with Parkinson’s disease 
6. 
Patients with active suicidal ideation or those with a suicide attempt history who 


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are considered ineligible for the study by the Investigator 
7. 
Patients with HbA1c (NGSP) of 8.4% or higher 
8. 
Patients with physical exhaustion accompanied by conditions such as dehydration 
and malnutrition 
9. 
Patients with a history of or complication(s) involving serious cardiovascular, 
hepatic, renal, organic brain, hematologic, endocrine, convulsive disease or other 
conditions, and who are considered ineligible for the study by the Investigator 
10. Patients with skin injuries, skin diseases or tattoos that preclude the application of 
the study drug to the back, chest, or abdomen  
11. Patients with a history of drug abuse, drug dependency, alcohol abuse, or alcohol 
dependency within 6 months (180 days) before screening  
12. Patients who received any depot preparation (sustained-release formulation) of an 
antipsychotics within 3 months (90 days) before screening 
13. Patients who received clozapine within 4 months (120 days) before screening 
14. Patients who are considered resistant to treatment for psychiatric symptoms by the 
Investigator. Treatment resistance is defined as failure to respond to 3 or more 
antipsychotics within 1 year (365 days) before screening 
15. Patients who previously received blonanserin 
16. Patients who received monoamine oxidase (MAO) inhibitors or fluoxetine within 1 
month (30 days) before screening 
17. Patients who received electroconvulsive therapy within 6 months (180 days) before 
screening 
18. Patients who are pregnant, or are nursing mothers 
19. Patients with a history or complication(s) of hypersensitivity to 2 or more drugs 
(patients with a history or complication(s) of drug-induced allergic reactions such 
as anaphylaxis, rash, and urticaria) 
20. Patients with a history or complication(s) of malignant tumor within 5 years before 
screening 
21. Patients who are currently infected with HIV 
22. Patients who received other investigational products or post-marketing clinical 
study drugs within 3 months (90 days) before screening or who have enrolled in 
but have not completed another clinical or post-marketing study before screening 
23. Patients who are otherwise considered ineligible for the study by the Investigator  
 


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Criteria for Subject Inclusion before randomization: 
Subjects who meet all the following criteria before randomization ( at Visit 2) will be 
randomized. 
1. 
Subjects with a PANSS score of 4 (moderate) or higher for 2 or more of the 
following 5 items: delusions (P1), conceptual disorganization (P2), hallucinations 
(P3), suspiciousness (P6), and unusual thought content (G9) 
2. 
Subjects with a PANSS total score of 80 or higher 
 
Criteria for Subject Exclusion before randomization: 
Subjects who meet any of the following criteria will be excluded from the study before 
randomization. 
1. 
Subjects with a 20% or more reduction in the PANSS total score between screening 
and randomization (at Visit 2) 
 
PANSS total score at screening － PANSS total score at randomization 
PANSS total score at screening － 30 
× 100 ≥ 20% 
 
2. 
Subjects who are otherwise considered ineligible for the study by the Investigator 
 
Criteria for Subject Inclusion before the open-label treatment phase: 
Subjects who meet the following criterion will enter the open-label treatment phase.   
1. 
Subjects who have completed the 6-week study treatment and all scheduled 
assessments at Visit 6 in the double-blind treatment phase, and who are considered 
eligible by the Investigator with no safety concerns 
 
Criteria for Subject Exclusion before the open-label treatment phase: 
Subjects who meet any of the following criteria will be excluded from the study before 
the open-label treatment phase.   
1. 
Subjects who are planning to become pregnant at any time before the end of the 
follow-up phase 
2. 
Subjects who are otherwise considered ineligible for the study by the Investigator 
 




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Study Endpoints:  
Primary Endpoint: 
The primary endpoint is the change in PANSS total score from baseline at Week 6. 
 
Secondary Endpoints:  
- Change in PANSS subscale scores from baseline at Week 6 
- Change in PANSS five-factor model scores from baseline at Week 6 
- Change in Clinical Global Impressions - Severity of Illness (CGI-S) score from 
baseline at Week 6 
- Change in PANSS total score from the last evaluation before the initial application of 
DSP-5423P at each visit 
- Change in PANSS subscales from the last evaluation before the initial application of 
DSP-5423P at each visit 
- Change in PANSS five-factor models from the last evaluation before the initial 
application of DSP-5423P at each visit 
- Proportion of subjects who achieve a response, defined as 20% or greater 
improvement from baseline in PANSS total score at Week 6 
- Change in CGI-S score from the last evaluation before the initial application of 
DSP-5423P at each visit 
- Time to treatment discontinuation from the initial application in the open-label 
treatment phase 
 
Safety Endpoints: 
- Adverse events (AEs) and adverse drug reactions (ADRs) 
- Extrapyramidal AEs and ADRs 
- Skin-related AEs and ADRs at the application site 
- Assessment of skin irritation reaction at the application site 
- Change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) total score 
(excluding overall severity) from baseline at Week 6 
- Change in individual DIEPSS scores from baseline at Week 6 
- Change in DIEPSS total score (excluding overall severity) from the last evaluation 
before the initial application of DSP-5423P at each visit 
- Change in individual DIEPSS scores (excluding overall severity) from the last 
evaluation before the initial application of DSP-5423P at each visit 
- Serum prolactin concentration 
- Electrocardiogram (ECG) parameters (QTc)  
- Concomitant use of antiparkinson drugs 


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- Assessment of suicide using Columbia-Suicide Severity Rating Scale (C-SSRS) 
- Laboratory test values, vital signs, and body weight 
Pharmacokinetics Endpoints: 
- Plasma concentrations of blonanserin  
- Plasma concentrations of metabolite M-1 (N-de-ethylated metabolite) 
Statistical Methods:  
Primary analysis: 
The primary analysis will be conducted on the modified intention-to-treat (mITT) 
population, which includes all subjects who are randomized, apply the study drug at 
least once in the double-blind treatment phase, and have a baseline and at least one 
post-baseline PANSS total score rated in the double-blind treatment phase.  
 
The primary efficacy variable for comparing the DSP-5423P 40 and 80 mg/day versus 
placebo is the change in PANSS total score from baseline at Week 6.  A mixed model 
for repeated measures (MMRM) will be used for the primary efficacy analysis.  The 
MMRM model will include treatment, visit, and pooled study center as categorical 
factor, baseline PANSS total score as covariate, and treatment-by-visit interaction.  An 
unstructured covariance matrix will be used for the within-subject correlation. 
Missing observations will not be imputed for this analysis.  
 
The Hochberg procedure will be used to control the overall type I error at 5% by taking 
into account multiple dose regimens for the primary efficacy analysis. 
 
Interim analysis: 
An unblinded interim analysis for futility will be performed after 50% of target number 
of subjects complete or prematurely discontinue the double-blind treatment phase.
The interim analysis will be performed on the change in PANSS total score from 
baseline in the mITT population.  If the conditional power based on the treatment 
differences in PANSS total score is less than the futility criteria of 8%, the study may be 
terminated early. Otherwise, the study will be continued. 
 
Sample Size: 
Effect size of DSP-5423P is estimated 0.45 for both DSP-5423P 40 and 80 mg/day 
versus placebo (See Section 15.1 Sample Size Determination).  A sample size of 133 
per group was estimated to yield a complete power (probability of rejecting both two 
null hypotheses) of 89% with a two-sided alpha of 5% significance level using the 
Hochberg procedure for multiplicity adjustment and taking an interim analysis for 


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futility into consideration.  The sample size was calculated by a Monte-Carlo 
simulation using SAS software (SAS Instititute).  Considering that there is possibility 
of patients discontinuing before completion of the double-blind treatment phase, the 
total sample size will need to be 501 patients or 167 patients per treatment group. 
 






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a Open-Day 1 is defined as the day of the initial application of the study drug in the open-label treatment phase. 
b All subjects can be inpatients or outpatients. 
c At Visit 109 and at the discontinuation visit, blood samples will be collected under fasting conditions (at least 10 hours after the last meal).  At other visits, blood 
samples should be collected under fasting conditions (at least 10 hours after the last meal) whenever possible.   
d To be performed only in female subjects who are premenopausal and of childbearing potential. 
e Must be performed before the beginning of post-treatment with antipsychotics excluding the study drug. 
f 
Discontinuation is defined as the last date of study drug application.  The subject will undergo the discontinuation assessments within 5 days since the last date of 
study drug application.  
g Completion of treatment or discontinuation is defined as the last date of study drug application.  The subject will undergo the follow-up assessments in 6 - 17 
days since the last date of study drug application. 
 




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a Open-Day 1 is defined as the day of the initial application of the study drug in the open-label treatment phase. 
b All subjects can be inpatients or outpatients 
c At Visit 112 and at the discontinuation visit, blood samples will be collected under fasting conditions (at least 10 hours after the last meal).  At other visits, Blood 
samples should be collected under fasting conditions (at least 10 hours after the last meal) whenever possible.   
d To be performed only in female subjects who are premenopausal and of childbearing potential. 
e Must be performed before the beginning of post-treatment with antipsychotics excluding the study drug. 
f 
Discontinuation is defined as the last date of study drug application.  The subject will undergo the discontinuation assessments within 5 days since the last date of 
study drug application.  
g Completion of treatment or discontinuation is defined as the last date of study drug application.  The subject will undergo the follow-up assessments in 6 - 17 
days since the last date of study drug application. 
 


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2. TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. SYNOPSIS ................................................................................................................. 1 
2. TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .............. 15 
3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................ 20 
4. INTRODUCTION .................................................................................................... 22 
4.1 
Background ....................................................................................................... 22 
4.2 
Study Conduct Rationale ................................................................................... 23 
5. STUDY OBJECTIVES............................................................................................. 24 
5.1 
Primary Objective.............................................................................................. 24 
5.2 
Secondary Objectives ........................................................................................ 24 
6. STUDY ENDPOINTS .............................................................................................. 24 
6.1 
Primary Endpoint .............................................................................................. 24 
6.2 
Secondary Endpoints ......................................................................................... 24 
6.3 
Safety Endpoints................................................................................................ 25 
6.4 
Pharmacokinetics Endpoints ............................................................................. 25 
7. INVESTIGATIONAL PLAN ................................................................................... 26 
7.1 
Overall Study Design ........................................................................................ 26 
7.2 
Rationale ............................................................................................................ 27 
7.2.1 
Rationale for the Study Design .................................................................. 27 
7.2.2 
Rationale for the Dosages .......................................................................... 27 
7.2.3 
Rationale for the Endpoints ....................................................................... 28 
7.2.4 
Rationale for change of the target number of subjects and the Interim 
Analysis ..................................................................................................... 28 
7.3 
Prevention of Missing Data ............................................................................... 29 
7.4 
Planned Study Period ........................................................................................ 29 
8. SELECTION OF SUBJECTS .................................................................................. 29 
8.1 
Criteria at screening........................................................................................... 29 
8.1.1 
Inclusion Criteria at screening ................................................................... 29 
8.1.2 
Exclusion Criteria at screening .................................................................. 30 
8.2 
Randomization Criteria ..................................................................................... 31 
8.2.1 
Inclusion Criteria before randomization .................................................... 31 
8.2.2 
Exclusion Criteria before randomization ................................................... 32 


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8.3 
Criteria before the open-label treatment phase.................................................. 32 
8.3.1 
Inclusion Criteria before the open-label treatment phase .......................... 32 
8.3.2 
Exclusion Criteria before the open-label treatment phase ......................... 32 
9. STUDY DRUG MATERIALS AND MANAGEMENT .......................................... 32 
9.1 
Description of Study Drug ................................................................................ 32 
9.2 
Study Drug Packaging and Labeling ................................................................. 33 
9.2.1 
Package Description .................................................................................. 33 
9.2.2 
Labeling Description .................................................................................. 33 
9.3 
Study Drug Storage ........................................................................................... 33 
9.4 
Dispensing of Study Drug ................................................................................. 34 
9.5 
Study Drug Accountability ................................................................................ 34 
9.6 
Study Drug Handling and Disposal ................................................................... 34 
10. TREATMENT OF SUBJECTS ................................................................................ 35 
10.1 Study Medication .............................................................................................. 35 
10.1.1 
The Washout Phase .................................................................................... 36 
10.1.2 
The Double-blind Treatment Phase ........................................................... 36 
10.1.3 
The Open-label Treatment Phase ............................................................... 36 
10.2 Dose Adjustment Criteria in the open-label treatment phase ............................ 37 
10.3 Concomitant Medications and Therapies .......................................................... 38 
10.3.1 
Antipsychotics ........................................................................................... 39 
10.3.2 
Antimanic and Antiepileptic drugs ............................................................ 40 
10.3.3 
Other Prohibited Medications .................................................................... 40 
10.3.4 
Prohibited Therapies .................................................................................. 41 
10.3.5 
Restricted Medications .............................................................................. 41 
10.3.6 
Medications for complications ................................................................... 44 
10.4 Inpatient or Outpatient....................................................................................... 44 
10.5 Contraception Requirements ............................................................................. 45 
10.6 Treatment Compliance ...................................................................................... 45 
10.7 Treatment Assignment and Blinding ................................................................. 45 
10.7.1 
Treatment Assignment ............................................................................... 45 
10.7.2 
Blinding ..................................................................................................... 46 
10.8 Emergency Unblinding Procedures ................................................................... 46 
11. STUDY ASSESSMENTS......................................................................................... 47 
11.1 Demographics and Baseline Characteristics ..................................................... 47 
11.2 Efficacy Assessments ........................................................................................ 47 
11.2.1 
Positive and Negative Syndrome Scale (PANSS） ................................... 48 


