"Brexpiprazole (Rexulti™) Safety and Efficacy Among Filipino Patients (RAISE) - A Post Marketing Surveillance Program"
Conditions: Schizophrenia, Major Depressive Disorder
Sponsor: Otsuka Pharmaceutical, Inc., Philippines

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OTSUKA (PHILIPPINES) PHARMACEUTICAL, INC. 
 
BREXPIPRAZOLE (REXULTI™)  
PROTOCOL 
 
Brexpiprazole (Rexulti™) Safety and Efficacy Among Filipino Patients 
(RAISE) -  
A Post Marketing Surveillance Program 
 
Protocol No.:  331-414-00243 
Version 1.4 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
 
 
 
 
Clinical Phase: 
IV 
Sponsor: 
Otsuka (Philippines) Pharmaceutical, Inc. 
3F, King’s Court II Building,  
2129 Chino Roces Avenue,  
Makati City, Philippines 
 
Medical Director 
Rodney Felimon De Peralta Dalisay, MD, 
DPBP, FPPA, FPCPsych 
Otsuka (Philippines) Pharmaceutical, Inc. 
 
Immediately Reportable Adverse Event 
Marinette O. Magbitang 
Otsuka (Philippines) Pharmaceutical, Inc. 
 
Protocol Version and Date 
Version 1.4 – November 12, 2020 
 
 
 
 
 
 

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LOCAL MEDICAL/SAFETY MONITORS 
 
  
Otsuka (Philippines) Pharmaceutical, Inc.: 
 
Ms. Marinette O. Magbitang  
Local Safety Manager  
Pharmacovigilance/Clinical Research Associate  
Email: oppi-pv@otsuka.com.ph  
 
Ms. Fatima Chelsea P. Perey 
Clinical Research Associate/ Post Marketing Surveillance Lead  
Email: oppi-pv@otsuka.com.ph  
 
Rodney D. Dalisay, MD, DPBP, FPPA, FPCPsych 
Medical Director  
Email: oppi-pv@otsuka.com.ph  
 
Otsuka (Philippines) Pharmaceutical, Inc.  
3F King’s Court II Building, 2129 Chino Roces Ave., corner Dela Rosa St., 1231 Makati City 
Tel: (632) 8888 6774 
Fax: (632) 8811.2279 
Email: oppi-pv@otsuka.com.ph 
 
 
 

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TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local Medical / Safety Monitors…………………………………………………………….. 
2 
Table of Contents ……………………………………………………………………….……. 
3 
Protocol Synopsis ……………………………..………………………….………………….. 
4 
Introduction ………………………………………………………………………………….. 
5 
1. Objective………………………………………………………………………................ 
12 
2. Methods…………………………………………………………………………………. 
13 
 2.1 Design of PMS…………………………………………………………………….. 
13 
 2.2 Procedures………………………………………….………………………………. 
13 
3. Management and Reporting of Safety Information………………………………………. 
13 
 3.1 Definition of Terms………………………………………………………………… 
13 
 3.2 Collection and Reporting of Safety Information……………………………………  
15 
 3.3 Reconciliation of Safety Information……………………………………………... 
16 
 3.4 Safety Contact Information………………………………………………………... 
16 
4. Evaluation Criteria……………………………………………………………………..… 
16 
 4.1 Safety Assessment………………………..……………………………………..…. 
16 
 4.2 Efficacy Assessment…………………….……………………………………….… 
16 
5. Statistical Analysis…….……………………………………………………………….… 
17 
6. PMS Milestones………………………………………………………………………….. 
17 
7. Amendments and Updates…………………………………………………………….…. 
17 
8. Handling of Case Report Forms……………………………………………………….… 
17 
9. References…………………………………………………………………………….…. 
17 
Annex I–Assessment Criteria ………………………………………………………………... 
18 
Annex II–General Instructions On Accomplishing The Case Report Forms………………… 
19 
Annex III–Local Safety Report Form ………………………………………………………... 
21 
Annex IV–Protocol Amendment History…………...………………………………………… 
23 

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PROTOCOL SYNOPSIS 
Name of Sponsor 
Otsuka (Philippines) Pharmaceutical, Inc 
 
Protocol No: 331-414-00243 
Name of Product 
Brexpiprazole (Rexulti™) Film-coated Tablet as 
Antipsychotic Agent 
Protocol Title 
Brexpiprazole (Rexulti™) Safety and Efficacy Among Filipino Patients (RAISE) 
- A Post Marketing Surveillance Program 
Clinical Phase 
Phase IV 
Treatment 
Indication(s) 
 
For the treatment of schizophrenia.  
 
