A Multicentre, 8-week, Single-arm, Open-label, Pragmatic Trial to Explore Acceptance and Performance of Using a Digital Medicine System With Healthcare Professionals and Adult Subjects With Schizophrenia, Schizoaffective Disorder, or First Episode Psychosis on an Oral Atypical Antipsychotic (Aripiprazole, Olanzapine, Quetiapine, or Risperidone)
Phase: PHASE4
Conditions: Schizophrenia, Schizoaffective Disorder, First Episode Psychosis
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Protocol 031-201-00186 
Confidential - Proprietary Information 
Protocol number: 031-201-00186
Document title: A Multicentre, 8-week, Single-aim, Open-label, 
Pragmatic Trial to Explore Acceptance and Perfonnance of Using a 
Digital Medicine System with Healthcare Professionals and Adult 
Subjects with Schizophrenia, Schizoaffective Disorder, or First 
Episode Psychosis on an Oral Atypical Antipsychotic (Aripiprazole, 
Olanzapine, Quetiapine, or Risperidone) 
Version number: 2.0
Date of the document: 04  January 2019
NCT number:    NCT03568500

Clinical Study Repo1·t 031-201-00186 
16.1.1 Protocol and Prntocol Amendments 
Otsuka Phannaceutical 
Development and Commercialization, Inc 
Medical Device 
OPC-14597 Digital 
CLINICAL PROTOCOL 
A Multicentre, 8-week, Single-aim, Open-label, Pragmatic Trial to Explore Acceptance 
and Perfonnance of Using a Digital Medicine System with Healthcare Professionals and 
Adult Subjects with Schizophrenia, Schizoaffective Disorder, or First Episode Psychosis 
on an Oral Atypical Antipsychotic (Aripiprazole, Olanzapine, Quetiapine, or 
Risperidone) 
Protocol No. 031-201-00186 
EudraCT No. 2017-004602-17 
CONFIDENTIAL- PROPRIETARY INFORMATION 
Clinical Development Phase: 
Sponsor: 
Associate Director, 
Global Clinical Development: 
Associate Director, 
Clinical Management: 
Senior Manager, Clinical Management 
Immediately Repo1iable Event 
4
Otsuka Phannaceutical Development and 
Commercialization, Inc 
2440 Research Boulevard 
Rockville, Maiyland 20850 
United States 
PD 
Phone:f.PD
E-mail: PD
pp 
Phone:f.PD
E-mail: PPD
PPD 
p one: PPD
PPD 
Global Safet and Phannacovigilance 
Phone: PD 
Global Fax: PPD-------
Global E-mail: 
PPD 
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confidential information and should not be duplicated or re-distributed without pl"ior wlitten consent of Otsuka. 
1 

Protocol 031-201-00186
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Amendment Issue Date:
04 Jan 2019
Version No.:
2.0
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Protocol 031-201-00186
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Protocol Synopsis 
Name of Sponsor: 
Otsuka Pharmaceutical Development and Commercialization, Inc
Name of Investigational Medicinal Product: Medical Device
(OPC-14597 Digital)
Protocol No.:
031-201-00186
EudraCT No.:
2017-004602-17
Protocol Title:
A Multicentre, 8-week, Single-arm, Open-label, Pragmatic 
Trial to Explore Acceptance and Performance of Using a
Digital Medicine System with Healthcare Professionals and 
Adult Subjects with Schizophrenia, Schizoaffective Disorder, 
or First Episode Psychosis on an Oral Atypical Antipsychotic 
(Aripiprazole, Olanzapine, Quetiapine, or Risperidone)
Clinical Phase:
4
Treatment Indication: Schizophrenia
Objective(s): 
Explore the acceptance and performance of the digital 
medicine system (DMS) with healthcare professionals (HCPs) 
and adult subjects with schizophrenia (SCH), schizoaffective 
disorder, or first episode psychosis.
Trial Design:
This is a multicentre, 8-week, single-arm, open-label, 
pragmatic trial to explore the acceptance and performance of 
using the DMS with HCPs and adult subjects with SCH, 
schizoaffective disorder, or first episode psychosis on an oral 
atypical antipsychotic (aripiprazole, olanzapine, quetiapine, or 
risperidone).
The DMS includes a drug-device combination of a 
CoEncapsulated (CoE) product (approved antipsychotic 
medication enclosed with an Ingestible Sensor Pill (Ingestible 
Sensor Pill is also called as a miniature ingestible event marker 
[IEM] in tablet [MIT]), a patch (Wearable Sensor), and an 
application software to convey level of activity and rest, and to 
mark events through the act of ingestion.
Subjects in this trial will receive an initial introduction to the 
DMS, and have HCP visits at screening/baseline, Week 4, 
Week 8/early termination (ET), and as directed by the HCP for 
the duration of the subject’s participation in the trial.
The HCPs will have access to a digital medicine (DM)
dashboard where notifications can be setup around medication 
ingestion.
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Screening/Baseline Visit (Days -7 to -1)
After providing the informed consent, subjects will enter the 
screening period for up to 1 week (7 days). Screening and 
baseline may occur at a single visit or may occur over 2 visits 
up to 7 days apart. The screening period may be extended at 
the discretion of the HCP. Subjects will be between 18 and 
65 years of age, inclusive, at the time of screening/baseline 
visit with a confirmed clinical diagnosis of SCH or 
schizoaffective disorder (defined by International 
Classification of Disease [ICD]-10 codes F20 and F25), or first 
episode psychosis using case note review. Subjects entering 
the trial will be treated with one of the oral atypical 
antipsychotics defined in the trial. The treatment medication 
decision will be determined by the HCPs and independent 
from the protocol. 
Assessment Period (8 Weeks):
Initiation of the DMS will commence at the baseline visit, with 
subjects ingesting the CoE product, wearing the patch, and 
using the smartphone application (app) for a total of 8 weeks
during the assessment period from baseline visit to Week 8
visit. 
During the assessment period from baseline visit to 
Week 8/ET visit:

Subjects will visit the HCP for clinical evaluations at 
Week 4;

Subjects will collect their DMS prescription refill at 
Week 4 visit for next 4 weeks until Week 8/ET visit; 

Subjects will visit the HCP at Week 8/ET and undergo 
another clinical evaluation.
Safety and tolerability data will be collected and evaluated on 
an ongoing basis, as assessed by the frequency and severity of 
serious adverse events (SAEs), and device-related nonserious
adverse events (AEs). 
Subjects will be monitored on the technology by the HCPs, 
who will review the HCP dashboard data at a minimum of 
every 2 weeks and make changes to current treatment plan and 
therapy at their discretion. The HCPs may request that a 
subject return to the site for unscheduled visits as deemed 
appropriate. In the event of an unscheduled visit, review of the 
DMS dashboard and safety events will be collected.
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Follow-up:
Week 8/ET visit evaluations will be completed for any subject 
withdrawn from the trial at any time (for any reason other than 
full withdrawal of the consent). 
Following the Week 8/ET visit, the subjects will not use the 
DMS and return to standard care (routine follow-up from care 
teams and continue non-DM medications). Subjects will have 
access to their trial account or data in the smartphone app up 
until 30 days after the last subject’s Week 8/ET visit. After this 
duration, the subjects will no longer have access to their data 
via the smartphone app.
A safety follow-up phone call will occur at 2 weeks after the 
Week 8/ET visit, which will be the last official subject contact. 
Healthcare Utilisation Record Evaluation:
Twenty-four weeks before and after the baseline visit (for a 
total of 48 weeks), all hospital admissions (psychiatric and 
non-psychiatric) would be recorded and assessed as either 
‘planned’ or ‘unplanned’ and ‘related’ or ‘unrelated’ to the 
psychiatric illness. Similarly, all encounters between any HCP
(psychiatric and non-psychiatric) and the subject will be 
recorded to obtain the following information:

The nature of the contact (eg, home visit, inpatient, 
outpatient, HCP visit, day centre);

The HCP role (eg, community psychiatric nurse);

Whether the contact was planned or not;

Whether or not the contact was initiated as a result of data 
from the DMS;

Any medication titration, adherence counseling, education, 
and lifestyle coaching.
This data will be reported in the data collection tool at 
Week 24 (or up to 7 days after this time point).
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Subject Population:
The trial will enrol approximately 60 male and female adult 
subjects between 18 and 65 years of age, inclusive, with a 
confirmed clinical diagnosis of SCH or schizoaffective 
disorder (defined by ICD-10 codes F20 and F25), or first 
episode psychosis who are prescribed either aripiprazole, 
olanzapine, quetiapine, or risperidone. There is no limit on the 
duration of illness for those with SCH or schizoaffective 
disorder but first episode psychosis is defined as less than 
3 years since presentation to the mental health team or first 
antipsychotic prescription. 
Inclusion/Exclusion 
Criteria: 
Key Inclusion Criteria:
1) Subject must be willing and able to give written (signed 
and dated) informed consent, which includes adherence to 
trial requirements and restrictions before enroling in the 
trial. Subject must be willing to adhere to trial procedures, 
including troubleshooting of the DMS by a third party if 
needed.
2) Subject must be able to read and understand English.
3) Male and female subjects 18 to 65 years of age, inclusive, 
at the time of informed consent.
4) Subject possessing  their own smartphone or a smartphone 
provided by the Sponsor, and being familiar with its use
and willing to download and interact with the DMS app, 
completing all tasks as well as adequately operate all
devices, as applicable. Caregiver/support person or other 
third party assistance can be utilised, if needed, although 
all subjects should be encouraged to attempt all tasks 
themselves.
5) Subject possesses the capacity to utilise the technology 
interfaces (eg, open and navigate software applications 
using the touch screen) and telephone features of a 
smartphone. The subject has satisfactory mobile phone 
reception (preferably 3 bars or more, or have Wi-Fi) at 
home and/or at work for trial-designated wireless carrier.
6) Subject is cooperative, able to ingest oral medication, 
willing to complete all aspects of trial, and capable of 
reporting AEs.
7) Clinical diagnosis of SCH or schizoaffective disorder 
(defined by ICD-10 codes F20 and F25) or first episode 
psychosis using case note review.
8) Subjects prescribed aripiprazole, olanzapine, quetiapine, or 
risperidone.
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9) Subject must fulfill at least one or more of the following: 

