Conditions: Schizophrenia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 200
Healthy volunteers: no

Brief summary:
The study evaluates the long term safety of DSP-5423P in patients with schizophrenia.

Detailed description:

Arms:
arm 1: Percutaneous

Interventions: intervention 1: DSP-5423P
Intervention descriptions: intervention 1: 40-80mg/day

Protocol document:
Prot_000.pdf: 
Protocol No. D4904040 1.02 
DSP-5423P 
 
 
Confidential and Proprietary 
 
30 October 2015 
 
 
 
 
DSP-5423P 
Study protocol 
Blonanserin 
D4904040 
Long-Term Study of DSP-5423P in Patients with Schizophrenia 
[Phase 3] 
 
 
 
 
 
 
 
 
Version number :1.02 
 
30 October 2015 
 
 
 
 
Sumitomo Dainippon Pharma Co., Ltd. 
1-13-1 Kyobashi, Chuo-ku, Tokyo 
 


Protocol No. D4904040 1.02 
DSP-5423P 
 
 
Confidential and Proprietary 
 
30 October 2015 
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. 




Protocol No. D4904040 1.02 
DSP-5423P 
1 
 
Confidential and Proprietary :30 October 2015 
1. SYNOPSIS 
Name of Sponsor: 
Sumitomo Dainippon Pharma Co., Ltd. 
Name of Investigational product: 
DSP-5423P 
Name of Active ingredient: 
Blonanserin 
Title of Study (study number): 
Long-Term 
Study 
of 
DSP-5423P 
in 
Patients 
with 
Schizophrenia [Phase III Study] (D4904040) 
Planned indication: 
Schizophrenia 
Phase of development: 
Phase III 
Study period (planned): 
December 2014 ~ July 2017 
(Last Date of Registration: May 2016) 
Study Objective: 
Primary objective: 
To evaluate the safety of DSP-5423P (40-80 mg/day) for 52-week treatment. 
 
Secondary objective: 
- To evaluate the safety and effectiveness of switching from DSP-5423 (tablet) to DSP-5423P. 
- To evaluate the effectiveness and pharmacokinetics of DSP-5423P (40-80 mg/day) for 52-week
treatment. 
Study design of clinical study: 
Multicenter, uncontrolled, open-label, flexible dose 
The study contains two cohorts: cohort 1 consists of DSP-5423 (tablet) treatment phase and DSP-
5423P treatment phase, and cohort 2 consists of DSP-5423P treatment phase. 
 
Study schematic (cohort 1) 
 
 
 
 
 
 
 
 
 
DSP-5423 
(Tablet) 
8~16 mg/day 
DSP-5423P 
40~80 mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 weeks 
52 weeks 
1-2 weeks 
 
 
Washout 
period* 
DSP-5423 
Tablet 
Treatment 
Phase 
DSP-5423P Treatment Phase 
Follow-up 
Phase 
 
* Prior to initiation/beginning of DSP-5423 (tablet) administration, washout period (up to 4 weeks) will be arranged
Informed consent 
Screening 
Registration 


Protocol No. D4904040 1.02 
DSP-5423P 
2 
 
Confidential and Proprietary :30 October 2015 
according to the dose of the prior antipsychotics (haloperidol equivalent). 
 
 
Study schematic (cohort 2) 
 
 
 
 
DSP-5423P 
40~80 mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
52 weeks 
1-2 weeks 
 
 
Washout 
period* 
DSP-5423P Treatment Phase 
Follow-up 
Phase 
 
* Prior to initiation/beginning of DSP-5423P application, washout period (up to 4 weeks) will be arranged according 
to the dose of the prior antipsychotics (haloperidol equivalent). 
Number of Subjects: 
Number of subjects of registration: 200 
- Number of subjects treated with DSP-5423P for 6 weeks of more in cohort 1: 50 subjects 
- Number of subjects treated with DSP-5423P for 52 weeks in cohort 1 and 2: 100 subjects 
Diagnosis: 
Schizophrenia 
 
Inclusion criteria: 
Patients who meet all of the following criteria. 
1) Patients who have schizophrenia diagnosed by Diagnostic and Statistical Manual of Mental 
Disorders, fifth edition (DSM-5), diagnostic criteria 
2) Patients who are aged 18 years or older at informed consent 
3) Patients who are fully informed of and understand the objective, 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, and if the patient is hospitalized 
involuntarily, written consent will be obtained from a legally acceptable representative Note 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. 
4) Patients with premenopausal female and of childbearing potential who have negative result for 
pregnancy laboratory test (urine) at screening 
5) Patients who have informed consent in adequate contraception to prevent pregnancy of the 
Screening 
Informed consent 
Registration 


Protocol No. D4904040 1.02 
DSP-5423P 
3 
 
Confidential and Proprietary :30 October 2015 
patients or their partners when they are female of childbearing potential. 
 
Exclusion criteria: 
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 topical 
use), or human immunodeficiency virus (HIV) protease inhibitors. 
4) Patients with medical history of hypersensitivity to bronanserin 
5) Patients with a history of or current neuroleptic malignant syndromes, tardive dyskinesia or 
water intoxication 
6) Patient with Parkinson's disease 
7) Patients with active suicidal ideation or those with a suicide attempt history who are considered 
ineligible for the study by the Investigator 
8) Patients with an HbA1c level (NGSP level) of 8.4% or higher 
9) Patients with physical exhaustion accompanied by conditions such as dehydration or 
malnutrition 
10) 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 
11) Patients with skin injuries, skin disease, or tattoos at the site of application (back, chest, or 
abdomen) that precludes adequate patch placement. 
12) Patients with a history of drug abuse, drug dependency, alcohol abuse, or alcohol dependency
within 6 months (180 days) before screening 
13) Patients who received any depot preparation (sustained-release formulation) of antipsychotics
within 3 months (90 days) before screening 
14) Patients who received clozapine administration within 4 months (120 days) before screening 
15) Patients who received administration of blonanserin within 1 Year (365 days) prior to screening 
and were considered resistant to treatment for blonanserin 
16) Patients who received monoamine oxidase (MAO) inhibitor administration within 1 month (30 
days) before screening 
17) Patients who received electroconvulsive therapy within 6 months (180 days) before screening
18) Pregnant or nursing mother 
19) Patients with a history or complication(s) of hypersensitivity to two or more drugs (patients 
with a history or complication(s) of drug-induced allergic reactions such as anaphylaxis, rash, 
and urticaria) 


Protocol No. D4904040 1.02 
DSP-5423P 
4 
 
Confidential and Proprietary :30 October 2015 
20) Patients with medical history or complication(s) of malignant tumor within 5 Years before 
screening 
21) HIV-infected patients 
22) Patients who received other investigational product or post-marketing clinical study drugs 
within 3 months (90 days) before screening, or patients who have enrolled in but not completed 
other clinical study or post-marketing study before screening 
23) Patients who are otherwise considered ineligible for the study by the investigator 


Protocol No. D4904040 1.02 
DSP-5423P 
5 
 
Confidential and Proprietary :30 October 2015 
Study drug, dose, mode of administration and duration of administration: 
Cohort 1: 
1) DSP-5423 (tablet) treatment phase 
DSP-5423 (tablets) will be administered orally twice daily (after breakfast and evening meal) 
for 6 weeks. The initial dose of DSP-5423 (tablet) will be 8mg/day. DSP-5423 (tablet) will be 
administered as flexible dose (8, 12, 16 mg/day) according to the dose adjustment criteria 
(section 10.2).  
2) DSP-5423P treatment phase 
DSP-5423P will be applied once daily for 52 weeks. The study drug will be applied to the 
subject’s back, chest, or abdomen. Start DSP-5423P application with the dosage according to 
the final dosage of DSP-5423 (Table 8 starting dose of DSP-5423P corresponding to DSP-5423 
(tablet) final dose). DSP-5423P will be applied as flexible dose (40, 60, 80 mg/day) according 
to the dose adjustment criteria (section 10.2). 
Cohort 2: 
DSP-5423P will be applied once daily for 52 weeks. The study drug will be applied to the subject’s 
back, chest, or abdomen. The initial dose of DSP-5423P will be 40 mg/day. DSP-5423P will be applied 
as flexible dose (40, 60, 80 mg/day) according to the dose adjustment criteria (section 10.2).  
 




Protocol No. D4904040 1.02 
DSP-5423P 
7 
 
Confidential and Proprietary :30 October 2015 
Study Endpoints: 
Efficacy endpoint 
1) Change in Positive and Negative Syndrome Scale (PANSS) total score from baseline note 1) 
2) Change in PANSS subscale total scores from baseline note 1) 
3) Change in by PANSS 5 Factor Model total score from baseline note 1) 
4) Change in Clinical Global Impressions–Severity of Illness(CGI-S) scores from baseline note 1) 
5) Time to treatment discontinuation from the initial application of DSP-5423P 
Note 1) Baseline of DSP-5423P treatment phase 
 
Safety endpoint 
6) Adverse events (AEs) and adverse drug reaction (ADRs) 
7) Extrapyramidal AEs and ADRs 
8) Skin-related AEs and ADRs at the application site 
9) Assessment of skin irritation reaction at the application site 
10) Change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) Total Score (excluding 
overall severity) from baseline 
11) Change in individual DIEPSS scores from baseline 
12) Serum prolactin concentration 
13) Electrocardiogram (ECG) parameters (QTc) 
14) Concomitant use of antiparkinson drug 
15) Assessment of suicides using Columbia-Suicide Severity Rating Scale(C-SSRS) 
16) Laboratory test values, vital signs and body weight 
 
Pharmacokinetic endpoints 
1) Plasma concentration of bronanserin 
2) Plasma concentration of bronanserin’s metabolites 
 
Other endpoints 
1) Total score of Drug Attitude Inventory-10(DAI-10) 
2) EuroQol-5 Dimension (EQ-5D) index values. 
3) Questionnaire on dosage form 
 
Statistical statistical method: 
For efficacy endpoints excluding time to treatment discontinuation from the initial application of 
DSP-5423P, summary statistics by visit will be provided. Time to treatment discontinuation from the 
initial application of DSP-5423P will be analyzed using Kaplan-Meier method. 




Protocol No. D4904040 1.02 
DSP-5423P 
9 
 
Confidential and Proprietary :30 October 2015 
a) Tab-Day 1 is defined as the day of the initial administration of DSP-5423 (tablet), and Day 1 is defined as the day of the initial application of DSP-5423P. 
b) At Visit 2 (before administration initiation of DSP-5423 (tablet)), Visit 6 (the end of DSP-5423 (tablet) treatment phase) and Visit 113 (the end of DSP-5423P treatment phase), 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. 
c) To be performed only in female subjects who are premenopausal and of childbearing potential. 
d) Must be performed before the beginning of treatment with DSP-5423 (tablet). For the subject treated with any antipsychotic, must be performed after discontinuation of antipsychotics and before 
the beginning of treatment with DSP-5423 (tablet). 
e) Must be performed before the beginning of treatment with DSP-5423P. 
f) If the subject discontinues the study drug during the DSP-5423 (tablet) treatment phase, the subject will undergo the following safety assessments: study treatment compliance, DIEPSS, C-SSRS, 
laboratory test, pregnancy test, 12-lead ECG, body weight, body temperature, blood pressure, pulse rate, and adverse event monitoring at the discontinuation visit. 
g) Must be performed before the initiation of post-treatment with antipsychotics excluding the study drug.




Protocol No. D4904040 1.02 
DSP-5423P 
11 
 
Confidential and Proprietary :30 October 2015 
c) To be performed only in female subjects who are premenopausal and of childbearing potential. 
d) Must be performed before the beginning of treatment with DSP-5423P. For the subject treated with any antipsychotic, must be performed after discontinuation of antipsychotics and before 
the beginning of treatment with DSP-5423P. 
e) Must be performed before the beginning of post-treatment with antipsychotics excluding the study drug. 


Protocol No. D4904040 1.02 
DSP-5423P 
12 
 
Confidential and Proprietary :30 October 2015 
2. Table of contents, list of tables, and list of figures 
Tables of contents 
1. SYNOPSIS ................................................................................................................................ 1 
2. Table of contents, list of tables, and list of figures .................................................................. 12 
3. List of Abbreviations and Definitions of Terms ...................................................................... 16 
4. Introduction ............................................................................................................................. 18 
4.1 Background ...................................................................................................................... 18 
4.2 Study Conduct Rationale .................................................................................................. 18 
5. Objective of the study .............................................................................................................. 20 
5.1 Primary objective ............................................................................................................. 20 
5.2 Secondary objective ......................................................................................................... 20 
6. Endpoints ................................................................................................................................. 20 
6.1 Efficacy endpoints ............................................................................................................ 20 
6.2 Safety endpoints ............................................................................................................... 20 
6.3 Pharmacokinetic endpoints ............................................................................................... 21 
6.4 Other endpoints ................................................................................................................ 21 
7. Investigational Plans ................................................................................................................ 21 
7.1 Overall study design of clinical study .............................................................................. 21 
7.1.1 Cohort 1..................................................................................................................... 21 
7.1.2 Cohort 2..................................................................................................................... 23 
7.2 Rationale .......................................................................................................................... 23 
7.2.1 Rationale for the study design ................................................................................... 23 
7.2.2 Rationale of dose, mode of administration and duration of administration .............. 24 
7.2.3 Rationale of endpoints............................................................................................... 25 
7.3 Measures to prevent missing data .................................................................................... 25 
7.4 Scheduled duration of clinical study ................................................................................ 26 
8. Subject selection ...................................................................................................................... 26 
8.1 Inclusion criteria ............................................................................................................... 26 
8.2 Exclusion criteria .............................................................................................................. 26 
9. Study drug materials and management .................................................................................... 28 
9.1 Description of Study drug ................................................................................................ 28 
9.2 Study drug packaging and labeling .................................................................................. 28 
9.2.1 Packaging description ............................................................................................... 28 
9.2.2 Labeling description .................................................................................................. 28 


Protocol No. D4904040 1.02 
DSP-5423P 
13 
 
Confidential and Proprietary :30 October 2015 
9.3 Study drug storage ............................................................................................................ 29 
9.4 Dispensing of study drug .................................................................................................. 29 
9.5 Study drug accountability ................................................................................................. 29 
9.6 Study drug handling and disposal .................................................................................... 29 
10. Treatment of subjects ............................................................................................................... 29 
10.1 Study medication .............................................................................................................. 30 
10.1.1 Cohort 1..................................................................................................................... 30 
10.1.2 Cohort 2..................................................................................................................... 31 
10.1.3 The guidance for application of DSP-5423P ............................................................. 31 
10.2 Dose adjustment criteria ................................................................................................... 32 
10.3 Concomitant medications and therapies ........................................................................... 33 
10.3.1 Prohibited concomitant medications ......................................................................... 34 
10.3.2 Prohibited Therapies ................................................................................................. 34 
10.3.3 Restrictions on concomitant medications .................................................................. 35 
10.3.4 Medications for complications .................................................................................. 37 
10.4 Contraception Requirements ............................................................................................ 37 
10.5 Treatment Compliance ..................................................................................................... 37 
10.6 Treatment Assignment and Blinding ................................................................................ 38 
11. STUDY ASSESSMENTS ....................................................................................................... 38 
11.1 Demographics and Baseline Characteristics..................................................................... 38 
11.2 Efficacy Assessments ....................................................................................................... 38 
11.2.1 PANSS....................................................................................................................... 38 
11.2.2 CGI-S ........................................................................................................................ 39 
11.3 Safety Assessments .......................................................................................................... 39 
11.3.1 Adverse events .......................................................................................................... 39 
11.3.2 DIEPSS ..................................................................................................................... 39 
11.3.3 C-SSRS ..................................................................................................................... 39 
11.3.4 Skin irritation assessment .......................................................................................... 39 
11.3.5 Clinical Laboratory Tests .......................................................................................... 40 
11.3.6 Vital Signs and Body Weight .................................................................................... 41 
11.3.7 12-lead ECGs ............................................................................................................ 41 
11.4 Pharmacokinetic Assessments .......................................................................................... 41 
11.5 Other assessments ............................................................................................................ 42 
11.5.1 DAI-10 ...................................................................................................................... 42 
11.5.2 EQ-5D ....................................................................................................................... 43 
11.5.3 Questionnaire on dosage form .................................................................................. 43 