Adjunctive therapy to antidepressants for the treatment of major depressive 
disorder  (MDD) 
Objective(s) 
To provide post marketing surveillance data on the safety and efficacy of 
Brexpiprazole (Rexulti™) Film-coated Tablet for schizophrenia and adjunctive 
therapy of major depressive disorder (MDD) in the Philippines. 
Study Design 
Center  
Multi-center 
Blinding  
Open 
Control  
Active 
Design 
Single Group 
Subject Population 
Planned # of subject 
A total of 300 subjects will be included in the trial. 
Gender 
Male and Female 
Age range 
Adults (18 years old and above) 
Healthy subjects or  
treatment condition 
Treatment condition 
Test Product, Dose, Mode of Administration 
Brand name (API) 
Rexulti™ 
Administration route 
Per Orem (PO) 
Dosage form  
Film-coated Tablet 
Dose, regimen 
Once a day 
Criteria for Evaluation 
Primary Outcome 
Variables 
Safety Assessment: Safety of Brexpiprazole (Rexulti™) Film-coated Tablet will 
be evaluated based on the reported AE’s per assessment. 
Secondary Outcome 
Variables 
Efficacy Assessment: Efficacy of Brexpiprazole (Rexulti™) Film-coated Tablet 
will be evaluated using the Clinical Global Impression (CGI) Scale:  
CGI – Severity 
- 
Numbers and proportions of responders (defined as patients with 
CGI severity (CGI-S) score of 1 (normal, not at all ill), 2 (borderline 
mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 
(severely ill), 7 (among the most extremely ill patients) 
CGI – Improvement 
- 
Numbers and proportions of responders (defined as patients with 
CGI improvement (CGI-I) score of 1 (very much improved), 2 (much 
improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 
6 (much worse), 7 (very much worse) 
Study Duration  
Treatment duration 
8 weeks 
Further Study Details 
Assessments will be done upon initiation, (Baseline visit), 4 weeks later (Visit 2), until completion of the 
study week 8 (Study Completion). Demographic information and vital signs will be collected. 

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 INTRODUCTION 
 
Schizophrenia is a serious mental disorder in which people interpret reality abnormally. Schizophrenia 
may result in some combination of hallucinations, delusions, and extremely disordered thinking and 
behavior that impairs daily functioning, and can be disabling. Depression is a mood disorder that 
causes a persistent feeling of sadness and loss of interest. It is also called as major depressive disorder 
or clinical depression which affects how you feel, think and behave and can lead to a variety of 
emotional and physical problems.1 
 
Brexpiprazole (RexultiTM) is used to treat the symptoms of schizophrenia. It is also used with an 
antidepressant to treat depression when symptoms cannot be controlled by an antidepressant alone. 
Brexpiprazole (RexultiTM) is an atypical antipsychotics or second generation antipsychotics. It works 
by changing the activity of certain natural substances in the brain. 
 
Brexpiprazole (RexultiTM) has partial agonist activity at serotonergic 5-HT1A and dopaminergic D2 
receptors, as well as antagonist activity at serotonergic 5-HT2A receptors. The drug also has activity at 
noradrenergic receptors. It is available as tablets in the following strengths: 0.25, 0.5, 1, 2, 3, and 4 
mg under the brand name RexultiTM.  
 
For schizophrenia, the proposed starting dose is 1 mg once daily for 4 days, increasing to 2 mg for 3 
days, and then 4 mg once daily (after Day 7) based on clinical response and tolerability. For 
adjunctive treatment of major depressive disorder (MDD), the proposed starting dose is 0.5 or 1 mg 
once daily, increasing to a target dose of 2 mg once daily based on clinical response and tolerability.  
 
The main objective of developing this post marketing surveillance is to monitor the safety and 
efficacy of the drug in the treatment of schizophrenia and major depressive disorder. Another 
objective is to enhance their chance for early recovery, eventual reintegration to the society and 
improved quality of life. 
 
Efficacy and tolerability of Brexpiprazole (RexultiTM) Film Coated Tablet 
For the treatment of Schizophrenia 
The efficacy of Brexpiprazole (RexultiTM) in the treatment of adults with schizophrenia was 
demonstrated in two 6-week, randomized, double-blind, placebo-controlled, fixed-dose clinical trials 
in patients who met DSM-IV-TR criteria for schizophrenia.   
 
In both studies, Study 231 (hereafter “Study 3”) and Study 230 (hereafter “Study 4”), patients were 
randomized to Brexpiprazole (RexultiTM) 2 or 4 mg once per day or placebo. Patients in the 
Brexpiprazole (RexultiTM) groups initiated treatment at 1 mg once daily on Days 1 to 4. The 

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Brexpiprazole (RexultiTM) dosage was increased to 2 mg on Days 5 to 7. The dosage was then either 
maintained at 2 mg once daily or increased to 4 mg once daily, depending on treatment assignment, 
for the 5 remaining weeks. 
 
The primary efficacy endpoint of both trials was the change from baseline to Week 6 in the Positive 
and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item scale that measures 
positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and 
general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); the total 
PANSS scores range from 30 (best) to 210 (worst).   
 
In Study 3, Brexpiprazole (RexultiTM) at both 2 mg/day and 4 mg/day was superior to placebo on the 
PANSS total score. In Study 4, Brexpiprazole (RexultiTM) 4 mg/day was superior to placebo on the 
PANSS total score (Table 12). Figure 5 shows the time course of response based on the primary 
efficacy measure (change from baseline in PANSS total score) in Study 3.  
 