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11.2.2 
Clinical Global Impressions scale-Severity of illness (CGI-S) ................. 48 
11.3 Safety Assessments............................................................................................ 48 
11.3.1 
Adverse Events .......................................................................................... 48 
11.3.2 
Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) ..................... 48 
11.3.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................. 49 
11.3.4 
Skin Irritation Assessment ......................................................................... 49 
11.3.5 
Clinical Laboratory Tests ........................................................................... 49 
11.3.6 
Vital Signs and Body Weight ..................................................................... 50 
11.3.7 
12-lead ECGs ............................................................................................. 51 
11.4 Pharmacokinetic Assessments ........................................................................... 51 
12. SAFETY REPORTING ............................................................................................ 52 
12.1 Definitions ......................................................................................................... 52 
12.1.1 
Adverse Events .......................................................................................... 52 
12.1.2 
Serious Adverse Events ............................................................................. 53 
12.2 Objective Findings ............................................................................................ 54 
12.3 Collection and Recording Adverse Events ........................................................ 54 
12.4 Immediately Reportable Events ........................................................................ 56 
12.4.1 
Serious Adverse Event ............................................................................... 56 
12.4.2 
Pregnancy ................................................................................................... 58 
13. TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ......................................................................................................... 59 
13.1 Criteria for Subject Termination ........................................................................ 59 
13.2 Clinical Assessments after Study Drug Discontinuation ................................... 59 
13.3 Early Termination of the Study for Futility ....................................................... 60 
14. STUDY TERMINATION ......................................................................................... 60 
15. STATISTICS ............................................................................................................. 61 
15.1 Sample Size Determination ............................................................................... 61 
15.2 Analysis Populations ......................................................................................... 63 
15.2.1 
Modified intention-to-treat population (mITT population) ....................... 63 
15.2.2 
Per-protocol population (PP population) ................................................... 63 
15.2.3 
Open-label population ................................................................................ 63 
15.2.4 
Safety population ....................................................................................... 64 
15.2.5 
DSP-5423P dosed population .................................................................... 64 
15.2.6 
Pharmacokinetic analysis population (PK population) .............................. 64 
15.3 Data Analysis ..................................................................................................... 64 
15.3.1 
Subject Disposition .................................................................................... 64 


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15.3.2 
Drug Exposure and Compliance ................................................................ 64 
15.3.3 
Important Protocol Deviations ................................................................... 65 
15.3.4 
Demographic and Baseline Characteristics ............................................... 65 
15.3.5 
Efficacy Analysis ....................................................................................... 65 
15.3.6 
Safety Analysis .......................................................................................... 67 
15.3.7 
Pharmacokinetic Analysis .......................................................................... 69 
15.3.8 
Handling of data ......................................................................................... 69 
15.4 Interim Analysis ................................................................................................ 70 
15.4.1 
Outlined Interim Analysis .......................................................................... 71 
15.4.2 
Independent Biostatistician and Steering Committee ................................ 71 
15.4.3 
Confidentiality of Interim Data and Analyses ........................................... 72 
16. PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ..................... 72 
16.1 Data Collection/Electronic Data Capture (EDC) .............................................. 72 
16.2 Study Monitoring .............................................................................................. 72 
16.3 Audits ................................................................................................................ 73 
16.4 Study Documentation ........................................................................................ 73 
16.5 Clinical Laboratory Certification and Normal Values ....................................... 73 
17. ETHICAL AND REGULATORY OBLIGATIONS ................................................. 73 
17.1 Study Conduct ................................................................................................... 73 
17.2 Institutional Review Board ................................................................................ 74 
17.3 Informed Consent .............................................................................................. 74 
17.4 Subject Privacy .................................................................................................. 75 
17.5 Protocol Amendments and Emergency Deviations ........................................... 76 
17.6 Records Retention ............................................................................................. 76 
17.7 Inspection of Records ........................................................................................ 76 
17.8 Publication Policy.............................................................................................. 76 
17.9 Compensation .................................................................................................... 77 
18. REFERENCES ......................................................................................................... 78 
19. Appendix List ........................................................................................................... 80 
 


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LIST OF TABLES 
Table 1  Emergency Contact Information (outside Japan) ........................................... 3 
Table 2 Emergency Contact Information (in Japan) ...................................................... 3 
Table 3  Schedule of Assessments (Double-blind treatment phase)* ........................ 10 
Table 4  Schedule of Assessments for outside Japan (Open-label treatment 
phase) .......................................................................................................... 11 
Table 5  Schedule of Assessments for Japan (Open-label treatment phase) .............. 13 
Table 6  List of Abbreviations .................................................................................... 20 
Table 7  The study drugs ............................................................................................ 33 
Table 8  The study drug patches to be applied in the double-blind treatment 
phase............................................................................................................ 36 
Table 9  The study drug patches to be applied  in the open-label treatment 
phase............................................................................................................ 37 
Table 10  Restrictions on concomitant medications/therapies ................................... 39 
Table 11  Permitted concomitant antiparkinson drugs ............................................... 42 
Table 12  Permitted concomitant psychotropic drug ................................................. 42 
Table 13  Permitted concomitant hypnotic drugs ....................................................... 43 
Table 14  Scoring of Skin Reactionsref.15 .................................................................... 49 
Table 15  Contents of laboratory variables ................................................................ 50 
Table 16  Change in PANSS total score ..................................................................... 62 
 
LIST OF FIGURES 
Figure 1  Study Schematic ......................................................................................... 27 
 






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4. INTRODUCTION 
4.1 
Background 
Schizophrenia generally appears in puberty or adolescence and is characterized by 
various psychiatric symptoms including positive symptoms (eg, hallucination, 
delusion) and negative symptoms (eg, blunted affect, disorganized thinking, lack of 
motivation).  Cognitive symptoms (eg, reduced ability to pursue goals or process 
information) also occur in some cases.  Schizophrenia is a chronic psychiatric disease 
with repeated relapses which can be triggered by drug refusal and self-medicating.   
 
Therefore, treatment adherence is of interest as a means of symptom control in order to 
involve patients in decision making processes regarding their therapeutic strategy and 
pursue aggressive treatment for schizophrenia.  Adherence is, however, one of the 
major challenges in for schizophrenia treatment.  Maintaining adherence to treatment 
is often difficult for patients with schizophreniaref.1.  Relapse of schizophrenia or 
re-hospitalization are mainly caused by poor adherence.  Among patients with 
schizophrenia, 35% of hospitalized patients are deemed non-adherent to medication 
regimensref.2.  Shared decision making (SDM) among physicians and patients 
regarding their therapeutic strategy is essential for improving adherence.  A useful 
way of implementing SDM may be to provide multiple therapeutic options to patients 
with schizophrenia and then to make a mutual decision, which takes the patient’s 
opinion into accountref.3,4.  
 
As factors affecting adherence, environmental, drug and patient factors have all been 
discussed.  Drug formulations have also been emphasized in recent yearsref.2, and 
various formulations have been or are being developed.  Transdermal formulations, 
which can reduce dosing frequency and invasiveness, are used for treating various 
diseases.  For schizophrenia treatment, however, no transdermal formulations are as 
yet available anywhere in the world and only injections or oral formulations (eg, tablet, 
powder, orally disintegrating tablets, liquids) are used..  If a transdermal formulation 
is available for schizophrenia treatment and is provided to patients as a new option 
during the SDM process, adherence may be improved ref.5.  
 
Blonanserin is a second-generation antipsychotic synthesized by Sumitomo Dainippon 
Pharma Co., Ltd..  Blonanserin, which is a potent antagonist of dopamine D2 and 
serotonin 5-HT2A receptors, with a lower affinity for adrenaline α1, serotonin 5-HT2c, 
histamine H1, and muscarinic M1 receptorsref.6, is approved and marketed for the 
treatment of schizophrenia in Japan (tablet and powder formulation) and Korea (tablet 


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formulation).  DSP-5423P, a transdermal blonanserin patch is currently being 
developed as a new formulation of blonanserin with the aim of improving adherence as 
described above. 
 
4.2 
Study Conduct Rationale 
In the clinical study in Japanese healthy adults, 1, 2, or 3 patches of DSP-5423P 
32 mg/40 cm2 were applied to 9 patients each for 24 hours.  In addition, 2 patches of 
DSP-5423P 32 mg/40 cm2 were applied to 9 patients once daily for 10 days.  The 
results showed that the plasma blonanserin concentration increased depending on the 
number of patches applied and that the steady state was nearly reached after repeated 
administration for 7 days.   
 
A new patch formulation, DSP-5423P 20 mg/40 cm2 was prepared.  Pharmacokinetics, 
after the application of a single patch, were compared between these 2 patch 
formulations.  The results showed that a comparable amount of blonanserin 
absorption was obtained with these 2 patch formulations.  Therefore, the new 
formulation, DSP-5423P 20 mg/40 cm2 was used in the following studies.  
 
The phase 2 study of DSP-5423P was conducted in patients with schizophrenia to 
determine the recommended doses for phase 3 studies.  Striatal dopamine D2 receptor 
occupancy and plasma drug concentrations after application of DSP-5423P at doses of 
10 to 80 mg/day for 2 weeks were compared with results obtained after administration 
of DSP-5423 (tablet formulation of blonanserin).  The results suggest that DSP-5423P 
40 mg/day and 80 mg/day may be comparable to DSP-5423 (tablet) 8 mg/day and 
16 mg/day, respectively.  Since the clinical efficacy of antipsychotics reportedly 
correlates with dopamine D2 receptor occupancyref.7, 8, DSP-5423P at doses of 40 and 
80 mg/day is expected to demonstrate efficacy corresponding to that of DSP-5423 
(tablet) at doses of 8 and 16 mg/day, respectively.  
 
In clinical studies of DSP-5423P in healthy adult volunteers or subjects with 
schizophrenia, no clinically significant adverse events have been reported at doses up 
to 80 mg, demonstrating tolerability on the skin of application sites.  
 
The phase 3 confirmatory study is designed to be conducted in a randomized, 
double-blind, placebo-controlled, parallel-group manner.  The primary endpoint will 
be the change in Positive and Negative Syndrome Scale (PANSS) total score from 
baseline at Week 6.  DSP-5423P will be applied for 6 weeks at doses of 40 and 


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80 mg/day.   
 
In addition, for the subjects who complete the 6-week, double-blind treatment phase of 
the study, the extensional open-label treatment phase will be conducted to evaluate the 
long-term safety and efficacy of DSP-5423P at doses of 40 to 80 mg/day.  
 
 
5. STUDY OBJECTIVES  
5.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of DSP-5423P (40 and 
80 mg/day) compared with placebo in patients with schizophrenia by assessing the 
mean change in Positive and Negative Syndrome Scale (PANSS) total score from 
baseline at Week 6. 
 
5.2 
Secondary Objectives 
The secondary objectives are to evaluate the safety of DSP-5423P compared with 
placebo for 6-week treatment, the long-term safety and efficacy of DSP-5423P, and the 
pharmacokinetics of DSP-5423P in patients with schizophrenia.   
 
 
6. STUDY ENDPOINTS 
6.1 
Primary Endpoint 
The primary endpoint is the change in PANSS total score from baseline at Week 6. 
 
6.2 
Secondary Endpoints 
- Change in PANSS subscale scores from baseline at Week 6 
- Change in PANSS five-factor modelNote scores from baseline at Week 6 
- Change in Clinical Global Impressions – Severity of Illness (CGI-S) score from 
baseline at Week 6 
- Change in PANSS total score from the last evaluation before the initial application 
of DSP-5423P at each visit 
- Change in PANSS subscales from the last evaluation before the initial application of 
DSP-5423P at each visit 
- Change in PANSS five-factor models from the last evaluation before the initial 
application of DSP-5423P at each visit 
- Proportion of subjects who achieve a response, defined as 20% or greater 
improvement from baseline in PANSS total score at Week 6 


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- Change in CGI-S score from the last evaluation before the initial application of 
DSP-5423P at each visit 
- Time to treatment discontinuation from the initial application in the open-label 
treatment phase 
Note 
PANSS five-factor model ref.9  
Negative symptoms: 
Blunted 
affect, 
emotional 
withdrawal, 
poor 
rapport, 
passive/apathetic social withdrawal, lack of spontaneity and 
flow of conversation, and active social avoidance 
Excitement: 
Excitement, hostility, tension, and poor impulse control 
Cognitive disorders: 
Conceptual disorganization, difficulty in abstract thinking, 
mannerisms and posturing, disorientation, and poor attention 
Positive symptoms: 
Delusions, grandiosity, suspiciousness/feelings of persecution, 
and unusual thought content 
Anxiety/depression: 
Hypochondria, anxiety, feelings of guilt, depression, and 
preoccupation 
 
6.3 
Safety Endpoints 
- Adverse events (AEs) and adverse drug reactions (ADRs) 
- Extrapyramidal AEs and ADRs 
- Skin-related AEs and ADRs at the application site 
- Assessment of skin irritation reaction at the application site 
- Change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) total score 
(excluding overall severity) from baseline at Week 6 
- Change in individual DIEPSS scores from baseline at Week 6 
- Change in DIEPSS total score (excluding overall severity) from the last evaluation 
before the initial application of DSP-5423P at each visit 
- Change in individual DIEPSS scores (excluding overall severity) from the last 
evaluation before the initial application of DSP-5423P at each visit 
- Serum prolactin concentration 
- Electrocardiogram (ECG) parameters (QTc)  
- Concomitant use of antiparkinson drugs 
- Assessment of suicide using Columbia-Suicide Severity Rating Scale (C-SSRS） 
- Laboratory test values, vital signs, and body weight 
 
6.4 
Pharmacokinetics Endpoints 
- Plasma concentrations of blonanserin  


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- Plasma concentrations of metabolite M-1 (N-de-ethylated metabolite) 
 
7. INVESTIGATIONAL PLAN 
7.1 
Overall Study Design 
A study schematic is presented in Figure 1.  The study consists of 4 phases: the 
washout phase, the double-blind treatment phase, the open-label treatment phase, and 
the follow-up phase.  The double-blind treatment phase is conducted in a multicenter, 
randomized, double-blind, placebo-controlled, parallel-group manner.   
 