Protocol No. D4904040 1.02 
DSP-5423P 
14 
 
Confidential and Proprietary :30 October 2015 
12. SAFETY REPORTING ........................................................................................................... 44 
12.1 Definition ......................................................................................................................... 44 
12.1.1 Adverse events .......................................................................................................... 44 
12.1.2 Serious adverse events .............................................................................................. 44 
12.2 Objective Findings ........................................................................................................... 45 
12.3 Collection and Recording of adverse events .................................................................... 46 
12.4 Immediately Reportable Events ....................................................................................... 47 
12.4.1 Serious adverse event ................................................................................................ 47 
12.4.2 Pregnancy .................................................................................................................. 48 
13. TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF STUDY 
DRUG ...................................................................................................................................... 49 
13.1 Criteria for Subject Termination ....................................................................................... 49 
13.2 Clinical Assessments after Study Drug Discontinuation .................................................. 49 
14. STUDY TERMINATION ........................................................................................................ 50 
15. Statistical analysis plan ............................................................................................................ 50 
15.1 Target sample size ............................................................................................................ 50 
15.2 Analysis population .......................................................................................................... 51 
15.2.1 Safety analysis population ......................................................................................... 51 
15.2.2 Pharmacokinetic analysis population ........................................................................ 51 
15.3 Data Analysis .................................................................................................................... 51 
15.3.1 Subject disposition .................................................................................................... 51 
15.3.2 Treatment exposure and Compliance ........................................................................ 51 
15.3.3 Important protocol deviations ................................................................................... 52 
15.3.4 Demographic and other reference range characteristics ............................................ 52 
15.3.5 Efficacy analysis ....................................................................................................... 52 
15.3.6 Safety analysis ........................................................................................................... 52 
15.3.7 Pharmacokinetic analysis .......................................................................................... 53 
15.4 Analysis of other endpoints .............................................................................................. 53 
15.4.1 Interim analysis ......................................................................................................... 54 
15.4.2 Data handling ............................................................................................................ 54 
16. PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA COLLECTION, 
MANAGEMENT, AND QUALITY ASSURANCE ............................................................... 54 
16.1 Data Collection/Electronic Data Capture (EDC).............................................................. 54 
16.2 Study Monitoring ............................................................................................................. 55 
16.3 Audits ............................................................................................................................... 55 
16.4 Study Documentation ....................................................................................................... 55 


Protocol No. D4904040 1.02 
DSP-5423P 
15 
 
Confidential and Proprietary :30 October 2015 
16.5 Clinical Laboratory Certification and Normal Values ...................................................... 56 
17. ETHICAL AND REGULATORY OBLIGATIONS ................................................................ 56 
17.1 Study Conduct .................................................................................................................. 56 
17.2 Institutional Review Board ............................................................................................... 56 
17.3 Informed Consent ............................................................................................................. 57 
17.4 Subject Privacy ................................................................................................................. 58 
17.5 Protocol amendments, Emergency deviations .................................................................. 58 
17.6 Records Retention ............................................................................................................ 58 
17.7 Inspection of Records ....................................................................................................... 58 
17.8 Publication Policy ............................................................................................................ 59 
17.9 Compensation ................................................................................................................... 59 
17.10 
Payment of transportation expenses to reduce the burden associated with this study 
participation ...................................................................................................................... 59 
18. Reference ................................................................................................................................. 60 
19. Appendix ................................................................................................................................. 62 
 
List of tables 
Table 1 emergency contact information1 .................................................................................... 3 
Table 2 Schedule of Assessments (Cohort 1)2 ............................................................................ 8 
Table 3 Schedule of Assessments (Cohort 2)3 .......................................................................... 10 
Table 4 List of abbreviations ..................................................................................................... 16 
Table 5 DSP-5423 P .................................................................................................................. 28 
TABLE 6 DSP-5423 (TABLETS) ............................................................................................ 28 
TABLE 7 DSP-5423 (TABLET) COMBINATIONS ................................................................ 30 
Table 8 starting dose of DSP-5423P corresponding to DSP-5423 (tablet) final dose8 ............. 31 
TABLE 9 DSP-5423P combinations ......................................................................................... 31 
Table 10 Restrictions on concomitant medications/therapies ................................................... 34 
TABLE 11 Permitted concomitant antiparkinson drugs ........................................................... 36 
Table 12 Permitted concomitant hypnotic drugs ....................................................................... 37 
Table 13 Scoring of Skin Reactionsref 19 .................................................................................... 40 
Table 14 Contents of laboratory variables ................................................................................ 40 
 
List of figures 
Fig 1 flowchart of clinical study (cohort 1) .............................................................................. 22 
Figure 2 flowchart of clinical study (cohort 2). ........................................................................ 23 






Protocol No. D4904040 1.02 
DSP-5423P 
18 
 
Confidential and Proprietary :30 October 2015 
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 improvedref 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 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 


Protocol No. D4904040 1.02 
DSP-5423P 
19 
 
Confidential and Proprietary :30 October 2015 
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. 
Considering these results, a phase 3 confirmatory study is currently being conducted in a 
randomized double-blind, placebo-controlled, parallel-group manner to confirm the superiority to 
placebo in order to evaluate the efficacy and safety of DSP-5423P. 
The phase 3 long-term study is designed to evaluate (1) the long-term safety, effectiveness and 
pharmacokinetics of DSP-5423P, (2) the safety and effectiveness of switching from DSP-5423 (tablet) 
to DSP-5423P in patients with schizophrenia. The clinical study is an uncontrolled, open-label study 
consisting of cohort 1 with DSP-5423P applied for 52 weeks after administration of the DSP-5423 
(tablet) for 6 weeks and cohort 2 with DSP-5423P applied for 52 weeks. The dose of DSP-5423P 
should be 40-80 mg/day, and the dose of DSP-5423 (tablet) should be 8-16 mg/day, the approved dose 
for maintenance. 
 
 




Protocol No. D4904040 1.02 
DSP-5423P 
21 
 
Confidential and Proprietary :30 October 2015 
10) Assessment of suicides using Columbia-Suicide Severity Rating Scale(C-SSRS) 
11) Laboratory test values, vital signs and body weight 
 
6.3 Pharmacokinetic endpoints 
- Plasma concentration of bronanserin 
- Plasma concentration of bronanserin’s metabolites note1) 
 
Note 1) metabolite to be measured 
Cohort 1: M-1 (N-de-ethylated metabolite), M-2 (N-oxidezed metabolite), M-3 (7OH) (hydroxided metabolite), M-
3 (8OH) (hydroxided metabolite), M-4 (ethylenediaminated metabolite), and M-8 (carboxylic acid). 
Cohort 2: M-1 (N-de-ethylated metabolite) 
 
6.4 Other endpoints 
1) Drug Attitude Inventory-10 (DAI-10) summed scores. 
2) EuroQol-5 Dimension (EQ-5 D) utility values. 
3) Questionnaire on dosage form 
 
 
7. Investigational Plans 
7.1 Overall study design of clinical study 
This clinical study is a multicenter, uncontrolled, open-label, long-term administration study 
consisting of two cohorts. The study schematics of clinical study are presented in Figures 1 (cohort 1) 
and 2 (cohort 2). Details of the study assessment and other procedures (assessment, observation, 
laboratory test) to be performed are presented in Tables 2 (cohort 1), 3 (cohort 2) and Chapter 11. In 
both cohorts, Day 1 is defined as the day of the initial application of DSP-5423P. 
Cohort 1, consisting of DSP-5423 (tablet) treatment phase and DSP-5423P treatment phase, and 
cohort 2, consisting only of DSP-5423P treatment phase, will be conducted in different subjects, and 
cohort 2 will be initiated after enrollment in cohort 1 has been completed. Enrollment in cohort 1 will 
be terminated when the number of total subjects whose DSP-5423P treatment duration is 6 weeks or 
more reached 50. At the completion of enrollment in cohort 1 and at the initiation of enrollment in 
cohort 2, the sponsor will notify the participating study centers of that. 
 
7.1.1 Cohort 1 
Cohort 1 consists of 3 phases: DSP-5423 (tablet) treatment phase (6 weeks), DSP-5423P treatment 
phase (52 weeks) and follow-up phase (1-2 weeks). Prior to initiation of DSP-5423 (tablet) treatment 
phase, washout period (up to 4 weeks) will be arranged (see Section 10.3.3.1) according to the dose 
of prior antipsychotics (haloperidol equivalent). 
DSP-5423 (tablet) treatment phase 
DSP-5423 (tablets) will be administered orally twice daily after breakfast and evening meal 


Protocol No. D4904040 1.02 
DSP-5423P 
22 
 
Confidential and Proprietary :30 October 2015 
for 6 weeks. The initial dose of DSP-5423 (tablet) will be 8mg/day. DSP-5423 (tablet) will be 
administered as flexible dose (8, 12, 16 mg/day) according to the dose adjustment criteria 
(section 10.2). 
DSP-5423P treatment phase 
DSP-5423P will be applied once daily for 52 weeks. The study drug will be applied to the 
subject’s back, chest, or abdomen. Start DSP-5423P application with the dosage according to 
the final dosage of DSP-5423 (Table 8 starting dose of DSP-5423P corresponding to DSP-5423 
(tablet) final dose). DSP-5423P will be applied as flexible dose (40, 60, 80 mg/day) according 
to the dose adjustment criteria (section 10.2). 
 
Figure 1 Study schematic (cohort 1) 
 
 
 
 
DSP-5423 
Tablet 
8~16 mg/day 
DSP-5423P 
40~80 mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 weeks 
52 weeks 
1-2 weeks
 
 
washout 
period* 
DSP-5423 
(Tablet) 
treatment 
phase 
DSP-5423P treatment phase 
Follow-up
Phase 
 
* If the dose of the prior antipsychotics is 12.0 mg/day or less (haloperidol equivalent), to initiate the administration of 
the DSP-5423 (tablet) after termination of the prior antipsychotics. Washout period may be arranged and down-
titration would be done as needed prior to termination. 
If the dose of the prior antipsychotics exceeds 12.0 mg/day (haloperidol equivalent), washout period will be 
arranged. First, the dose is reduced to 12.0 mg/day or less, then down-titration would be done as needed. After 
termination of the prior antipsychotics, to initiate the administration of the DSP-5423 (tablet). 
Washout period should be up to 4 weeks (28 days) from the screening. 
** The registration procedure is presented in section 10. 
 
Informed consent 
Screening 
Registratio
n
** 


Protocol No. D4904040 1.02 
DSP-5423P 
23 
 
Confidential and Proprietary :30 October 2015 
7.1.2 Cohort 2 
Cohort 2 consists of 2 phase: DSP-5423P treatment phase (52 weeks) and follow-up phase (1-2 
weeks). During the DSP-5423P treatment phase, DSP-5423P will be applied once daily for 52 weeks. 
The study drug will be applied to the subject’s back, chest, or abdomen. The initial dose of DSP-5423P 
will be 40 mg/day. DSP-5423P will be applied as flexible dose (40, 60, 80 mg/day) according to the 
dose adjustment criteria (section 10.2). Prior to initiation of DSP-5423P treatment phase, a washout 
period (up to 4 weeks) will be arranged (see Section 10.3.3.1) according to the dose of prior 
antipsychotics (haloperidol equivalent). 
 
Figure 2 Study schematic (cohort 2). 
 
 
 
 
DSP-5423P 
40~80 mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
52 weeks 
1-2 weeks 
 
 
washout 
period* 
DSP-5423P treatment phase 
Follow-up 
Phase 
 
* If the dose of the prior antipsychotics is 12.0 mg/day or less (haloperidol equivalent), to initiate the application 
of the DSP-5423P after termination of the prior antipsychotics. Washout period may be arranged and down-
titration would be done as needed prior to termination. 
If the dose of the prior antipsychotics exceeds 12.0 mg/day (haloperidol equivalent), washout period will be 
arranged. First, the dose is reduced to 12.0 mg/day or less, then down-titration would be done as needed. 
After termination of the prior antipsychotics, to initiate the administration of the DSP-5423P. 
Washout period should be up to 4 weeks (28 days) from the screening. 
** The registration procedure is presented in section 10 
 
7.2 Rationale 
7.2.1 Rationale for the study design 
The study is designed to evaluate the long-term safety and effectiveness of DSP-5423P as an 
uncontrolled open-label study with treatment duration of 52 weeks. The dosage of DSP-5423 (tablet) 
and DSP-5423P was selected as flexible-dose. 
Switching from oral bronanserin to DSP-5423P is potential regimen when DSP-5423P is marketed. 
In addition, in the result of a phase II study (PET study, D4904019) which was conducted in order to 
evaluate dopamine D2 receptor occupancy by positron emission tomography (PET) in patients with 
schizophrenia, the result suggests that a higher concentration of plasma bronanserin than DSP-5423 
(tablet) is needed for DSP-5423P to achieve a similar dopamine D2 receptor occupancy as DSP-5423 
(tablet). Therefore, we decided to design a DSP-5423P treatment phase after DSP-5423 (tablet) 
treatment phase that the initial dose of DSP-5423P is determined by the final dose of DSP-5423 (tablet) 
Screening 
Informed consent 
Registration 
** 


Protocol No. D4904040 1.02 
DSP-5423P 
24 
 
Confidential and Proprietary :30 October 2015 
in order to evaluate the effect of safety and effectiveness in the case of the switching from oral 
bronanserin to DSP-5423P 
. 
7.2.2 Rationale of dose, mode of administration and duration of administration 
DSP-5423P 
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.  
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 -80 mg/day are to be used in this study. 
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). 
Based on the Yakushin (Pharmaceutical Affairs Bureau Examination Division ：PAB/ED) 
notification No. 592 of May 24th 1995, "Recommendation on the numbers of patients and duration of 
exposure for the safety evaluation of drugs intended for the long-term treatment of non-lifethreatening 
conditions" one year (52 weeks) was selected as the duration of administration. 
 
DSP-5423 (tablets) 
Based on the approved dose of blonanserin tablet, the initial dose of DSP-5423 (tablet) was set at 
8 mg/day and the dose was increased or decreased according to the maintenance dose (8-16 mg/day). 
Oral administration was planned after meal (in the morning and in the evening) in accordance with the 
approved treatment regimen of blonanserin tablet. 
Since initial dose was set at 8 mg/day, it was considered necessary to determine the optimal dose 


Protocol No. D4904040 1.02 
DSP-5423P 
25 
 
Confidential and Proprietary :30 October 2015 
for 2 weeks. It has been reported that the treatment response assessment of antipsychotics should be 
performed 2 to 4 weeks after administration initiation ref 11). Furthermore, in the clinical studies of 
DSP-5423 (tablets) conducted in Japan, most of the common/frequent adverse events, including 
akathisia, tremors, insomnia, and increased blood prolactin, have been observed in 4 weeks after 
administration initiation. Therefore, 6-week was set as the duration enough to collect effectiveness and 
safety data on DSP-5423 (tablet). 
 
7.2.3 Rationale of endpoints 
Efficacy endpoints 
PANSS and CGI-S, which are frequently used as endpoints in the clinical study of antipsychotics, 
were set. In addition, because treatment of antipsychotics is often terminated due to adverse drug 
reaction and/or lack of efficacy, we considered that duration of DSP-5423P would be helpful in 
evaluating the effectiveness of antipsychotic drugs and decided to be endpoints. 
Pharmacokinetic endpoints 
To investigate the pharmacokinetics of DSP-5423P application, bronanserin and the main 
metabolite, M-1, are measured in both cohort 1 and cohort 2. In addition, in cohort 1, the metabolites 
other than M-1 are also measured in order to compare the pharmacokinetics of DSP-5423P application 
with that of DSP-5423 (tablet) administration, which has a higher metabolite production ratio, in the 
same subject. 
Safety endpoints 
Since DSP-5423P is transdermal formulation, skin-related adverse event/ adverse drug reaction at 
the application site and skin irritation assessment were set. 
Other endpoints 
Because DAI-10 is one of the commonly used measures of adherence, and because EQ-5D is one 
of the commonly used measures of health-related Quality of life (QOL) as a comprehensive measure, 
DAI-10 and EQ-5D were set. In addition, questionnaires on the dosage form were set to investigate 
the impressions of subject on the DSP-5423P. 
 
7.3 Measures to prevent missing data 
The following study design and conduct elements are implemented in an effort to minimize the 
number of subjects who are terminated from the study before the completion; 
1) Depending on the dose of prior antipsychotics, washout period can be arranged. 
2) Adequately wide visit windows were set for each Visit. 
3) During the entire study period, concomitant use of antiparkinson drugs, lorazepam, and 
hypnotic drugs are allowed for extrapyramidal symptoms, psychiatric symptoms, and insomnia 
respectively. 
4) Rescue use of antipsychotics is allowed for urgent psychiatric symptoms. 


Protocol No. D4904040 1.02 
DSP-5423P 
26 
 
Confidential and Proprietary :30 October 2015 
5) Flexible dose adjustment is allowed based on effectiveness or tolerability. 
6) 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. 
7) Monitor data collection for adherence during the study. 
 