Examination of population subgroups based on age, gender and race did not suggest differential 
responsiveness. 
Table 12: Summary of Efficacy Results for Studies in Schizophrenia 
Study 
Treatment Group 
N 
Primary Efficacy Measure: PANSS 
 
 
Mean Baseline Score 
(SD) 
LS Mean Change 
from Baseline (SE) 
Placebo-subtracted 
Differencea (95% CI) 
3 
REXULTI (2 mg/day)*  
180 
95.9 (13.8) 
-20.7 (1.5) 
-8.7 (-13.1, -4.4) 
 
REXULTI (4 mg/day)*  
178 
94.7 (12.1) 
-19.7 (1.5) 
-7.6 (-12.0, -3.1) 
Placebo  
178 
95.7 (11.5) 
-12.0 (1.6) 
-- 
4 
REXULTI (2 mg/day)  
179 
96.3 (12.9) 
-16.6 (1.5) 
-3.1 (-7.2, 1.1) 
REXULTI (4 mg/day)*  
181 
95.0 (12.4) 
-20.0 (1.5) 
-6.5 (-10.6, -2.4) 
 
Placebo  
180 
94.6 (12.8) 
-13.5 (1.5) 
-- 
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence 
interval. 
* Dosages statistically significantly superior to placebo. 
A Difference (drug minus placebo) in least-squares mean change from baseline. 

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Figure 5: Change from Baseline in PANSS Total Score by Study Visit (Week) in Patients with 
Schizophrenia in Study 3 
 
 
The safety and efficacy of Brexpiprazole (RexultiTM) as maintenance treatment in adults with 
schizophrenia aged 18 to 65 years were demonstrated in the maintenance phase of a randomized 
withdrawal trial (Study 331-10-232, hereafter “Study 5”). Patients were stabilized for at least 12 
weeks on 1 to 4 mg/day of Brexpiprazole (RexultiTM) (N=202). They were then randomized in the 
double-blind treatment phase to either continue Brexpiprazole (RexultiTM) at their achieved stable 
dose (N=97), or to switch to placebo (N=105). 
 
The primary endpoint in Study 5 was time from randomization to impending relapse during the 
double-blind phase, defined as: 1) CGI-Improvement score of ≥5 (minimally worse) and an increase 
to a score > 4 on PANSS  conceptual disorganization, hallucinatory behavior, suspiciousness, or 
unusual thought content items, with either a ≥2 increase on a specific item or ≥4 point increase on the 
combined four PANSS items, 2) hospitalization due to worsening of psychotic symptoms, 3) current 
suicidal behavior, or 4) violent/aggressive behavior. 
 
A pre-specified interim analysis demonstrated a statistically significantly longer time to relapse in 
patients randomized to the Brexpiprazole (RexultiTM) group compared to placebo-treated patients. The 
trial was subsequently terminated early because maintenance of efficacy had been demonstrated.  The 
Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind 
treatment phase for Brexpiprazole (RexultiTM) and placebo groups are shown in Figure 6. The key 
secondary endpoint, the proportion of subjects who met the criteria for impending relapse, was 

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statistically significantly lower in Brexpiprazole (RexultiTM) treated patients compared with placebo 
group. 
 
Figure 6: Kaplan Meier Estimation of Percent Impending Relapse in Study 5 
 
 
Note: A total of 202 subjects were randomized. Among them, one placebo subject did not take 
investigational medicinal product and one Brexpiprazole (RexultiTM) subject did not have post-
randomization efficacy evaluations.  These two subjects were excluded from the efficacy analysis. 
As Adjunctive Treatment of Major Depressive Disorder 
The efficacy of Brexpiprazole (RexultiTM) in the adjunctive treatment of major depressive disorder 
(MDD) was evaluated in two 6-week, double-blind, placebo-controlled, fixed-dose trials of adult 
patients meeting DSM-IV-TR criteria for MDD, with or without symptoms of anxiety, who had an 
inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who 
had also demonstrated an inadequate response throughout the 8 weeks of prospective antidepressant 
treatment (with escitalopram, fluoxetine, paroxetine controlled-release, sertraline, duloxetine delayed 
release, or venlafaxine extended-release). Inadequate response during the prospective antidepressant 
treatment phase was defined as having persistent symptoms without substantial improvement 
throughout the course of treatment.  
 
Patients in Study 228 (hereafter “Study 1”) were randomized to Brexpiprazole (RexultiTM) 2 mg once 
a day or placebo. Patients in Study 227 (hereafter “Study 2”) were randomized to Brexpiprazole 

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(RexultiTM) 1 or 3 mg once a day or placebo. For patients randomized to Brexpiprazole (RexultiTM), 
all patients initiated treatment at 0.5 mg once daily during Week 1. At Week 2, the Brexpiprazole 
(RexultiTM) dosage was increased to 1 mg in all treatment groups, and either maintained at 1 mg or 
increased to 2 mg or 3 mg once daily, based on treatment assignment, from Week 3 onwards. The 
dosages were then maintained for the 4 remaining weeks. 
 
The primary endpoint was change from baseline to Week 6 in the Montgomery-Asberg Depression 
Rating Scale (MADRS), a 10-item clinician-related scale used to assess the degree of depressive 
symptomatology, with 0 representing no symptoms, and 60 representing worst symptoms. 
At randomization, the mean MADRS total score was 27. In Studies 1 and 2, Brexpiprazole 
(RexultiTM) [+ antidepressant (ADT)] 2 mg/day and 3 mg/day were superior to placebo + ADT in 
reducing mean MADRS total scores. Results from the primary efficacy parameters for both fixed dose 
trials are shown below in Table 11. Figure 4 below shows the time course of response based on the 
primary efficacy measure (MADRS) in Study 1.  
 