In the washout phase, placebo will be applied once daily for 1 week (at least 3 days) in 
a single-blind manner.  After the washout phase, subjects will be randomized to one 
of three treatments: 40 mg of DSP-5423P, 80 mg of DSP-5423P, and placebo, at 1:1:1 
ratio in the double-blind treatment phase.  The study drugs will be applied once daily 
for 6 weeks.  Subjects who complete the double-blind treatment phase can enter the 
open-label treatment phase.  In the open-label treatment phase, DSP-5423P will be 
applied as flexible dose (40, 60, or 80 mg) once daily for 28 weeks (outside Japan) or 
52 weeks (in Japan).  The study drug will be applied to the back, chest, or abdomen.   
 
Subjects who complete the open-label treatment phase or who prematurely discontinue 
the study drug after entering the double-blind treatment phase will undergo the 
follow-up assessments in 1 to 2 weeks after the termination of the study drug.  Details 
of the study assessments and other procedures to be performed at each visit are 
presented in Table 3,Table 4, and Table 5 Schedule of Assessments (p10 to 13), and 
Section11 STUDY ASSESSMENTS (p47). 
 
Day 1 is defined as the day of the initial application of the study drug in the 
double-blind treatment phase.  Open-Day 1 is also defined as the day of the initial 
application of the study drug in the open-label treatment phase. 
 
After the current study started, an unblinded interim analysis for futility is decided to 
be performed.  The interim analysis will be performed after 50% of target number of 
subjects complete or prematurely discontinue the double-blind treatment phase.  The 
study will be continued with no temporary suspension of enrollment or randomization 
of subjects until the Sponsor decides whether to continue or early terminate the study 
after the interim analysis.  Detailed procedure of the interim analysis and the futility 
criteria are defined in Section15.4 Interim Analysis (p70). 


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Figure 1  Study Schematic 
 
 
 
 
 
<Placebo group> 
 
 
 
 
 
 
 
 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<DSP-5423P 40 mg group > 
outside
DSP-5423P 
 40～80 mg/day 
28 weeks 
 
 
 
 
Japan
 
 
 
 
Placebo 
 
DSP-5423P 40 mg/ day 
 
 
 
Follow-up
observation 
 
  
 
 
 
 
 
 
 
 
 
 
 
<DSP-5423P 80 mg group> 
Japan
DSP-5423P 
 40～80 mg/day 
52 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSP-5423P 80 mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Randomization 
 
 
 
 
 
 
 
 Washout phase 
(single-blind)
Double-blind treatment phase
（6 weeks） 
Open-label treatment phase 
Follow-up 
phase 
 
 
 
1 week 
(At least  
3 days) 
2 
weeks 
4 weeks 
28 weeks (outside Japan) 
 or 52 weeks (in Japan) 
1 to 2 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient mandatory 
Inpatient or  
outpatient 
Inpatient or outpatient 
 
 
 
 
7.2 
Rationale 
7.2.1 
Rationale for the Study Design 
The washout phase is designed to adequately evaluate the efficacy of DSP-5423P by 
excluding the placebo responders.  Since placebo may worsen symptoms, the duration 
of the washout phase with placebo will be 1 week in principle, but must be at least 3 
days.  To evaluate long-term efficacy and safety, DSP-5423P will be applied as 
flexible dose in the open-label treatment phase.  To evaluate the safety of a subject 
after completing or prematurely discontinuing the study drug, the follow-up 
observations will be performed in 1 to 2 weeks after completion or discontinuation of 
study treatment, despite the possibility of the study drug being replaced with other 
antipsychotics. 
 
7.2.2 
Rationale for the Dosages 
A once-daily regimen was selected since plasma drug concentrations were maintained 
with minimal change within 24-hour intervals over time in the phase 1 study (Study No. 
D4904016) of DSP-5423P in Japanese healthy adults.  
 
Informed Consent 
Screening 


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Striatal dopamine D2 receptor occupancy after administration of DSP-5423 (tablet) or 
application of DSP-5423P was evaluated in subjects with schizophrenia by positron 
emission tomography (PET) in the phase 2 study (Study No. D4904019). 
 
In a comparison of occupancy between subjects treated with 8 mg/day of DSP-5423 
(tablet) and those treated with 40 mg/day of DSP-5423P or between subjects treated 
with 16 mg/day of DSP-5423 (tablet) and those treated with 80 mg/day of DSP-5423P, 
occupancy after application of DSP-5423P was within the range after administration of 
DSP-5423 (tablet) at the first (trough) and second (peak) measurements.   
 
The DSP-5423P dose is selected based on the above occupancy results.  DSP-5423P 
doses of 40 mg/day and 80 mg/day are considered to be comparable to DSP-5423 
(tablet) at doses of 8 mg/day and 16 mg/day, respectively.  DSP-5423 (tablet) at doses 
ranging from 8 to 16 mg/day is approved for the treatment of schizophrenia.  For 
DSP-5423P, 40 mg/day, and 80 mg/day are to be used in this study.  
 
The duration of the double-blind treatment phase will be 6 weeks, which is commonly 
used in comparative studies of atypical antipsychotics and is considered sufficient for 
the efficacy evaluation of these atypical antipsychotics. ref.10   
 
From the results of the single dose study (Study No.D4904016) and the location of the 
application comparative study (Study No.D4904059), the amounts of absorption after 
application to the chest, the lower back, the upper arm, or the abdomen were 
comparable to that after application to the upper back.  Therefore, the back, chest, and 
abdomen were selected as the locations of application in this study.  The upper arm, 
which is more likely to be exposed to light, is excluded because DSP-5423P may be a 
photosensitizer (nonclinical study, No.P110808).   
 
7.2.3 
Rationale for the Endpoints 
PANSS was selected since it is a comprehensive evaluation scale of the severity of 
various psychiatric symptoms in schizophrenia, and is frequently used in clinical 
studies for the evaluation of antipsychotics.ref10, 11 
 
7.2.4 
Rationale for change of the target number of subjects and the Interim 
Analysis 
After the current study started, the Sponsor reconsidered the statistical power (80%) 
might not be enough and decided to increase it to approximately 90% with the same 


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effect size estimates.  The target number of subjects is changed from 360 to 501.  
Considering the increase in the number of subjects exposed to the study drug, to avoid 
unnecessary exposure of more subjects if an investigational treatment has no value, an 
unblinded interim analysis for futility is added to the study design.   
 
7.3 
Prevention of Missing Data 
In an effort to minimize the number of subjects who are terminated from the study 
before study completion, the following study design and conduct elements are 
implemented; (i) during the entire study period, concomitant use of antiparkinson 
drugs, lorazepam, and hypnotic drugs are allowed for extrapyramidal symptoms, 
psychiatric symptoms, and insomnia respectively, (ii) during the open-label treatment 
phase, rescue use of antipsychotics is allowed for urgent psychiatric symptoms, (iii) 
subjects are allowed to be discharged from the study center after Visit 4 (Week 2) or 
remain in the study center for the entire study duration, based on their medical 
condition, (iv) during the open-label treatment phase, flexible dose adjustment is 
allowed based on efficacy or tolerability, (v) use of study centers with a good track 
record of enrolling and following eligible subjects, (vi) train the study centers on the 
importance of continued follow-up and on the informed consent process, ensuring 
subjects understand the commitment they are making, including the intent to complete 
the trial, and (vii) monitor data collection for adherence during the study. 
 
7.4 
Planned Study Period 
August 2014 ~ December 2018 (enrollment period, August 2014 ~ September 2017) 
 
 
8. SELECTION OF SUBJECTS 
The Investigator will evaluate patient eligibility for the study at screening, 
randomization, and before the open-label treatment phase.  When a patient is not 
eligible, the Investigator will specify which inclusion/exclusion criteria to exclude a 
patient from the study, and record the specified inclusion/exclusion criteria by number 
in the CRF. 
 
8.1 
Criteria at screening 
8.1.1 
Inclusion Criteria at screening 
＜The procedure in Japan is described in the Japan Appendix.> 
Patients who meet all the following criteria at screening will be included in the study: 
1. 
Patients who have schizophrenia diagnosed by Diagnostic and Statistical Manual 


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of Mental Disorders, fifth edition (DSM-5), diagnostic criteria 
2. 
Patients who have psychiatric symptoms (eg, aggravated delusions) with 
schizophrenia showing exacerbation within 2 months (60 days) before screening 
3. 
Patients with a PANSS score of 4 (moderate) or higher for 2 or more of the 
following 5 items: delusions (P1), conceptual disorganization (P2), hallucinations 
(P3), suspiciousness (P6), and unusual thought content (G9) 
4. 
Patients with a total PANSS score of 80 or higher 
5. 
Patients who can be hospitalized from screening until the scheduled date of Visit 4 
6. 
Patients who are aged 18 years or older at informed consent 
7. 
Patients who are fully informed of and understand the objectives, procedures, and 
possible benefits and risks of the study and who voluntarily provide written 
consent to participate in the study.  If the patient is a minor at informed consent, 
written consent will be obtained from a legally acceptable representativeNote in 
addition to that obtained from the patient. 
Note: A legally acceptable representative is defined as a person within the second degree of 
kinship, in principle, who can act in the patient’s best interest in the context of daily 
lifestyle and the existing mental relationship between the two parties. 
 
8. 
Female patients, who are premenopausal and of childbearing potential, with 
negative pregnancy test (urine) results at screening  
9. 
Patients who agree to practice appropriate contraception, when the patients or 
their partners are of childbearing potential 
 
8.1.2 
Exclusion Criteria at screening 
Patients who meet any of the following criteria will be excluded from the study. 
1. 
Patients in a coma 
2. 
Patients under the strong influence of central nervous system depressants such as 
barbituric acid derivatives 
3. 
Patients receiving treatment with adrenaline, azole antifungals (excluding drugs 
for external use), or human immunodeficiency virus (HIV) protease inhibitors 
4. 
Patients with a history of or current neuroleptic malignant syndrome, tardive 
dyskinesia, or water intoxication 
5. 
Patients with Parkinson’s disease 
6. 
Patients with active suicidal ideation or those with a suicide attempt history who 
are considered ineligible for the study by the Investigator 
7. 
Patients with HbA1c (NGSP) of 8.4% or higher 
8. 
Patients with physical exhaustion accompanied by conditions such as dehydration 
and malnutrition 


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9. 
Patients with a history of or complication(s) involving serious cardiovascular, 
hepatic, renal, organic brain, hematologic, endocrine, convulsive disease or other 
conditions, and who are considered ineligible for the study by the Investigator 
10. Patients with skin injuries, skin diseases or tattoos that preclude the application of 
the study drug to the back, chest, or abdomen 
11. Patients with a history of drug abuse, drug dependency, alcohol abuse, or alcohol 
dependency within 6 months (180 days) before screening  
12. Patients who received any depot preparation (sustained-release formulation) of an 
antipsychotics within 3 months (90 days) before screening 
13. Patients who received clozapine within 4 months (120 days) before screening 
14. Patients who are considered resistant to treatment for psychiatric symptoms by the 
Investigator. Treatment resistance is defined as failure to respond to 3 or more 
antipsychotics within 1 year (365 days) before screening 
15. Patients who previously received blonanserin 
16. Patients who received monoamine oxidase (MAO) inhibitors or fluoxetine within 
1 month (30 days) before screening 
17. Patients who received electroconvulsive therapy within 6 months (180 days) 
before screening 
18. Patients who are pregnant, or are nursing mothers 
19. Patients with a history or complication(s) of hypersensitivity to 2 or more drugs 
(patients with a history or complication(s) of drug-induced allergic reactions such 
as anaphylaxis, rash, and urticaria) 
20. Patients with a history or complication(s) of malignant tumor within 5 years 
before screening 
21. Patients who are currently infected with HIV 
22. Patients who received other investigational products or post-marketing clinical 
study drugs within 3 months (90 days) before screening or who have enrolled in 
but have not completed another clinical or post-marketing study before screening 
23. Patients who are otherwise considered ineligible for the study by the Investigator  
 
8.2 
Randomization Criteria 
8.2.1 
Inclusion Criteria before randomization 
Subjects who meet all the following criteria before randomization ( at Visit 2) will be 
randomized. 
1. 
Subjects with a PANSS score of 4 (moderate) or higher for 2 or more of the 
following 5 items: delusions (P1), conceptual disorganization (P2), hallucinations 
(P3), suspiciousness (P6), and unusual thought content (G9) 


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2. 
Subjects with a PANSS total score of 80 or higher 
 
8.2.2 
Exclusion Criteria before randomization 
Subjects who meet any of the following criteria will be excluded from the study before 
randomization. 
1. 
Subjects with a 20% or more reduction in the PANSS total score between 
screening and randomization (at Visit 2) 
PANSS total score at screening － PANSS total score at randomization 
PANSS total score at screening － 30 
× 100 ≥ 20% 
 
2. 
Subjects who are otherwise considered ineligible for the study by the Investigator 
 
8.3 
Criteria before the open-label treatment phase 
8.3.1 
Inclusion Criteria before the open-label treatment phase 
Subjects who meet the following criterion will enter the open-label treatment phase.   
1. 
Subjects who have completed the 6-week study treatment and all scheduled 
assessments at Visit 6 in the double-blind treatment phase, and who are considered 
eligible by the Investigator with no safety concerns 
 
8.3.2 
Exclusion Criteria before the open-label treatment phase 
Subjects who meet any of the following criteria will be excluded from the study before 
the open-label treatment phase.   
1. 
Subjects who are planning to become pregnant at any time before the end of the 
follow-up phase 
2. 
Subjects who are otherwise considered ineligible for the study by the Investigator 
 
 
9. STUDY DRUG MATERIALS AND MANAGEMENT 
9.1 
Description of Study Drug 
The study drugs are shown in Table 7.  The study drugs will be transdermal patches 
(DSP-5423P 20 mg patches, DSP-5423P 40 mg patches, and placebo patches) covered 
with a transparent protective liner on their adhesive side.   
 