7.4 Scheduled duration of clinical study 
December 2014 ~July 2017 (Enrollment period: ~ May 2016) 
 
 
8. Subject selection 
8.1 Inclusion criteria 
Patients who meet all of the following criteria. 
1) Patients who have schizophrenia diagnosed by Diagnostic and Statistical Manual of Mental 
Disorders, fifth edition (DSM-5), diagnostic criteria 
2) Patients who are aged 18 years or older at informed consent 
3) Patients who are fully informed of and understand the objective, 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, and if the patient is hospitalized 
involuntarily, written consent will be obtained from a legally acceptable representative Note 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. 
4) Patients with premenopausal female and of childbearing potential who have negative result for 
pregnancy laboratory test (urine) at screening 
5) Patients who have informed consent in adequate contraception to prevent pregnancy of the 
patients or their partners when they are female of childbearing potential. 
 
8.2 Exclusion criteria 
Exclusion from this clinical study if any of the following applies: 
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 topical 
use), or human immunodeficiency virus (HIV) protease inhibitors. 
4) Patients with medical history of hypersensitivity to bronanserin 


Protocol No. D4904040 1.02 
DSP-5423P 
27 
 
Confidential and Proprietary :30 October 2015 
5) Patients with a history of or current neuroleptic malignant syndromes, tardive dyskinesia or 
water intoxication 
6) Patient with Parkinson's disease 
7) Patients with active suicidal ideation or those with a suicide attempt history who are considered 
ineligible for the study by the Investigator 
8) Patients with an HbA1c level (NGSP level) of 8.4% or higher 
9) Patients with physical exhaustion accompanied by conditions such as dehydration or 
malnutrition 
10) 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 
11) Patients with skin injuries, skin disease, or tattoos at the site of application (back, chest, or 
abdomen) that precludes adequate patch placement. 
12) Patients with a history of drug abuse, drug dependency, alcohol abuse, or alcohol dependency 
within 6 months (180 days) before screening 
13) Patients who received any depot preparation (sustained-release formulation) of antipsychotics 
within 3 months (90 days) before screening 
14) Patients who received clozapine administration within 4 months (120 days) before screening 
15) Patients who received administration of blonanserin within 1 Year (365 days) prior to screening 
and were considered resistant to treatment for blonanserin 
16) Patients who received monoamine oxidase (MAO) inhibitor administration within 1 month (30 
days) before screening 
17) Patients who received electroconvulsive therapy within 6 months (180 days) before screening 
18) Pregnant or nursing mother 
19) Patients with a history or complication(s) of hypersensitivity to two or more drugs (patients 
with a history or complication(s) of drug-induced allergic reactions such as anaphylaxis, rash, 
and urticaria) 
20) Patients with medical history or complication(s) of malignant tumor within 5 Years before 
screening 
21) HIV-infected patients 
22) Patients who received other investigational product or post-marketing clinical study drugs 
within 3 months (90 days) before screening, or patients who have enrolled in but not completed 
other clinical study or post-marketing study before screening 
23) Patients who are otherwise considered ineligible for the study by the investigator 
 
 




Protocol No. D4904040 1.02 
DSP-5423P 
29 
 
Confidential and Proprietary :30 October 2015 
sponsor’s name and address. 
 
9.3 Study drug storage 
All study drugs should be stored under appropriate storage conditions in a secure location to which 
only the Investigators and designated persons have access. The appropriate storage conditions for 
study drugs storage will be specified in the guidance for drug accountability provided by the sponsor. 
 
9.4 Dispensing of study drug 
The Investigators will dispense the study drug to be used until the next visit to the subject at the 
current study visit. 
 
9.5 Study drug accountability 
Sponsor will dispense the study drug to designated persons after the clinical study contract between 
sponsor and the site has been concluded. The study drug will be stored and managed in accordance 
with the guidance procedures and the designated persons at the site is responsible for maintaining 
adequate records of drug disposition in order to control the status of study drug use. Study drug should 
not be used other than the clinical study. 
 
9.6 Study drug handling and disposal 
The designated persons for handling of the study drug at the site should handle the study drug in 
accordance with the guidance for drug accountability. If there is study drug of unused or return from 
subject, the designated persons are required to return all unused study drugs to the sponsor as instructed. 
In the event that a study drug is accidentally disposed of or lost at the site, the designated persons will 
report study drug disposal or loss to the sponsor while recording in the drug accountability records. 
The designated persons will provide a copy of the drug accountability records to the sponsor after 
completion of study drug administration and application. The sponsor ensures that the drug 
accountability records, the quantity of study drug that has been unused or returned from a subject, and 
the content of the case report form are consistent. If there is any inconsistency, the Primary investigator 
is required to immediately investigate the cause and take the necessary action. 
 
10. Treatment of subjects 
Identification and registration of the subject will be carried out according to the following 
procedures. 
 
(1) Subject identification number assignment 
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 






Protocol No. D4904040 1.02 
DSP-5423P 
32 
 
Confidential and Proprietary :30 October 2015 
1) The DSP-5423P will be applied directly to normal healthy skin after removing the transparent 
liner. 
2) DSP-5423P will be replaced every day. When DSP-5423P patches are replaced, new DSP-
5423P will be applied as soon as possible In addition, 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. 
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 DSP-5423P will be protected from water.  Before taking a bath 
or shower, DSP-5423P should be removed.  After taking a bath or shower, new patches 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 DSP-5423P 
application until the follow-up visit. 
6) No other adhesive skin patches are to be overlaid on the current application site of DSP-5423P.  
No liniments should be used at the current application site of DSP-5423P.  The study drug 
should not be applied to any site where liniments are used. 
7) Surgical tape should be used to maintain DSP-5423P at the application site if any patches are 
detached or are about to become detached.  When patches which have detached from the 
application site cannot be reapplied, no new patches will be applied until the next scheduled 
application. 
8) The used patches will be adequately disposed to prevent anyone else from misusing them. 
 
10.2 Dose adjustment criteria 
The DSP-5423P dose can be increased or reduced by 20 mg/day at each adjustment within a range 
of 40 mg/day, 60 mg/day or 80 mg/day according to the following dose adjustment criteria.  The 
DSP-5423 (tablet) dose can be increased or reduced by 4 mg/day at each adjustment within a range of 
8 mg/day, 12 mg/day or 16 mg/day according to the following dose adjustment criteria. 
 
Regulatory Assessment timing 
- When the CGI-S score is between 4 and 7 and when no safety concerns arise, the DSP-
5423P/DSP4323 (tablet) dose should be increased. 
- When the CGI-S score is 3 or lower with no safety concerns and when the Investigator expects 
further efficacy of DSP-5423P/DSP4323 (tablet), the DSP-5423P/DSP4323 (tablet) dose can 
be increased. 


Protocol No. D4904040 1.02 
DSP-5423P 
33 
 
Confidential and Proprietary :30 October 2015 
As necessary 
- When the Investigator considers a higher dose of DSP-5423P/DSP4323 (tablet) to be necessary 
due to insufficient efficacy, the DSP-5423P/DSP4323 (tablet) dose can be increased. 
- When the Investigator considers a lower dose of DSP-5423P/DSP4323 (tablet) to be necessary 
due to the AEs, the DSP-5423P/DSP4323 (tablet) dose can be reduced. 
 
PANSS and CGI-S should be evaluated before the dose adjustment at each unscheduled visit 
(Section 11.2 Efficacy Assessments).  DIEPSS should be evaluated as well as PANSS and CGI-S 
when the DSP-5423P/DSP4323 (tablet) dose is reduced due to extrapyramidal symptoms (Section11.3 
Safety Assessments). 
After the dose adjustment, the Investigator will record the reason for the dose adjustment in the 
CRFs.  The DSP-5423P/DSP4323 (tablet) 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 initiation of DSP-5423 administration until 
the follow-up visit in cohort1 or initiation of DSP-5423P application until the follow-up visit in cohort 
2 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 
and during wash-out period will also be recorded in the CRFs 
 
In this section (Section 10.3), beginning of DSP-5423 (tablet) administration in cohort 1 or 
beginning of the DSP-5423P application in cohort 2 is defined as "beginning of study drug 
administration/application". 
 
Table 10 shows restrictions on concomitant medications/therapies. 
 




Protocol No. D4904040 1.02 
DSP-5423P 
35 
 
Confidential and Proprietary :30 October 2015 
 
10.3.3 Restrictions on concomitant medications 
10.3.3.1 Antipsychotics 
Antipsychotics except for the study drug will be restricted as follows: 
1) For the subjects not treated with antipsychotics at screening 
Antipsychotics will be prohibited from screening until completion of assessments at the last 
visit (Visit 113) of the DSP-5423P application period or the discontinuation visit. 
2) For the subjects treated with any antipsychotics at screening (prior antipsychotics) 
The antipsychotics should be tapered and completely discontinued according to procedures 
a) or b) below, the study drug administration/application will be started. The wash-out period 
for tapering prior antipsychotics should be up to 4 weeks (28 days) from the screening. 
Antipsychotics will be prohibited from beginning of study drug administration/application 
until completion of assessments at the last visit (Visit 113) of the DSP-5423P application period 
or the discontinuation visit.  
a) If the prior antipsychotics dose is 12.0 mg/day or less (haloperidol equivalent) 
The prior antipsyochotics should be completely discontinued, through tapering during the 
wash-out period, if needed. 
b) If the prior antipsychotics dose is over 12.0 mg/day (haloperidol equivalent) 
The prior antipsyochotics should be tapered. After the dose of the prior antipsychotics is 
12 mg/day or less (haloperidol equivalent), these antipsychotics should be completely 
discontinued, through tapering during the wash-out period, if needed.  
 
If urgent treatment is required because of psychiatric symptoms such as acute psychomotor 
excitability, 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 should be 10 days or less 
through DSP-5423 (tablet) administration period and DSP-5423P application period. 
 
10.3.3.2 Antiparkinson drugs 
Antiparkinson drugs will be restricted as follows: 
1) For the subjects not treated with antiparkinson drugs at screening 
Antiparkinson drugs will be prohibited from screening until completion of assessments at 
the last visit (Visit 113) of the DSP-5423P application period or the discontinuation visit. 
2) For the subjects treated with antiparkinson drugs at screening 
Antiparkinson drugs will be tapered and completely discontinued before beginning of the 
study drug administration/application.  Antiparkinson drugs will be prohibited from the 


Protocol No. D4904040 1.02 
DSP-5423P 
36 
 
Confidential and Proprietary :30 October 2015 
beginning of the study drug administration/application until completion of assessments at the 
last visit (Visit 113) of the DSP-5423P application period or the discontinuation visit. 
 
If extrapyramidal symptoms occur or worsen during the DSP-5423 (tablet) period or DSP-5423P 
application period, antiparkinson drugs may be used. While the drugs listed in Table 11 are 
recommended, other antiparkinson drugs will be permitted.  If the extrapyramidal symptoms improve, 
antiparkinson drugs may be tapered or discontinued.  
Note that for the subjects who started the administration of antiparkinson due to extrapyramidal 
symptom occurred or worsen during the DSP-5423 (tablet) period in cohort 1, if the subject continued 
the antiparkinson drugs at transition to the DSP-5423P application period, the antiparkinson drugs 
should be tapered and discontinued in 2 weeks beginning of the DSP-5423P application, as much as 
possible. 
 
TABLE 11 Permitted concomitant antiparkinson drugs  
Trihexyphenidyl 
Biperiden 
Promethazine 
 
10.3.3.3 Antimanic and Antiepileptic Drugs 
Antimanic and antiepileptic drugs will be restricted as follows: 
1) For the subjects not treated with antimanic or antiepileptic drugs at screening 
Administration should be avoided whenever possible from screening until completion of 
assessments at the last visit (Visit 113) of the DSP-5423P application period or the 
discontinuation visit 
2) For the subjects treated with antimanic or antiepileptic drugs at screening 
The regimen will not be changed as much as possible from beginning of study drug 
administration/application until completion of assessments at the last visit (Visit 113) of the 
DSP-5423P application period or the discontinuation visit 
 
If the psychiatric symptoms improve, antimanic and antiepileptic drugs may be tapered or 
discontinued. 
 
10.3.3.4 Hypnotic drugs 
When insomnia occurs or worsens during the DSP-5423 (tablet) period or DSP-5423P application 
period, the hypnotic drugs will be permitted. While the drugs listed in Table 12 are recommended, 
other benzodiazepine receptor agonists may be used. However, all hypnotic drugs will be prohibited 
within 12 hours before the PANSS, CGI-S, and C-SSRS assessments. 


Protocol No. D4904040 1.02 
DSP-5423P 
37 
 
Confidential and Proprietary :30 October 2015 
If the insomnia improves, hypnotic drugs may be tapered or discontinued. 
 
Table 12 Permitted concomitant hypnotic drugs  
Eszopiclone 
Zopiclone 
Zolpidem 
Triazolam 
Brotizolam 
Rilmazafone 
Lormetazepam 
 
10.3.3.5 Psychotropic drugs (eg, anxiolytics, antidepressants) 
When psychiatric symptoms, such as anxiety, agitation and irritation, occur during the DSP-5423 
(tablet) period or DSP-5423P application period, benzodiazepine receptor agonists (eg, lorazepam) 
may be used.  However, all psychotropics will be prohibited within 12 hours before assessments of 
the PANSS, CGI-S, and C-SSRS. 
 
10.3.4 Medications for complications 
All drugs used for the treatment for complications (eg, hypertension, hyperlipidemia, diabetes) at 
screening should be continued without any dosage modification as much as possible from beginning 
of study drug administration/application until the last visit (Visit 113) of DSP-5423P application period 
or the discontinuation visit. If the complications worsen or improve, the dosage of the concomitant 
drugs for these complications may be changed accordingly. 
 
10.4 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. 
 
10.5 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 administrations and the number of 
administered tablets for each dose during the DSP-5423 (tablet) administration period.  
The Investigator will record the dates of the initial and final applications and the number of applied 


Protocol No. D4904040 1.02 
DSP-5423P 
38 
 
Confidential and Proprietary :30 October 2015 
patches for each dose during theDSP-5423P application period, and the date of final removal of the 
study drug.  
 
10.6 Treatment Assignment and Blinding 
This study is not a randomized study. All subject will be unblinded and will receive the same study 
drug administration/application with dose adjusted for each cohort. 
 
 
11. STUDY ASSESSMENTS 
A study schematic is presented in Figure 1 and Figure 2.  A summary of assessments to be 
conducted at each visit is presented in Table 2 and Table 3 Schedule of Assessments.  Assessments 
will be conducted within the time frames specified. The timeframes will be calculated from the 
initiation date of DSP-5423P application for each subject in both cohort 1 and 2. In the DSP-5423 
(tablet) administration period of cohort 1, however, it will be calculated from the initiation date of 
DSP-5423 (tablet) administration for each subject. 
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, and inpatient/outpatient status 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.  When the efficacy assessments are conducted, the concomitant use of 
restricted medications will be recorded in the CRFs. 
 
11.2.1 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 and will be certified by the Sponsor 


Protocol No. D4904040 1.02 
DSP-5423P 
39 
 
Confidential and Proprietary :30 October 2015 
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. 
 
11.2.2 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. 
 
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. 
AEs and SAEs will be monitored throughout the study at all visits including telephone assessments.  
 
11.3.2 DIEPSS 
The DIEPSSref17)  is a rating tool of extrapyramidal symptoms induced by antipsychotics and 
consists of 8 individual items; gait, bradykinesia, sialorrhea, muscle rigidity, tremor, akathisia, 
dystonia, and dyskinesia; and one global assessment; overall severity.  The severity of each item is 
on a 5-point scale of 0 to 4.  Dates of the assessments and the results will be recorded in the CRFs. 
 
11.3.3 C-SSRS 
The C-SSRS ref 18 is a rating tool designed to systematically assess and track suicidal behavior and 
suicidal ideation throughout the study.  The C-SSRS can comprehensively identify suicidal events 
and limit the over-identification of suicidal behavior.   
 
The Investigators will receive specific training before their initial assessment of C-SSRS.  Date of 
the assessments and the results will be recorded in the CRFs 
 
11.3.4 Skin irritation assessment 
The Investigator will evaluate any skin reactions at the application sites according to the Table 13 




Protocol No. D4904040 1.02 
DSP-5423P 
41 
 
Confidential and Proprietary :30 October 2015 
DSP-5423P application in the cohort 1 and cohort 2 each). At other visits, blood samples should be 
collected under fasting conditions, whenever possible. 
 