Table 11: Summary of Efficacy Results for Studies 1 and 2 for the Adjunctive Treatment of 
MDD 
 
 
 
Primary Efficacy Measure: MADRS 
Study Treatment Group 
N 
Mean Baseline 
Score (SD) 
LS Mean Change 
from Baseline (SE) 
Placebo-subtracted 
Differencea (95% CI) 
 1 
REXULTI (2 mg/day) +ADT* 
175 
26.9 (5.7) 
-8.4 (0.6) 
-3.2 (-4.9, -1.5) 
 
Placebo +ADT 
178 
27.3 (5.6) 
-5.2 (0.6) 
-- 
 2 
REXULTI (1 mg/day) +ADT  
211 
26.5 (5.6) 
-7.6 (0.5) 
-1.3 (-2.7, 0.1) 
 
REXULTI (3 mg/day) +ADT  
213 
26.5 (5.3) 
-8.3 (0.5) 
-2.0 (-3.4, -0.5) 
 
Placebo +ADT 
203 
26.5 (5.2) 
-6.3 (0.5) 
-- 
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence 
interval. 
* Dosages statistically significantly superior to placebo. 
a  Difference (drug minus placebo) in least-squares mean change from baseline. 
 
An examination of population subgroups did not suggest differential response based on age, gender, 
race or choice of prospective antidepressant. 
 
 
 
 

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Figure 4: Change from Baseline in MADRS Total Score by Study Visit (Week) in Patients with 
MDD in Study 1 
 
 
Dosage of Brexpiprazole (RexultiTM) Film-coated Tablet  
 
For the treatment of schizophrenia, the recommended starting dosage for Brexpiprazole (Rexulti™) is 
1 mg once daily on Days 1 to 4, taken orally with or without food. The recommended target 
Brexpiprazole (Rexulti™) dosage is 2 mg to 4 mg once daily. Titrate to 2 mg once daily on Day 5 
through Day 7, then to 4 mg on Day 8 based on the patient’s clinical response and tolerability. The 
maximum recommended daily dosage is 4 mg.  
 
The recommended starting dosage for Brexpiprazole (Rexulti™) as adjunctive therapy for MDD is 
0.5 mg or 1 mg once daily, taken orally with or without food. Titrate to 1 mg once daily, then up to 
the target dosage of 2 mg once daily. Dosage increases should occur at weekly intervals based on the 
patient’s clinical response and tolerability. The maximum recommended daily dosage is 3 mg. It must 
be periodically reassess to determine the continued need and appropriate dosage for treatment. 
 
For patients with moderate to severe hepatic impairment (Child-Pugh score ≥7), the maximum 
recommended dosage is 2 mg once daily for patients with MDD, and 3 mg once daily for patients 
with schizophrenia. 
 

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For patients with moderate, severe or end-stage renal impairment (creatinine clearance CLcr<60 
mL/minute), the maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg 
once daily for patients with schizophrenia. 
 
Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor 
metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong 
CYP3A4 inducers. If the coadministered drug is discontinued, adjust the Brexpiprazole (Rexulti™) 
dosage to its original level. If the coadministered CYP3A4 inducer is discontinued, reduce the 
Brexpiprazole (Rexulti™) dosage to the original level over 1 to 2 weeks. 
 
Pharmacology of Brexpiprazole (RexultiTM) Film-coated Tablet  
The mechanism of action of Brexpiprazole (RexultiTM) in the treatment of schizophrenia or adjuctive 
therapy of MDD is unknown. However, the efficacy of Brexpiprazole (RexultiTM) may be mediated 
through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and 
antagonist activity at serotonin 5-HT2A receptors. 
 
Brexpiprazole (RexultiTM) has affinity (expressed as Ki) for multiple monoaminergic receptors 
including serotonin 5-HT1A (0.12 nM), 5-HT2A (0.47 nM), 5-HT2B (1.9 nM), 5-HT7 (3.7 nM), 
dopamine D2 (0.30 nM), D3 (1.1 nM), and noradrenergic α1A (3.8 nM), α1B (0.17 nM), α1D (2.6 nM), 
and α2C (0.59 nM) receptors. Brexpiprazole (RexultiTM) acts as a partial agonist at the 5-HT1A, D2, and 
D3 receptors and as an antagonist at 5-HT2A, 5-HT2B, 5-HT7, α1A, α1B, α1D, and α2C receptors. 
Brexpiprazole (RexultiTM) also exhibits affinity for histamine H1 receptor (19 nM) and for muscarinic 
M1 receptor (67% inhibition at 10 µM).  
 
Cardiac Electrophysiology 
At 3-times the maximum recommended human dose (MRHD) for the treatment of schizophrenia and 
4-times the MRHD for adjunctive therapy to antidepressants for the treatment of MDD, Brexpiprazole 
(RexultiTM) does not prolong the QTc interval to any clinically relevant extent. 
 
Absorption 
After a single dose administration of Brexpiprazole (RexultiTM) tablets, the peak plasma 
Brexpiprazole (RexultiTM) concentrations occurred within 4 hours after administration; and the 
absolute oral bioavailability was 95%. Brexpiprazole (RexultiTM) steady-state concentrations were 
attained within 10-12 days of dosing. Brexpiprazole (RexultiTM) can be administered with or without 
food. Administration of a 4 mg Brexpiprazole (RexultiTM) tablet with a standard high fat meal did not 
significantly affect the maximum concentration (Cmax) or Area under the curve (AUC) of 
Brexpiprazole (RexultiTM). After single and multiple once daily dose administration, Brexpiprazole 
(RexultiTM) exposure (Cmax and AUC) increased in proportion to the dose administered. In vitro 

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studies of Brexpiprazole (RexultiTM) did not indicate that Brexpiprazole (RexultiTM) is a substrate of 
efflux transporters such as multidrug resistance MDR1 (P-gp) and breast cancer resistance protein 
(BCRP). 
 