Discharge from a hospital admission (within 7 days of 
discharge) to an acute intervention team; 

Referral to an acute intervention team, prior to any 
hospital admission;

Referral from an acute intervention team to a 
community team;

Managed by community services (inclusive of patients 
on Care Programme Approach);

Inclusion within early intervention caseload (< 3 years 
from initial symptoms);

HCP determines the subject would benefit from using 
DMS.
10) Subject’s general medical condition such that participation 
in the trial does not pose any additional risk as per HCP’s 
judgment.
11) Skin on the anterior chest just above the lower edge of the 
rib cage that is free of any dermatological problems (eg, 
dermatosis or dermatitis, open wounds, or other skin 
disorders such as warts, rashes, atopic dermatitis, or 
irritations).
Key Exclusion Criteria:
1) Subject with any disorder including but not limited to 
intellectual developmental delay or disorder, major 
neurocognitive disorder or other condition that may impact 
the subject’s ability to participate in the trial or interact 
with the smartphone app.
2) Subject who is likely to be incapable of using the DMS 
technology, even with assistance.
3) Subject who has a history or evidence of a medical 
condition that would expose them to an undue risk of a 
significant AE or interfere with assessments of safety or 
usability during the course of the trial, including but not 
limited to, hepatic, renal, respiratory, cardiovascular, 
endocrine, neurologic, hematologic, or immunologic 
disease as determined by the clinical judgment of the HCP.
4) Subject with a known allergy to adhesive tape or any 
pertinent components of the patch or CoE product.
5) Prisoner must not be enroled into this trial.
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6) Subject who is hospitalised due to mental or physical 
illness (inpatient) at the time of screening/baseline must 
not be enroled into this trial.
7) Any subject who, in the opinion of the HCP, should not 
participate in the trial.
8) Any subject who, through religious or lifestyle choices, 
will not take gelatin capsules.
9) Female (females of childbearing potential [FOCBP]) who 
are breast-feeding and/or who have a positive pregnancy 
test result prior to receiving trial enrolment, or who plans
to become pregnant during the trial.
Trial Site(s):
Approximately 4 sites in the United Kingdom.
Device, Dose, 
Dosage Regimen, 
Treatment Period, 
Formulation, Mode 
of Administration:
The DMS consists of a:

CoE product which contains an approved antipsychotic 
medication enclosed with an Ingestible Sensor Pill
(Ingestible Sensor Pill is also referred as an MIT);

Compatible medical device, which is the Proteus Patch and 
Proteus® Medical Device Data Systems (MDDS). These 
are collectively referred to as the Patch + MDDS. Data 
received from the Proteus Patch is processed in the Patch 
Analytics Block and is transferred to the Proteus MDDS, 
both of which reside on the paired mobile computing 
device (eg, smartphone or tablet computer); and

Otsuka Medical Software, which has the following 
software components: 
1) Otsuka Patient Component, which resides on the paired 
mobile computing device and receives data from the 
Proteus MDDS; 
2) Otsuka Cloud-based Server; 
3) Otsuka Healthcare Provider Web Portal; 
4) Otsuka Caregiver Web Portal.
The CoE product contains MIT and drug originator tablet of
either aripiprazole, olanzapine, quetiapine, or risperidone
(known as DM-Aripiprazole, DM-Olanzapine, 
DM-Quetiapine, or DM-Risperidone within the smartphone 
app).
The treatment medication decision will be determined by the 
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HCPs and independent from the protocol. 
Trial Assessments:
Acceptance and Performance: 

Using feedback from subjects, HCPs, and 
caregivers/support person on the use of the DMS:

Subject Usability and Satisfaction Scale; 

HCP Utility Survey;

Caregiver/Support Person Involvement Scale (if 
applicable).

Additional variables to better understand outcomes that 
may impact use of the DMS or be impacted by the use of 
the DMS:

Patient Activation Measure-Mental Health (PAM-MH);