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 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.  Detailed instructions regarding12-lead ECG can 
refer to the instructions manual provided by the Sponsor 
 
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 metabolites Note 1 
 
Note 1) metabolites to be measured 
Cohort 1: M-1 (N-de-ethylated), M-2 (N-oxide), M-3 (7OH) (hydroxide), M-3 (8OH) (hydroxide), M-4 
(ethylenediamine), and M-8 (carboxylic acid). 
Cohort 2: M-1 (N-de-ethylated) 
 
Recording 
The following information will be recorded in the CRFs. When a subject is discontinued, the 
information will be recorded to CRFs according to the period of discontinuation [DSP-5423 (tablet) 
administration period or DSP-5423P application period]. 
 
(1) DSP-5423 (tablet) administration period: 
1) Dates and times of blood sample collection 
2) Dates and times of the last two administrations of DSP-5423 (tablet) before blood sample 
collection 
3) DSP-5423 (tablet) doses of the last two administrations before blood sample collection 


Protocol No. D4904040 1.02 
DSP-5423P 
42 
 
Confidential and Proprietary :30 October 2015 
4) Yes or no for the question whether had a meal immediately before administrations of DSP-
5423 (tablet) of the last two administrations before blood sample collection 
 
(2) DSP-5423P application period: 
1) Dates and times of blood sample collection 
2) Dates and times of the last two applications of DSP-5423P before blood sample collection 
3) DSP-5423P doses of the last two applications before blood sample collection 
4) Locations for the last two applications of DSP-5423P before blood sample collection 
 
Timing and volume of blood collection 
Six milliliters of blood will be collected at each time point. 
 
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). 
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) 
 
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 
metabolites and prepare a bioanalysis report. 
 
11.5 Other assessments 
11.5.1 DAI-10 
DAI-10's ref 12 is an assessment for evaluating a drug adherence by adding the patient’s attitude to 
the drug treatment compliance. Investigator will survey the subject's drug attitude ("true" or "false") 
for the following 10 items and record the assessment Date and the results to CRFs. 
Good things about medication outweigh the bad 
1) Feel like a zombie 
2) Take of my own free choice 


Protocol No. D4904040 1.02 
DSP-5423P 
43 
 
Confidential and Proprietary :30 October 2015 
3) Feel more relaxed 
4) Feel tired and sluggish 
5) Take only when sick 
6) Feel more normal 
7) Unnatural for my mind and body to be controlled by medications 
8) Thoughts are clearer 
9) By staying on medication I can prevent a breakdown 
 
11.5.2 EQ-5D 
EQ-5D's ref 13) is a self-administered, comprehensive rating scale developed to measure health-
related quality of life. Investigator will use the questionnaire to investigate the following 5 items and 
record the assessment Date and the result to CRFs. 
 
1) MOBILITY 
<1: I have no problems in walking about, 2: I have slight problems in walking about, 3: I 
have moderate problems in walking about, 4: I have severe problems in walking about, 5: I am 
unable to walk about> 
2) SELF-CARE 
<1: I have no problems washing or dressing myself, 2: I have slight problems washing or 
dressing myself, 3: I have moderate problems washing or dressing myself, 4: I have severe 
problems washing or dressing myself, 5: I am unable to wash or dress myself 
3) USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
<1: I have no problems doing my usual activities, 2: I have slight problems doing my usual 
activities, 3: I have moderate problems doing my usual activities, 4: I have severe problems 
doing my usual activities, 5: I am unable to do my usual activities. 
4) PAIN / DISCOMFORT 
<1: I have no pain or discomfort, 2: I have slight pain or discomfort, 3: I have moderate pain 
or discomfort, 4: I have severe pain or discomfort, 5: I have extreme pain or discomfort> 
5) ANXIETY / DEPRESSION 
<1: I am not anxious or depressed, 2: I am slightly anxious or depressed, 3: I am moderately 
anxious or depressed, 4: I am severely anxious or depressed, 5: I am extremely anxious or 
depressed> 
 
11.5.3 Questionnaire on dosage form 
Investigator will ask Question 1 and Question 2 regarding the patch dosage form of antipsychotic, 
Question 3 regarding the DSP-5423P, and record the assessment Date and the results to CRFs. 
- Would you like the patch dosage form to be available?? 


Protocol No. D4904040 1.02 
DSP-5423P 
44 
 
Confidential and Proprietary :30 October 2015 
Response) "Yes" or "No" 
- Is it easy for you to continue treatment with patches compared with tablets? 
Response) "Yes," "Equal" or "No." 
- Question 3 Would you like to use the patches that you used during this study in the future? 
Response) "Yes" or "No" 
 
 
12. SAFETY REPORTING 
12.1 Definition 
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 DSP-5423 (tablet) 
administration until the follow-up visit in the cohort 1, or from the beginning of the DSP-5423P 
application until the follow-up visit in the cohort 2, for instance, events occurring in association with 
study-related procedures or assessments, or those occurring under placebo treatment. 
In the cohort 1. AEs that occur during the DSP-5423 (tablet) administration period and worsen 
during the DSP-5423P application period will be recorded as AEs in the DSP-5423 (tablet) 
administration period and also as AEs in the DSP-5423P application period. The date of worsening 
will be recorded as the onset date of the worsening AE. In addition, AEs that occur during the DSP-
5423 (tablet) administration period without further worsening in the DSP-5423P application period 
will be recorded as AEs in the DSP-5423 (tablet) administration period.  
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. 


Protocol No. D4904040 1.02 
DSP-5423P 
45 
 
Confidential and Proprietary :30 October 2015 
- 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); 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 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 


Protocol No. D4904040 1.02 
DSP-5423P 
46 
 
Confidential and Proprietary :30 October 2015 
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 of 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 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: 
- Drug Withdrawn – Study drug stopped permanently. 
- Dose Reduced. 
- Dose Increased. 
- Dose Not Changed.  
- Not Applicable. 
-  
The outcome of the AE: 
- Recovered/Resolved. 
- Recovering/Resolving. 


Protocol No. D4904040 1.02 
DSP-5423P 
47 
 
Confidential and Proprietary :30 October 2015 
- 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 Sponsor is the contact person.  The contact information as well as other emergency contact 
information can be found in Table 1 Emergency Contact Information. 
 
12.4 Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor: 
- SAE 
- Pregnancy 
Emergency contact information can be found in Table 1 Emergency Contact Information. 
 
12.4.1 Serious adverse event 
If the Investigator or staff of study centers becomes aware of SAE that occurs in a study subject 
from the beginning of the DSP-5423 (tablet) administration until the follow-up visit in the cohort 1, 
or from the beginning of the DSP-5423P application until the follow-up visit in the cohort 2, this must 
be reported immediately to the Sponsor whether considered related or unrelated to the study drug.  
SAEs occurring during above period must be recorded in the CRFs. 
Following the end of subject participation in the study, the Investigator should report SAEs 
“spontaneously” to the Sponsor if considered at least possibly related to the study drug.  
 


Protocol No. D4904040 1.02 
DSP-5423P 
48 
 
Confidential and Proprietary :30 October 2015 
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 (Table 1 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; 
- History of any ADRs, relevant special conditions of the subject, history of the current disease 
and treatment for the disease, details of the SAE, treatment for the SAE and details on course 
of the SAE 
- If the subject died, date of death, cause of death, relationship between the SAE and death, 
anatomic findings (if available) 
These SAEs must be promptly reported in writing to the head of the study center by the Principal 
Investigator. The Principal Investigator should report available information in writing 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 will promptly notify all study centers and Investigators of a SAE that is determined to 
be expedited to the Regulatory Authority in accordance with applicable law(s) and regulation(s). 
 
12.4.2 Pregnancy 
Pregnancies that occur from the beginning of the DSP-5423 (tablet) administration until the follow-
up visit in the cohort 1, or from the beginning of the DSP-5423P application until the follow-up visit 
in the cohort 2 will be collected and reported to the Sponsor.  
If a subject becomes pregnant during the above period, 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.  The Investigator must complete the Pregnancy Event Form 
and send it to the Sponsor.   
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 were detected. 
 
 


Protocol No. D4904040 1.02 
DSP-5423P 
49 
 
Confidential and Proprietary :30 October 2015 
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 subjects treated with study drug prematurely discontinuing the 
study drug, regardless of cause, to undergo final evaluation procedures, in accordance with the 
discontinuation visit and the follow-up visit.  Required assessment should be conducted at 
discontinuation visit accordance with the table 2 or 3 (DSP-5423 (tablet administration period or DSP-
5423P application period). If a subject discontinues during the DSP-5423P application period, the 
subject will undergo all the discontinuation assessments in accordance with the discontinuation visit 
as described in Table 2 and 3.  If a subject discontinues during the DSP-5423 (tablet) administration 
period, the subject will undergo the following safety assessments: study treatment compliance, 
DIEPSS, C-SSRS, laboratory test, pregnancy test, 12-lead ECG, body weight, body temperature, blood 
pressure, pulse rate, and adverse event monitoring at the discontinuation visit. 
The subject will undergo the discontinuation assessments within 5 days of the last study drug 


Protocol No. D4904040 1.02 
DSP-5423P 
50 
 
Confidential and Proprietary :30 October 2015 
administration/application.  
 
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.  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. 
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 
 
 
15. Statistical analysis plan 
Details of the statistical methods will be specified in the statistical analysis plan. The sponsor will 
determine detailed data handling, including adoption or rejection for each subject to analysis 
populations before database hard lock. When separately analyzing the pharmacokinetics and PK-PD, 
the details of the analytical procedures will be specified in an analysis plan and if appropriate pooled 
analysis with other studies will be performed and reported separately. 
 
15.1 Target sample size 
Number of subjects enrolled: 200 subjects 
- Number of subjects treated with DSP-5423P for 6 weeks and more in cohort 1: 50 subjects 
- Number of subjects treated with DSP-5423P for 52 weeks in either cohort 1 or cohort 2: 100 
subjects 
The new enrollment can be terminated at the time when 100 subjects with 52-week exposure of 
DSP-5423P are collected, together with a separate confirmatory study [Confirmatory Study of DSP-
5423P in Patients with Schizophrenia <Phase 3> (protocol: D4904020)]. 
 
Rationale 
Based on the guideline, THE EXTENT OF POPULATION EXPOSURE TO ASSESS CLINICAL 
SAFETY FOR DRUGS INTENDED FOR LONG-TERM TREATMENT OF NON-LIFE-
THREATENING CONDITIONS dated 24 May 1995, 100 subjects with one year (52 weeks) exposure 
of DSP-5423P will be collected in cohort 1 and 2. In addition, to investigate the safety and efficacy of 
switching DSP-5423 (tablet) to DSP-5423P, approximately half of the target number of subjects will 
be enrolled in cohort 1 as subjects who switched DSP-5423 (tablet) to DSP-5423P. Considering 
approximately half of enrolled subjects early terminated in previous studies of DSP-5423 (tablet), 


Protocol No. D4904040 1.02 
DSP-5423P 
51 
 
Confidential and Proprietary :30 October 2015 
target number of subjects was set to 200. No statistical consideration was applied.  
 
15.2 Analysis population 
15.2.1 Safety analysis population 
Subjects with at least one application of DSP-5423P. 
Efficacy analysis will also be performed based on the safety analysis population. 
 
15.2.2 Pharmacokinetic analysis population 
Subjects with at least one application of DSP-5423P, and with measurements of plasma bronanserin 
concentration after application of DSP-5423P. 
 
15.3 Data Analysis 
Baseline definitions are provided in 15.3.10.3. 
15.3.1 Subject disposition 
The following is done for each cohort. 
1) Cohort 1 
Subjects with informed consent, subjects took DSP-5423 (tablet) in DSP-5423 (tablet) 
treatment period, subjects who didn’t apply DSP-5423P in DSP-5423P application period, 
subjects who applied DSP-5423P in DSP-5423P application period, subjects who completed 
DSP-5423P application period, and subject who early terminated from DSP-5423P application 
period. 
2) Cohort 2 
Subjects with informed consent, subjects applied DSP-5423P in DSP-5423P application 
period, subjects who completed DSP-5423P application period, and subject who early 
terminated from DSP-5423P application period. 
 
15.3.2 Treatment exposure and Compliance 
For each analysis population, perform the following for each cohort. 
1) Cohort 1 
Total dose, compliance and treatment duration of DSP-5423 (tablet) administration period, 
and total dose, compliance and treatment duration of DSP-5423P patch period will be 
summarized in descriptive statistics. 
2) Cohort 2 
Ttotal dose, compliance and treatment duration of DSP-5423P patch period will be 
summarized in descriptive statistics. 
 


Protocol No. D4904040 1.02 
DSP-5423P 
52 
 
Confidential and Proprietary :30 October 2015 
15.3.3 Important protocol deviations 
Important protocol deviation (IPDs) will be confirmed after reviewing deviations as potential IPDs. 
The potential IPDs will be identified through programming checks of the data and reviews of the 
extracted data. Subjects seems have potential IPDs include, but are not limited to, the following: 
- Subject who deviated inclusion/exclusion criteria 
- Subject who took prohibited concomitant medication/therapy 
The number and percentage of subjects with IPD will be summarized by cohort and IPDs catogory. 
For Cohort1, IPDs in DSP-5423(tablet) treatment period and ones in DSP-5423P application period 
will be summarized separately. IPDs will be listed. 
 
15.3.4 Demographic and other reference range characteristics 
Demographic and baseline characteristics will be summarized based on each analysis population 
for each cohort.  
 
15.3.5 Efficacy analysis 
The efficacy analysis will be performed for each cohort based on safety analysis population. 
15.3.5.1 PANSS and CGI-S 
Summary statistics will be calculated for the following endpoints.  
1) Change from Baseline in PANSS Sum Score 
2) Change in total scores by PANSS subscale from baseline 
3) Change in sum scores by PANSS 5 factors model from baseline 
4) Change in CGI-S scores from baseline 
 
15.3.5.2 Time to treatment discontinuation from the initial application of DSP-5423P  
Kaplan-Meier method will be applied for the analysis. 
 
15.3.5.3 Adjusting the multiplicity 
No adjustments for multiplicity are performed. 
 
15.3.6 Safety analysis 
The following safety analysis will be performed by cohorts based on safety analysis population. 
 
15.3.6.1 Adverse event 
Treatment-emergent adverse event(TEAE) will be summarized. TEAE is defined as the adverse 
events with start date on or after Day 1. A treatment-related TEAE is defined as a TEAE for which the 
causal relationship to the study treatment is either ‘definite’, ‘probable’, or ‘possible’.  
The number and percentage of subjects who have TEAE or treatment-related TEAE will be 


Protocol No. D4904040 1.02 
DSP-5423P 
53 
 
Confidential and Proprietary :30 October 2015 
summarized. Death, Serious TEAE, TEAE leading to treatment discontinuation, severe TEAE, 
extrapyramidal TEAE, and skin related TEAE will be summarized in the same manner.  
 
15.3.6.2 DIEPSS 
1) Change from Baseline in DIEPSS total score (excluding overall severity) 
Summary statistics will be caluculated by visits. 
2) Change from Baseline to DIEPSS item scores 
For each item score, a shift table will be created based on the baseline to the highest scores 
per subjects. 
 
15.3.6.3 Laboratory test, ECGs, and vital sign 
The summary statistics of measurements will be caluculated by visits. 
 
15.3.6.4 Concomitant use of antiparkinson drug 
The number and percentage of subjects with concomitant use of antiparkinson drugs in DSP-5423P 
application period will be summarized. 
 
15.3.6.5 C-SSRS 
The number and percentage of subjects with either suicidal ideation or suicidal behavior at least 
once in DSP-5423P application period will be summarized. 
 
15.3.6.6 Skin irritation assessment 
Distribution of maximum score will be presented.  
 
15.3.7 Pharmacokinetic analysis 
The summary statistics of the following variables will be provided by visits based on 
pharmacokinetic analysis population. 
1) Plasma concentration of bronanserin 
2) Plasma concentration of Note 1) metabolites 
Note 1) metabolite of interest 
Cohort 1: M-1 (N-de-ethylated), M-2 (N-oxide), M-3 (7OH) (hydroxide), M-3 (8OH) 
(hydroxide), M-4 (ethylenediamine), and M-8 (carboxylic acid) 
Cohort 2: M-1 (N-de-ethylated) 
 
 
15.3.8 Analysis of other endpoints 
The following analysis will be performed based on safety analysis population. 
1) DAI-10 total scores 


Protocol No. D4904040 1.02 
DSP-5423P 
54 
 
Confidential and Proprietary :30 October 2015 
Summary statistics will be calculated by visits. 
2) EQ-5D index score 
Summary statistics will be calculated by visits. 
3) Questionnaire on dosage form 
The number and percentage of subjects by each question will be summarized.  
 
15.3.9 Interim analysis 
Interim analysis to judge study continuation is not performed. However, for submission purpose, it 
might be conducted before final database lock. 
 
15.3.10 Data handling 
15.3.10.1 
Day 1 
Day 1 is defined as the day of the initial application of DSP-5423P for each subject.  
 