Distribution 
The volume of distribution of Brexpiprazole (RexultiTM) following intravenous administration is high 
(1.56±0.42 L/kg), indicating extravascular distribution. Brexpiprazole (RexultiTM) is highly protein 
bound in plasma (greater than 99%) to serum albumin and α1-acid glycoprotein, and its protein 
binding is not affected by renal or hepatic impairment. Based on results of in vitro studies, 
Brexpiprazole (RexultiTM) protein binding is not affected by warfarin, diazepam, or digitoxin. 
 
Elimination 
Metabolism 
Based on in vitro metabolism studies of Brexpiprazole (RexultiTM) using recombinant human 
cytochrome P450 (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4), the 
metabolism of Brexpiprazole (RexultiTM) was shown to be mainly mediated by CYP3A4 and 
CYP2D6. In vivo Brexpiprazole (RexultiTM) is metabolized primarily by CYP3A4 and 
CYP2D6 enzymes. After single- and multiple-dose administrations, Brexpiprazole 
(RexultiTM) and its major metabolite, DM-3411, were the predominant drug moieties in the 
systemic circulation. At steady-state, DM-3411 represented 23% to 48% of Brexpiprazole 
(RexultiTM) exposure (AUC) in plasma. DM-3411 is considered not to contribute to the 
therapeutic effects of Brexpiprazole (RexultiTM). Based on in vitro data, Brexpiprazole 
(RexultiTM) showed little to no inhibition of CYP450 isozymes. 
 
Excretion 
Following a single oral dose of [14C]-labeled Brexpiprazole (RexultiTM), approximately 25% 
and 46% of the administered radioactivity was recovered in the urine and feces, respectively. 
Less than 1% of unchanged Brexpiprazole (RexultiTM) was excreted in the urine and 
approximately 14% of the oral dose was recovered unchanged in the feces. Apparent oral 
clearance of a Brexpiprazole (RexultiTM) oral tablet after once daily administration is 19.8 
(±11.4) mL/h/kg. After multiple once daily administration of Brexpiprazole (RexultiTM), the 
terminal elimination half-lives of Brexpiprazole (RexultiTM) and its major metabolite, DM-
3411, were 91 hours and 86 hours, respectively. 
 
1. OBJECTIVE 
The objective of this post marketing surveillance is to further gather local data on the safety and 
efficacy of Brexpiprazole (RexultiTM) Film-coated Tablet in the treatment of schizophrenia and 
adjunctive therapy of MDD. 

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2. METHODS 
 
2.1. DESIGN OF THE PMS 
This is a post marketing surveillance of 8 weeks duration, on 300 male or female patients 
diagnosed to have schizophrenia and MDD in the Philippines. 
 
2.2. PROCEDURES 
Based on his clinical decision, the attending physician will enroll patients with schizophrenia and 
MDD to the program. The attending physician will explain to the patient or his legal guardian the 
purpose of the PMS and will obtain the patient or legal guardian’s consent that Brexpiprazole 
(RexultiTM) Film-coated Tablet will be administered.    
 
Data on the safety aspects of Brexpiprazole (RexultiTM) Film-coated Tablet will be collected in 
terms of adverse events. Efficacy will be measured using the Clinical Global Impression (CGI) 
Scale:  
CGI-Severity 
- Numbers and proportions of responders (defined as patients with CGI severity (CGI-S) 
score of 1 (normal, not at all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 
(moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among the most extremely ill 
patients) 
CGI-Improvement 
- Numbers and proportions of responders (defined as patients with CGI improvement 
(CGI-I) score of 1 (very much improved), 2 (much improved), 3 (minimally improved), 
4 (no change), 5 (minimally worse), 6 (much worse), 7 (very much worse) after the first 
and last Brexpiprazole (RexultiTM) Film-coated Tablet dose. Assessments will be done 
upon initiation, (Baseline visit), and 4 weeks later (Visit 2), until completion of the 
study week 8 (Study completion). Demographic information and vital signs will be 
collected. 
 
3. MANAGEMENT AND REPORTING OF SAFETY INFORMATION 
 
3.1.     DEFINITION OF TERMS  
Safety information 
Information from any source containing one or more of 
the following concepts: 
 
▪ Adverse Events 
▪ Special Situations 
▪ Off label use 
▪ Device Vigilance Information 
 
Adverse Event (AE) 
Any untoward medicinal occurrence in a patient or 

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clinical study subject administered a medicinal product 
and which does not necessarily have a causal 
relationship with this treatment (see Annex Ⅳ, ICH-
E2A guideline).  
An adverse event can therefore be any unfavorable and 
unintended sign (e.g. abnormal laboratory finding), 
symptom, or disease temporally associated with the 
use of a medicinal product, whether or not it is 
considered causally related to the medicinal product. 
 