Clinical Global Impression-Severity of Illness Scale
(CGI-S).
Safety: Safety will be assessed by SAEs, device-related 
nonserious AEs, and suicidality assessment.
Criteria for 
Evaluation:
Primary Endpoint:
The primary endpoint is the proportion of days with good 
patch coverage during the trial, which will be calculated by the 
number of days with good patch coverage divided by the total 
number of trial days for each subject. The good patch coverage 
is defined as having at least 80% patch data available or MITs 
detected within the 24-hour period for each day while the 
subject is on the trial.
Secondary Endpoint:
The secondary endpoint is subject’s adherence metric, which is 
the proportion of detected MITs over the expected MITs 
ingested during the trial days with good patch coverage.
Exploratory Endpoints:
1) To explore the acceptance and performance of the
DMS with HCPs and adult subjects with SCH, 
schizoaffective disorder, or first episode psychosis as 
measured by:
The proportion of time during the trial period when 
the subject wears their patch. 
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The engagement and satisfaction of subjects, HCPs, 
and caregivers/support persons (if applicable), as 
determined by surveys (Subject Usability and 
Satisfaction Scale, HCP Utility Survey, and 
Caregiver/Support Person Involvement Scale [if 
applicable]).
The proportion of days subjects are using the 
application and the proportion of days that 
investigators are using the HCP dashboard during 
the trial.
The proportion of ingested MITs registered on the 
digital health data server versus expected MITs
ingested.
2) Additional variables will be captured to better 
understand outcomes that may impact use of the DMS 
or be impacted by the use of the DMS including: 
Change from baseline to Week 8 in CGI-S;
HCP visits and associated setting of care;
Details surrounding any hospitalisations; 
Occurrence and timing of community/home visits; 
Any referrals during the observation period. 
Safety Variables: 
Evaluate the safety and tolerability of the DMS, as 
assessed by the frequency and severity of SAEs, and 
device-related nonserious AEs;
Evaluate any product quality complaints that arise.
Statistical Methods:
The analysis will be conducted based on the intent-to-treat 
sample (ie, all subjects who enter the trial and use the DMS). 
Descriptive statistics will be provided for all primary, 
secondary, and exploratory endpoints and safety variables in 
general. Continuous variables will be summarised by 
tabulations of mean, median, range, and standard deviation. 
Tabulations of frequency distributions will be provided for 
categorical variables.
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Trial Duration:
The total trial duration per subject from screening to the end of 
healthcare utilisation record evaluation will be up to 25 weeks.
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Table of Contents 
Protocol Synopsis...........................................................................................3
Table of Contents.........................................................................................12
List of In-text Tables ...................................................................................17
List of In-text Figures..................................................................................18
List of Appendices........................................................................................19
List of Abbreviations and Definitions of Terms .......................................20
1
Introduction ........................................................................................22
1.1
Nonclinical Data................................................................................................26
1.2
Clinical Data......................................................................................................26
1.2.1
The Digital Medicine System.........................................................................30
1.3
Known and Potential Risks and Benefits ..........................................................31
1.3.1
Overview.........................................................................................................31
1.3.2
Risks Related to the Digital Medicine System ...............................................33
1.3.2.1
Skin Findings at the Site of the Patch Attachment......................................33
1.3.2.2
Allergic Reaction ........................................................................................34
1.3.2.3
Changes in Stool Habits..............................................................................34
1.3.2.4
Anxiety From the Use of the Digital Medicine System..............................34
1.3.2.5
Potential Theoretical Digital Medicine System-related Risks ....................35
1.3.2.5.1
Procedure-related Risks...........................................................................35
1.3.2.5.1.1
Communications-related Risks............................................................35
1.3.2.5.1.2
Less Significant Procedure-related Risks ............................................35
1.3.3
Benefits...........................................................................................................35
1.3.4
Potential Benefits of the Digital Medicine System.........................................36
1.3.4.1
Limitations of Current Medication Adherence Measures...........................36
1.3.4.2
Potential Benefits of the Digital Medicine System Adherence 
Measures .....................................................................................................37
2
Trial Rationale and Objectives..........................................................38
2.1
Trial Rationale...................................................................................................38
2.2
Dosing Rationale...............................................................................................38
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2.3
Trial Objectives.................................................................................................38
3
Trial Design.........................................................................................39
3.1
Type/Design of Trial .........................................................................................39
3.2
Trial Treatments ................................................................................................43
3.2.1
Digital Medicine System Components and Use.............................................43
3.2.1.1
Digital Medicine System Onboarding.........................................................45
3.2.1.2
Digital Medicine System Patch Use............................................................46
3.2.1.3
Digital Medicine System Versions .............................................................47
3.3
Trial Population.................................................................................................47
3.3.1
Number of Subjects and Description of Population .......................................47
3.3.2
Subject Selection and Numbering ..................................................................48
3.4
Eligibility Criteria..............................................................................................48
3.4.1
Informed Consent ...........................................................................................48
3.4.2
Inclusion Criteria ............................................................................................49
3.4.3
Exclusion Criteria...........................................................................................50
3.5
Endpoints...........................................................................................................51
3.5.1
Primary Endpoint............................................................................................51
3.5.2
Secondary Endpoint........................................................................................51
3.5.3
Exploratory Endpoints....................................................................................51
3.5.4
Safety Variables..............................................................................................52
3.6
Measures to Minimize/Avoid Bias....................................................................52
3.7
Trial Procedures ................................................................................................52
3.7.1
Schedule of Assessments................................................................................56
3.7.1.1
Screening/Baseline Visit.............................................................................56
3.7.1.2
Assessment Period ......................................................................................57
3.7.1.2.1
Week 1 Through Week 4 (Between HCP Visits)....................................57
3.7.1.2.1.1
Week 2 .................................................................................................57
3.7.1.2.1.2
Week 4 .................................................................................................58
3.7.1.2.2
Week 5 Through Week 8 (Between HCP Visits)....................................58
3.7.1.2.2.1
Week 6 .................................................................................................58
3.7.1.2.2.2
Week 8/Early Termination Visit..........................................................59
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3.7.1.3
Safety and Safety Follow-up.......................................................................59
3.7.1.4
Healthcare Utilisation Record Evaluation...................................................59
3.7.2
Outcome Assessments ....................................................................................60
3.7.2.1
Scales to Evaluate Usability of the Digital Medicine System.....................60
3.7.2.2
Patient Activation Measure-Mental Health Scale.......................................60
3.7.2.3
Clinical Global Impression-Severity of Illness Scale .................................61
3.7.3
Safety Assessments.........................................................................................61
3.7.3.1
Serious Adverse Events, Device-related Adverse Events, and 
Unanticipated Adverse Device Events........................................................61
3.7.3.2
Clinical Laboratory Assessments................................................................62
3.7.3.3
Suicidality Assessment ...............................................................................62
3.7.3.4
Other Assessments ......................................................................................62
3.7.3.4.1
Personal and Social Performance Scale ..................................................62
3.7.4
End of Trial.....................................................................................................62
3.8
Stopping Rules, Withdrawal Criteria, and Procedures......................................62
3.8.1
Entire Trial......................................................................................................62
3.8.2
Individual Trial Site........................................................................................62
3.8.3
Individual Subjects .........................................................................................63
3.8.3.1
Discontinuation of Digital Medicine System..............................................63
3.8.3.2
Documenting Reasons for Treatment Discontinuation...............................63
3.8.3.3
Withdrawal of Consent ...............................................................................64
3.8.3.4
Procedures to Encourage Continued Trial Participation.............................65
3.9
Screen Failures ..................................................................................................65
3.10
Definition of Completed Subjects.....................................................................65
3.11
Definition of Subjects Lost to Follow-up..........................................................65
3.12
Subject Compliance...........................................................................................66
3.13
Protocol Deviations...........................................................................................66
4
Restrictions..........................................................................................66
4.1
Prohibited Medications......................................................................................66
4.2
Other Restrictions..............................................................................................66
4.2.1
Restricted Therapies and Precautions.............................................................66
4.2.2
Non-therapy Precautions and Restrictions......................................................67
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4.2.2.1
Precautions..................................................................................................67
4.2.2.2
Restrictions..................................................................................................67
5
Reporting of Adverse Events.............................................................67
5.1
Definitions.........................................................................................................67
5.1.1
Drug-related Serious Adverse Events.............................................................67
5.1.2
Device-related Serious Adverse Events..........................................................68
5.1.3
Device-related Nonserious Adverse Events ...................................................69
5.1.4
Nonserious Adverse Events............................................................................69
5.1.5
Immediately Reportable Event .......................................................................69
5.1.6
Abnormal Clinical Laboratory Test Changes.................................................69
5.1.7
Severity...........................................................................................................70
5.1.8
Digital Medicine System Causality ................................................................70
5.2
Eliciting and Reporting Serious Adverse Events ..............................................70
5.3
Immediately Reportable Events ........................................................................71
5.4
Potential Drug-induced Liver Injury.................................................................71
5.5
Pregnancy..........................................................................................................71
5.6
Follow-up of Serious Adverse Events...............................................................73
5.6.1
Follow-up and Reporting of Serious Adverse Events Occurring after 
Last Scheduled Contact ..................................................................................74
6
Statistical Analysis..............................................................................74
6.1
Sample Size.......................................................................................................74
6.2
Datasets for Analysis.........................................................................................74
6.3
Handling of Missing Data .................................................................................75
6.4
Primary, Secondary, and Exploratory Endpoint Analyses................................75
6.4.1
Primary Endpoint Analysis.............................................................................75
6.4.2
Secondary Endpoint Analysis.........................................................................75
6.4.3
Exploratory Endpoint Analyses......................................................................76
6.5
Analysis of Demographic and Baseline Characteristics....................................76
6.6
Safety Analysis..................................................................................................76
6.6.1
Adverse Events ...............................................................................................77
6.6.5.1
Suicidality Assessment ...............................................................................77
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7
Management of Digital Medicine System.........................................78
7.1
Packaging and Labeling ....................................................................................78
7.2
Storage...............................................................................................................78
7.3
Accountability ...................................................................................................78
7.4
Returns and Destruction....................................................................................78
7.5
Reporting of Product Quality Complaints.........................................................78
7.5.1
Eliciting and Reporting Product Quality Complaints.....................................79
7.5.2
Information Required for Reporting Purposes ...............................................79
7.5.3
Return Process ................................................................................................80
7.5.4
Assessment/Evaluation...................................................................................80
8
Records Management.........................................................................80
8.1
Source Documents.............................................................................................80
8.2
Data Collection..................................................................................................80
8.3
File Management at the Trial Site.....................................................................81
8.4
Records Retention at the Trial Site....................................................................81
9
Quality Control and Quality Assurance...........................................82
9.1
Monitoring.........................................................................................................82
9.2
Auditing.............................................................................................................82
10
Ethics and Responsibility...................................................................82
11
Confidentiality ....................................................................................83
12
Amendment Policy..............................................................................83
13
Publication Authorship Requirements.............................................85
14
References............................................................................................85
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List of In-text Tables
Table 3.4.2-1
Inclusion Criteria ...........................................................................49
Table 3.4.3-1
Exclusion Criteria ..........................................................................50
Table 3.7-1
Schedule of Assessments...............................................................54
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List of In-text Figures
Figure 1-1
Digital Medicine System: Antipsychotic Medication with 
Ingestible Event Marker and Compatible Medical Device............25
Figure 1.3.4.1-1
Methods Used to Assess Antipsychotic Medication 
Nonadherence for up to 6 Months .................................................36
Figure 1.3.4.1-2
Methods Used to Measure Antipsychotic Medication 
Adherence for up to 12 Weeks.......................................................37
Figure 3.1-1
Trial Design Schematic..................................................................42
Figure 3.2.1.1-1
Patch Placement Zone....................................................................45
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List of Appendices
Appendix 1
Sponsor Personnel..........................................................................88
Appendix 2
Safety Reporting ............................................................................89
Appendix 3
Digital Medicine System Contents ................................................90
Appendix 4
Subject Usability and Satisfaction Scale........................................91
Appendix 5
Healthcare Professional Utility Survey..........................................95
Appendix 6
Caregiver/Support Person Involvement Scale ...............................99
Appendix 7
Patient Activation Measure-Mental Health Scale........................101
Appendix 8
Clinical Global Impression-Severity of Illness Scale..................104
Appendix 9
Personal and Social Performance Scale.......................................105
Appendix 10
Skin Irritation Scoring System.....................................................107
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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
AE
Adverse event
A and E
Accident and emergency
app
(smartphone or mobile) application
BP
Bipolar disorder
BP 1
Bipolar 1 disorder
BSI
The British Standards Institute
CE
Conformité Européene
CGI-S
Clinical Global Impression-Severity of Illness Scale
CI
Confidence interval
CoE
CoEncapsulated
CRIS
Clinical Interactive Record Search
DILI
Drug-Induced Liver Injury
DM
Digital medicine
DMS
Digital medicine system
DW5
Disposable Wearable Sensor Version 5
EHR
Electronic health record
ET
Early termination
EU
European Union
EudraCT
European Clinical Trial Data Base
FDA
(United States) Food and Drug Administration
FOCBP
Females of childbearing potential
GCP
Good Clinical Practice
HCP
Healthcare professional
IB
Investigator’s Brochure
ICD
International Classification of Disease
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IEC
Independent ethics committee
IEM
Ingestible event marker
IRE
Immediately reportable event
ITT
Intent-to-treat
MAA
Marketing authorisation application
MDD
Major depressive disorder
MDDS
Medical Device Data Systems
MHA
Mental Health Act
MIT
Miniature IEM in tablet
MRP
Mutual Recognition Procedure
OPC
Otsuka Pharmaceutical Co.
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OPDC
Otsuka Pharmaceutical Development and Commercialization, Inc
OPEL
Otsuka Pharmaceutical Europe Ltd.
PAM-MH
Patient Activation Measure-Mental Health
PQC
Product Quality Complaint
PSP
Personal and Social Performance Scale
SAE
Serious adverse event
SCH
Schizophrenia
SD
Standard deviation
SOP
Standard operating procedure
TEAE
Treatment-emergent adverse event
UADE
Unanticipated adverse device effects
ULN
Upper limit of normal
US or USA
United States or United States of America
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1
Introduction
The digital medicine system (DMS) has been designed to assist individuals with the 
management of their daily health, wellness, and medication use.
The DMS is being developed as a healthcare management tool to objectively and 
precisely measure medication adherence, and to potentially enhance adherence. This 
advancement in the treatment of mental health patients will enable healthcare 
professionals (HCPs) to assess suboptimal adherence and make more informed treatment 
decisions. In addition, the DMS will provide a platform for engagement between 
subjects, HCPs, and caregivers/support persons.
The feasibility and validity of patient assessment (ie, completion of electronic 
questionnaires) using personal digital assistant or Palm handheld computers has been 
demonstrated in diverse schizophrenia (SCH) samples including hospitalised inpatients,1
outpatients2 and patients exhibiting high levels of paranoia.3 For short trials of 
approximately 1 week, compliance rates with device and assessments have been 
promising, ranging from 87% to 97.7%4,5 and subjects have rated the experiences 
positively.4 Furthermore, SCH patients have reported a willingness to complete mobile 
phone assessments for 5 weeks or longer.6 However, a more common observation in 
eHealth trials is large attrition curves (ie, a substantial proportion of participants drop out 
before completion or stop using the application).7 In one of the longest mobile phone 
trials in SCH, approximately 20% of subjects did not complete the 12-week intervention 
and these “non-completer” subjects were characterized, as compared with “completer” 
subjects, by certain characteristics including lower self-reported living skills, more severe 
negative symptoms as measured by the Positive and Negative Syndrome Scale, and lower 
estimated premorbid verbal intelligence score as measured by the American National 
Adult Reading Test.2
Usability testing is key to the development process of mobile applications (app) and 
ensures the technology is understandable, attractive, and usable for the targeted patient
population. However, outside of one-time laboratory settings, an additional challenge is 
demonstrating that a technology system is usable in the real-world environment for 
patients and across time. Although there have been a number of mobile phone trials in 
SCH, the DMS is a 3-part system which can measure medication adherence if subjects 
successfully engage in a number of processes across the 8-week trial. 
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The DMS is composed of:

An approved antipsychotic medication enclosed with an Ingestible Sensor Pill which 
is otherwise also referred to in this document as CoEncapsulated (CoE) product. 
Ingestible Sensor Pill is also referred to as a miniature ingestible event marker (IEM) 
[from Proteus Digital Health Inc. (Proteus Ingestible Sensor™)] in a tablet (MIT);

Compatible medical device, which is the Proteus Patch (Wearable Sensor) and 
Proteus® Medical Device Data Systems (MDDS). These are collectively referred to 
as the Patch + MDDS. Data received from the Proteus Patch is processed in the Patch 
Analytics Block and is transferred to the Proteus MDDS, both of which reside on the 
paired mobile computing device (eg, smartphone or tablet computer); and

Otsuka Medical Software, which has the following software components: 

Otsuka Patient Component, which resides on the paired mobile computing device 
and receives data from the Proteus MDDS; 

Otsuka Cloud-based Server; 

Otsuka Healthcare Provider Web Portal; 

Otsuka Caregiver Web Portal. 
The CoE product comprises a MIT and a drug originator tablet. The MIT includes an 
embedded IEM (also known as the Proteus Ingestible Sensor). The drug originator tablet 
is an approved antipsychotic medication of either aripiprazole, olanzapine, quetiapine, or 
risperidone, which will be also known as digital medicine (DM)-Aripiprazole, 
DM-Olanzapine, DM-Quetiapine or DM-Risperidone within the smartphone application 
(app). 
The subject worn patch measures physical parameters, such as activity and rest, as well as 
a time stamp of when the atypical antipsychotic medication combined with an ingestion 
sensor are taken. This data is transferred from the patch to the subjects’ smartphone and 
to a secure cloud-based server.
The subject can view the time of tablet ingestion each day (or missed/multiple doses) 
together with their daily duration of rest and activity and manually enter their current 
mood and quality of rest. In addition, the subject’s selected HCPs and selected 
caregivers/support persons can view this information via the cloud-based server with 
appropriate subject’s consent. HCPs can set up missed dose notifications to monitor any 
lapses in subject’s adherence.
The first DMS product (Abilify MyCite®) is approved by the United States (US) Food 
and Drug Administration (FDA).
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Background
Poor adherence to medication is a well-recognized problem in psychiatric patients that 
can be improved to varying degrees by planned interventions, such as medication 
monitoring.8 A variety of treatment models have been developed to improve management 
of patients in general and medication adherence in particular. These methods include 
therapeutic drug monitoring and medication event monitoring, among others. Despite 
availability of these types of management systems, poor medication adherence remains a 
major barrier to achieving optimal health. Current medical event monitoring devices do 
not provide a reliable proxy for actual medication ingestion, and therapeutic drug 
monitoring may be invasive and expensive for routine clinical use.
Several studies have shown that patients with severe mental illness have interest in 
managing their physical and mental health care through digital technologies such as 
smartphones. A meta-analysis of cross-sectional studies involving people with psychosis 
(n = 2129) showed the extent of adopting digital technology. In this trial, 66% of patients 
owned a mobile device with 57% on average using the device daily. When patients with 
psychotic disorders (n = 1172) were questioned regarding utility of the device, tracking 
and monitoring their mental health (60%), receiving information about their physical or 
mental health (56%), reminders about taking their medication (56%), and facilitating 
patient contact with health professionals (51%) were top reasons cited for engagement 
with a mobile device.9 Additional studies showed that patients diagnosed with SCH were 
willing to use electronic devices daily to complete electronic questionnaires in both 
hospitalised and outpatient setting.1,10 Further, another trial noted that patients found 
engagement for self-monitoring and self-report of activity to be non-stigmatizing and 
easy to integrate into their daily lives.11
Otsuka Pharmaceutical Company Ltd. (Otsuka) is developing a combination drug-device 
consisting of CoE product. The antipsychotic medication which will be used in the trial
will be either aripiprazole, olanzapine, quetiapine, or risperidone (see Section 1.3.1). 
An earlier version of this 3-part system has been examined in a 4-week observational trial 
with 12 bipolar disorder (BP) and 16 SCH subjects with weekly site visits.12 However, 
the extent of weekly face-to-face support/training necessary for patients to successfully 
use this 3-part system across a longer period is unknown. Further, other support factors 
such as caregiver/support person involvement or integrated call centre availability were 
not reported and may be important in supporting ongoing usability of the system. Self-
reported usability and acceptability ratings from patient and HCPs are also important in 
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demonstrating that the system is usable in its entirety. Finally, it is important to know if 
there are patient characteristics which predict patient competence and willingness to use 
the system. Such data will help identify patients who can successfully use the DMS, and 
provide information to the sponsor about the specific enhancement of the device or 
support services which could help to extend the range of patient users.
Ingestible Event Marker 
The IEM is a Conformité Européene (CE)-marked class IIa medical device (CE 559373) 
indicated to time stamp, via ingestion, any discrete event. The IEM communicates 
medication ingestion to a compatible medical device, such as the Wearable Sensor (or 
Proteus Patch), CE-marked class IIa medical device (in 2010 by The British Standards 
Institute (BSI), Proteus Digital Health’s European Union [EU] notified body). This 
information, along with additional physiologic data, is processed, displayed, and stored 
on the subject’s compatible computing device, and made available to the subject’s HCP.
Proteus’s IEM is approved for marketing in the EU and in the United States (US) as a 
medical device.
The entire information chain from IEM to compatible medical device is part of the DMS, 
as depicted in Figure 1-1.
Figure 1-1
Digital Medicine System: Antipsychotic Medication with Ingestible 
Event Marker and Compatible Medical Device
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The rationale for developing the DMS is to integrate a clinically important behavioural
diagnostic capability into treatment that will quantify subject medication ingestion in a 
manner functionally equivalent to direct observation, with the goal of improving 
management and compliance of subjects who are at risk of worsening disease. The 
overall clinical development plan is to demonstrate the ability of the DMS to safely 
measure medication adherence in subjects, improve outcomes, and provide HCPs with 
adherence data to make better informed treatment decisions.
1.1
Nonclinical Data
Please refer to the Investigator’s Brochure (IB) for more detailed information regarding 
nonclinical data.13
1.2
Clinical Data
A prototype of a digital health feedback system has been studied previously in subjects 
with bipolar disorder and SCH by Proteus Digital Health, Inc. In that 4-week 
observational trial, 12 bipolar and 16 SCH adult subjects utilised a networked system to 
electronically confirm ingestions of oral medications using ingestible markers. All 
subjects were on a stable regimen of oral medication and wore a Wearable Sensor 
(version RP2 and also called a Patch) and co-ingested one placebo + 2 IEM-Tablet 
assemblies (each consisting of a placebo tablet having one Ingestible Sensor affixed to 
one of the tablet's surfaces) with every ingestion of prescribed medication. Upon 
ingestion, each marker was activated by stomach fluid electrolytes and communicated a 
unique identification (ID) to an adhesive Wearable Sensor (version RP2 and also called a 
Patch) that logged the marker’s ingestion date and time. The Wearable Sensor also 
collected biometrics, and periodically transferred its stored data via a smartphone to a 
password-protected server using secure encryptions. Subjects and caregivers/support 
person, if designated by each subject, were able to view collected data on a dedicated 
website. No interventions were planned based upon the collected data. 
Twenty-seven subjects (96%) completed the trial. Mean taking adherence was 74% (95% 
confidence interval [CI]: 64, 84%) and 67% (95% CI: 55, 79%) of doses were taken 
within 4 hours of the prescribed dosing time. Activity consisted of 845 to 15930 steps 
daily and sleep ranged from 3.2 to 15.2 hours daily. For individual subjects, average sleep 
disruption was as low as 5% and as high 43% for the entire trial period. Minor skin 
irritation occurred at the site of the adhesive Wearable Sensor in 5 subjects (18%). No 
adverse events (AEs) occurred from the ingestion marker. No subject developed paranoid
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ideation while using the system. The majority of subjects regarded the DMS favorably 
and believed that it could be useful in the management of their health.
In addition, the following clinical trials evaluating components of the DMS have been 
conducted by Otsuka. 
Trial 316-13-205 was an open-label, phase 1 trial conducted to evaluate the skin irritation 
potential for, and adhesion to the skin of, the RP4 patch from Proteus Digital Health Inc. 
This trial was conducted as an investigational new drug or investigational device 
exemption trial. This trial used a cumulative skin irritation patch test (modified Draize 