15.3.10.2 
Analysis visit 
All data will be organized and analyzed according to the scheduled timing as outlined in Table 2 
and 3 Schedule of Assessments and according to the visit denoted in the CRFs. Unscheduled visits 
may not be used for any analysis unless otherwise specified. The data collected at the discontinuation 
visit within 7 days from the final application of study drug are mapped to the next scheduled visit of 
the actual discontinuation date and utilized for analysis. 
 
15.3.10.3 
Baseline 
Baseline value for analysis is defined as the last non-missing data on or prior to Day 1. 
 
15.3.10.4 
LOCF endpoint 
The LOCF endpoint is defined as the last data captured on Day 1 through 7 days after the final 
application of DSP-5423P. 
 
15.3.10.5 
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.  
 
 
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 


Protocol No. D4904040 1.02 
DSP-5423P 
55 
 
Confidential and Proprietary :30 October 2015 
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:    
1) The outcome, severity, seriousness of AEs 
2) Causal relationship to the study treatment 
3) The reasons for concomitant use 
4) The reasons for dose changing of study drugs 
5) The reason for discontinuation 
 
16.2 Study Monitoring 
This study will be monitored from initiation to completion by the Sponsor or its 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.  


Protocol No. D4904040 1.02 
DSP-5423P 
56 
 
Confidential and Proprietary :30 October 2015 
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 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 with laboratory certification and a current, dated copy of normal range values. 
 
 
17. ETHICAL AND REGULATORY OBLIGATIONS 
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 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 the “Investigator Approval" page. 
 
 
17.2 Institutional Review Board  
Documented approval for conducting the study from the appropriate Institutional Review Board 
(IRB) 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 approval must be obtained and also forwarded to the Sponsor. 
 
A copy of written IRB approval or a favorable opinion of the protocol, informed consent form and 
subject recruitment material (if applicable) must be provided to the Sponsor before start of the study. 
The Investigator is responsible for obtaining from the IRB 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.  The Sponsor must be supplied with written 
documentation of continued review of the clinical research.  
 


Protocol No. D4904040 1.02 
DSP-5423P 
57 
 
Confidential and Proprietary :30 October 2015 
The Investigator must promptly inform the IRB of all SAEs reported by subjects enrolled in the 
study or other safety information reported from the Sponsor 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 for 
approval before submission to the IRB.  The informed consent form will be approved by the Sponsor 
before submission to the IRB.   
 
The Sponsor may provide a template informed consent form to be qualified by each research facility 
to conform to local requirements.  All informed consent forms must contain the minimum elements 
as mandated by ICH GCP, applicable local law(s) and regulations and will be approved by the Sponsor 
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 


Protocol No. D4904040 1.02 
DSP-5423P 
58 
 
Confidential and Proprietary :30 October 2015 
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 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, Emergency deviations 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor and 
the appropriate IRB.  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, except where 
necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB 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 and the IRB 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 
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. 
 


Protocol No. D4904040 1.02 
DSP-5423P 
59 
 
Confidential and Proprietary :30 October 2015 
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 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. However, excluding the cases a) to d) below. 
a) When the (causal) relationship between this study and the adverse event or injury is denied, 
it does not constitute a study subject of compensation. 
b) It shall not be a study subject of compensation in the event that adverse event or injury 
occurs due to participating medical institution or a reason attributable to the liability of a 
third party. 
c) If the expected effects of the drug or other benefits cannot be offered, it should not be a 
study subject of compensation. 
d) Damage to health due to intentional or serious negligence on the part of the subject may not 
be compensated or may be restrict. 
6) The sponsor shall take necessary measures, such as enrolling in clinical study insurance for 
compensation. 
 
17.10 Payment of transportation expenses to reduce the burden associated 
with this study participation 
In order to reduce the burden associated with this clinical study participation, the subject may be 
paid for transportation expenses, etc. in accordance with the rule of the site. 


Protocol No. D4904040 1.02 
DSP-5423P 
60 
 
Confidential and Proprietary :30 October 2015 
18. Reference 
1) Koyama T. Adherence to schizophrenia treatment [in Japanese]. Jpn J Clin Psychopharmacol. 
2008; 11: 729-39. 
2) Sawada N, Watanabe K. Adherence of schizophrenia[in Japanese]. Jpn J Clin 
Psychopharmacol. 2008; 11: 1633-44. 
3) Day JC, Bentall RP, Roberts C, Randall F, Rogers A, Cattell D, et al. Attitudes toward 
antipsychotic medication; The impact of clinical variables and relationships with health 
professionals. Arch. Gen. Psychiatry. 2005;62:717-24. 
4) Johannes H. The introduction of Shared Decision Making [SDM] in psychiatric management 
[in Japanese]. Jpn J Clin Psychopharmacol. 2011; 14: 678-87. 
5) Yoshio T. The present conditions/problems of the drug therapy that a pharmacist examines and 
future development–Does the choice of the formation improve adherence of the patient?– [in 
Japanese]. Jpn J Clin Psychopharmacol. 2007; 10: 2142-9. 
6) Une T, Kurumiya S. Pharmacological profile of blonanserin [in Japanese]. Jpn J Clin 
Psychopharmacol. 2007; 10: 1263-72. 
7) Farde L, Wiesel FA, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in 
schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988;45(1):71-
6. 
8) Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D2 
occupancy, clinical response, and side effects: A double-blind PET study of first-episode 
schizophrenia. Am J Psychiatry. 2000;157:514-20. 
9) Lindenmayer JP, Bernstein-Hyman R, Grochowski S. A new five factor model of schizophrenia. 
Psychiatric Quarterly. 1994;65(4):299-322. 
10) Note for guidance on the clinical investigation of medicinal products in the treatment of 
schizophrenia, CPMP/EWP/559/95 (Feb. 26, 1998). European Agency of medicinal Products, 
HumanMedicines Evaluation Unit. 
11) Perkins DO, Stroup TS, Lieberman JA. Psychotic disorders measures. In: Handbook of 
Psychiatric Measures. Washington DC: American Psychiatric Association; 2000. P.485-513. 
12) Owashi T, Kamijima T. VIII Treatment assessment 1. Treatment Compliance and adherence. 
Japanese journal of clinical psychiatry. 2004;599-616. 
13) EuroQol Group. EuroQol; A new facility for the measurement of health-related quality of life. 
Health Policy. 1990;16(3):199-208. 
14) Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO et al. Practice 
guideline for the treatment of patients with schizophrenia second edition. APA Practice 
guideline. 
15) Sato M, Niwa S,Inoue S, edit. Schizophrenia treatment guideline. 2nd edition, Tokyo. IGAKU 
SHOIN. 2008:60-6. 


Protocol No. D4904040 1.02 
DSP-5423P 
61 
 
Confidential and Proprietary :30 October 2015 
16) Williams JBW. Mental health status, functioning, and disabilities measures. In: Handbook of 
Psychiatric Measures. Washington, D.C.: American Psychiatric Association, 2000 p. 93-115. 
17) Inada T, Beasley CM Jr, Tanaka Y, Walker DJ. Extrapyramidal symptom profiles assessed with 
the Drug-Induced Extrapyramidal Symptom Scale: comparison with Western scales in the 
clinical double-blind studies of schizophrenic patients treated with either olanzapine or 
haloperidol. Int Clin Psychopharmacol. 2003; 18(1): 39-48. 
18) Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings from Three 
Multisite Studies with Adolescents and Adults. Am J Psychiatry. 2011;168:1266-77. 
19) Kawamura T, Sasagawa S, Masuda T, Honda S, Kinoshita M, Harada S, et al. Basic Studies on 
the Standerdization of Patch Test [in Japanese]. Jpn. J. dermatol. 1970; 80: 301-14. 
 
 
 


Protocol No. D4904040 1.02 
DSP-5423P 
62 
 
Confidential and Proprietary :30 October 2015 
19. Appendix 
- Clinical study implementation system 
 
 

SAP_001.pdf: 
 1
 
 
Statistical Analysis Plan 
 
Long-Term Study of DSP-5423P in Patients with Schizophrenia 
[Phase 3] 
 
Protocol: D4904040 
 
Sumitomo Dainippon Pharma Co., Ltd. 
 
Version number: 2.0 
Date :8JUN2017 
 
 


 2
 
Signature 
 
Study Biostatistician: 
 
 
 
 
 
                                                   
 
Fellow, Biostatistics and HTA Statistics, Data Science 
 
 
 
 
 
                         
Date 
Head of Biostatistics: 
 
 
 
 
 
                                                   
 
Group Manager, Biostatistics Group, Data Science 
 
 
 
 
 
                         
Approval Date 
Medical Lead: 
 
 
 
 
                                                   
 
Fellow, Regional Functional Head of CNS Research 
 
 
 
 
 
                         
Approval Date 
Head of Clinical Pharmacology: 
 
 
 
 
                                                   
 
Group Manager, Clinical Pharmacology, Clinical Research
 
 
 
                         
Approval Date 
 


 3
Modification History 
 
Version 
Study 
Biostatistician 
Date of the 
Document 
Version 
Approvers 
Significant Changes from  
Previous Authorized Version 
1.0 
 
25APR2017
 
Not Applicable – First Version
2.0 
 
On the cover
 
 
 
• Since the discontinuation 
rate after DSP-5423P patch 
initiation was less than 
50%, rates of subjects 
continued Week 28 and/or 
Week 52 were added in 
analysis of DSP-5423P 
treatment duration. 
(Section 9.11.4, 10.1) 
• Table 14.2.5 Time to 
All-Cases Treatment 
Discontinuation by Prior 
Antipsychotics was added. 
• The sum of cohort was 
added in the summary of 
plasma drug concentration. 
(Section 9.14.1) 
 


 4
Contents 
1. Introduction ....................................................................................................................................... 1 
2. Abbreviation ...................................................................................................................................... 1 
3. Change from analysis specified in study protocol ............................................................................ 2 
4. Objective of the study ....................................................................................................................... 2 
4.1 Primary objective ........................................................................................................................ 2 
4.2 Secondary objective .................................................................................................................... 2 
4.3 Overall study design of clinical study ......................................................................................... 2 
4.3.1 Cohort 1 ............................................................................................................................... 3 
4.3.2 Cohort 2 ............................................................................................................................... 4 
4.4 Schedule of assessments ............................................................................................................. 5 
5. Target sample size ............................................................................................................................. 9 
6. Analysis population ........................................................................................................................... 9 
6.1 Safety analysis population .......................................................................................................... 9 
6.2 Pharmacokinetic analysis population .......................................................................................... 9 
7. Endpoints .......................................................................................................................................... 9 
7.1 Efficacy endpoints ...................................................................................................................... 9 
7.1.1 PANSS ................................................................................................................................. 9 
7.1.2 Clinical Global Impression – Severity of Illness (CGI-S) ................................................. 10 
7.1.3 DSP-5423P patch duration ................................................................................................. 10 
7.2 Safety endpoints ........................................................................................................................ 11 
7.2.1 Adverse event ..................................................................................................................... 11 
7.2.2 Concomitant drug and concomitant therapy ...................................................................... 11 
7.2.3 Laboratory test ................................................................................................................... 12 
7.2.4 Vital Sign and Body Weight ............................................................................................... 12 
7.2.5 12-lead ECGs ..................................................................................................................... 12 
7.2.6 Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) ................................................ 13 
7.2.7 Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................................... 13 
7.2.8 Skin irritation assessment .................................................................................................. 13 
7.3 Other assessments ..................................................................................................................... 14 
7.3.1 DAI-10 ............................................................................................................................... 14 
7.3.2 EQ-5D ................................................................................................................................ 14 
7.3.3 Questionnaire on dosage form ........................................................................................... 15 
7.4 Pharmacokinetic variable .......................................................................................................... 15 
7.4.1 Measurement ...................................................................................................................... 15 


 5
7.4.2 Survey variable .................................................................................................................. 15 
8. Statistical Analysis .......................................................................................................................... 16 
8.1 General Considerations ............................................................................................................. 16 
8.2 Derived variables ...................................................................................................................... 16 
8.3 Day 1 ......................................................................................................................................... 17 
8.4 Baseline ..................................................................................................................................... 18 
8.5 Analysis Visit ............................................................................................................................ 18 
8.6 LOCF endpoint ......................................................................................................................... 19 
8.7 Missing data .............................................................................................................................. 20 
9. Statistical Method ........................................................................................................................... 22 
9.1 Subject Disposition ................................................................................................................... 22 
9.2 Analysis Population .................................................................................................................. 22 
9.3 Important Protocol Deviations .................................................................................................. 22 
9.4 Demographics and Other Baseline Characteristics ................................................................... 23 
9.5 Psychiatric History .................................................................................................................... 23 
9.6 Medical History ........................................................................................................................ 24 
9.7 Prior and Concomitant Medications ......................................................................................... 24 
9.8 Treatment Compliance .............................................................................................................. 25 
9.9 Duration of Exposure ................................................................................................................ 25 
9.10 Daily dose and Cumulative dose ............................................................................................. 25 
9.11 Efficacy Analysis .................................................................................................................... 26 
9.11.1 PANSS Total Score .......................................................................................................... 26 
9.11.2 PANSS subscale scores and PANSS five-factor model scores ......................................... 26 
9.11.3 Clinical Global Impression - Severity of Illness (CGI-S) ................................................ 26 
9.11.4 Time to Treatment Discontinuation .................................................................................. 26 
9.11.5 Subgroup analysis for efficacy ......................................................................................... 27 
9.12 Safety Analysis ....................................................................................................................... 27 
9.12.1 Adverse event ................................................................................................................... 27 
9.12.2 Laboratory test ................................................................................................................. 29 
9.12.3 Vital sign and body weight ............................................................................................... 30 
9.12.4 12-lead ECGs ................................................................................................................... 31 
9.12.5 DIEPSS ............................................................................................................................ 32 
9.12.6 C-SSRS ............................................................................................................................ 32 
9.12.7 Skin irritation assessment................................................................................................. 33 
9.12.8 Subgroup analysis for safety ............................................................................................ 33 
9.13 Analysis of Other endpoints .................................................................................................... 34 


 6
9.13.1 DAI-10 ............................................................................................................................. 34 
9.13.2 EQ-5D .............................................................................................................................. 34 
9.13.3 Questionnaire on dosage form ......................................................................................... 34 
9.14 Pharmacokinetic analysis ........................................................................................................ 34 
9.14.1 Plasma drug concentration ............................................................................................... 34 
9.14.2 Subgroup analysis ............................................................................................................ 35 
10. Appendix ....................................................................................................................................... 36 
10.1 SAS Code ................................................................................................................................ 36 
10.2 Title of Tables, Listings, and Figures ...................................................................................... 37 
 






 
3
and cohort 2 will be initiated after enrollment in cohort 1 has been completed. Enrollment in cohort 
1 will be terminated when the number of total subjects whose DSP-5423P treatment duration is 6 
weeks or more reached 50. At the completion of enrollment in cohort 1 and at the initiation of 
enrollment in cohort 2, the sponsor will notify the participating study centers of that. 
 
4.3.1  Cohort 1 
Cohort 1 consists of 3 periods: DSP-5423 (tablet) treatment period (6 weeks), DSP-5423P 
treatment period (52 weeks) and follow-up period (1-2 weeks). Prior to initiation of DSP-5423 
(tablet) treatment period, washout period (up to 4 weeks) will be arranged according to the dose of 
prior antipsychotics (haloperidol equivalent). 
1) DSP-5423 (tablet) treatment period 
DSP-5423 (tablets) will be administered orally twice daily after breakfast and evening meal for 6 
weeks. The initial dose of DSP-5423 (tablet) will be 8mg/day. DSP-5423 (tablet) will be 
administered as flexible dose (8, 12, 16 mg/day) according to the dose adjustment criteria. 
2) DSP-5423P treatment period 
DSP-5423P will be applied once daily for 52 weeks. The study drug will be applied to the 
subject’s back, chest, or abdomen. Start DSP-5423P application with the dosage according to the 
final dosage of DSP-5423. DSP-5423P will be applied as flexible dose (40, 60, 80 mg/day) 
according to the dose adjustment criteria. 
 
Figure 1 Study schematic (cohort 1)  
 
 
 
 
DSP-5423 
Tablet 
8~16 mg/day 
DSP-5423P 
40~80 mg/day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 weeks 
52 weeks 
1-2 weeks
 
 
Washout 
period* 
DSP-5423 
(Tablet) 
treatment 
phase 
DSP-5423P treatment phase 
Follow-up 
phase 
* If the dose of the prior antipsychotics is 12.0 mg/day or less (haloperidol equivalent), to initiate the administration 
of the DSP-5423 (tablet) after termination of the prior antipsychotics. Washout period may be arranged and 
down-titration would be done as needed prior to termination. 
If the dose of the prior antipsychotics exceeds 12.0 mg/day (haloperidol equivalent), washout period will be 
arranged. First, the dose is reduced to 12.0 mg/day or less, then down-titration would be done as needed. After 
termination of the prior antipsychotics, to initiate the administration of the DSP-5423 (tablet). 
Washout period should be up to 4 weeks (28 days) from the screening. 
** The registration procedure is presented in section 10 in the protocol.  
 