Special Situations 
Situations related to the use of an Otsuka product 
which may or may not be associated with an adverse 
event: 
- 
Maternal (pregnancy and breastfeeding) or 
paternal (via semen) exposure; 
- 
Exposure during breastfeeding; 
- 
Overdose/Incorrect dosage, misuse, abuse (e.g. 
patient sharing products); 
- 
Medication errors (e.g. patient took wrong 
dose); 
- 
Lack of therapeutic efficacy (e.g. the product 
doesn’t work); 
- 
Occupational 
exposure 
(e.g.: 
nurse 
administering the product is exposed); 
- 
Cases of suspected transmission of infectious 
agents; 
- 
Use of suspected or confirmed falsified 
product(s) or quality defect of the product(s);  
- 
Withdrawal reactions; 
- 
Accidental exposure (e.g.: child takes parent’s 
product); 
- 
Drug-drug/drug-food interactions; 
- 
Unintentional use of product in a non-approved 
population (e.g.: pediatric or  geriatric 
population); 
- 
Disease progression/exacerbation of existing 
disease 
 
Off-label Use 
Refers to situations where a product is intentionally 
used for a medical purpose not in accordance with the 
authorized product information.  Off-label use also 
includes the intentional use in non-authorized 
population categories not indicated in the label 
 
Device Vigilance Information 
is a death or serious injury that was or may have been 
attributed to a medical device component of an Otsuka 
product, or that a medical device component was or 
may have been a factor in a death or serious injury, 
including events occurring as a result of: 
- 
Failure, 
- 
Malfunction, 
- 
Improper or inadequate design, 
- 
Manufacture, 
- 
Labeling or instructions for use, or 

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- 
User error 
 
Serious Adverse Event (SAE) 
Any adverse drug experience/event occurring at any 
dose which 
 results in death, 
 is life-threatening,  
 requires inpatient hospitalization or prolonged of 
existing hospitalization  
 results in persistent or significant disability or 
incapacity, 
 is a congenital anomaly/birth defect, 
 is medically significant 
 
Life-threatening refers to an event in which the patient 
was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused 
death if more severe. 
 
A medically significant event is an important medical 
event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or 
hospitalization but, based on appropriate medical and 
scientific judgment, may jeopardize the patient/subject 
or may require intervention (e.g. medical, surgical) to 
prevent one of the other outcomes listed in the 
definition above) might be considered serious as well, 
examples of such include, but not limited to, intensive 
treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias; or convulsions that 
do not result in hospitalization; or development of drug 
dependency of drug abuse. 
 
Non-Serious Adverse Event  
All AEs that do not meet the definition of a serious 
Adverse Event (SAE) are considered non-serious AEs. 
Unexpected Adverse Event/Adverse 
Drug Reaction 
An AE/ADR, the nature, severity, or outcome of which 
is not consistent with the current Investigator’s 
Brochure (IB) or the approved labeling of the (I)MP. 
Class-related reactions which are mentioned in the IB, 
or the approved labeling but which are not specifically 
described as occurring under the (I)MP are also 
considered ‘unexpected’.  
For the determination of expectedness, an AE/ADR is 
considered unexpected only if it is not mentioned in 
the Adverse Reactions or Undesirable Effects section 
of the CCDS/SmPC (for MPs) or if it is not clearly 
described as an expected AE/ADR in section 6 of the 
IB (for IMPs). Exceptions are reactions related to 
overdose (considered unexpected if not mentioned in 
section Overdose) and/or interactions (considered 
unexpected if not mentioned in section Interaction).  
The determination of unexpectedness is used for the 
purpose of expedited reporting and periodic reporting.  
Date of First Receipt (DFR) 
The date when an Otsuka colleague, its Alliance 
Company/Collaborating Company or External Service 

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Provider, any third party providing services (e.g. a 
CRO), to or on behalf of Otsuka first becomes aware 
of a case/event. Email and fax headers usually record 
the date of receipt of communication, and it should be 
considered as the date of first receipt (calendar day 0).  
 
 
3.2. COLLECTION AND REPORTING OF SAFETY INFORMATION  
All safety information that occur during (defined as occurring after patient enrollment until 
the study completion, or within 30 days of the final dose of Brexpiprazole (RexultiTM) Film-
coated Tablet) the study will be documented by the physician. At each visit, the patient will 
be asked about any symptoms or unexpected occurrences since the last visit. All safety 
information, regardless of severity or relationship to the Brexpiprazole (RexultiTM) Film-
coated Tablet will be reported by the physician to the OPPI using the AE Form (Otsuka 
Global PV Safety Information Reporting Form in Annex III) immediately or within 24 hours.  
 
3.3. RECONCILIATION OF SAFETY INFORMATION 
Reconciliation of Adverse Event between the Safety Database and the study database (or 
safety database if study database is not obtainable) will be performed annually every 10th 
business day of December and at the end of the study. 
 
3.4. SAFETY CONTACT INFORMATION 
Otsuka (Philippines) 
Pharmaceutical, Inc.  
3F King’s Court II Building, 2129 
Chino Roces Ave., corner Dela 
Rosa St., 1231 Makati City, 
Philippines  
Tel: (632) 888 6774 
Fax: (632) 811.2279 
Email: oppi-pv@otsuka.com.ph 
Marinette O. Magbitang  
Local Safety Manager  
Pharmacovigilance/Clinical 
Research Associate  
Fatima Chelsea P. Perey  
Clinical Research Associate/ Post 
Marketing Surveillance Lead 
Rodney D. Dalisay, MD, 
DPBP, FPPA, FPCPsych 
 
Medical Director  
 
 
 
4. EVALUATION CRITERIA 
The Clinical Global Impression Scale (see Annex I) will be used to provide a rating of illness 
severity, improvement and response to treatment. 
 