scale) to determine the total cumulative and mean skin irritation scores for the RP4 patch. 
The total and mean adhesion scores were also determined. The overall safety and 
tolerability of the patch were evaluated.
Approximately 30 healthy males and nonpregnant females, 18 to 45 years of age, were 
randomly assigned in a 1:1 ratio (once screening was completed and the subject was 
deemed eligible to participate in this trial) to receive the RP4 patch on either the right or 
left side of the body, just above the lower edge of the rib cage. The same location on the 
opposite side was used for application of the control patch (Webril™ pad attached to a 
nonporous, plastic film adhesive bandage). The subjects were to wear the RP4 patch and 
the control patch for 7 days, at which time a new RP4 patch and control patch were 
applied; this was to be repeated an additional 3 times for a total wear duration of 28 days. 
Skin irritation scores were determined for the RP4 patch and control patch sites before 
the initial application, and 30 minutes after removal of the patches following each 7-day 
wear period. Adhesion scores were collected 1 hour after the initial application of the 
patches and before they were removed following each 7-day wear period. Overall, there 
were no erythema or edema AEs noted for either the RP4 patch or the control patch. The 
adhesiveness of the RP4 patch was similar to that observed for the control patch.
Please refer to the IB for more detailed information.13
Trial 316-13-204 was a phase 4, exploratory, open-label, single-arm, observational 
investigational device exemption trial to obtain feedback from the subject and 
caregiver/support person (if applicable) about the use of the DM prototype and any 
application (ie, software) updates that were made during the trial. The trial was conducted 
at 2 research sites and was designed to include approximately 45 male and female 
subjects, 18 years of age or older, with a current diagnosis of bipolar 1 disorder (BP 1) or 
major depressive disorder (MDD), according to the Diagnostic and Statistical Manual of 
Mental Disorders, Fourth Edition, Text Revision, who were deemed stable by the clinical 
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investigator (eg, symptoms and medication) for a period of 3 months before enroling in 
the trial. Subjects were enroled in 2 cohorts consisting of 35 subjects with BP1 and 
23 subjects with MDD, who were in the stable phase of their disease. Subjects wore a 
patch and co-ingested one placebo + IEM tablet with every ingestion of prescribed 
medication, which may have been once daily or at multiple times of the day, depending 
on the subject’s prescribed dosing regimen for 16 weeks. 
At the last trial visit, 88.2% of the subjects agreed that the Otsuka application was easy to 
use, and 68.6% of subjects felt it was comfortable to wear the patch. In addition, 74.5% 
of subjects and 78.6% of caregivers reported that they felt satisfied with the DMS, and 
74.5% of subjects and 72.0% of caregivers reported they would be interested in using the 
DMS in the future. There were no unanticipated adverse device effects (UADEs) reported 
during the trial.  
Trial 316-13-206a was a phase 4, exploratory substudy in 30 healthy male and 
nonpregnant female subjects 18 to 65 years of age and this was the first trial for a subject 
to ingest a tablet where the IEM was embedded in the aripiprazole. The objective was to 
measure the accuracy of the IEM detection by the DMS and the latency period between 
ingestion after fasting and after a high-fat meal, and detection. The subjects ingested one 
IEM tablet approximately every 2 hours for a total of 4 ingestions. The subjects ingested 
one 10-mg aripiprazole + IEM tablet without food (hour 0), one placebo + IEM tablet 
without food (approximately hour 2), one placebo + IEM tablet with a high-fat meal 
(approximately hour 4), and one placebo + IEM tablet without food (approximately hour 
6). The clinic staff recorded the time of each IEM ingestion, and the time that ingestion 
was detected by the software application on the smartphone. The primary endpoint, 
accuracy of IEM detection following ingestion, was 76.7% overall. The secondary 
endpoint, latency between IEM ingestion and time of detection by the smartphone was a
mean of 1.1 minutes for placebo + IEM and a mean of 5.1 minutes for aripiprazole + 
IEM.
Trial 316-13-206b was a phase 4, exploratory substudy in 29 healthy male and 
nonpregnant female subjects 18 to 65 years of age. The primary objective was to measure 
the accuracy of IEM detection by the disposable Wearable Sensor Version 5 (DW5)
patch following application of a single patch to the subject followed by 4 IEM ingestions. 
Subjects ingested one placebo + IEM tablet approximately every 2 hours (hours 0, 2, 4, 
and 6) for a total of 4 ingestions. Clinic staff paired and placed the patch and recorded the 
time of each ingestion. The smartphone was checked at 30 minute intervals for detection 
of the IEM and the time it was detected was recorded. The proportions of IEMs ingested 
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that were detected by the patch were 96.6%, 93.1%, 96.6%, and 100% at hours 0, 2, 4, 
and 6, respectively. The mean latency periods between ingestion of the IEM to patch 
detection were 1.2, 1.3, 1.1, and 1.3 minutes at hours 0, 2, 4, and 6, respectively. The 
mean latency periods from patch detection (acquisition time) to the time of detection in 
the Otsuka Cloud-based server (server time) were 7.5, 10.3, 6.2, and 6.2 minutes at hours 
0, 2, 4, and 6, respectively. The range of the latency period at all scheduled time points 
was 0.4 to 123.2 minutes.
Trial 316-14-220 was a phase 2a, open-label trial in male and nonpregnant females 18 to 
65 years of age (inclusive) with SCH who were stable on oral aripiprazole. During the 
trial, the subjects continued on same strength tablets consisting of aripiprazole embedded 
with an IEM. Subjects enroled under the original version of the protocol (using the RP4 
patch with the Otsuka Medical Software component v1.4.5 and healthcare provider portal 
v1.4) comprised a first cohort (Cohort 1), while subjects enroled under Amendment 1 
(using the DW5 patch with the Otsuka Medical Software component v1.5.2 and 
healthcare provider portal v1.5) comprised a second cohort (Cohort 2). Each cohort 
included only one treatment group; there was no control group. A total of 37 subjects 
were enroled and treated in Cohort 1, and a total of 30 subjects were enroled and treated 
in Cohort 2.
The primary objective was to measure the usability of the DMS with regard to pairing 
and applying the patch independently by the end of the Week 8 visit. The secondary 
endpoints were: the proportion of subjects who were able to pair and apply a patch 
successfully by the end of the Week 8 visit (or early termination [ET] if applicable) 
independently or with minimum assistance, and the proportion of time during the trial 
period when subjects wore the patches. The primary endpoint for successful pairing was 
defined as a score of 91 to 100 on the Subject Ability to Use System Scale–HCP version; 
the secondary endpoint for successful pairing was a score of 71 to 100 on the same scale.
The trial included a screening period of ≤ 2 weeks, a treatment period of 8 weeks, and a 
safety follow-up period of 2 weeks. There were 2 phases of the treatment period; a 
3-week training phase during the first part of the treatment period, and then a 5-week 
independent phase during the second part of the treatment period. For the primary 
endpoint, over half of the subjects overall (37 of 67, 55.2%) were able to pair and apply a 
patch independently and successfully by Week 8 (95% CI: 42.6%, 67.4%). Results were 
similar between Cohorts 1 and 2. For the secondary endpoints: 55 of 67 (82.1%) subjects 
were able to pair and apply a patch independently or with minimal assistance by Week 8 
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(95% CI: 70.8%, 90.4%). Overall, subjects wore their patches for a mean (standard 
deviation [SD]) of 70.7% (24.7%) of the trial period. 
Trial 316-14-221 was an exploratory, noninterventional, open-label, 4-week trial in 
37 healthy volunteers (sponsor employees), age range 28 to 63 years. The objective was 
to develop the functionality of the digital health data platform and confirm successful 
integration of appropriate data streams generated within DM source databases. 
Corresponding primary endpoints were the following: establishing data streams from the 
DM source, collecting data via live data streams, and developing an operational web-
based dashboard. Results showed these endpoints were adequately achieved. 
Furthermore, results from this trial helped guide changes to enhance long-term 
performance and data collection strategies.  
Trial 316-13-215 was a phase 2 multicentre, 8-week, open-label, single-arm, exploratory 
trial in 49 males and nonpregnant females 18 to 65 years of age (inclusive) with SCH, 
MDD, or BP1 who were stable on oral aripiprazole. During the trial, the subjects 
continued on same strength tablets consisting of aripiprazole embedded with an IEM. The 
objectives of this trial were to assess the functionality of an integrated call centre for the 
DMS and to explore the use of the DMS as measured by patch wear time, subject and 
HCP engagement, and subject satisfaction with the system. Results showed these 
endpoints were adequately achieved and for nearly all questions on the engagement and 
satisfaction questionnaires, the majority of subjects, physician and caregivers chose 
favorable responses.
The primary objective of the current trial is to explore the acceptance and performance of 
the DMS with HCPs and adult subjects with SCH, schizoaffective disorder, or first 
episode psychosis.
1.2.1
The Digital Medicine System
In this trial, the DMS consists of:

CoEncapsulated product - an approved antipsychotic drug co-encapsulated with 
CE-marked MIT (CoE product);

Patch + MDDS - an CE-marked compatible medical device; and 

Otsuka Medical Software - a local and remote computing application.
In addition, the system includes computing applications that reside both locally (eg, on a 
mobile computing device) and remotely (eg, on remote server, “cloud-based”) and enable 
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data transfer and display on the subject’s mobile computing device (eg, smartphone) and 
on a secure web dashboard for the HCP and caregiver/support person (if applicable).
The ingestible sensor (ie, IEM) is food particle-sized and consists of minute amounts of 
essential minerals which occur naturally in the body and in food. It has dimensions of 
1.0 × 1.0 × 0.33 mm with a core of silicon, an outer layer of cuprous chloride (CuCl) 
(5.3 mcg Cu extractable), and an opposing outer layer of magnesium (Mg) (5.6 mcg 
extractable). The ingestible sensor is contained within a placebo (Pill) that is composed 
entirely of excipients that are listed in Generally Recognized as Safe guidance and by the 
International Pharmaceutical Excipients Counsel. The major excipient (approximately 
97%) is microcrystalline cellulose which is commonly used in approved medicinal 
tablets. The device is a CE-marked class IIa medical device (CE 559373) by the BSI.13
The first DMS product (Abilify MyCite®) is approved by the US FDA.
1.3
Known and Potential Risks and Benefits
1.3.1
Overview
The technology that underlies the DMS has received CE marking status in the EU and 
FDA clearance in the US. For safety, toxicology, and efficacy of the IEM, reference is 
made to Proteus Digital Health 510(k)s K113070 (DEN120011), K131009, K131524, 
K133263, and CE 559373. For additional information, please see the IB.13
To date, all of the clinical investigations of the prototype Proteus Digital Health Feedback 
System™ and its patch component in the US have been designated as nonsignificant risk 
trials because they have met the established regulatory criteria for a nonsignificant risk 
device trial. 
Specifically, the system and the patch are not:

An implant used to support or to sustain human life;

Being used for substantially diagnosing, curing, mitigating or treating disease or 
preventing impairment of human health; or

A potential serious risk to the health, safety, or welfare of subjects.
No serious treatment-emergent adverse events (TEAEs) and no UADEs have been 
reported. The vast majority of the device-related nonserious AEs that have been reported 
in completed trials have been classified as mild in severity.
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The risk profiles of aripiprazole, olanzapine, quetiapine, and risperidone are well 
understood and are detailed in the approved product summary of product 
characteristics.14,15,16,17
Nonclinical studies, pharmacokinetic/pharmacodynamic trials, and other clinical trials 
demonstrate the efficacy and safety of aripiprazole, olanzapine, quetiapine, and 
risperidone. 
The marketing authorisation application (MAA) for aripiprazole was approved via the 
centralized procedure in the EU in 2004 for the treatment of SCH in adults and in 
adolescents aged 15 years and older. It is indicated for the treatment of moderate to 
severe manic episodes in BP 1 disorder and for the prevention of a new manic episode in 
adults who experienced predominantly manic episodes and whose manic episodes 
responded to aripiprazole treatment. It is indicated for the treatment up to 12 weeks of 
moderate to severe manic episodes in BP 1 disorder in adolescents aged 13 years and 
older. 
The MAA for risperidone was approved via the Mutual Recognition Procedure (MRP) in 
the EU in 1997 for the treatment SCH, moderate to severe manic episodes associated 
with bipolar disorders, short-term treatment (up to 6 weeks) of persistent aggression in 
patients with moderate to severe Alzheimer's dementia unresponsive to non-
pharmacological approaches and when there is a risk of harm to self or others. 
For the short-term symptomatic treatment (up to 6 weeks) of persistent aggression in 
conduct disorder in children from the age of 5 years and adolescents with subaverage 
intellectual functioning or mental retardation diagnosed according to Diagnostic and 
Statistical Manual of Mental Disorders, fourth edition criteria, in whom the severity of 
aggressive or other disruptive behaviours require pharmacologic treatment.
The MAA for olanzapine was approved via the centralized procedure in the EU in 1996 
for the treatment of SCH, in maintaining the clinical improvement during continuation 
therapy in patients who have shown an initial treatment response. Olanzapine is indicated 
for the treatment of moderate to severe manic episode. In patients whose manic episode 
has responded to olanzapine treatment, olanzapine is indicated for the prevention of 
recurrence in patients with bipolar disorder.
The MAA for quetiapine was approved via the MRP in the EU in 2000 for the treatment 
of SCH, BP disorder (moderate to severe manic), major depressive episodes in BP 
disorder and for the prevention of recurrence of manic or depressed episodes in patients 
with BP disorder who previously responded to quetiapine treatment.
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1.3.2
Risks Related to the Digital Medicine System
1.3.2.1
Skin Findings at the Site of the Patch Attachment
The most common AEs associated with the patch in previous trials have been related to 
skin irritation at the site of the patch placement. This phenomenon has generally been 
mild in intensity, involving itching, localised redness, small papules, and/or elevation of 
the skin under or at the edges of the adhesive. Fine scabbing at the edges of the patch 
occurred rarely without significant ulceration. The mechanism of these skin changes, 
which are transient in nature, is related to irritant contact dermatitis, a 
nonimmune-mediated phenomenon that is commonly seen with adhesive medical 
products, arising from mechanical irritation, chemical irritation, and decreased 
breathability of the skin under the patch. In a small number of cases, irritant contact 
dermatitis leads to transient discoloration of the skin that may last weeks to months.
Several mitigations will be implemented to reduce the risk of these hazards. From a 
materials standpoint, the patch has been designed and manufactured by a respected 
medical device vendor, under Good Manufacturing Practices, from components and 
medical-grade materials that have individually passed required biocompatibility testing. 
The patch adhesive meets the International Organization for Standardization 10993 
standards on biocompatibility. These facts underpin a favorable biocompatibility 
assessment of the patch (see the IB13 “Biocompatibility” for more details). 
Skin will be monitored for irritation or changes at the site(s) of patch placement by the 
HCPs during HCP visits. Subjects will be trained to self-monitor their skin at the sites of 
patch placement between HCP visits. The patch should be replaced once per week 
(ie, once every 7 days) during the trial (Section 3.2.1.2). It should be noted that in early 
trials, the protocol-required repeated placement of the patch over the xyphoid, which may 
have contributed to the incidence of cutaneous AEs; in contrast, the subjects in the 
present trial will have latitude to rotate the patch location. Should skin changes arise, then 
the simplest intervention will be to move the patch to a different site on the torso. 
Subjects will also be told that they are free to remove the patch at any time, and that if 
they do they must inform trial staff immediately (see Section 3.2.1.2). Subjects whose 
frequency or intensity of skin changes is unacceptable can be withdrawn from the trial by 
the HCPs.
Finally, since the patch has an adhesive backing for long-term wear, some skin irritation 
may result from removing the patch because it retains a significant amount of adhesion. 
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To reduce this possibility, subjects will be provided adhesive remover wipes, which can 
be used to ease any discomfort from patch removal. 
If the patch falls off, the subject should replace it with another available patch and inform 
the site staff.
The DMS is not expected to add any appreciable risk to the inherent risks of the trial 
population.
1.3.2.2
Allergic Reaction
An allergic reaction could potentially arise from exposure to components of the CoE
product or the patch, including the following: Adhesive on the patch; microchip of the 
IEM; minerals of the IEM; excipient materials in the IEM and IEM tablet dose forms; 
excipient materials in the IEM formulations; and/or dyes used in the IEM formulations. 
To mitigate the risk of this potential hazard, prospective subjects who have a known 
allergy to any of the components listed above will be excluded from the trial. Allergy to 
tape will be specifically queried. Trial subjects will be monitored for symptoms and signs 
of allergic reaction throughout the course of the trial. If symptoms should arise, the 
subject will be treated promptly and accordingly.
1.3.2.3
Changes in Stool Habits
The majority of the excipient materials used in the CoE product (and internal components 
of the IEM formulations) are cellulose-based. Cellulose in high oral doses is commonly 
used as a stool softener. Stool softeners typically increase the bulk and potentially the 
frequency of bowel movements, but they rarely cause diarrhea. However, the quantities 
of cellulose-based excipients in a daily dose of a CoE product in this trial are several fold 
smaller than the therapeutic dose used for stool-softening purposes. No increased stool 
frequency was reported by subjects in previous trials, while 2 instances of constipation 
were reported.
Therefore, it is the opinion of the sponsor that the probability of changes in stool habits is 
low and, were they to occur, the clinical implications would likely be minor.
1.3.2.4
Anxiety from the Use of the Digital Medicine System
Subjects may experience anxiety related to swallowing the CoE product, wearing the 
patch, or using the smartphone. Moreover, it is theoretically possible that subjects could 
feel uncomfortable with the concept of 24-hour data collection. To reduce potential 
subject anxiety, adequate training time along with clinical and technical support will be
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made readily available during the trial. Moreover, familiarity with a smartphone is an 
inclusion criterion (see Section 3.4.2).
1.3.2.5
Potential Theoretical Digital Medicine System-related Risks
1.3.2.5.1
Procedure-related Risks
1.3.2.5.1.1
Communications-related Risks
Subjects will be required to use a mobile smartphone during the trial to upload and later 
to view data. Through misapprehension of the use instructions or technical failures, 
subjects could experience confusion or frustration. 
To mitigate this problem, only the subjects who have the capacity to utilise the 
technology interfaces (eg, open and navigate software applications using the touch 
screen) and telephone features of a smartphone will be enroled in this trial (see 
Section 3.4.2). 
Moreover, subject privacy is essential. It is theoretically possible that in the process of 
communicating through the DMS, privacy could become compromised. This could occur 
when data are being transmitted by the DMS.
To mitigate this risk, industry-standard encryption protocols will be used for data 
transmission from the patch to the computing device and from the computing device to 
the server via the cellular network. The access information for the DMS data are stored 
only on the sponsor’s servers, which are also protected with industry-standard security 
features. 
All aspects of the DMS are compliant to Health Insurance Portability and Accountability 
Act of 1996 requirements and European General Data Protection Regulation.
Therefore, it is the opinion of the sponsor that the risk of adverse clinical consequences 
from the planned trial communications is very low.
1.3.2.5.1.2
Less Significant Procedure-related Risks
Subjects may feel uncomfortable about answering personal health questions. The risks 
are very unlikely to result in significant adverse clinical outcomes, but research personnel 
will be sensitive to this issue.
Additional information may be found in the IB.13
1.3.3
Benefits
There is a potential benefit from participating in the trial, in that subjects may have a 
better understanding of their medication-taking pattern and the relationship to their
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illness. In addition, subjects may have a better understanding of their personal 
physiologic status (eg, activity, rest) by viewing the individualised health data on their 
smartphone. 
The sponsor’s intent is to develop a system that will be of significant benefit to future 
subjects by providing a novel, convenient method to track medication-taking behaviour in 
an objective manner, and to monitor important physiologic parameters on an ambulatory 
basis. The execution of the present trial would represent an opportunity to gather 
feedback regarding the use of the DMS in the trial population. Thus, data gathered in the 
trial will be important for refining the DMS to help future patients who may use the 
system.
1.3.4
Potential Benefits of the Digital Medicine System
1.3.4.1
Limitations of Current Medication Adherence Measures
Consequences of adherence problems in psychiatry include relapse, hospitalisation, 
suicide, and poor prognosis. 
Physician and self-report are most commonly used to assess adherence18 yet trials have 
constantly found that HCPs’ subjective judgment of medication adherence are often 
inaccurate, with a tendency for practitioners to overestimate subject adherence. As 
illustrated in Figure 1.3.4.1-1, Byerly and colleagues found electronic medication cap 
checks detected significantly greater nonadherence rates than prescribers.19
Figure 1.3.4.1-1
Methods Used to Assess Antipsychotic Medication 
Nonadherence for up to 6 Months
(Adapted from Byerly et al, 2007)19
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Drawing on a wider suite of adherence measures, one published report indicated there 
was an underestimation of the extent of nonadherence by subjects and physicians 
compared with more objective adherence measures18,20; methods used to measure 
antipsychotic medication adherence for up 12 weeks in SCH subjects are summarised in 
Figure 1.3.4.1-2. The tendency for physician overestimation of adherence has also been 
reported in bipolar disorder.21
Figure 1.3.4.1-2
Methods Used to Measure Antipsychotic Medication 
Adherence for up to 12 Weeks
(Adapted from Velligan et al, 2007)22
1.3.4.2
Potential Benefits of the Digital Medicine System Adherence 
Measures
The DMS includes a CoE product providing an advance on the available proxy measured 
by the following:

Ability to provide confirmation of medication ingestion thereby enabling accurate 
detection of subject adherence status;

Ability to provide information to assess whether uncontroled symptoms may be 
explained by nonadherence or indicate treatment nonresponse;

Ability to assess adherence on a continuous (near real-time) basis;

Ability to provide adherence electronic feedback to subject, HCP, and/or 
caregiver/support person (if applicable).
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The sponsor’s intent is to develop a system that will benefit future patients by providing 
the ability to track their medication-taking behaviour in an objective manner, and being 
able to monitor several physiologic parameters.
2
Trial Rationale and Objectives
2.1
Trial Rationale
A number of subject behaviours are known to be either barrier to successful treatment 
and/or predictors of worsening of psychiatric condition. The use of devices and mobile 
health technologies have become available that may improve health management and 
subject outcome in mental health disorders. Otsuka Pharmaceutical Company Ltd. is 
developing a DMS to measure subject parameters to facilitate better care for mental 
health service users and better outcomes for the healthcare system. 
The intention of the DMS is 2-fold. Firstly, it will enable subjects and HCPs to use the 
available data to support subjects care and engage the subjects in their ongoing disease 
management, encouraging greater self-management and behaviour change through access 
to information. Secondly, the system will allow HCPs and caregivers/support persons to 
use this information to improve the subjects care.
2.2
Dosing Rationale
The subjects in this pragmatic trial will receive CoE MIT and drug originator tablet of 
either aripiprazole, olanzapine, quetiapine, or risperidone as prescribed by their HCPs.
The treatment medication decision will be determined by the HCPs and independent from 
the protocol. 
2.3
Trial Objectives
The primary objective of this trial is to explore the acceptance and performance of the 
DMS with HCPs and adult subjects with SCH, schizoaffective disorder, or first episode 
psychosis.
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3
Trial Design
3.1
Type/Design of Trial
This is a multicentre, 8-week, single-arm, open-label, pragmatic trial to explore the 
acceptance and performance of using the DMS with HCPs and adult subjects with SCH, 
schizoaffective disorder, or first episode psychosis on an oral atypical antipsychotic 
(aripiprazole, olanzapine, quetiapine, or risperidone).
This trial includes a screening/baseline visit (up to 7 days), an assessment period 
(8 weeks), safety follow-up phone call (2 weeks after Week 8/ET visit), and the 
healthcare utilisation record evaluation (24 weeks before and after the baseline visit for a 
total of 48 weeks).
Subjects in this trial will receive an initial introduction to the DMS, and have HCP visits 
at screening/baseline, Week 4, Week 8/ET, and as directed by the HCP for the duration of 
the subject’s participation in the trial. 
Subjects entering the trial will be treated with one of the oral atypical antipsychotics 
defined in the trial. The treatment medication decision will be determined by the HCPs 
and independent from the protocol. 
The HCPs will have access to a DM dashboard where notifications can be setup around 
medication ingestion.
Screening/Baseline Visit (Days -7 to -1)
After providing the informed consent, subjects will enter the screening period for up to 
1 week (7 days). Screening and baseline may occur at a single visit or may occur over 
2 visits up to 7 days apart. The screening period may be extended at the discretion of the 
HCP. 
Recruitment will be facilitated by firstly using the research sites sharing information 
about research remote function call procedure, which records subject’s preferences in 
relation to being directly contacted by researchers about any future research studies for 
which they may be eligible. Their electronic health records (EHR) reflect this ‘opt in’ 
status. The subjects who have already ‘opted in’ to be contacted about future research 
will be approached by the research team.  
Secondly, Clinical Interactive Record Search (CRIS) will be utilised to interrogate 
de-identified patient records for those who have opted into CRIS. The trial will be 
submitted to the CRIS monitoring group for approval to access the CRIS application.
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Assessment Period (8 weeks):
Initiation of the DMS will commence at the baseline visit, with subjects ingesting the 
CoE product, wearing the patch, and using the smartphone app for a total of 8 weeks 
during the assessment period from baseline visit to Week 8 visit. 
During the assessment period from baseline visit to Week 8/ET visit:

Subjects will visit the HCP for clinical evaluations at Week 4;

Subjects will collect their DMS prescription refill at Week 4 visit for next 4 weeks 
until Week 8/ET visit; 