Screening 
Informed consent 
Registration** 


 
4
4.3.2  Cohort 2 
Cohort 2 consists of 2 period: DSP-5423P treatment period (52 weeks) and follow-up period (1-2 
weeks). During the DSP-5423P treatment period, DSP-5423P will be applied once daily for 52 
weeks. The study drug will be applied to the subject’s back, chest, or abdomen. The initial dose of 
DSP-5423P will be 40 mg/day. DSP-5423P will be applied as flexible dose (40, 60, 80 mg/day) 
according to the dose adjustment criteria. Prior to initiation of DSP-5423P treatment period, a 
washout period (up to 4 weeks) will be arranged according to the dose of prior antipsychotics 
(haloperidol equivalent). 
 
Figure 2 Study schematic (cohort 2).  
 
 
 
 
DSP-5423P 
40~80 mg/Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
52 weeks 
1-2 weeks 
 
 
washout 
period* 
DSP-5423P treatment phase 
Follow-up 
phase 
* If the dose of the prior antipsychotics is 12.0 mg/day or less (haloperidol equivalent), to initiate the application of 
the DSP-5423P after termination of the prior antipsychotics. Washout period may be arranged and down-titration 
would be done as needed prior to termination.  
If the dose of the prior antipsychotics exceeds 12.0 mg/day (haloperidol equivalent), washout period will be 
arranged. First, the dose is reduced to 12.0 mg/day or less, then down-titration would be done as needed. After 
termination of the prior antipsychotics, to initiate the administration of the DSP-5423P. 
Washout period should be up to 4 weeks (28 days) from the screening. 
** The registration procedure is presented in section 10 in the protocol.  
 
 
 
Registration** 
 
Screening 
Informed consent 




 
6
 
 
 
DSP-5423 (tablet) treatment phase (6 
weeks) 
DSP-5423P treatment phase (52 weeks) 
 
Follow-up 
phase 
(1-2 weeks) 
Visit No. 
- 
1 
2 
3 
4 
5 
6 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
111 
112 
113 
Discontinuation
Follow-up visit 
 
 
 
Timeline from initiation of DSP-5423 
(tablet) administration 
Timeline from initiation of DSP-5423P application 
Study timeline a) 
Week 
- Screening
Tab-
Baseline
Tab- 
Week 1
Tab- 
Week 2
Tab- 
Week 4
Tab-Week 
6 
/baseline
Week 1
Week 2
Week 4
Week 6
Week 8 Week 12 Week 16 Week 20 Week 24 Week 28 Week 36 Week 44 Week 52
6 ~ 17 days after 
completion of 
treatment or 
dicontinuation 
Visit window (Day) 
 
Tab 
-28~ 
Tab 
-2~1 
Tab 
5~11 
Tab 
12~18
Tab 
26~32
Tab 
40~43 
5~11 
12~18
26~32
40~46
54~60 
78~92
106~120
134~148
162~176
190~204
239~267
295~323
351~379
At 
discontinuation
+5 
Blood sampling for PK 
 
 
 
 
X 
 
X e) 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
a) DSP-5423 (tablet) date of initial administration is the Tab-Day 1, and DSP-5423P patch initiation/beginning Date is the Day 1. 
b) DSP-5423 (tablet) Visit 2 before administration initiation/beginning (perform), DSP-5423 (tablet) at the end of administration period (Visit 6) and at the end of DSP-5423P patch 
period (Visit 113) always in in fasting state/conditions (End fast 10 hours prior to blood collection/drawing/sampling). Perform to in fasting state/conditions as much as possible in the 
rest of the Visit. 
c) Pregnancy only perform in premenopausal women available. 
d) Perform prior to administration initiation/beginning of DSP-5423 (tablet). Prior therapy If antipsychotics are present, prior therapy after termination of antipsychotics, perform prior 
to DSP-5423 (tablet) administration initiation/beginning. 
e) Perform prior to initiation/beginning of attachment of the DSP-5423P. 
f) In the event of termination to DSP-5423 (tablet) administration period, treatment compliance status, DIEPSS, C-SSRS, laboratory test, bone pregnancy laboratory test, 12-lead 
electrocardiogram, body weight, bone termination, and Visit survey, observation, and laboratory test of the survey, observation, and laboratory test of the adverse event at the time of 
body temperature ・blood pressure ・pulse rate, among others, perform status, laboratory test, pregnancy, laboratory test, 12-lead electrocardiogram. 
g) Investigational drug except perform prior to administration initiation/beginning of antipsychotics. 




 
8
c) Pregnancy only perform in premenopausal women available. 
d) Perform prior to initiation/beginning of attachment of the DSP-5423P. Prior therapy If antipsychotics are present, prior therapy after termination of antipsychotics, perform prior to 
initiation/beginning of DSP-5423P placement. 
e) Investigational drug except perform prior to administration initiation/beginning of antipsychotics. 


 
 
9
5.  Target sample size 
Number of subjects enrolled: 200 subjects 
- Number of subjects treated with DSP-5423P for 6 weeks and more in cohort 1: 50 subjects 
- Number of subjects treated with DSP-5423P for 52 weeks in either cohort 1 or cohort 2: 100 
subjects 
The new enrollment can be terminated at the time when 100 subjects with 52-week exposure of 
DSP-5423P are collected, together with a separate confirmatory study [Confirmatory Study of 
DSP-5423P in Patients with Schizophrenia <Phase 3> (protocol: D4904020)]. 
 
6.  Analysis population 
Prior to database hard lock, a data review meeting will be conducted and subject assignments to 
analysis set/population will be determined. 
 
6.1  Safety analysis population 
Subjects with at least one application of DSP-5423P. 
Efficacy analysis will also be performed based on the safety analysis population. 
 
6.2  Pharmacokinetic analysis population 
Subjects with at least one application of DSP-5423P, and with measurements of plasma 
bronanserin concentration after application of DSP-5423P. 
 
7.  Endpoints 
7.1  Efficacy endpoints 
1) Change in PANSS total score from baseline note 1) 
2) Change in PANSS subscale total scores from baseline note 1) 
3) Change in by PANSS 5 Factor Model total score from baseline note 1) 
4) Change in CGI-S scores from baseline note 1) 
5) Time to treatment discontinuation from the initial application of DSP-5423P 
Note 1) Baseline of DSP-5423P treatment period 
 
7.1.1  PANSS 
The PANSS 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 and will be 
certified by the Sponsor before his/her initial assessment of PANSS.  The certified rater will rate 
30 items on a 7-point scale of 1 to 7 and record dates and results of the assessments in the CRFs. 
When the study treatment is completed or prematurely discontinued, PANSS will be rated before 
starting post-treatment with other antipsychotics. 


 
 
10
The PANSS total score is the sum of all 30 item scores. 
 
PANSS subscale 
Positive subscale: 
Delusions, conceptual disorganization, hallucinatory behavior, excitement, 
grandiosity, suspiciousness/persecution, and hostility 
Negative subscale: 
Blunted affect, emotional withdrawal, poor rapport, passive/apathetic social 
withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of 
conversation, and stereotyped thinking 
General psychopathology subscale: 
Somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, 
depression, motor retardation, uncooperativeness, unusual thought content, 
disorientation, poor attention, lack of judgment and insight, disturbance of 
volition, poor impulse control, preoccupation, and active social avoidance 
Each PANSS subscale score is the sum of item scores defined respectively as each subscale.     
 
PANSS 5 factors models 
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/persecution, and unusual thought 
content 
Anxiety/depression: Hypochondria, anxiety, feelings of guilt, depression, and preoccupation 
PANSS 5 factor model score is the sum of item scores defined respectively as each factor. 
 
7.1.2  Clinical Global Impression – Severity of Illness (CGI-S) 
CGI-S 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. 
 
7.1.3  DSP-5423P patch duration 
The treatment duration of DSP-5423P will be the one from the initial application date to the last 
application date of DSP-5423P. Termination of application (for any reason) will be an event and 


 
 
11
completion of treatment will be a censor. That is to say, time to event based on treatment duration 
from start to termination of treatment will be analyzed. In this analysis, subjects who complete 
study treatment will be censored not as an event, considering those subjects can pursue study 
treatment even after treatment completion. 
 
7.2  Safety endpoints 
1) Adverse events (AEs) and adverse drug reaction (ADRs) 
2) Extrapyramidal AEs and ADRs 
3) Skin-related AEs and ADRs at the application site 
4) Assessment of skin irritation reaction at the application site 
5) Change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) Total Score (excluding 
overall severity) from baseline 
6) Change in individual DIEPSS scores from baseline 
7) Serum prolactin concentration 
8) Electrocardiogram (ECG) parameters (QTc) 
9) Concomitant use of antiparkinson drug 
10) Assessment of suicides using Columbia-Suicide Severity Rating Scale(C-SSRS) 
11) Laboratory test values, vital signs and body weight 
 
7.2.1  Adverse event 
In this study, relevant events occurred from the treatment initiation of DSP-5423 (tablet) to 
follow-up visit in cohort 1 and ones occurred from the initiation of DSP-5423P application to 
follow-up visit in cohort 2 will be captured as adverse events. 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. 
 
In the cohort 1, AEs that occur during the DSP-5423 (tablet) treatment period and worsen during 
the DSP-5423P application period will be recorded as both AEs in the DSP-5423 (tablet) 
administration period and also as AEs in the DSP-5423P application period with start date as the 
onset date of the worsening AE. AEs that occur during the DSP-5423 (tablet) treatment period 
without further worsening in the DSP-5423P application period will be recorded as AEs only in the 
DSP-5423 (tablet) treatment period 
 
7.2.2  Concomitant drug and concomitant therapy 
The following information on all medications used from initiation of DSP-5423(tablet) treatment 
until the follow-up visit in cohort1 or initiation of DSP-5423P application until the follow-up visit 


 
 
12
in cohort 2 will be recorded in the CRFs. For antipsychotics and antiparkinson drugs, the 
information on the usage for 7 days before screening and during wash-out period will also 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) 
 
7.2.3  Laboratory test 
Blood and urine samples will be collected for clinical laboratory tests.  The Investigators will 
record the date of collection and whether or not the subject is under 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 3. Detailed instructions 
regarding clinical laboratory procedures, sampling, shipping, and reporting can refer to the 
instructions manual provided by the Sponsor. 
 
Table 3 Contents of laboratory variables  
Hematology test 
white blood cell count, red blood cell count, hemoglobin, hematocrit, 
platelet count, differential white blood cell count (neutrophils, eosinophils, 
basophils, monocytes, and lymphocytes) 
Biochemical 
laboratory 
test 
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  
 
7.2.4  Vital Sign and Body Weight 
Investigator measure the following variable and record Dates of measurements and the results in 
the CRFs 
- Systolic and diastolic blood pressures (sitting), pulse rate, body temperature (axilla), and body 
weight 
 
7.2.5  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 




 
 
14
7.3  Other assessments 
7.3.1  DAI-10 
DAI-10's is an assessment for evaluating a drug adherence by adding the patient’s attitude to the 
drug treatment compliance. Investigator will survey the subject's drug attitude ("true" or "false") for 
the following 10 items and record the assessment Date and the results to CRFs. 
1) Good things about medication outweigh the bad 
2) Feel like a zombie 
3) Take of my own free choice 
4) Feel more relaxed 
5) Feel tired and sluggish 
6) Take only when sick 
7) Feel more normal 
8) Unnatural for my mind and body to be controlled by medications 
9) Thoughts are clearer 
10) By staying on medication I can prevent a breakdown 
 
7.3.2  EQ-5D 
EQ-5D's is a self-administered, comprehensive rating scale developed to measure health-related 
quality of life. Investigator will use the questionnaire to investigate the following 5 items and 
record the assessment Date and the result to CRFs. 
 
1) MOBILITY 
1: I have no problems in walking about,  
2: I have slight problems in walking about,  
3: I have moderate problems in walking about,  
4: I have severe problems in walking about,  
5: I am unable to walk about 
2) SELF-CARE 
1: I have no problems washing or dressing myself,  
2: I have slight problems washing or dressing myself,  
3: I have moderate problems washing or dressing myself,  
4: I have severe problems washing or dressing myself,  
5: I am unable to wash or dress myself 
3) USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
1: I have no problems doing my usual activities,  
2: I have slight problems doing my usual activities,  
3: I have moderate problems doing my usual activities,  


 
 
15
4: I have severe problems doing my usual activities,  
5: I am unable to do my usual activities. 
4) PAIN / DISCOMFORT 
1: I have no pain or discomfort,  
2: I have slight pain or discomfort,  
3: I have moderate pain or discomfort,  
4: I have severe pain or discomfort,  
5: I have extreme pain or discomfort 
5) ANXIETY / DEPRESSION 
1: I am not anxious or depressed,  
2: I am slightly anxious or depressed,  
3: I am moderately anxious or depressed,  
4: I am severely anxious or depressed,  
5: I am extremely anxious or depressed 
 
7.3.3  Questionnaire on dosage form 
Investigator will ask Question 1 and Question 2 regarding the patch dosage form of antipsychotic, 
Question 3 regarding the DSP-5423P, and record the assessment Date and the results to CRFs. 
- Would you like the patch dosage form to be available?? 
Response) "Yes" or "No" 
- Is it easy for you to continue treatment with patches compared with tablets? 
Response) "Yes," "Equal" or "No." 
- Question 3 Would you like to use the patches that you used during this study in the future? 
Response) "Yes" or "No" 
 
7.4  Pharmacokinetic variable 
7.4.1  Measurement 
- Plasma concentration of bronanserin 
- Plasma metabolite concentration 
Cohort 1: M-1 (N-de-ethylated), M-2 (N-oxide), M-3 (7OH) (hydroxide), M-3 (8OH) 
(hydroxide), M-4 (ethylenediamine), and M-8 (carboxylic acid) 
Cohort 2: M-1 (N-de-ethylated) 
 
7.4.2  Survey variable 
Investigator will record the following variable in CRFs. When subjects early terminate the study 
treatment, investigator will record the survey variables according to period at the time of 
termination [DSP-5423(tablet) or DSP-5423P]. 


 
 
16
DSP-5423 (tablet) treatment period: 
Dates and times of blood sample collection, Dates and times of the last two 
administrations of DSP-5423 (tablet) before blood sample collection, DSP-5423 (tablet) 
doses of the last two administrations before blood sample collection, Yes or no for the 
question whether had a meal immediately before administrations of DSP-5423 (tablet) 
of the last two administrations before blood sample collection 
DSP-5423P application period: 
Dates and times of blood sample collection, Dates and times of the last two applications 
of DSP-5423P before blood sample collection, DSP-5423P doses of the last two 
applications before blood sample collection, Locations for the last two applications of 
DSP-5423P before blood sample collection 
 
8.  Statistical Analysis 
8.1  General Considerations 
For categorical variables, the number of subjects and percentage for each category will be 
calculated. Unless otherwise specified, all options in a category in CRFs should be presented 
regardless of whether they are actually selected. Missing (if no option in CRFs was selected) are 
presented as missing unless otherwise specified. The percentages are rounded to one decimal place. 
However, 0% is set to be a blank. 
For continuous variables, summary statistic (n, Mean, SD, Min, Median, Max) will be calculated 
unless otherwise specified. Unless otherwise specified, mean and median should be rounded to one 
more decimal place of the observed value and SDs to two more of the observed value. If the 
summary statistic cannot be calculated (e.g., if the standard deviation is calculated with single data), 
period (.) should be presented. In summary of plasma drug concentration, the Geometric mean is 
rounded to one mode decimal place of observed value, and the CV% and Geometric CV% are 
rounded to one decimal place. 
In summary of observed values and change, subjects with both baseline and each visit values are 
utilized for analysis. 
All analyses will be conducted using SAS (Statistical Analysis System: SAS Institute, North 
Carolina, USA) version 9.4 or higher 
 
8.2  Derived variables 
When analysis is performed using derived variables, derived variables are handled without 
rounding, and the results are expressed with pre-specified digits. The derived variables in listing are 
presented based on pre-specified digits. 
- BMI (kg/m²): Weight (kg) / (height (m) x height (m)). [one decimal point] 
- Age at initial onset of schizophrenia (years): FLOOR ((onset date of initial episode – date of 


 
 
17
birth)/365.25). [integer] 
- Duration of illness (years): (date of informed consent – onset date of initial episode)/365.25. 
[integer] 
- Duration of current episode (months): (date of informed consent – onset date of current episode)/ 
(365.25/12). [integer] 
 
The following item are calculated for DSP-5423 (tablet) treatment period and DSP-5423P 
treatment period, respectively. 
- Duration of exposure (days): Last dose date –first dose date +1 [integer] 
- The first dose date and last dose date: the initial administration date and the final administration 
date for each period. The final application date for patch and the date for completion of the patch 
are identical and those are the final application date for patch, not final removal date for patch. 
- Treatment compliance (%): (total number of tablets/patches actually taken/applied x 100) / total 
number of tablets/patches that should have been taken/applied during each treatment period. 
[integer] If number of tablets/patches actually taken/applied is unknown, the treatment 
compliance is set to a missing. 
- Mean daily dose (mg/day): Average of prescribed daily dose (mg). [integer] 
- Maximum daily dose (mg/day): Maximum of prescribed daily dose (mg). [integer] 
- Modal daily dose (mg/day): Most frequently of prescribed daily dose (mg/day). In the case that 
two or more dose are the most frequent dose, the maximum of them will be the modal daily dose. 
- Last daily dose (mg/day): Prescribed daily dose of the last dose date (mg/day). [integer] 
- Cumulative dose (mg): Sum of prescribed daily dose (mg/day) x duration of each prescription 
(days). [integer] 
In calculation for number of tablets that should have been taken, if last date of prior description 
period and start date of following description period are same, prior description period are seen 
as up to day before of its last date. That is, the number of tablets prescribed and dose at last date 
of prior description period are seen as the number of tablets prescribed and dose in the 
subsequent period, and utilized for calculations. 
- DAI-10 total score: sum of 1 (item 1,3,4,7,9, or 10 are true and item 2,5,6, or 8 are false) and −1 
for other cases. [integer] 
- Ratio of plasma metabolite concentration to plasma blonanserin concentration: plasma 
concentration of metabolite/plasma concentration of blonanserin [three decimal places] 
 
8.3  Day 1 
Day 1 is defined as the day of the initial application of DSP-5423P for each subject. Tab-Day1 is 
defined as the day of initial administration of DSP-5423(tablet) for subjects in Cohort 1.  
 