DSP-5423P 40 mg patches and placebo patches, which will be used in the double-blind 
treatment phase, are indistinguishable in color, shape, size, and packaging.  
 




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appropriate storage condition will be specified in the guidance for drug accountability 
provided by the Sponsor/CRO. 
 
9.4 
Dispensing of Study Drug  
The washout phase and the double-blind treatment phase 
The investigator or designee will access the Interactive voice response system/ 
Interactive web response system(IVRS/IWRS) for dispensing the study drug to 
subjects at Visits 1 to 5.  The IVRS/IWRS will assign a Kit ID of the study drug that 
is to be dispensed to the subject.  The Kit ID of the study drug dispensed to the 
subject will be recorded in the CRFs. 
 
The open-label treatment phase 
The investigator or designee will access the IVRS/IWRS at Visit 6, Visits 101~108 
(outside Japan), and Visits 101~111 (in Japan) for recording the quantity of the study 
drug to be dispensed to the subject. 
 
9.5 
Study Drug Accountability 
<The procedure in Japan is described in the Japan Appendix.>  
The Investigator or designee is responsible for storing the study drug in a secure 
location and for maintaining adequate records of drug disposition including the dates, 
quantity, and use by subjects.  If the study is stopped for any reason or completed, all 
unused supplies of the drug will be returned to the Sponsor/CRO, unless other 
instructions are provided in writing by the Sponsor/CRO. 
 
The study drug will not be dispensed to any person who is not a study subject under 
this protocol. 
 
9.6 
Study Drug Handling and Disposal 
The Investigator or designee must on an ongoing basis maintain a drug inventory 
record of supplied, received, dispensed, and returned medication.  The Investigator or 
designee is required to return all unused study drugs to the Sponsor/CRO as instructed.  
The Investigator or designee is required to maintain copies of medication shipping 
receipts (outside Japan), drug accountability records, and records of return or final 
disposal of the study drug. 
 
 


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10. TREATMENT OF SUBJECTS 
The Investigator will assign a unique subject number consisting of 5 digits to each 
patient who provides informed consent.  The subject number consists of 5 digits, 
which specify study center (3 digits), and patient (2 digits numbered sequentially in 
each study center) (eg, 10603 denotes Study center 106 and Patient 03).  The subject 
number will be used for patient identification in all procedures throughout the study. 
 
10.1 Study Medication  
The study drug (patches) will be applied to the subject’s back, chest, or abdomen once 
daily around the same time of the day from the beginning of the washout phase until 
the end of the open-label treatment phase.  All patches for each day should be applied 
to only one location, ie, the back, the chest, or the abdomen.  The study drug will be 
replaced every day.  When the study drug patches are to be replaced, the new patches 
will be applied to the location different from that of the last application, or a site 
different from that of the last application on the same location. 
 
The guidance for application of the study drugs 
The subjects will be instructed as below: 
1. 
The study drug will be applied directly to normal healthy skin after removing the 
transparent liner. 
2. 
When the study drug patches are replaced, new patches of the study drug will be 
applied as soon as possible.     
3. 
The current application site of the study drug will be protected from heat.  For 
instance, the application site should not be warmed with a portable body warmer 
or hot air from a heater.   
4. 
The current application site of the study drug will be protected from water.  
Before taking a bath or shower, the study drug should be removed.  After taking 
a bath or shower, new patches of the study drug should be immediately applied to 
thoroughly dried skin (within approximately 1 hour after removing the previous 
patches). 
5. 
The locations of previous and current applications of the study drug will be 
protected from light outdoors by clothing or other appropriate measures from the 
beginning of the washout phase until the follow-up visit. 
6. 
No other adhesive skin patches are to be overlaid on the current application site of 
the study drug.  No liniments should be used at the current application site of the 
study drug.  The study drug should not be applied to any site where liniments are 
used.   






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adjustment in the CRFs.  The DSP-5423P dose should not be changed for at least 1 
week in principle, after the dose adjustment. 
 
10.3 Concomitant Medications and Therapies 
The following information on all medications used from screening until the follow-up 
visit will be recorded in the CRFs:    
- drug name 
- route 
- start date 
- stop date 
- the reason for concomitant use 
- drug category 
- daily dose (for antipsychotics and antiparkinson drugs only) 
 
For antipsychotics and antiparkinson drugs, the information on the usage for 7 days 
before screening will also be recorded in the CRFs.   
 
Table 10 shows restrictions on concomitant medications/therapies from screening until 
the end of the follow-up phase. 
 




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If urgent treatment is required because of psychiatric symptoms such as acute 
psychomotor excitability during the open-label treatment phase, at the discretion of the 
Investigator, only one antipsychotic drug excluding depot neuroleptics and blonanserin 
can be used concomitantly on an as-needed basis.  However, all antipsychotics will be 
prohibited within 48 hours before the PANSS, CGI-S, and C-SSRS assessments.  The 
total duration of concomitant use of antipsychotics for urgent treatment during the 
open-label treatment phase should be 5 days or less outside Japan, and 10 days or less 
in Japan. 
 
10.3.2 
Antimanic and Antiepileptic drugs 
Antimanic and antiepileptic drugs will be prohibited from screening until completion 
of assessments at the last visit (Visit 109 outside Japan or Visit 112 in Japan) of the 
open-label treatment phase or the discontinuation visit. If a subject completes the 
double-blind treatment phase and discontinues before entering the open-label treatment 
phase, antimanic and antiepileptic drugs will be prohibited until completion of 
assessments at Visit 6. When psychiatric symptoms worsen during the open-label 
treatment phase, antimanic and antiepileptic drugs may be used.  If the psychiatric 
symptoms improve, antimanic and antiepileptic drugs may be tapered or discontinued. 
 
10.3.3 
Other Prohibited Medications 
The concomitant use of the following drugs, food, and beverages will be prohibited 
from screening until completion of assessments at the last visit (Visit 109 outside Japan 
or Visit 112 in Japan) of the open-label treatment phase or the discontinuation visit. If a 
subject completes the double-blind treatment phase and discontinues before entering 
the open-label treatment phase, the concomitant use of the following drugs, food, and 
beverages will be prohibited until completion of assessments at Visit 6.  
 
- Monoamine oxidase (MAO) inhibitors 
- Cytochrome P-450 enzyme 3A4 (CYP3A4) inducers (eg, phenytoin, carbamazepine, 
rifampin, Saint-John’s wort).  External drugs for topical use can be used with no 
restrictions. 
- CYP3A4 inhibitors (eg, itraconazole, fluconazole, erythromycin, foods and 
beverages containing grapefruit).  External drugs for topical use can be used with 
no restrictions. 
- Adrenaline (excluding use for emergency treatment of anaphylaxis) 
- Other investigational products or post-marketing clinical study products 
 


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CYP3A4 inhibitors, adrenaline (excluding use for emergency treatment of 
anaphylaxis), other investigational products and post-marketing clinical study products 
will also be prohibited until the follow-up visit. 
 
10.3.4 
Prohibited Therapies 
Electroconvulsive therapy will be prohibited from screening until completion of 
assessments at the last visit (Visit 109 outside Japan or Visit 112 in Japan) of the 
open-label treatment phase or the discontinuation visit. If a subject completes the 
double-blind treatment phase and discontinues before entering the open-label treatment 
phase, electroconvulsive therapy will be prohibited until completion of assessments at 
Visit 6. 
 
10.3.5 
Restricted Medications 
10.3.5.1 
Antiparkinson drugs 
Antiparkinson drugs will be restricted as follows: 
 
(1) From screening until the end of the double-blind treatment phase  
- For the subjects not treated with antiparkinson drugs at screening 
Antiparkinson drugs will be prohibited from screening until completion of DIEPSS 
assessments at Visit 6 or the discontinuation visit. 
- For the subjects treated with antiparkinson drugs at screening 
Antiparkinson drugs will be tapered and completely discontinued before beginning 
of the washout phase.  Antiparkinson drugs will be prohibited from the beginning 
of the washout phase until completion of DIEPSS assessments at Visit 6 or the 
discontinuation visit. 
 
If extrapyramidal symptoms occur or worsen during the washout phase or double-blind 
treatment phase, only one of the antiparkinson drugs listed in Table 11 may be used 
and the dose may not exceed the maximum daily dose.  If the antiparkinson drug is 
not effective, the drug may be swiched to another antiparkinson drug listed in Table 11.  
If the drugs listed in Table 11 are not available outside Japan, another similar drug at an 
equivalent dose will be permitted with prior authorization of the medical monitor 
(Table 1 Emergency Contact Information for outside Japan, p3).  If the 
extrapyramidal symptoms improve, antiparkinson drugs may be tapered or 
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(2) During the open-label treatment phase 
For the subjects treated with a hypnotic drug at the end of the double-blind treatment 
phase (Visit 6), the hypnotic drug may be continued with no dosage modification.  
When insomnia occurs or worsens, the hypnotic drugs listed in Table 13 or 
benzodiazepine receptor agonists may be used.   
 
However, all hypnotic drugs will be prohibited within 12 hours before assessments of 
the PANSS, CGI-S, and C-SSRS.  If the insomnia improves, hypnotic drugs may be 
tapered or discontinued. 
 
10.3.6 
Medications for complications 
All drugs used for the treatment for complications (eg, hypertension, hyperlipidemia, 
diabetes) at screening should be continued without any dosage modification from 
screening until the last visit (Visit 109 outside Japan or Visit 112 in Japan) of the 
open-label treatment phase or the discontinuation visit. If a subject completes the 
double-blind treatment phase and discontinues before entering the open-label treatment 
phase, any dose modification of the concomitant drugs will be prohibited until 
completion of assessments at Visit 6. If the complications worsen or improve, the 
dosage of the concomitant drugs for these complications may be changed accordingly. 
 
10.4 Inpatient or Outpatient 
All subjects will be hospitalized from screening until Day 14 (Visit 4) in the 
double-blind treatment phase.  After Day 14 and completion of assessments at Visit 4, 
any subject who meets all the following criteria can be an outpatient.   
- The subject has family members or care-givers (eg, a social worker, case worker, 
nurse) who can aid in applying the study drug to the subject and visit the study 
center. 
- The Investigator considers the subject, whose psychiatric symptoms are stable 
without safety concerns, can be an outpatient.  
 
During the inpatient/hospitalized period in the double-blind treatment phase, all 
subjects will be permitted to stay outside of the study center only twice, for 3 days and 
2 nights each time, as needed.  The subject who are currently hospitalized must return 
to the study center the day before each scheduled visit.  All subjects can be 
discharged from the study center after the treatment in the double-blind treatment 
phase and completion of assessments at Visit 6, or after completion of assessments at 
the discontinuation visit.  In the open-label treatment phase, the subjects can be 


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inpatients or outpatients.   
 
The Investigator will record the dates of hospitalization and discharge in the CRFs. 
 
10.5 Contraception Requirements 
Subjects who are of childbearing potential, and whose partners are of childbearing 
potential must practice adequate contraception from informed consent until the 
follow-up visit.  Adequate contraception is defined as continuous use of a barrier 
method (eg, condoms, diaphragms and intrauterine contraceptive device or system), a 
hormonal contraceptive, or abstinence. 
 
10.6 Treatment Compliance 
The Investigator will instruct subjects that the subjects will return any unused study 
drugs at each visit.  The Investigator will monitor the treatment compliance at each 
visit. 
 
The Investigator will record the dates of the initial and final applications, the date of 
the final removal of the study drug, and the number of applied patches during the 
washout phase and the double-blind treatment phase in the CRFs. 
 
The Investigator will record the dates of the initial and final applications and the 
number of applied patches for each dose during the open-label treatment phase, and the 
date of final removal of the study drug.  
 
10.7 Treatment Assignment and Blinding 
10.7.1 
Treatment Assignment 
Subjects, who will be eligible at Visit 2, will be randomly assigned to receive one of 
the following three treatments in a double-blind fashion (1:1:1) by a Kit ID obtained 
from the IVRS/IWRS. 
- DSP-5423P 40 mg/day 
- DSP-5423P 80 mg/day 
- Placebo 
 
In the subsequent visits (Visit 3, 4 and 5), the Kit ID will be allocated to a subject to a 
particular treatment group through IVRS/IWRS.  The Kit ID identifies the subject for 
data collection purpose and not be reused. 
 