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4.1. SAFETY ASSESSMENT 
Safety of Brexpiprazole (RexultiTM) Film-coated Tablet will be evaluated based on the reported 
AEs per assessment. 
 
4.2. EFFICACY ASSESSMENT 
Efficacy of Brexpiprazole (RexultiTM) Film-coated Tablet will be evaluated using: 
1. Clinical Global Impression-Severity (CGI-S) Scale:  
Numbers and proportions of responders (defined as patients with CGI severity (CGI-S) 
score of 1 (normal, not at all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 
(markedly ill), 6 (severely ill), 7 (among the most extremely ill patients) 
 
2. Efficacy will be evaluated using Clinical Global Impression-Improvement (CGI-I) Scale: 
Numbers and proportions of responders (defined as patients with CGI improvement (CGI-I) 
score of 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 
5 (minimally worse), 6 (much worse), 7 (very much worse) 
 
5. STATISTICAL ANALYSIS 
Analysis of data will be limited to descriptive statistics only. Safety will be evaluated based on the 
reported AEs per assessment. Efficacy will be evaluated using the Clinical Global Impression-
Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) Scales to monitor 
severity and improvement from mean baseline score (before initial dose) up to the last assessment 
(Week 8 – Study Completion). 
 
6. PMS MILESTONES 
All timelines and milestones written below might be subject to change based on the movement 
and situation during the study. End of data collection shall not be more than 1 week after the date 
of the last patient last visit (LPLV).  The final Clinical Study Report shall be completed within 
one year of the end of data collection.  
7. AMENDMENTS AND UPDATES 
All significant changes and updates to this protocol shall be documented in Annex V.   
 
ACTIVITY 
ESTIMATED TIMELINE 
GSL Approval 
April 2019 
GPORT Approval 
June 2019 
PFDA Approval 
August 2019 
Start of Study 
November 2019 
First Patient Visit 
December 2019 
Start of Data Collection 
February 2020 
Interim Statistical Report 
Q2 2022 
Last Patient Visit 
Q1 2023 
End of Data Collection 
Q1 2023 
Final Clinical Study Report 
Q1 2024 

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8. HANDLING OF CASE REPORT FORMS 
For instructions on filling out, editing, and transit of the CRFs, see Annex II. 
 
9.   REFERENCES 
1. https://www.mayoclinic.org/diseases-conditions/schizophrenia/symptoms-causes/syc-203544431 
2. https://www.mayoclinic.org/diseases-conditions/depression/symptoms-causes/syc-203560071 
3. Brexpiprazole (Rexulti™) Film-coated Tablet package insert 

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ANNEX I 
ASSESSMENT CRITERIA 
 
i. 
Safety  
- 
All adverse events will be collected on Visit 1 and Study Completion. See Annex III for other 
safety information. 
 
ii. 
Efficacy 
 
Baseline visit (Day 0): 
Clinical Global Impression - Severity of Illness 
[1] Normal, not at all ill                                    [5] Markedly ill   
[2] Borderline mentally ill                                [6] Severely ill   
[3] Mildly ill                                                     [7] Among the most extremely ill patients 
[4] Moderately ill   
  
 
           Visit 1 (after 4 weeks) and Study Completion (after 8 weeks): 
Clinical Global Impression - Severity of Illness 
[1] Normal, not at all ill                                    [5] Markedly ill   
[2] Borderline mentally ill                                [6] Severely ill   
[3] Mildly ill                                                     [7] Among the most extremely ill patients 
[4] Moderately ill   
 
Clinical Global Impression - Improvement 
 
[1]Very much improved                                  [5] Minimally worse   
[2] Much improved                                         [6] Much worse 
[3] Minimally improved                                  [7] Very much worse 
[4] No change   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ANNEX II 
GENERAL INSTRUCTIONS ON ACCOMPLISHING THE CASE REPORT FORMS 
 
1. Consent shall be obtained from the patient prior to enrollment in this program (see Informed 
consent form) 
2. Data privacy is present to uphold the rights of individual and the patient involved in the study 
3. Enter all required data on the CRFs specifically designed for this PMS. Each physician is 
ultimately responsible for ensuring that data on the CRFs are complete, accurate and legible. 
4. Complete the CRFs using a black ballpoint pen. Make sure that all entries are legible. 
5. Enter/write, check/tick, or encircle the appropriate response/s in the required fields. All text must 
be written in English using uppercase letters and Arabic numerals. 
6. Dates should be entered as MM/DD/YY i.e. January 17, 2012 should be written as 01/17/12 
7. Avoid using symbols and abbreviations  
8. Recording missing data: 
 
For fields with tick boxes, please write ND for “no data” 
 
For fields with fill-out boxes, please mark the empty box with a dash 
9. Making corrections: 
 
Cross-out errors with a single horizontal line. Clearly enter the new information next to 
the error (anywhere below or above or adjacent to the crossed-out entry). Write your 
initials and date next to the correct entry. 
 
Do not erase nor use opaque/white out correction fluids in making corrections. 
 