 
 
18
8.4  Baseline 
Baseline value for analysis (for the DSP-5423P treatment period) is defined as the last 
non-missing data on or prior to Day 1. 
Regarding to Cohort 1, baseline value for the DSP-5423 (tablet) administration period 
(Tab-Baseline) is defined as the last non-missing data on or prior to the day of initial administration 
of DSP-5423(tablet). 
 
8.5  Analysis Visit 
Data of DSP-5423P treatment period is defined as the data captured on Day 1 through 7 days 
after the final application of DSP-5423P.   
All data will be organized and analyzed according to the scheduled timing as outlined in Tables 1 
and 2 Schedule of Assessments and according to the visit denoted in the CRFs. Unscheduled visits 
may not be used for any analysis unless otherwise specified. However, the data collected at the 
discontinuation visit within 7 days from the final application of study drug are mapped to the next 
scheduled visit of the actual discontinuation date. In listing, all data including unscheduled visit 
data should be presented. 
 
1) CRF discontinuation visits in DSP-5423 (tablet) treatment period 
Assessments and tests 
Relative Day 
Analysis Visit 
PANSS, CGI-S,  
DIEPSS, body weight,  
body temperature,  
blood pressure, pulse rate 
Tab-Day 1 to 11 
Tab-W1, 2, 4, 6 
Tab-Day 12 to 18 
Tab-W2, 4, 6 
Tab-Day 19 to 32 
Tab-W4, 6 
Tab-Day 33 or later
Tab-W6 
Laboratory test, ECG 
Tab-Day 1 to 18 
Tab-W2, 6 
Tab-Day 18 or later
Tab-W 6 
The Tab-Day 1 is defined as the date of initial administration of DSP-5423 (tablet). CRF 
discontinuation visits in DSP-5423 (tablet) treatment period is defined as data on first non-missing 
(ex. no visit or results are missing) visit which meets all above requirements. Laboratory test and 
vital sign (body temperature, blood pressure, pulse rate) are performed visit handling for each item. 
Others are not considered as missing if they have any one component. 
 
2) CRF discontinuation visits in DSP-5423P application period 
Assessments and tests 
Relative Day 
Analysis Visit 
PANSS, CGI-S,  
DIEPSS, C-SSRS,  
Day 1 to 11 
W1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, 44, 52 
Day 12 to 18 
W2, 4, 6, 8, 12, 16, 20, 24, 28, 36, 44, 52 


 
 
19
Assessments and tests 
Relative Day 
Analysis Visit 
Skin irritation assessment, 
body weight,  
body temperature,  
blood pressure, pulse rate 
Day 19 to 32 
W4, 6, 8, 12, 16, 20, 24, 28, 36, 44, 52 
Day 33 to 46 
W6, 8, 12, 16, 20, 24, 28, 36, 44, 52 
Day 47 to 60 
W8, 12, 16, 20, 24, 28, 36, 44, 52 
Day 61 to 92 
W12, 16, 20, 24, 28, 36, 44, 52 
Day 93 to 120 
W16, 20, 24, 28, 36, 44, 52 
Day 121 to 148 
W20, 24, 28, 36, 44, 52 
Day 149 to 176 
W24, 28, 36, 44, 52 
Day 177 to 204 
W28, 36, 44, 52 
Day 205 to 267 
W36, 44, 52 
Day 268 to 323 
W44, 52 
Day 324 or later 
W52 
Laboratory test, ECG  
Day 1 to 18 
W2, 6, 12, 20, 28, 36, 44, 52 
Day 19 to 46 
W6, 12, 20, 28, 36, 44, 52 
Day 47 to 92 
W12, 20, 28, 36, 44, 52 
Day 93 to 148 
W20, 28, 36, 44, 52 
Day 149 to 204 
W28, 36, 44, 52 
Day 205 to 267 
W36, 44, 52 
Day 268 to 323 
W44, 52 
Day 324 or later 
W52 
DAI-10, EQ-5D,  
Plasma drug concentration 
Day 1 to 46 
W2, 6, 12, 20, 28, 36, 44, 52 
Day 47 to 204 
W28, 36, 44, 52 
Day 205 or later 
W52 
Day 1 is defined as the day of the initial application of DSP-5423P for each subject. CRF 
discontinuation visits in DSP-5423P treatment period is defined as data on first non-missing (ex. no 
visit or results are missing) visit which meets all above requirements. Laboratory test and vital sign 
(body temperature, blood pressure, pulse rate) are performed visit handling for each item. Others 
are not considered as missing if they have any one component. 
 
8.6  LOCF endpoint 
The last observation from Day 1 through 7 days after the final application of DSP-5423P, except 
for baseline data defined in section 8.4, will be carried forward and will be defined as the Week 52 
(LOCF).  


 
 
20
 
8.7  Missing data 
Individual missing item in any scale will not be imputed. 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 case that any value derived in EDC and one calculated along with the SAP are 
different, the later will be adopted for the analysis. 
 
Missing/partial date will be imputed according to the following rules. In the listings, the original 
date without any imputation will be presented. The last visit date is the last date of visit among all 
visits including follow-up visits and unscheduled visits.  
1) Adverse event 
End date should be imputed first, and then Start date will be imputed based on imputed end 
date. 
End Date: 
1. If ongoing is checked, no imputation will be performed. 
2. If ongoing is not checked and end date is totally missing or year is missing, then end 
date will be imputed as the last visit date. 
3. If only day of end date is missing, end date will be imputed as the earlier one of 
following dates: the last day of that month and the last visit date. 
4. If both month and day (or only month) of end date is missing, end date will be imputed 
as the earlier one of following dates: the last day (Dec31) in that year or the last visit 
date. 
Start Date: 
1. If start date is totally missing and end date is also missing (ongoing), no imputation will 
be performed. For subjects applied DSP-5423P, although the events are summarized as 
TEAE, those are not included in summaries by the initial onset date of the event. 
2. If start date is totally missing and end date is not missing, start date will be imputed as 
the earlier one of following dates: end date of AE or date of the initial application date 
of DSP-5423P. 
3. If only day of start date is missing, and start date is in the same year and month of 
initial application date of DSP-5423P, start date will be imputed as earlier one of 
following non-missing dates: end date of AE or date of the initial application date of 
DSP-5423P. 
4. If only day of start date is missing, and start date is not in the same month of initial 
application date of DSP-5423P, start date will be imputed as the first day in that month. 
5. If both month and day (or only month) of start date is missing, and start date is in the 
same year of initial application date of DSP-5423P, start date will be imputed as earlier 


 
 
21
one of following non-missing dates: end date of AE or date of the initial application 
date of DSP-5423P. 
6. If both month and day (or only month) of start date is missing, and start date is not in 
the same year of initial application date of DSP-5423P, start date will be imputed as the 
first day (Jan01) in that year. 
 
2) Prior/Concomitant Medication 
End Date: 
1. If ongoing is checked, no imputation will be performed. 
2. If ongoing is not checked and end date is totally missing or year is missing, then end 
date will be imputed as the last visit date. 
3. If only day of end date is missing, end date will be imputed as the earlier one of 
following dates: the last day of that month and the last visit date. 
4. If both month and day (or only month) of end date is missing, end date will be imputed 
as the earlier one of following dates: the last day (Dec31) in that year or the last visit 
date. 
Start Date: 
1. If the medication is ‘started prior to study’ (checked in the CRF), no imputation will be 
performed (That medication should be defined as prior medication). 
2. If the medication is not ‘started prior to study’ (checked in the CRF) and start date is 
totally missing, no imputation will be performed (That medication should be defined as 
neither prior medication nor concomitant medication). 
3. If only day of start date is missing, start date will be imputed as the first day in that 
month. 
4. If both month and day (or only month) of start date is missing, start date will be 
imputed as the first day (Jan01) in that year. 
 
3) Initial/Current Episode of Schizophrenia 
For the purpose of the estimation of Duration of illness and duration of current episode, the 
day of onset date of initial/current episode will be imputed according to the followings; 
1. If onset date is totally missing, no imputation will be performed. 
2. If only date of onset date is missing, onset date will be imputed as the first day in that 
month. 
3. If only month of onset date is missing, and onset date is in the same year of informed 
consent, onset date will be imputed as previous day of informed consent. 
4. If only month of onset date is missing, and onset date is not in the same year of 
informed consent, onset date will be imputed as June 30th. 


 
 
22
 
9.  Statistical Method 
All efficacy, safety and other analysis are based on Safety Analysis Population, and PK analysis 
are based on PK analysis population. All subjects and data collected will be presented in listings. 
 
9.1  Subject Disposition 
The subject will be categorized for each cohort. 
1) Cohort 1 
Subjects with informed consent, subjects discontinued before administration of 
DSP-5423P (tablet), subjects took DSP-5423 (tablet) in DSP-5423 (tablet) treatment period, 
subjects who didn’t apply DSP-5423P after completion of DSP-5423 (tablet), subjects who 
applied DSP-5423P in DSP-5423P application period, subjects who completed DSP-5423P 
application period, and subject who early terminated from DSP-5423P application period. 
2) Cohort 2 
Subjects with informed consent, subjects discontinued before application of DSP-5423P, 
subjects took DSP-5423P in DSP-5423P application period, subjects who completed 
DSP-5423P application period, and subject who early terminated from DSP-5423P 
application period. 
List of the study disposition, list of subject who discontinued the treatment of DSP-5423 (tablet) 
treatment period, and list of subject who discontinued the treatment of DSP-5423P application 
period. 
 
9.2  Analysis Population 
The number and percentage of subjects who are included in each analysis population or treated 
with DSP-5423P will be summarized for each cohort and cohort total. The list of analysis 
population and subjects who excluded from each population will be presented. 
 
9.3  Important Protocol Deviations 
IPDs will be discussed and determined at a blind data review meeting before DBL. Potential 
IPDs will be identified through data review by programmatically and manually and review for the 
deviation log. Subjects with potential IPDs can be, but not limited to:   
- Subject who deviated inclusion/exclusion criteria 
- Subject who took prohibited concomitant medication/therapy 
The number of IPDs, and the number and percentage of subjects with IPD will be summarized 
by cohort and IPDs defined in Table 5. For Cohort1, IPDs in DSP-5423(tablet) treatment period and 
ones in DSP-5423P application period will be summarized separately. If a subject has same IPD 
multiple times, the subject will be counted only one times as such IPD. IPDs will be listed. 




 
 
24
PANSS composite subscale at baseline: Positive subscale score > Negative subscale score; 
Positive subscale score = Negative subscale score; 
Positive subscale score < Negative subscale score 
Baseline PANSS total score: summary statistics 
Baseline PANSS total score: 59 or less, 60 to 79, 80 or above 
Baseline CGI-S score: summary statistics and frequency 
Baseline DIEPSS total score (excluding overall severity): summary statistics 
* at informed consent, 1 year = 365.25 days 
 
9.6  Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
[Version 19.1], and number and percentage of subjects with any medical history by system organ 
class (SOC) and preferred term (PT), as well as ones of subjects with any concomitant disease, will 
be summarized for each cohort and cohort total. All medical history will be listed. 
 
9.7  Prior and Concomitant Medications 
For Cohort 1, prior medications are defined as those taken prior to initial dose of DSP-5423 
(tablet). For Cohort 2, prior medications are defined as those taken prior to initial application of 
DSP-5423P. Prior medications will include medications that had been used before participation of 
the study, which are collected as “Started prior to study” on the CRF. 
For Cohort 1, concomitant medications during DSP-5423 (tablet) treatment period are defined as 
those taken from the initial dose date of DSP-5423 (tablet) through the last dose date of DSP-5423 
(tablet). For both Cohort 1 and Cohort 2, concomitant medications during DSP-5423P application 
period are defined as those taken from the initial application date of DSP-5423P through the last 
application date of DSP-5423P. Note that the concomitant and prior medications are not mutually 
exclusive, ie, a medication can be classified as both prior and concomitant medication.  
Prior and concomitant medications will be coded using the WHO Drug Dictionary [March 1, 
2014 version], Anatomical Therapeutic Chemical (ATC) Classification codes and preferred term 
(PT, Standardized Medication Name), and summarized for each cohort and cohort total. The 
number and percentage of subjects who took prior or concomitant medications will be summarized 
as well. 
Prior and concomitant medications will be summarized as the number and percentage of subjects 
by ATC level and PT for each cohort. If a subjects took same medications in terms of ATC level or 
PT multiple times, the subject will be counted one time into associated ATC level or PT. In addition, 
Prior and concomitant medications will be summarized as to following categories defined on the 
CRF;  
Antipsychotics 


 
 
25
Antiparkinson drugs 
Psychotropic drugs 
Hypnotic drugs 
The number and percentage of subjects with concomitant use of antiparkinson drugs will be 
summarized by cohorts and visits. Denominator for visit base summary will be subjects who 
received DSP-5423 (tablet) during relevant periods or subjects who received DSP-5423P during 
relevant periods. Note that denominator at Day -1 and one for overall period will be all subjects in 
Safety Analysis Population. Subgroup analysis for subjects who didn’t use antiparkinson drugs at 
Day -1 will be repeated in the same fashion. 
DSP-5423 (tablet) treatment period: (overall) 
DSP-5423P application period: Day -1, Week 1 to 2, 3 to 4, 5 to 6, 7 to 12, 13 to 24, 25 to 
36, 37 or later, overall (Week 1=Day 1 to 7, Week 2=Day 8 to 14) 
 
Prior or concomitant mediations will be listed respectively. 
 
9.8  Treatment Compliance 
The percentage of treatment compliance will be calculated for DSP-5423 (tablet) or DSP-5423P 
according to derivation in section 8.2. Treatment Compliant is defined as a subject with 80% to 
120% compliance in condition with no rounding for treatment compliance. Other subjects and also 
subjects with missing treatment compliance will be seen as non-compliant to study treatment. 
Summary statistics of treatment compliance will be calculated by visits for each cohort and cohort 
total as well as the number and percentage of subjects who dropped into the following categories. 
Treatment compliance will be listed with rounding to one decimal point. 
Treatment Compliance: <80%; 80% to 120%; >120% 
 
9.9  Duration of Exposure 
Duration of exposure will be calculated following section 8.2. Summary statistics will be 
calculated by visits for each cohort and cohort total as well as the number and percentage of 
subjects who dropped into the following categories. Duration of exposure will be listed.  
Duration of Exposure (days): 
DSP-5423 (tablet) treatment period: 1 to 7; 8 to 14; 15 to 28; 29 to 43; 44 or more 
DSP-5423P application period: 
 
 
1 to 42; 43 to 84; 85 to 168; 169 to 252; 253 to 336; 337 or more 
 
9.10  Daily dose and Cumulative dose 
Each kind of daily dose will be calculated following section 8.2. Mean daily dose (mg/day), 
Maximum daily dose (mg/day) and Modal daily dose (mg/day) will derived as specified in section 


 
 
26
8.2. Those summary statistics will be calculated by visits for each cohort and cohort total, and also 
the number and percentage of subjects with each dose will be summarized. Those daily doses will 
be listed. 
Cumulative dose will be calculated as specified in section 8.2 and its summary statistics will be 
calculated by visits for each cohort and cohort total. Cumulative dose will be listed. 
 