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10.7.2 
Blinding 
This study will contain the double-blind treatment phase.  The subjects, Investigators, 
staff of the study centers, persons performing the assessments, clinical operations 
personnel, data analysts, personnel at central laboratories, the central ECG reader, and 
the principal ECG analyst will remain blinded to the identity of the treatment from 
randomization until the database lock and unblinding for the double-blind treatment 
phase, as follows: 
 
- The randomization code will be kept strictly confidential until the unblinding, and 
will not be accessible by anyone except for the personnel performing the 
pharmacokinetic analysis and an appointed independent biostatistician and 
programmer(s) performing the interim analysis (see Section 15.4.3 Confidentiality 
of Interim Data and Analyses, p72) . 
- In the double-blind treatment phase, the study drugs will be identical in packaging, 
labeling, and appearance. 
- PANSS and CGI-S at Week 6 will be evaluated before the beginning of the 
open-label treatment phase.  The data will be recorded in the CRFs before the 
initial assessments in the open-label treatment phase (Open-Week 1 [Week 7] ).  
PANSS and CGI-S data from screening to Week 6 recorded in the CRFs may only be 
revised if there is a valid reason (eg, incorrect input). 
- Serum prolactin concentrations measured from screening until the end of the 
double-blind treatment phase will not be disclosed before all other data from the 
double-blind treatment phase have been locked. 
- Plasma concentrations of blonanserin and its metabolite M-1 will not be disclosed 
before the database lock and the unblinding of the double-blind treatment phase. 
 
10.8 Emergency Unblinding Procedures 
In the case of medical emergencies when the Principal Investigator or the authorized 
delegate needs to know what study treatment has been applied to a subject to ensure 
the subject’s safety, he or she should contact the Sponsor, the designee or the medical 
monitor about the unblinding (Table 1 and Table 2 Emergency Contact Information, 
p3).  If possible, the reason for or the necessity of the unblinding should be discussed 
before unblinding. 
 
A 24-hour code-break service will be available via the IVRS/IWRS for the Principal 
Investigator.  All treatment code breaks must be fully documented and signed with the 
time, date, reason, and name of the person responsible for breaking the code and 


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tracked on the unblinding log.  The unblinding must result in the withdrawal of the 
subject from the study, and the subject should return to the study center and complete 
the discontinuation assessments within 5 days of the drug application last study. 
 
The Sponsor will retain the right to break the randomization code for a subject who 
develops any serious adverse events (SAEs) that are unexpected and are suspected to 
be causally related to the study drug, and that potentially require expedited reporting to 
regulatory authorities.  The randomization codes will not be broken for the planned 
analyses of the double-blind treatment phase until all data excluding prolactin 
concentrations in the double-blind treatment phase will be locked, except the 
randomization codes will be revealed to the independent biostatistician and the 
programmer(s) performing the interim analysis. 
 
 
11. STUDY ASSESSMENTS 
A study schematic is presented in Figure 1.  A summary of assessments to be 
conducted at each visit is presented in Table 3 to 5 Schedule of Assessments (p10~p13).  
Assessments will be conducted within the time frames specified.  Day 1 is defined as 
the day of the initial application of the study drug in the double-blind treatment phase.  
Open-Day 1 is also defined as the day of the initial application of the study drug in the 
open-label treatment phase. 
  
Laboratory findings and results of the study assessments will be recorded in source 
documents.  The following data will be recorded in the CRFs. 
 
11.1 Demographics and Baseline Characteristics 
Demographics: 
Ethnicity, race, sex, date of birth, height, body weight, inpatient/outpatient status at 
informed consent, and duration of hospitalization at informed consent 
Disease information: 
Time of the first onset of schizophrenia, the number of previous episodes of 
schizophrenia, time of onset of the current episode, and complications 
 
11.2 Efficacy Assessments 
The concomitant use of medications is restricted, as described in Section 10.3 
Concomitant Medications and Therapies (p38).  When the efficacy assessments are 
conducted, the concomitant use of restricted medications will be recorded in the CRFs. 


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11.2.1 
Positive and Negative Syndrome Scale (PANSS） 
The PANSSref.11 is an interview-based measure of the severity of psychopathology in 
adults with psychotic disorders.   
 
A person, who will be a certified rater for PANSS assessments, will receive specific 
training and education for the PANSS assessment provided by the Sponsor/CRO and 
will be certified by the Sponsor/CRO before his/her initial assessment of PANSS.  
The certified rater will rate 30 items on a 7-point scale of 1 to 7.  Dates of the 
assessments and the results will be recorded in the CRFs.   
 
When the study treatment is completed or prematurely discontinued, PANSS will be 
rated before the first post-treatment with other antipsychotics.  When the DSP-5423P 
dose is changed at an unscheduled visit in the open-label treatment phase, PANSS will 
be rated before dose adjustment. 
 
11.2.2 
Clinical Global Impressions scale-Severity of illness (CGI-S) 
CGI-S ref.12 is a research rating tool of the subject’s current disease state on a 7-point 
scale of 1 to 7.  The Investigators will receive specific training before their initial 
assessment of CGI-S.  Dates of the assessments and the results will be recorded in the 
CRFs.   
 
When the study treatment is completed or prematurely discontinued, CGI-S will be 
rated before the first post-treatment with other antipsychotics.  When the DSP-5423P 
dose is changed at an unscheduled visit in the open-label treatment phase, CGI-S will 
be rated before dose adjustment. 
 
11.3 Safety Assessments 
11.3.1 
Adverse Events 
Adverse events will be collected for each subject.  Subjects should be queried in a 
non-leading manner, without specific prompting (eg, “Has there been any change in 
your health status since your last visit?”).  See Section 12 SAFETY REPORTING 
(p52). 
AEs and SAEs will be monitored throughout the study at all visits including telephone 
assessments.  
 
11.3.2 
Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) 
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fasting conditions (at least 10 hours after the last meal) in the CRFs.  All clinical 
laboratory tests will be performed centrally.   
 
The clinical laboratory tests required by the protocol are listed in Table 15.  Detailed 
instructions regarding clinical laboratory procedures, sampling, shipping, and reporting 
can refer to the instructions manual provided by the Sponsor/CRO. 
 
Guidance for Blood sample Collection 
- From screening until the end of the double-blind treatment phase 
Blood samples will be collected under fasting conditions (at least 10 hours after the 
last meal). 
- During the open-label treatment phase 
Blood samples will be collected under fasting conditions (at least 10 hours after the 
last meal) at the last visit (Visit 109 outside Japan or Visit 112 in Japan).  At other 
visits, blood samples should be collected under fasting conditions, whenever 
possible. 
- At the discontinuation visit 
Blood samples will be collected under fasting conditions (at least 10 hours after the 
last meal).  
 
Table 15  Contents of laboratory variables 
Hematology 
white blood cell count, red blood cell count, hemoglobin, 
hematocrit, platelet count, differential white blood cell count 
(neutrophils, eosinophils, basophils, monocytes, and 
lymphocytes) 
Blood biochemistry 
total protein, total bilirubin, AST, ALT, ALP, γ-GTP, LDH, 
total cholesterol, triglycerides, BUN, creatinine, CK, Na, K, 
Cl, blood glucose, HbA1c, serum prolactin* 
Urinalysis (Qualitative) 
glucose, protein, occult blood, urobilinogen 
Pregnancy test 
(premenopausal women 
of childbearing potential 
only) 
urine chorionic gonadotropin 
* Serum prolactin concentrations measured from screening until the end of the double-blind treatment 
phase will not be disclosed until the other data of the double-blind treatment phase have been locked. 
 
 
11.3.6 
Vital Signs and Body Weight 
Systolic and diastolic blood pressures (sitting), pulse rate, body temperature (axilla), 
and body weight will be measured.  Dates of measurements and the results will be 


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recorded in the CRFs.  
 
11.3.7 
12-lead ECGs 
The Investigator will perform 12-lead ECG at rest and record the dates and times of 
assessments in the CRFs.  The Investigator will retain ECG tracings and send them 
electronically to the central ECG reader.  The central ECG reader will analyze ECG 
tracings and calculate the following ECG parameters: RR interval, QT interval, PR 
interval, QRS interval, and QTc interval (QTc Fridericia [QTcF] and QTc Bazett 
[QTcB]).  The central ECG reader will report analysis results and ECG parameters to 
the Sponsor and the Investigator.   
 
The principal ECG analyst will comprehensively evaluate the effect of study treatment 
on QTc prolongation. 
 
11.4 Pharmacokinetic Assessments 
Measurement 
- Plasma concentrations of blonanserin 
- Plasma concentrations of M-1 (N-de-ethylated metabolite) 
 
Recording 
The following information will be recorded in the CRFs:  
- Dates and times of blood sample collection 
- Dates and times of the last two applications of DSP-5423P before blood sample 
collection 
- Locations for the last two applications of DSP-5423P before blood sample collection 
- DSP-5423P doses of the last two applications before blood sample collection (in the 
open-label treatment phase only) 
 
Timing and volume of blood collection 
Six milliliters of blood will be collected at each time point shown in Table 3 to 5 
Schedule of Assessments.  
 
Processing of blood collection 
Blood samples will be collected into heparinized (heparin sodium) blood collection 
tubes and should be stored in ice before being centrifuged (4°C, 3000 rpm 
[approximately 1700 g], 10 minutes).  The entire volume of plasma will be placed in 
a container and stored in a freezer (set at −20°C or lower). 


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When a centrifuge with cooling system is not available, ice chilled blood samples 
should be centrifuged (at room temperature, 3000 rpm [approximately 1700 g], 
10 minutes) as immediately as possible.  The entire volume of plasma should be also 
placed in a container as immediately as possible and will be stored in a freezer (set at 
−20°C or lower). 
 
Shipment of specimens 
All specimens for drug concentration measurements will be collected by the clinical 
laboratory and shipped to the bioanalysis laboratory.  
 
Measurements and Reporting 
The bioanalysis laboratory will measure the plasma concentrations of blonanserin and 
its metabolite M-1 and prepare a bioanalysis report.  Results obtained in the 
double-blind treatment phase will be reported to the Sponsor after unblinding.  
 
 
12. SAFETY REPORTING 
12.1 Definitions 
12.1.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a study subject 
administered a medicinal (investigational) product and which does not necessarily have 
a causal relationship with this treatment.  An AE can, therefore, be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
occurring after the administration of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product.  AEs may include 
the onset of new illness and the exacerbation of pre-existing conditions.  AEs will be 
collected from the beginning of the study treatment in the washout phase until the 
follow-up visit.  AEs also include other untoward events occurring from the 
beginning of the study treatment in the washout phase until the follow-up visit, for 
instance, events occurring in association with study-related procedures or assessments, 
or those occurring under placebo treatment. 
 
AEs that occur during the washout phase and worsen during the double-blind treatment 
phase will be recorded as AEs in the washout phase and also as AEs in the 
double-blind treatment phase.  AEs that occur during the washout phase and worsen 
during the open-label treatment phase will be recorded as AEs in the washout phase 
and also as AEs in the open-label treatment phase.  The date of worsening will be 


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recorded as the onset date of the worsening AE.  Likewise, AEs that occur during the 
double-blind treatment phase and worsen during the open-label treatment phase will be 
recorded as AEs in the double-blind treatment phase and also as AEs in the open-label 
treatment phase, with the date of worsening as the onset date.  In addition, AEs that 
occur during the washout phase or double-blind treatment phase without further 
worsening in the following phase will be recorded as AEs in the washout phase or a 
AEs in the double-blind treatment phase, respectively. 
 
Lack of efficacy may be an expected potential outcome and should not be reported as 
an AE unless the event is unusual in some way.  New signs and symptoms of the 
underlying disease, or signs and symptoms of an emerging disease should be recorded 
as AEs. 
 
The Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
recorded as the AE and not the individual signs/symptoms. 
 
12.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is an AE that meets one or more of the following 
criteria: 
- Results in death. 
- Is life-threatening (ie, a subject is at immediate risk of death at the time of the event, 
not an event where occurrence in a more severe form might have caused death). 
- Requires hospitalization or prolongation of existing hospitalization. 
- Results in persistent or significant disability or incapacity. 
- Is a congenital anomaly or birth defect. 
- Is an important medical event that may jeopardize the subject or may require a 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization. 
 
The term "severe" is often used to describe the severity of a specific event (as in mild, 
moderate, or severe myocardial infarction) (see Section 12.3 Collection and Recording 
Adverse Events, p54); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This is not the same as "serious," which is 
based on subject/event outcome or action criteria usually associated with events that 


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pose a threat to a subject's life or functioning as defined by the criteria above.  
 
During the study, if a subject has a hospitalization or procedure that was scheduled 
before the study entry, ie, before informed consent for an event/condition that occurred 
before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE.  However, if the event/condition worsens during the study, it should 
be reported as an AE (or SAE, if the event/condition results in a serious outcome such 
as prolongation of hospitalization). 
 
12.2 Objective Findings 
Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG 
value, and physical examination observation) will also be recorded as AEs.  When a 
clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be 
recorded as the AE, not transaminase elevation).  If a definite diagnosis is not 
available, then record the sign (eg, clinically significant elevation of transaminase 
levels) or symptom (eg, abdominal pain) as the AE. 
 
Clinical laboratory test results will be reviewed by the Investigator.  The Investigator 
must determine the clinical significance of all out of range values.  Clinical laboratory 
test with possibly drug-related or clinically relevant abnormal values of uncertain 
causality may be repeated.  Any abnormal values that persist should be followed at 
the discretion of the Investigator.  Laboratory reports will be initialed and dated by 
the Investigator. 
 
All ECG tracings at the study center and ECG over-read reports by the central ECG 
reader will be reviewed by the Investigator.  The Investigator must determine the 
clinical significance of all abnormal ECGs.  An ECG with possibly drug-related or 
clinically relevant abnormal findings of uncertain causality may be repeated.  Any 
abnormal ECGs that persist should be followed at the discretion of the Investigator.  
ECG tracings will be initialed and dated by the Investigator. 
 