SPECIFIC INSTRUCTIONS ON ACCOMPLISHING THE CASE REPORT FORMS 
 
CRF PARTS 
INSTRUCTIONS 
DEMOGRAPHY 
/ SUMMARY 
CRF Number 
 
 To be provided by the Sponsor/Company 
Patient Initials 
 Three characters in the following order (First Name, 
Middle Name, Last Name) 
o Example:  
Juan Gomez Cruz is written as JGC 
          Juan Gomez dela Cruz is written as “JGC” 
          Juan del Gomez Cruz is written as “JGC” 
Date of birth 
 Patient birth in MM/DD/YY format 
Age 
 Patient age 
Weight 
 Indicate the unit of the patient’s weight (must be in kg) 
Height 
 Indicate the unit of the patient’s height (must be in cm) 
Sex 
 Tick/check appropriate box 
Indication/Diagnosis 
 Tick/check appropriate box 
Concomitant medications 
 Tick/check appropriate box 
 If yes, indicate the generic name, brand name, dose 
and frequency on page 2 
Treatment completion 
 Tick/check appropriate box 
Date of the baseline, visit 2 
and study completion  
 In MM/DD/YY format 

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Dose administered during 
baseline, visit 2 and study 
completion 
 Indicate the dose 
CGI-S score before the 
initial dose 
 To write the corresponding scale 
CGI-I and CGI-S score of 
Illness 4 weeks after initial 
dosing (Baseline) 
 To write the corresponding scale 
 
CGI-I and CGI-S score of 
Illness 8 weeks after initial 
dosing (Baseline) 
 To write the corresponding scale  
Discontinuation section 
 Tick/check appropriate box 
Investigator name, 
signature and date 
 To be signed by the Investigator/ Physician 
BASELINE 
Vital signs 
 Weight of the patient (in kg) 
 Patient’s blood pressure (BP) 
 Patient’s heart rate (HR) 
 Patient’s respiratory rate (RR) 
 Patient’s temperature (in Celsius) 
Psychotropic medications 
 Tick/check appropriate box 
CGI-S score before the 
initial dose 
 To write the corresponding scale 
VISIT 2 & 
STUDY 
COMPLETION 
Adverse Events 
 Tick/check appropriate box 
 List all AE and indicate severity of event by putting a 
tick on the appropriate box. 
CGI-I and CGI-S score of 
illness 8 weeks after initial 
dosing (Baseline) 
 Please encircle the corresponding score 
 
 
HANDLING AND CARE OF THE COMPLETED CRFs 
 
Once the patient has completed the PMS or has been prematurely discontinued from the PMS, the 
physician can submit the CRFs of these patients to the PSR. The PSR checks the CRF for 
completeness and legibility and submits the CRF to Medical Affairs (MA).   MA collates the CRF and 
submits clear copies to Data Management for encoding and analysis.  
 
To minimize delay in encoding and analysis, the PSR should carefully check the completed CRF 
before submitting MA. Queries from the Data Management should be forwarded to MA who will 
check the CRFs. All the copies of the CRFs will be collected back in the event that an entry on the 
CRF needs to be edited.  
 
 
 
 
 

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ANNEX III 
STUDY RESEARCH SAFETY REPORTING FORM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Reporting time frame for safety information 
All safety information should be reported by the physician to Otsuka (Philippines) Pharmaceutical, 
Inc. (OPPI) immediately or not later than 24 hours.  
 
Safety Contact Information 
Otsuka (Philippines) 
Pharmaceutical, Inc. 
 
3F King’s Court II Building, 2129 
Chino Roces Ave., corner Dela 
Rosa St., 1231 Makati City 
 
Tel: (632) 8888 6774 
Fax: (632) 8811.2279 
Email: oppi-pv@otsuka.com.ph 
Marinette O. Magbitang 
 
Local Safety Manager 
Pharmacovigilance/Clinical 
Research Associate 
 
 
Rodney D. Dalisay, MD, DPBP, 
FPPA, FPCPsych 
 
Medical Director 
Fatima Chelsea P. Perey 
 
Clinical Research Associate/ Post 
Marketing Surveillance Lead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Annex IV 
PROTOCOL AMENDMENT HISTORY 
 
Old  
Version 
Number 
New 
Version 
Number 
Description of 
Amendment 
Justification 
Reference Section 
Date of  
Amendment 
1.0 
1.1 
Update of Safety 
Reporting Form 
To follow Global 
SOP (PV-3000-
TMP-003) 
PV-3000-TMP-003 
July 3, 2019 
1.1 
1.2 
Doctor’s 
evaluation of 
patients 
improvement 
Specified 
evaluation of 
doctors for patients 
with schizophrenia  
Case Report Form: 
Assessment after 4 
weeks, Visit 2 
(page 4) and 
Assessment after 8 
weeks, Study 
completion (page 
5) 
March 8, 
2020 
1.2 
1.3 
Update of Safety 
Reporting Form 
 
 
Update in 
Definition of 
Terms 
To follow Global 
SOP (PV-3000-
TMP-003 v2.0) 
 
To follow Global 
SOP 
PV-3000-TMP-003 
v2.0 
 
 
Global SOP 
 
 
August 6, 
2020 
1.3 
1.4 
Update in 
Reconciliation of 
Safety Information 
To specify the 
frequency of 
reconciliation 
within the scope of 
CO-7000-WP-001 
CO-7000-WP-001 
November 
12, 2020