9.11  Efficacy Analysis 
The efficacy analysis will be performed for each cohort based on safety analysis population. 
 
9.11.1  PANSS Total Score 
Observed PANSS total score and change from baseline of DSP-5423P application period will be 
summarized by visits (including LOCF endpoint) for each cohort. The overtime change of mean of 
the change from baseline of DSP-5423P application period will be plotted for each cohort with 
+/-SD. 
For DSP-5423(tablet) treatment period in Cohort 1, observed PANSS total score and change 
from baseline of DSP-5423(tablet) treatment period will be summarized by visits. For both 
DSP-5423(tablet) and DSP-5423P periods in Cohort 1, the overtime change of mean of the change 
from baseline of DSP-5423(tablet) treatment period will be plotted with +/-SD. 
PANSS score will be listed. 
 
9.11.2  PANSS subscale scores and PANSS five-factor model scores 
PANSS subscale scores and PANSS five-factor model scores will be summarized in same fashion 
as PANSS total score, and listed. 
 
9.11.3  Clinical Global Impression - Severity of Illness (CGI-S) 
Observed CGI-S score and change from baseline of DSP-5423P application period will be 
summarized by visits (including LOCF endpoint) for each cohort. The overtime change of mean of 
the change from baseline of DSP-5423P application period will be plotted for each cohort with 
+/-SD. 
For DSP-5423(tablet) treatment period in Cohort 1, observed CGI-S score and change from 
baseline of DSP-5423(tablet) treatment period will be summarized by visits. For entire period in 
Cohort 1, the overtime change of mean of the change from baseline of DSP-5423(tablet) treatment 
period will be plotted with +/-SD. 
CGI-S score will be listed. 
 
9.11.4  Time to Treatment Discontinuation 
All cause discontinuation of DSP-5423P is considered as an event and completion of DSP-5423P 


 
 
27
application is considered as a censor, and Kaplan-Meier estimate for 50 percentiles and its 95% CI 
for time to event will be analyzed. Also the number and percentage of subjects who applied 
DSP-5423P for 28 weeks or 52 weeks will be summarized. Those analyses will be performed for 
each cohort overall and also by use of prior antipsychotics (Blonanserin and Other/None). 
The final application date of DSP-5423P can be either event date or date of censored. 
Kaplan-Meier plots for each cohort will be provided. One for each cohort by use of prior 
antipsychotics will also be provided. Time to Treatment Discontinuation will be listed. 
 
9.11.5  Subgroup analysis for efficacy 
For each subgroup, observed PANSS total score and change from baseline of DSP-5423P 
application period will be summarized by visits (including LOCF endpoint) for each cohort. 
Subgroups include Sex, Age (years), use of Prior antipsychotics, Hospitalization status at 
Screening, Duration of illness (years), and Baseline PANSS total score specified as following. A 
subject with missing value will not be included in appropriate summary and then ‘missing’ category 
is not expected to be presented in the tables. 
Sex: Male, Female 
Age (years): < 65, >= 65 
Prior antipsychotics: No, Yes 
Duration of illness (years): < 5, >= 5 to < 10, >= 10 to < 20, >= 20, Unknown 
Hospitalization status at Screening: Inpatient, Outpatient 
Baseline PANSS total score: 59 or less, 60 to 79, 80 or above 
 
9.12  Safety Analysis 
Safety analysis will be performed for each cohort and cohort total based on safety population, 
besides C-SSRS summaries only for each cohort.  
 
9.12.1  Adverse event 
The adverse event will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 19.1. Treatment-emergent adverse event (TEAE) is defined as adverse events 
with start date on or after Day 1. Regardless of cohort, adverse events occurred on same date as the 
initial date of application of DSP-5423P will be defined as TEAE. All adverse events, regardless of 
TEAE or not, will be listed. A treatment-related TEAE is defined as a TEAE for which the causal 
relationship to the study treatment is either ‘definite’, ‘probable’, or ‘possible’. 
The summary of TEAE will include the number of event, and the number and percentage of 
subjects which are classified in the following TEAE or treatment-related TEAE categories. 
Extrapyramidal (EPS) adverse event will be defined based on MedDRA PT and determined at 
blinded data review meeting. The skin-related adverse event will be defined as an adverse event 


 
 
28
with any application sites collected on EDC. 
Adverse event (any TEAE) 
Death (TEAE leading to death) 
Serious adverse event (serious TEAE) 
Adverse event leading to treatment discontinuation  
(TEAE leading to treatment discontinuation)  
Severe adverse event (severe TEAE) 
Extrapyramidal adverse event (extrapyramidal TEAE) 
Skin-related adverse event at the application site (skin related TEAE)  
 
The number and percentage of subjects who have TEAE or treatment-related TEAE will be 
summarized by SOC/PT for each cohort. If a subject has multiple events categorized in same 
SOC/PT, the subject will be counted only one time into the SOC/PT. SOCs are sorted by 
alphabetically and PTs are sorted within SOC in descending order of frequency of cohort total. If 
there are ties, PTs are sorted by alphabetically. TEAE leading to treatment discontinuation will be 
summarized in the same manner. 
Common TEAE are PT of TEAEs experienced by 2% or more subjects in cohort total. Common 
TEAE and common treatment-related TEAE will be summarized by SOC/PT. 
The number and percentage of subjects who have TEAE or treatment-related TEAE will be 
summarized by SOC/PT and maximum severity. For this summaries, if a subject experienced more 
than one episode of a TEAE within a PT, the subject is counted only once in the PT at the 
maximum severity. If the maximum severity is missing, the episode will be kept as missing (not 
specified). In determining maximum severity, severities are ranked from missing (not specified), 
mild, moderate, to severe. 
The number and percentage of subjects who have TEAE or treatment-related TEAE will be 
summarized by SOC/PT and first onset date. If a subject experienced more than one event within a 
PT, the subject is counted only once in the PT based on the earliest event started on the same or 
closer to Day 1. Denominator of percentage for each period of interest is the number of subjects 
who were treated with DSP-5423P in each period. 
Onset: Day 1 to 7, Day 8 to 14, Day 15 to 28, Day 29 to 42; Week 1 to 6; 
 Week 1 to 13; Week 14 to 26; Week 27 to 39; Week 40 or later 
 (Week 1=Day 1 to 7, Week 2=Day 8 to 14) 
 
As TEAE of interests, Extrapyramidal TEAE and skin related TEAE will be summarized by 
SOC/PT. Additionally, those TEAE will be summarized by maximum severity or first onset date in 
same manner as summaries of TEAE. In summary tables, the frequencies for entire TEAE related 
to extrapyramidal symptoms or TEAE related to skin, not just by SOC/PT, will be presented. 




 
 
30
> 150 mEq/L 
K/Potassium 
< 3 mEq/L 
> 5.5 mEq/L 
Cl/Chloride 
< 90 mEq/L 
> 115 mEq/L 
Blood Glucose (fasting) 
< 50 mg/dL 
> 250 mg/dL 
HbA1c 
>= 7.5% 
Total Bilirubin 
> 2 x ULN 
Blood Urea Nitrogen 
> 30 mg/dL 
Creatinine 
> 2.0 mg/dL 
CK 
> 3 x ULN 
Serum Prolactin 
>= 5 x ULN 
Triglycerides (fasting) 
> 300 mg/dL 
Total Cholesterol (fasting) 
> 300 mg/dL 
Note: A value is considered MAPLV if it is outside the Markedly Abnormal Range. 
Note: Blood glucose, triglycerides, and total cholesterol are limited for blood samples collected in fasting state. 
 
Box plot of observed value of the hematology and blood chemistry parameters will be provided 
by visits including baseline of DSP-5423P application period and LOCF endpoint. 
 
For DSP-5423(tablet) treatment period in Cohort 1, observed values and changes from baseline 
at DSP-5423(tablet) treatment period for the hematology, and blood chemistry parameters will be 
summarized by visits including LOCF endpoints. For urinalysis parameters, the number and 
percentage of subjects in each category of parameters will be summarized at baseline of 
DSP-5423(tablet) treatment period, each visit, and LOCF endpoint. Box plot of observed value of 
the hematology and blood chemistry parameters will be provided by visits including baseline of 
DSP-5423(tablet) treatment period. 
 
9.12.3  Vital sign and body weight 
BMI is calculated based on the height at Screening and weight at each visit. 
Observed values and changes from baseline at DSP-5423P application period for the vital sign, 
weight and BMI will be summarized by visits including LOCF endpoints. The vital sign, weight 
and BMI will be listed. 
Criteria for Markedly Abnormal Post-Baseline Vital Signs (MAPVS) for abnormal values in the 
vital sign can be found in Table 7. The frequencies and percentages of subjects who met MAPVS 
criteria at least once in the DSP-5423P post-baseline (including unscheduled visits) will be 




 
 
32
 
For DSP-5423(tablet) treatment period in Cohort 1, observed values and changes from baseline 
in DSP-5423(tablet) treatment period for the ECG parameters will be summarized by visits 
including LOCF endpoints.  
 
9.12.5  DIEPSS 
Observed values and changes from baseline in DSP-5423P application period in DIEPSS total 
score excluding overall severity and item scores will be summarized by visits (including LOCF 
endpoint). The overtime change from baseline of DSP-5423P application period in DIEPSS total 
score excluding overall severity will be plotted for each cohort with +/-SD. 
For DSP-5423(tablet) treatment period in Cohort 1, observed value and change from baseline in 
DSP-5423(tablet) treatment period in DIEPSS total score excluding overall severity and item scores 
will be summarized by visits. For both DSP-5423(tablet) and DSP-5423P periods in Cohort 1, the 
overtime change from baseline of DSP-5423(tablet) treatment period in DIEPSS total score 
excluding overall severity will be plotted with +/-SD. 
DIEPSS total score and item scores will be listed. 
 
9.12.6  C-SSRS 
C-SSRS will be summarized for each cohort and cohort total, and baseline for Cohort 1 is 
defined as baseline at DSP-5423(tablet) treatment period and one for Cohort 2 is defined as 
baseline at DSP-5423P application period. 
For ‘Suicidal ideation’, the number and percentage of subjects by items, with any suicidal 
ideation, with no suicidal ideation, with serious suicidal ideation defined as ‘Yes’ in item 4 or item 
5, will be summarized at baseline, each visit, entire DSP-5423(tablet) treatment period, and entire 
DSP-5423P application period. 
Suicidal ideation 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods [not plan] without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
 
For ‘Suicidal behavior’, the number and percentage of subjects by items, with any suicidal 
behavior, and with no suicidal behavior will be summarized at baseline, each visit, entire 
DSP-5423(tablet) treatment period, and entire DSP-5423P application period. 
Suicidal behavior 
1. Any actual attempts 


 
 
33
2. Any interrupted attempts 
3. Any aborted attempts 
4. Any preparatory acts or behavior 
 
The number and percentage of subjects with either suicidal ideation or suicidal behavior as ‘any 
suicidality’, and with no suicidality will be summarized at baseline, each visit, entire 
DSP-5423(tablet) treatment period, and entire DSP-5423P application period.  
 
The subjects* with ‘emergence of suicidal ideation’ defined as subjects without suicidal ideation 
at baseline, but not in post-baseline of DSP-5423P application period, subjects* with ‘serious 
emergence of suicidal ideation’ defined as subjects with ‘No’ in both item 4 and item 5**, but not 
in post-baseline of DSP-5423P application period, subjects* with ‘emergence of suicidal behavior’ 
defined as subjects with no suicidal behavior at baseline, but not in post-baseline of DSP-5423P 
application period, subjects* with “emergence of suicidality” defined as subjects with neither 
suicidal ideation nor suicidal behavior, but either/both in post-baseline of DSP-5423P application 
period, subjects with ‘any completed suicide’, will be summarized based on the number and 
percentages. 
* Subject with ‘Yes’ at baseline are not included in the denominator of percentages. 
** If item 2 of suicidal ideation is ‘No’, and item 3, 4, and 5 are null, item 3, 4, and 5 are counted 
as ‘No’. The C-SSRS is designed to ask item 3, 4, and 5 to subjects only when item 2 is ’Yes’. 
 
C-SSRS will be listed. 
 
9.12.7  Skin irritation assessment 
The number and percentages of subjects in each score of skin irritation assessment will be 
summarized by visits, baseline in DSP-5423P application period, each visit, LOCF endpoint, and 
also maximum score throughout the DSP-5423P post-baseline period. Skin irritation assessment 
scores will be listed. 
 
9.12.8  Subgroup analysis for safety 
The summary of TEAE and treatment-related TEAE and also their summary by SOC/PT will be 
presented by subgroups. The subgroups include Sex, Age(years), Duration of illness (years), and 
Hospitalization status at Screening defined as below. Subjects with missing data for any subgroup 
categories will not be included subgroup analysis without setting ‘missing’ category. 
Sex: Male, Female 
Age (years): < 65, >= 65 
Duration of illness (years): < 5, >= 5 to < 10, >= 10 to < 20, >= 20, Unknown 


 
 
34
Hospitalization status at Screening: Inpatient, Outpatient 
 
9.13  Analysis of Other endpoints 
All analysis of other endpoints will be conducted based on Safety population by each cohort and 
cohort total. 
 
9.13.1  DAI-10 
DAI-10 item scores will be summarized at baseline of DSP-5423P application period, each visit, 
and LOCF endpoints using number and percentage of subjects. For DAI-10 total score, the number 
and percentage of subjects and also descriptive summaries in change from baseline of DSP-5423P 
application period will be provided by each visit including LOCF endpoints. DAI-10 will be listed. 
 
9.13.2  EQ-5D 
For EQ-5D item scores, the number and percentage of subjects by scores will be summarized at 
baseline of DSP-5423P application period, each visit and LOCF endpoint. Observed value and 
change 
from 
baseline 
of 
DSP-5423P 
application 
period 
in 
EQ-5D 
Index 
value
（QS.QTESTCD=EQTOT）will be summarized by each visit and LOCF endpoints. EQ-5D will be 
listed. 
 
9.13.3  Questionnaire on dosage form 
The number and percentage of subjects by each question at LOCF endpoint will be summarized. 
Summary will be repeated for subjects who completed the study, discontinued the study, and 
overall. Questionnaire on dosage form will be listed. 
 
9.14  Pharmacokinetic analysis 
9.14.1  Plasma drug concentration 
Summary statistics of plasma concentrations of blonanserin and metabolites specified in section 
7.4.2, will be calculated by visits for each cohort and cohort total. Summary statistics will include n, 
Mean, SD, Min, Median, Max, CV%, Geometric Mean and Geometric CV%. This analysis will be 
repeated by visits, cohorts including cohort total, the latest dose prior to the PK sampling (ie, 40, 60, 
or 80 MG), and the latest application site (abdomen, back, chest, overall). For DSP-5423(tablet) 
administration period in Cohort 1, this analysis will also be repeated by fasting status, fasting, 
non-fasting and overall. The BLQ will not be included in the summary statistics. 
Additionally, Summary statistics of the ratio of plasma concentration of metabolites to 
blonanserin (ie, M1/blonanserin) will be calculated by visits for each cohort and cohort total. 
Plasma drug concentration and the ratio of plasma concentration of metabolites to blonanserin 
will be listed. 


 
 
35
 
9.14.2  Subgroup analysis 
Summary statistics of plasma concentration of blonanserin, and metabolites will also be 
summarized by subgroup. Subgroups will include sex and age group.  
Sex: Male; Female 
Age (years): < 65; >= 65 


 
 
36
10.  Appendix 
10.1  SAS Code 
Kaplan-Meier 
Proc lifetest plots=survival(atrisk) outsurv=sdf; 
  Strata COHORT; 
  Time TTE*CENSOR(1); 
  Ods output quartiles=MST; 
* TTE is time to discontinuation (ie, the last dose date – the first dose date + 1); 
* If completer then CENSOR=1; else CENSOR=0; 
* SURVIVAL, SDF_LCL, SDF_UCL variables in OUTSURV dataset will be tabulated where the TTE 
is closest (and smaller) to 28 weeks (196 days) and 52 weeks (364 days);