12.3 Collection and Recording Adverse Events 
All AEs will be, in principle, followed up until resolution, stabilization of the condition, 
the event is otherwise explained, or the subject is lost to follow-up.  All AEs must be 
collected and recorded in the subject’s study records/source documents, in accordance 
with the Investigator’s normal clinical practice.  AEs will be recorded in the CRFs 


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from the beginning of the study treatment in the washout phase until the follow-up 
visit.     
 
Each AE is to be evaluated for duration, severity, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment.  If any AEs 
related to skin disorders occur at the application site, the Investigator will record the 
location (the back, chest or abdomen) of AEs occurrence.   
 
Definitions for severity, action taken with the study treatment, outcome, and causal 
relationship to the study treatment are presented below.  
 
The severity of AE: 
- Mild – Ordinarily transient symptoms that do not influence performance of subject’s 
daily activities. Other treatment is not ordinarily indicated. 
- Moderate – Marked symptoms sufficient to make the subject uncomfortable. 
Moderate influence on performance of subject’s daily activities. Other treatment 
may be necessary. 
- Severe – Symptoms cause considerable discomfort. Substantial influence on 
subject’s daily activities. May be unable to continue the study, and other treatment 
may be necessary. 
 
The action taken with the study treatment: 
During the washout phase 
- Drug Withdrawn – Study drug stopped permanently. 
- Dose Not Changed. 
- Not Applicable. 
During the double-blind treatment phase 
- Drug Withdrawn – Study drug stopped permanently. 
- Dose Not Changed. 
- Not Applicable. 
During the open-label treatment phase 
- Drug Withdrawn – Study drug stopped permanently. 
- Dose Reduced. 
- Dose Increased. 
- Dose Not Changed.  
- Not Applicable. 
 


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The outcome of the AE: 
- Recovered/Resolved. 
- Recovering/Resolving. 
- Not Recovered/Not Resolved. 
- Recovered/Resolved with Sequelae. 
- Fatal. 
- Unknown. 
 
The causal relationship of the AE to the study treatment:  
Not related   
- Not related – Improbable temporal relationship and is plausibly related to other 
drugs or underlying disease. 
Related 
- Possible – occurred in a reasonable time after study drug administration 
(application), but could be related to concurrent drugs or underlying disease. 
- Probable – occurred in a reasonable time after study drug administration 
(application), is unlikely to be attributable to concurrent drugs or underlying disease, 
and there is a plausible mechanism to implicate the study drug.  
- Definite – occurred in a reasonable time after study drug administration (application) 
and cannot be explained by concurrent drugs or underlying disease.  The adverse 
event should respond to dechallenge/rechallenge, however, this is not mandatory 
before assigning a definite causality. 
 
The Medical Monitor is the initial contact person outside Japan for protocol related 
questions or discussion of AEs.  In Japan, the Sponsor or the designees are the contact 
persons.  The contact information as well as other emergency contact information can 
be found in Table 1 and 2 Emergency Contact Information (p3). 
 
12.4 Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor/CRO: 
- SAE 
- Pregnancy 
Emergency contact information can be found in Table 1 and 2 Emergency Contact 
Information (p3). 
 
12.4.1 
Serious Adverse Event  
If the Investigator or staff of study centers becomes aware of SAE that occurs in a 


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study subject from the beginning of the study treatment in the washout phase until the 
follow-up visit, this must be reported immediately to the Sponsor/CRO whether 
considered related or unrelated to the study drug.  SAEs occurring from the beginning 
of the study treatment in the washout phase until the follow-up visit must be recorded 
in the CRFs. 
 
Following the end of subject participation in the study, the Investigator should report 
SAEs “spontaneously” to the Sponsor/CRO if considered at least possibly related to 
the study drug.  
 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or 
the event is otherwise explained.  
 
The Investigator must inform the Sponsor/CRO (Table 1 and 2 Emergency Contact 
Information) of any SAEs that occur during the course of the study within 24 hours of 
the Investigator becoming aware of the SAE.  
 
The SAE report should include the following information: 
1. 
Study number (D4904020) 
2. 
Subject number 
3. 
Sex 
4. 
Date of birth 
5. 
Name of investigator and study site 
6. 
Nature of SAE 
7. 
Criterion for classification as “serious” 
8. 
Date of initial administration of the study drug 
9. 
Start date of SAE 
10. Causality (if sufficient information is available to make this classification) 
11. History of any ADRs 
12. Relevant special conditions of the subject 
13. History of the current disease and treatment for the disease 
14. Details of the SAE 
15. Treatment for the SAE 
16. Details of study treatments 
17. Details of concomitant medications 
18. Details on course of the SAE 
19. If the subject died, date of death, cause of death, relationship between the SAE 


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and death, anatomic findings (if available) 
 
As a minimum requirement for the first report, information on items 1 to 10 described 
above should be provided directly or in a form of a report, by facsimile, or by 
telephone.  The Principal Investigator should report available information in writing 
within 7 calendar days after the first reporting (this procedure is not mandatory in the 
case that the Principal Investigator has already submitted the first report, including all 
necessary information listed above).  The Principal Investigator should report other 
necessary information not included in the first and second reports in writing as it 
becomes available.  The Sponsor/CRO may request additional information, if deemed 
necessary. 
 
The Sponsor or designee will promptly notify all study centers and Investigators of a 
SAE that is determined to be expedited to the Regulatory Authorities in accordance 
with applicable law(s) and regulation(s).  These SAEs must be promptly reported to 
the Institutional Review Board (IRB)/IEC by the Principal Investigator or the 
appropriate person at the study center.  In Japan, these SAEs must be promptly 
reported in writing to the head of the study center by the Principal Investigator. 
 
12.4.2 
Pregnancy 
Pregnancies that occur from the beginning of the study treatment in the washout phase 
until the follow-up visit will be collected and reported to the Sponsor/CRO. 
 
If a subject becomes pregnant from the beginning of the study treatment in the washout 
phase until the follow-up visit, she will be instructed to commence discontinuation of 
the study medication.  Further, the subject (or female partner of a male subject) will 
be instructed to return promptly after the first notification of pregnancy to the study 
center and undergo a serum pregnancy test, as confirmation of pregnancy.  If positive, 
the subject will no longer receive any additional study medication.  All pregnancies 
will be followed until resolution (ie, termination [voluntary or spontaneous] or birth).  
If the Investigator becomes aware of pregnancies, this must be promptly reported 
directly or by telephone or facsimile to the Sponsor/CRO (Table 1 and 2 Emergency 
Contact Information).  The Investigator must complete the Pregnancy Event Form 
and send it to the Sponsor/CRO.   
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug 
may have interfered with the effectiveness of a contraceptive medication or other AEs 


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were detected. 
 
 
13. TERMINATION OF SUBJECT FROM 
STUDY/DISCONTINUATION OF STUDY DRUG  
13.1 Criteria for Subject Termination 
Subjects may terminate the study participation at any time for any reason.  
 
The possible reasons for the termination of study participation are as follows: 
- Adverse event 
- Suicide ideation 
- Study drug discontinuation 
- Lack of efficacy 
- Lost to follow-up 
- Pregnancy 
- Withdrawal by subject 
- Failure to apply >50% of the study medication since the last visit 
- Protocol violation 
- Other 
 
If at any time during the course of the study, in the opinion of the Investigator, the 
subject may no longer safely participate due to a change in medical status (eg, 
experiences an AE or suicide ideation, becomes pregnant), or discontinuation of the 
study drug should be considered, the subject must be discontinued from the study 
treatment. 
 
The date of discontinuation and the reason for discontinuation will be recorded in the 
appropriate CRF.  Subjects who prematurely terminate the study participation will not 
be replaced.  
 
13.2 Clinical Assessments after Study Drug Discontinuation 
Every effort should be made for all randomized subjects prematurely discontinuing the 
study drug, regardless of cause, to undergo final evaluation procedures, in accordance 
with the discontinuation visit and the follow-up visit as described in Table 4 Schedule 
of Assessments for outside Japan (p11) or Table 5 Schedule of Assessments for Japan 
(p13).  The subject will undergo the discontinuation assessments within 5 days of the 
last study drug application. However, if a subject completes the double-blind treatment 


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phase and discontinues before entering the open-label treatment phase, the subject will 
undergo the follow-up visit in Table 4 or that in Table 5. 
 
Subjects with study drug application during the washout phase and prematurely 
discontinuing before randomization, will undergo the following safety assessments: 
study treatment compliance, skin irritation assessment, laboratory test, 12-lead ECG, 
body weight, body temperature, blood pressure, pulse rate, and adverse event 
monitoring at the discontinuation visit in Table 4 Schedule of Assessments for outside 
Japan (p11) or Table 5 Schedule of Assessments for Japan (p13). 
 
13.3 Early Termination of the Study for Futility 
If the Sponsor decides early termination of the study for futility on the basis of the 
interim analysis, Investigators must stop obtaining consent from any new subjects and 
stop enrolling any subjects into the study.  Investigators will inform all subjects 
already enrolled about the study termination.  All subjects must be discontinued from 
the study treatment at any time during the course of the study and will undergo the 
clinical assessments described in Section13.2 Clinical Assessments after Study Drug 
Discontinuation. 
 
 
14. STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at multiple study centers for 
safety or administrative reasons at any time while ensuring that early termination does 
not compromise the safety or well-being of the subjects.  In particular, a study center 
that does not recruit at an acceptable rate may be closed.  Should the study be 
terminated and/or the study center closed for whatever reason, study medications 
pertaining to the study must be returned to the Sponsor/CRO. 
 
If the Sponsor decides to prematurely terminate the study, the Sponsor will inform the 
Investigator and regulatory authorities of this termination and its reason, and in 
addition, the head of the study center in Japan must be informed.  In the event of 
study or study center termination, the subjects will be provided with access to standard 
care. 
 
 


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15. STATISTICS 
A statistical analysis plan (SAP) will provide details on the statistical analysis method 
planned for the study.  The SAP will be finalized before unblinding.  Unblinding and 
data analysis for the double-blind treatment phase will occur after all subjects have 
completed or discontinued the double-blind treatment phase, the database for the 
double-blind treatment phase has been finalized, and the analysis populations other 
than the open-label population have been determined.  The analysis for the entire 
duration of the study will be conducted at the time of regulatory submission as well as 
after the study completion.  For the analysis for the entire duration of the study, we 
will combine data from databases for both double-blind phase and open-label phase. 
 
For the analysis of pharmacokinetics (PK) or pharmacokinetics-pharmacodynamics 
(PK-PD) not defined in the protocol, detailed procedures will be described in PK or 
PK-PD analysis plan.  If necessary, PK or PK-PD data will be combined with those of 
other studies and analyzed.  Results will be reported separately from the clinical study 
report.  
 
In the current study, the unblinded interim analysis for futility will be performed 
(Section15.4 Interim Analysis, p70).  The interim analysis plan describing further 
detail of interim analysis will be finalized before performing of the interim analysis, 
separately from the SAP.  When the study is continued, the analyses will be 
performed as per the protocol and the SAP.  When the study is early terminated after 
the interim analysis, the final analysis will be performed. 
 
15.1 Sample Size Determination 
Double-blind treatment phase 
The target number of randomized subjects is 501.  
 
 DSP-5423P 40 mg group  
167 
 
DSP-5423P 80 mg group  
167 
 
Placebo group 
 
 
167 
 
Rationale 
The sample size for the study has already been determined by a Monte-Carlo 
simulation using Statistical Analysis Software (SAS Version 9.3, SAS Institute).  The 
sample size calculation is based on the number of subjects required for the primary 
analysis in the modified intention-to-treat (mITT) population, wherein the primary 
analysis is to be performed on the change in PANSS total score from baseline at 


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Week 6.  The Hochberg procedure will be utilized for the multiplicity adjustment to 
the multiple comparisons between each DSP-5423P (40 and 80 mg/day) group and the 
placebo group.  Neither a placebo-controlled study nor an active-controlled study of 
DSP-5423P has been conducted.  In contrast, a double-blind placebo-controlled study 
of DSP-5423 (tablets, 2.5, 5 and 10 mg/day) treatment for 6 weeks for comparison 
with the placebo has been conductedref.16.  The results of the study are shown in Table 
16.  The sample size for the study has been determined on the basis of the effect size 
estimated using the result of each DSP-5423 group except DSP-5423 2.5 mg/day in 
this study because DSP-5423P doses in the study were chosen to correspond to 
DSP-5423 8 and 16 mg/day. 
 
Table 16  Change in PANSS total score 
 
 
Change in PANSS total score from baseline 
Treatment group 
N 
Mean ± SD 
Effect Size (95% CI) 
DSP-5423 2.5 mg 
60 
-20.433±21.101 
-0.338 (-0.689, 0.021) 
DSP-5423 5 mg 
57 
-27.123±17.461 
-0.650 (-1.020, -0.279) 
DSP-5423 10 mg 
62 
-29.516±24.721 
-0.667 (-1.030, -0.304) 
HPD 10 mg 
58 
-27.569±17.623 
-0.669 (-1.038, -0.299) 
Placebo 
61 
-12.213±26.840 
- 
Abbreviation: HPD=haloperidol 
 
The effect sizeref.17 was estimated to be 0.650 for DSP-5423 5 mg/day and 0.667 for 
DSP-5423 10 mg/day based on this study.  It is considered that the change in PANSS 
total score from baseline will be smaller than in past study because in the earlier study, 
in which the enrollment criteria targeted outpatients or inpatients hospitalized within 
two weeks according to acute aggravation, more patients with a newly exacerbated 
psychotic state were enrolled than in this study.  In addition, a trend for drug-placebo 
differences in the clinical trial to be diminishing annually in the field of schizophrenia 
has been pointed outref. 18.  For the reasons noted above, the effect size in the present 
study is assumed to be 0.45 which is about two-thirds of the effect size of DSP-5423 
5 mg/day and DSP-5423 10 mg/day.  A sample size of 133 per group was estimated to 
yield a complete power (probability of rejecting 2 null hypotheses) of 89% with a 
two-sided 5% significance level using the Hochberg procedure for multiplicity 
adjustment and taking an interim analysis for futility into consideration.  Considering 
that there is the possibility of subjects discontinuing before completion of the 
double-blind treatment phase, the total sample size will need to be 501 subjects or 167 
subjects per treatment group. 


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15.2 Analysis Populations 
The primary efficacy analysis will be performed in the modified intention-to-treat 
(mITT) population.  The efficacy analysis on the primary variable will also be 
performed in the per-protocol (PP) population for sensitivity analysis.  Some efficacy 
data in the open-label treatment phase will be analyzed for the open-label treatment 
phase population.  The safety analysis will be performed in the safety population.  
Efficacy and safety analyses for DSP-5423P treatment period will be performed on 
DSP-5423P dosed population.  The mITT analysis will be performed using the 
assigned treatment groups, and the safety analysis using the groups of the treatment 
actually received.   
 
15.2.1 
Modified intention-to-treat population (mITT population) 
The mITT population will consist of all subjects who meet all the following: 
- Subjects who are randomized and apply the study drug at least once in the 
double-blind treatment phase. 
- Subjects who have baseline and at least one post-baseline PANSS total score rated in 
the double-blind treatment phase. 
 
15.2.2 
Per-protocol population (PP population) 
The PP population will consist of subjects of the mITT population who meet all the 
following: 
- Subjects who meet the inclusion criteria at screening (1) to (4), and (7) and do not 
meet any of the exclusion criteria at screening (12) to (17), and (22)  
- Subjects who meet all of the inclusion criteria at randomization and do not meet the 
exclusion criterion at randomization (1)  
- Subjects who apply at least 80% of the study treatment in the double-blind treatment 
phase 
- Subjects who receive no antipsychotics during the washout phase and the 
double-blind treatment phase.   
- Subjects who have no other important protocol deviations with an impact on the 
efficacy analyses as determined by a blinded data review 
 
15.2.3 
Open-label population 
The open-label population will consist of all subjects who apply DSP-5423P at least 
once in the open-label treatment phase. 
 


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15.2.4 
Safety population 
The safety population will consist of all subjects who are randomized and apply the 
study drug at least once during the study. 
 
15.2.5 
DSP-5423P dosed population 
The DSP-5423P dosed population will consist of all subjects who apply DSP-5423P at 
least once during the study.   
 
15.2.6 
Pharmacokinetic analysis population (PK population) 
The PK population will consist of all subjects who meet all the following: 
- Subjects who are randomized and apply DSP-5423P at least once during the study 
- Subjects who have at least one plasma concentration of blonanserin after application 
of DSP-5423P 
 
15.3 Data Analysis 
15.3.1 
Subject Disposition  
The number of subjects who provide informed consent, enroll in the wash-out phase, 
are randomized, not apply the study drug in the double-blind treatment phase, apply 
the study drug in the double-blind treatment phase and complete or discontinue the 
double-blind treatment phase will be presented by treatment group.   
 
Also, the number of subjects who complete the double blind treatment phase, 
discontinue the open-label treatment phase before the initial application in the 
open-label treatment phase, apply DSP-5423P in the open-label treatment phase at 
least once, and complete or discontinue the open-label treatment phase will be 
presented both overall and by treatment group. 
 
15.3.2 
Drug Exposure and Compliance 
15.3.2.1 
Double-blind treatment phase 
Duration of treatment and compliance with the study drug in the double-blind 
treatment phase will be summarized by treatment group for all of the analysis 
populations. 
 
15.3.2.2 
Open-label treatment phase 
Duration of treatment, mean, modal, and last daily dose, and compliance with 
DSP-5423P in the open-label treatment phase will be summarized both overall and by 
treatment group for all of the analysis populations. 


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15.3.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) will be identified by a blinded data review 
before unblinding.  IPDs will be presented in the data listing. 
 
15.3.4 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized both overall and by 
treatment group for all of the analysis populations. 
 
15.3.5 
Efficacy Analysis 
15.3.5.1 
Hypothesis 
Let μ40, μ80, and μplacebo represent the mean changes in PANSS total score from baseline 
at Week 6 in the DSP-5423P 40 mg group, DSP-5423P 80 mg group, and placebo 
group, respectively.  The following two hypotheses will be tested to compare the 
mean changes at Week 6 of each DSP-5423P group with that of the placebo group: 
- H01: μ40=μ placebo versus the alternate H11: μ40 ≠μ placebo. 
- H02: μ80 =μ placebo versus the alternate H12: μ80 ≠μ placebo. 
 
15.3.5.2 
Primary analysis 
The primary efficacy variable is the change in PANSS total score from baseline at 
Week 6 for testing the superiority of DSP-5423P (40 or 80 mg/day) to placebo.  A 
mixed model for repeated measurements (MMRM) method will be used in the mITT 
population.  The MMRM model will include treatment as a categorical factor, visit 
(Week 1, 2, 4, and 6; as a categorical factor), pooled study center, baseline PANSS total 
score as a covariate, and the treatment-by-visit interaction.  An unstructured 
covariance matrix will be used for the within-subject correlation and the Kenward- 
Rogers approximation will be used to calculate the denominator degree of freedom.  
In case of a convergence problem with the unstructured covariance matrix, the 
following structures with a robust sandwich estimator for the standard error of the 
fixed effect estimates will be assessed in a sequential fashion: heterogeneous Toeplitz, 
heterogeneous first-order autoregressive, and Toeplitz.  Of the above three covariance 
structures, the first covariance structure yielding convergence will be used for the 
MMRM analysis.  P-values for comparisons of the primary efficacy variable at 
Week 6 between DSP-5423P groups and the placebo group will be adjusted using the 
Hochberg procedure. 
 
An analysis of sensitivity for the primary efficacy variable will be performed using an 


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analysis of covariance (ANCOVA) model on the mITT population.  The response 
variable for the model will be the change in PANSS total score from baseline at the 
LOCF endpoint.  The ANCOVA model will include treatment as a categorical factor, 
pooled study center, and baseline PANSS total score as a covariate.  The MMRM and 
LOCF ANCOVA analysis will also be performed in the PP population to obtain 
additional information on the robustness of the results.   
 
15.3.5.3 
Secondary Efficacy Endpoint Analysis 
15.3.5.3.1 
Double-blind treatment phase 
1. 
Change in PANSS subscale scores from baseline at Week 6 
2. 
Change in PANSS five-factor model scores from baseline at Week 6 
3. 
Change in CGI-S score from baseline at Week 6  
4. 
Proportion of subjects who achieve a response, defined as 20% or greater 
improvement from baseline in PANSS total score at Week 6 
 
The secondary variables (1) to (3) will be analyzed using the MMRM method 
described above for the primary efficacy variable in the mITT population.  The 
secondary variables (1) and (3) will also be analyzed using the LOCF ANCOVA on the 
mITT population, by the method described above for the primary efficacy variable.  
The secondary variable (4) will be analyzed using a logistic regression model, which 
will include baseline PANSS total score, pooled study center, and treatment. 
 
15.3.5.3.2 
Open-label treatment phase 
The time to treatment discontinuation from the initial application in the open-label 
treatment phase will be analyzed using the Kaplan-Meier method for the open-label 
population.  The Kaplan-Meier curves will be shown overall and by treatment group 
in the double-blind treatment phase. 
 
15.3.5.3.3 
DSP-5423P Treatment Period 
1. 
Change in PANSS total score from the last evaluation before the initial application 
of DSP-5423P at each visit 
2. 
Change in PANSS subscale scores from the last evaluation before the initial 
application of DSP-5423P at each visit 
3. 
Change in PANSS five-factor model scores from the last evaluation before the 
initial application of DSP-5423P at each visit 
4. 
Change in CGI-S score from the last evaluation before the initial application of 
DSP-5423P at each visit 


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Summary statistics for the secondary variables (1) to (4) will be provided for each visit 
and LOCF endpoint by treatment group for the DSP-5423P dosed population. 
 
15.3.5.4 
Adjustment for Multiplicity  
The Hochberg procedure will be used to control the overall Type I error at 5% by 
taking into account multiple dose regimens for the primary efficacy analysis. 
The interim analysis for futility does not inflate the overall Type 1 error as the 
significance level of the final analysis will not be accounted for the futility 
stopping ref.19,20. 
 
15.3.5.5 
Subgroup Analysis 
Subgroup analysis will be performed for the change in PANSS total score and CGI-S 
score from baseline at Week 6.  The subgroup analysis will include sex and age.  
Inferential analysis of treatment-by-subgroup interaction at Week 6 will be performed 
for each subgroup variable using the MMRM method on the mITT population.  The 
model will include treatment, visit, baseline data, pooled study center, subgroup, 
treatment-by-subgroup, 
treatment-by-visit, 
visit-by-subgroup, 
and 
treatment-by-subgroup-by-visit interactions. 
 
15.3.6 
Safety Analysis 
15.3.6.1 
Adverse Events 
The summary of AEs will be limited to treatment-emergent AEs (TEAEs), which are 
defined as AEs with onset on or after Day 1.  An ADR will be defined as an AE 
related to the study treatment; an AE of which causality with study drug is related, 
probably related, or possibly related. 
 
The number and percentage of subjects with at least one AE or ADR in the 
double-blind treatment phase for each preferred term and system organ class will be 
summarized by treatment group.  Also, the number and percentage of subjects with at 
least one AE or ADR developing after applying DSP-5423P during the entire study 
duration will be summarized overall and by treatment group.  This summary will be 
repeated for death, SAEs, AEs leading to study discontinuation, severe AEs, 
extrapyramidal AEs, and skin-related AEs at the application site. 
 
15.3.6.2 
DIEPSS 
1. 
Change in DIEPSS total score (excluding overall severity) from baseline at 


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Week 6 
2. 
Change in individual DIEPSS scores from baseline at Week 6 
3. 
Change in DIEPSS total score (excluding overall severity) from the last evaluation 
before the initial application of DSP-5423P at each visit 
4. 
Change in individual DIEPSS scores (excluding overall severity) from the last 
evaluation before the initial application of DSP-5423P at each visit 
 
The safety variables (1) will be analyzed using the MMRM method and the LOCF 
ANCOVA described above for the primary efficacy variable.   
Summary statistics for the safety variables (2), (3) and (4) will be provided for each 
visit and LOCF endpoint by treatment group. 
 
15.3.6.3 
C-SSRS 
The numbers and percentages of subjects with suicidal ideation and suicidal behavior 
will be summarized by treatment group. 
 
15.3.6.4 
Skin irritation assessment 
The distribution of the worst score in the skin irritation assessment for each subject 
during the double-blind treatment phase, and the DSP-5423P treatment period will be 
shown. 
 
15.3.6.5 
Laboratory tests, vital signs, body weight, and 12-lead ECG 
Summary statistics for laboratory tests, vital signs, body weights, and 12-lead ECG 
parameters will be provided at each visit by treatment group. 
 
15.3.6.6 
Concomitant Medications 
The number and percentage of subjects with concomitant use of antiparkinson drugs in 
the double-blind treatment phase will be summarized by treatment group.  The 
number and percentage of subjects with concomitant use of antiparkinson drugs for the 
DSP-5423P treatment period will be summarized overall and by treatment group.   
 
15.3.6.7 
Subgroup Analysis 
Subgroup analysis will be performed for AEs and changes in DIEPSS total score 
(excluding overall severity) from baseline at Week 6 (LOCF).  The subgroup analysis 
will include sex and age. 
 


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15.3.7 
Pharmacokinetic Analysis 
15.3.7.1 
Double-blind treatment phase 
Plasma concentrations of blonanserin and M-1 will be summarized at each visit by 
treatment group.  Plasma concentration ratio of M-1 to blonanserin will be 
summarized at each visit by treatment group. 
 
15.3.7.2 
Open-label treatment phase 
Plasma concentrations of blonanserin and M-1 will be summarized at each visit by the 
last application before the visit.  Plasma concentration ratio of M-1 to bonanserin will 
be summarized at each visit by the last application before the visit. 
 
15.3.7.3 
Subgroup Analysis 
Subgroup analysis will be performed for plasma concentrations of blonanserin at 
Week 6 and Week 34.  The subgroup analysis will include sex and age.  The ratio of 
the geometric mean of plasma concentrations of blonanserin at Week 6 in elderly 
adults to non-elderly adults and the corresponding 90% confidence interval will be 
presented by treatment group.  Also, the ratio of the geometric mean of plasma 
concentrations of blonanserin at Week 34 in elderly adults to non-elderly adults and the 
corresponding 90% confidence interval will be presented by the last application before 
the visit. 
 
15.3.8 
Handling of data 
15.3.8.1 
Day 1 
Day 1 is defined as the day of the initial application in the double-blind treatment 
phase. 
 
15.3.8.2 
Analysis visits, baseline, and post-baseline measures 
All data will be organized and analyzed according to the scheduled timing as outlined 
in Table 3 to 5 Schedule of Assessments (p10~13) and according to the visit denoted in 
the CRFs.  Unscheduled visits may be used if scheduled visits are not available, and 
details will be prespecified in the statistical analysis plan before the interim analysis is 
performed. The baseline data for statistical analyses will be defined as the last 
non-missing data on or before Day 1.  In analysis for the open-label treatment phase 
and the DSP-5423P treatment period, the baseline data of the subjects in the Placebo 
group will be defined as the last non-missing data before the beginning of DSP-5423P 
application.  Post-baseline data for statistical analysis will be defined as the 
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application of the study drug (excluding baseline).  The data collected at the 
discontinuation visit will be mapped to the next scheduled visit of the actual 
discontinuation date. 
 
15.3.8.3 
Missing Data 
For the rating scales that consist of more than one item, if any item is missing, then the 
total and subscale scores will also be handled as missing.   
 
In the efficacy analysis on data collected in the double-blind treatment phase, the 
primary method for handling of missing data will be the MMRM without explicit 
imputations for missing data.  The LOCF method will be used for an analysis of 
sensitivity.  The final post-baseline data in the double-blind treatment phase will be 
carried forward and will be defined as the Week 6 (LOCF).  The final post-baseline 
value of the entire study duration will be defined as LOCF endpoint for all subjects.   
 
In the safety analysis, the final post-baseline data in the double-blind treatment phase 
will be carried forward and will be defined as the Week 6 (LOCF).  The final 
post-baseline value of the entire study duration will be defined as the LOCF endpoint 
for all subjects.   
 
15.4 Interim Analysis 
An interim analysis for futility will be performed after 50% of target number of 
subjects complete or prematurely discontinue the double-blind treatment phase.  The 
interim analysis will be performed on the change in PANSS total score from baseline 
in the mITT population.  If the conditional power based on the treatment differences 
in PANSS total score is less than the futility criteria of 8%, the study may be 
terminated early. Otherwise, the study will be continued.  The interim analysis will be 
performed in accordance with the protocol and a charter for the interim analysis which 
describes well-defined procedures for the interim analysis.  Analysis method for 
interim analysis is outlined in Section 15.4.1 (p71) and will be detailed in an interim 
analysis plan. 
 
Separated from the formal interim analysis described above, after all subjects have 
completed the double-blind treatment phase or prematurely terminated the study, the 
efficacy and safety data up to 6 weeks will be analyzed.  After all subjects have 
completed at Visit 108 in the open-label treatment phase or discontinued from the study, 
the study data will be analyzed for the purpose of the regulatory submission before the 


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database lock.  Details of the analyses conducted for the regulatory submission will 
be provided in the statistical analysis plan. 
 
15.4.1 
Outlined Interim Analysis 
The analysis population for the interim analysis will be mITT population and 
determined by a blinded data review before the interim analysis.  PANSS data at all 
scheduled visits, discontinuation visits, and unscheduled visits of double-blind 
treatment phase of the analysis population for the interim analysis will be collected and 
cleaned.  The primary variable for the interim analysis will be the change in PANSS 
total score from baseline and its treatment difference between DSP-5423P and placebo 
will be used for estimating the conditional power.  The conditional power under an 
empirical assumption will be compared with the futility boundary of 8%, where the 
empirical assumption assumes that the observed trend in treatment difference will 
continue to the end of studyref.19.  Any safety data will not be reviewed in unblinded 
manner at the interim analysis.  
 
15.4.2 
Independent Biostatistician and Steering Committee 
An independent biostatistician will be appointed in a CRO not delegated any study 
procedure for the study.  The Sponsor steering committee (SC) member(s) will be 
those who are not involved in conducting the study.  The charter for the interim 
analysis will specify roles and responsibilities of the appointed independent 
biostatistician and the SC, and include procedures to provide the recommendation from 
the independent biostatistician to the SC, and specify the detailed futility criteria. 
 
The independent biostatistician will perform the interim analysis and make a 
recommendation to the SC based on interim analysis results and the futility criteria 
specified in the charter for interim analysis.  If the conditional power is below the 
boundary, the Sponsor will be recommended to early terminate the study for futility, 
otherwise, to continue the study as planned.  The SC is responsible to make a decision 
whether to continue or early terminate the study.  The decision of SC (not including 
the recommendation) will be informed to the study team.   
 
Data monitoring committee (DMC) will not be organized for the interim analysis 
because any safety concern of DSP-5423P to require the use of DMC has not been 
identified from previous and ongoing studies. 
 


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15.4.3 
Confidentiality of Interim Data and Analyses 
For the interim analysis, the randomization code will be revealed only to the appointed 
independent biostatistician and programmer(s) performing the interim analysis.  The 
independent biostatistician will make the recommendation only to the SC and will not 
disclose any information revealing unblinded interim results to anyone until the 
database lock and unblinding thoroughly for the double-blind treatment phase.  The 
SC will also keep the recommendation confidential until the study unblinding. 
 
 
16. PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL 
/DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
16.1 Data Collection/Electronic Data Capture (EDC) 
The study data of subjects who provide informed consent will be captured in the CRFs 
through the electronic data capture (EDC) system.  The users of this system should 
receive EDC training from the Sponsor or its delegate.  The data will be recorded in 
the CRFs in English as soon as data are available for entry.  Each set of completed 
CRFs must be reviewed and electronically signed and dated by the Investigator.  
 
The Sponsor will provide copies of the original CRFs for the Principal Investigator, 
and he/she will retain them.  If data are inconsistent with source documents, the 
Investigator will clarify the lack of consistency and record the reason.  The record 
will be provided to the Sponsor.  The Principal Investigator will keep copies of the 
record. 
If the data need to be revised, the Investigator will comply with the guidance for CRF 
provided by the Sponsor.  
 
Of the data recorded in the CRF, the source documents of the following can be CRFs 
per se:    
- The outcome, severity, seriousness of AEs 
- Causal relationship to the study treatment 
- The reasons for concomitant use 
- The reasons for dose changing of study drugs 
- The reason for discontinuation  
 
16.2 Study Monitoring 
This study will be monitored from initiation to completion by the Sponsor or its 


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representative.  Monitoring will include personal visits and telephone communication 
to assure that the investigation is conducted according to the protocol and in order to 
comply with ICH GCP and local regulations.  On-site review of CRFs will include a 
review of forms for completeness and clarity, and consistency with the source 
documents available for each subject. 
 
16.3 Audits 
The study may be subject to audit by the Sponsor or designee.  If such an audit occurs, 
the Investigator must agree to allow access to required subject records.  This is 
dependent on the subject granting consent by signing the ICF.  By signing this 
protocol (affixing a seal with the name on this protocol will be also acceptable in 
Japan), the Investigator grants permission to personnel from the Sponsor or its 
representatives for on-site monitoring and auditing of all appropriate study 
documentation, as well as on-site review of the procedures employed in CRF 
generation, where clinically appropriate. 
 
16.4 Study Documentation 
Study records are comprised of source documents, CRFs, and all other administrative 
documents.  A source document is defined as any hand written or computer generated 
document that contains medical information or test results that have been collected for 
or are in support of the protocol specifications. 
 
16.5 Clinical Laboratory Certification and Normal Values 
A central laboratory will be used for analysis of most of the clinical laboratory tests for 
this study.  The central laboratory will provide the Investigator, Sponsor/CRO with 
laboratory certification(s), and a dated copy of normal range values for the central 
clinical laboratory selected to analyze clinical specimens.  If an exception is granted 
to use a local laboratory, the Investigator must supply the Sponsor/CRO with 
laboratory certification and a current, dated copy of normal range values.  
 
 
17. ETHICAL AND REGULATORY OBLIGATIONS 
<The procedure for Section 17 in Japan is described in the Japan Appendix.>  
 
17.1 Study Conduct 
The Investigator agrees that the study will be conducted according to the protocol, ICH 
Good Clinical Practice (GCP) and the ethical principles that have their origin in the 


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Declaration of Helsinki.  The Investigator will conduct all aspects of the study in 
accordance with applicable local law(s) and regulation(s). 
 
The Investigator will assure proper implementation and conduct of the study including 
those study-related duties delegated to other appropriately qualified individuals.  The 
Investigator will assure that study staff cooperate with monitoring and audits. 
 
The Investigator must sign and return to the Sponsor/CRO the “Investigator Approval" 
page. 
 
17.2 Institutional Review Board 
Documented approval for conducting the study from the appropriate Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) will be obtained for all 
participating centers before initiation of the study, according to ICH GCP, applicable 
local law(s) and regulation(s).  When necessary, an extension, amendment or renewal 
of the IRB/IEC approval must be obtained and also forwarded to the Sponsor. 
 
A copy of written IRB/IEC approval or a favorable opinion of the protocol, informed 
consent form and subject recruitment material (if applicable) must be provided to the 
Sponsor/CRO before start of the study. 
The Investigator/CRO is responsible for obtaining from the IRB/IEC continued review 
of the clinical research or submitting periodic progress reports, in accordance with 
applicable regulations, at intervals not to exceed one year or as otherwise specified by 
the IRB/IEC.  The Sponsor must be supplied with written documentation of continued 
review of the clinical research.  
 
The Investigator must promptly inform the IRB/IEC of all SAEs reported by subjects 
enrolled in the study or other safety information reported from the Sponsor/CRO in 
accordance with applicable law(s) and regulation(s). 
 
17.3 Informed Consent 
The Investigator will prepare the informed consent form and provide the form to 
Sponsor/CRO for approval before submission to the IRB.  The informed consent form 
will be approved by the Sponsor/CRO before submission to the IRB.   
 
The Sponsor/CRO may provide a template informed consent form to be qualified by 
each research facility to conform to local requirements.  All informed consent forms 


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must contain the minimum elements as mandated by ICH GCP, applicable local law(s) 
and regulations and will be approved by the Sponsor/CRO as well as the IRB. 
   
For patients who are under the adult age based on the local regulation in each country 
at informed consent, consent should be obtained from the patient’s legally acceptable 
representative (guardian) in addition to the consent from the patient. 
 
Before recruitment and enrollment, each prospective subject and guardian (as needed) 
will be given a full explanation of the study, allowed to read the approved informed 
consent form and be provided ample time and the opportunity to ask any questions that 
may arise.  Once all questions have been answered and the Investigator is assured that 
the prospective subject and guardian (as needed) understand the implications of 
participating in the study, the prospective subject and guardian (as needed) will be 
asked to give consent to participate in the study by signing the informed consent form.  
As part of the consent process, each prospective subject and guardian (as needed) must 
consent to direct access to his/her medical records for study-related monitoring, 
auditing, IRB review, and regulatory inspection.  It should be clearly explained to 
each prospective subject and guardian (as needed) that participation in each and every 
clinical visit and assessment is expected.  The subject may be discontinued from 
study medication, but that does not necessarily negate the expectation that the subject 
will continue to participate in the study through the final visit/assessment.  The 
Investigator will provide a copy of the signed informed consent form to each subject 
and guardian (as needed), and will record the date of the informed consent in the CRF.  
 
If an amendment to the protocol changes the subject participation schedule in scope or 
activity, or if important new information becomes available that may be relevant to the 
subject’s or guardian’s (as needed) consent, the informed consent form must be revised, 
submitted to the IRB for review and approval or a favorable opinion.  The revised 
informed consent form must be used to obtain consent from a subject and guardian (as 
needed) currently enrolled in the study if he or she is affected by the amendment.  The 
revised informed consent form must be used to obtain consent from any new subjects 
who are enrolled into the study after the date of approval or a favorable opinion of the 
protocol amendment. 
 
17.4 Subject Privacy 
The Sponsor (or Sponsor’s representative) or any designees affirm uphold the subjects 
confidentiality.  The subject will be identified by a unique code only; full names will 


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be masked before transmission to the Sponsor.  The confidentiality of the subject’s 
personal data shall be protected in accordance with appropriate laws and regulations.  
When any formal presentation or publications of data collected as a direct or indirect 
result of the study are made, the subject privacy will be protected 
 
17.5 Protocol Amendments and Emergency Deviations 
All revisions and/or amendments to this protocol must be approved in writing by the 
Sponsor and the appropriate IRB/IEC.  The Investigator will not make any changes to 
the conduct of the study or the protocol without first obtaining written approval from 
the Sponsor and the IRB/IEC, except where necessary to eliminate an apparent 
immediate hazard to a study subject. 
 
Emergency deviations or modifications may be initiated without Sponsor or IRB/IEC 
approval or a favorable opinion, only in cases where the deviation or modification is 
necessary to eliminate or avoid an immediate apparent hazard to subjects.  Emergency 
deviations or modifications must be reported to the Sponsor/CRO and the IRB/IEC 
immediately or in accordance with applicable regulatory requirements. 
 
17.6 Records Retention 
The Investigator/the site must arrange for retention of study records at the study center 
in accordance with applicable regulations and Sponsor SOPs.  The Investigator/site 
should take measures to prevent accidental or premature destruction of these 
documents.  Documents cannot be destroyed without written Sponsor authorization.  
The Sponsor will inform the Investigator/the site when the destruction of documents is 
permitted. 
 
17.7 Inspection of Records 
In the event of an inspection, the Investigator agrees to allow the Sponsor, its 
representative and the regulatory authorities’ access to all study records.  The 
Investigator will promptly notify the Sponsor/CRO of all requests to inspect a  
Sumitomo Dainippon Pharma Co., Ltd.-sponsored study by government agencies and 
will promptly forward a copy of all such inspection reports. 
 
17.8 Publication Policy  
Any formal presentation or publication of data collected as a direct or indirect result of 
the study will be considered a joint publication by the coordinating investigators or the 
Investigators and the appropriate personnel of the Sponsor.  For multicenter studies, it 


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is mandatory that the first publication is based on all data obtained from all analyses as 
stipulated in the protocol.  Investigators participating in multicenter studies must 
agree not to present data gathered individually or by a subgroup of centers before the 
full, initial publication, unless this has been agreed to by all other Investigators and by 
the Sponsor. 
 
17.9 Compensation 
If subjects have any adverse event or injury directly resulting from the study 
medications or procedures, the Sponsor will appropriately compensate in accordance 
with applicable regulatory requirements. 
 
 


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