Subjects will visit the HCP at Week 8/ET and undergo another clinical evaluation.
Safety and tolerability data will be collected and evaluated on an ongoing basis, as 
assessed by the frequency and severity of serious adverse events (SAEs), and device-
related nonserious AEs. 
Subjects will be monitored on the technology by the HCPs, who will review the HCP 
dashboard data at a minimum of every 2 weeks and make changes to current treatment 
plan and therapy at their discretion. The HCPs may request that a subject return to the site 
for unscheduled visits as deemed appropriate. In the event of an unscheduled visit, review 
of the DMS dashboard and safety events will be collected.
Follow-up:
Week 8/ET visit evaluations will be completed for any subject withdrawn from the trial at 
any time (for any reason other than full withdrawal of the consent). 
Following the Week 8/ET visit, the subjects will not use the DMS and return to standard 
care (routine follow-up from care teams and continue non-DM medications). Subjects 
will have access to their trial account or data in the smartphone app up until 30 days after 
the last subject’s Week 8/ET visit. After this duration, the subjects will no longer have 
access to their data via the smartphone app.
A safety follow-up phone call will occur at 2 weeks after the Week 8/ET visit, which will 
be the last official subject contact. 
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Healthcare Utilisation Record Evaluation (24 weeks before and after the baseline visit):
Twenty-four weeks before and after the baseline visit (for a total of 48 weeks), all 
hospital admissions (psychiatric and non-psychiatric) would be recorded and assessed as 
either ‘planned’ or ‘unplanned’ and ‘related’ or ‘unrelated’ to the psychiatric illness. 
Similarly, all encounters between any HCP (psychiatric and non-psychiatric) and the 
subject will be recorded to obtain the following information:

The nature of the contact (eg, home visit, inpatient, outpatient, HCP visit, day centre); 

The HCP role (eg, community psychiatric nurse);

Whether the contact was planned or not;

Whether or not the contact was initiated as a result of data from the DMS;

Any medication titration, adherence counseling, education, and lifestyle coaching.
This data will be reported in the data collection tool at Week 24 (or up to 7 days after this
time point).
The trial schematic is summarised in Figure 3.1-1.
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Screening
(Up to 
7 days)
Assessment Period
(8 weeks)
Safety 
Follow-up
(2 weeks)a
Healthcare 
Utilisation 
Record 
Evaluation 
(24 weeks)c
Baseline 
Visitb
Week 2
Week 4 
Visitb
    Week 6
Week 
8/ET 
Visitb
Healthcare 
Utilisation Record 
Evaluation
(24 weeks)c
HCPs will review HCP dashboard at Weeks 2, 4, 6 and 8 and make treatment changes at their discretion.
aSafety follow-up phone call will occur 2 weeks after Week 8/ET visit.
bSubject visits will occur at baseline, Week 4 and Week 8/ET. Other visits will be at the discretion of the HCP.
cHealthcare utilisation will be recorded 24 weeks before and after baseline visit (for a total of 48 weeks), at Week 24.
Figure 3.1-1
Trial Design Schematic 
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3.2
Trial Treatments
The subjects will receive CoE MIT and drug originator tablet of either aripiprazole, 
olanzapine, quetiapine, or risperidone as prescribed by their HCPs (see Section 2.2). The 
originator drug tablet will be known as either DM-Aripiprazole, DM-Olanzapine, 
DM-Quetiapine, or DM-Risperidone within the smartphone app.
The subject and the HCP will initiate the system at the baseline and use it for 8 weeks 
(from baseline to the Week 8/ET visit). Following this period, the use of the DMS will be 
stopped and the subject will return to standard care (routine follow-up from care teams 
and continue non-DM medications). The DMS may be started and stopped as clinically 
appropriate based on HCP’s judgment during the 8-week assessment period of the trial.
Following the Week 8/ET visit, the subjects will not use the DMS and return to standard 
care (routine follow-up from care teams and continue non-DM medications). Subjects 
will have access to their trial account or data in the smartphone app up until 30 days after 
the last subject’s Week 8/ET visit. After this duration, the subjects will no longer have 
access to their data.
3.2.1
Digital Medicine System Components and Use
The DMS includes a drug-device combination of a CoE product, a patch, and an 
application software to convey level of activity and rest, and to mark events through the 
act of ingestion.
The CoE product is the drug-device combination which consists of an antipsychotic 
medication and MIT. The active drug-device combination in this trial will be the drug 
originator tablet of either aripiprazole, olanzapine, quetiapine, or risperidone + IEM.
The patch is a separate compatible medical device, which consists of a Wearable Sensor 
and an associated compatible medical device software application from Proteus Digital 
Health Inc. The patch is an unmedicated adhesive device that is worn within a specified 
torso area on the left side (Section 3.2.1.1). Each patch is designed for 7-day wear; extra 
patches will be provided should the subject be required to change the patch more 
frequently (ie, patch falls off prematurely or patch becomes partially adherent to skin). 
The patch detects and time-stamps each IEM ingestion as well as measures and records 
other date- and time-stamped physiologic and behavioural data, such as heart rate, 
physical activity (ie, step count), and amount of rest. The patch connects wirelessly to a 
commercially available mobile computing device (ie, smartphone) to transfer data 
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captured by the patch via the compatible medical device software application to a secure 
server for aggregation and processing. 
The DMS software applications, which include elements that reside both locally (eg, on a 
mobile computing device) and remotely (eg, on remote server), enable data transfer and 
display on the subject’s mobile computing device (ie, smartphone) and on the HCP 
web-based dashboard. As part of the DM software application, subjects may enter their 
subjective rest quality on a daily basis and their subjective mood rating up to several 
times a day.
Subjects should own a commercially available smartphone or a smartphone will be 
provided by the Sponsor, and be familiar with its use (ie, iPhone 7s and 10.x, android 
Samsung s8 and Os 7.x). The smartphone should be charged daily (however, it is noted 
that if the smartphone battery becomes fully depleted, the DMS data will not be lost, as 
the data will remain stored on the patch). Subjects will be requested to carry the 
smartphone with them as much as possible, and to plug in the device at a dedicated 
location at home where they have easy and frequent access when not being carried. The 
preferred location is on a bedside table or location immediately adjacent to where the 
subject sleeps. 
The subject may view his/her data at will on the smartphone. In addition, the subject’s 
selected HCPs and selected caregivers/support person (if applicable) can view this 
information via the cloud-based server. HCPs can set up missed dose notifications to 
monitor any lapses in subject’s adherence. HCPs will review for HCP dashboard at 
Weeks 2, 4, 6 and 8 at minimum and make treatment changes at their discretion.
Each HCP will be provided with a printed DMS reference guide that will provide explicit 
directions for normal use and troubleshooting.
At each visit, subjects will be reminded by the HCP to contact the integrated call centre 
with any technical questions about the DMS. The call centre will operate from Monday to
Friday from 9 AM to 5 PM (Greenwich Mean Time).
If there are any technical issues with the DMS that the integrated call centre is unable to 
resolve, the subject will be routed to a technology support representative. If a subject 
contacts the integrated call centre with clinical issues including reporting of SAEs, the 
integrated call centre will document the event and forward the information to the trial site 
for additional follow-up, as needed.
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3.2.1.1
Digital Medicine System Onboarding
Onboarding involves the pairing of a patch with the application contained on a 
smartphone and then applying that patch to the skin in the proper location.
The patch is to be placed on the left side of the torso within a defined zone just above the 
lower edge of the rib cage. 
The defined zone on the torso must meet all of the following parameters: 

On the left side;

Just above the left costal margin;

From the xyphoid process to the left mid-axillary line;
Placement should be on the lower chest with the lower edge of the patch on the lower 
edge of the rib cage, and NOT on the abdomen. 
Patch placement location is depicted visually in Figure 3.2.1.1-1.
Figure 3.2.1.1-1
Patch Placement Zone
A simple skin preparation procedure, consisting of gently cleaning the skin surface with 
an alcohol wipe and allowing the area to dry, is recommended. On some subjects, 
clipping of body hair in the placement zone may be required to allow secure device 
adhesion. Placement of the patch should avoid locations below the bottom of the rib cage 
or areas where the patch was previously worn. Use of lotions on the skin where the patch 
will be place is not recommended. The patch can be worn during regular activities, 
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including showering, but new patches should not be applied for a few hours after 
showering or other physical activities to ensure the adhesive sticks properly. Patches can 
be worn up to 7 days, at which point, the smartphone app will remind patients that the 
patch needs to be changed.
During the DMS onboarding process, the smartphone app will provide a message to 
prompt the subject to ingest a CoE product to verify and confirm the proper setup of the 
DMS. 
A patch may be placed anywhere in the zone depicted in Figure 3.2.1.1-1; however, when 
an old patch is replaced with a new patch, each new patch must be placed on a different 
skin location (with no overlap) from where the last one was just removed. 
Upon completion of each patch application, before a new patch can be paired and 
applied, the wireless connection between the Wearable Sensor and the smartphone app 
must be confirmed so that all data have been transferred appropriately (see 
Section 3.2.1.2). 
3.2.1.2
Digital Medicine System Patch Use
Once every 7 days throughout the assessment period, the subject will pair a new patch 
with the application and then apply it to his or her torso in the proper location. Each patch 
should be removed on the seventh day after the day of the initial application of that patch; 
no patch should remain applied to a subject’s skin for longer than 7 days. 
Following the initial patch pairing and placement during the baseline visit, a subject will 
be instructed to wear a patch continuously (eg, 24 hours per day, 7 days per week), if 
possible. The patch can be worn throughout different daily activities, including bathing 
and swimming. 
A subject will be told that it is allowable to remove the patch for any reason (especially 
for evidence of local skin irritation/inflammation), but that it is preferred that the patch be 
kept on as much as is tolerable and safe. The subject should note, as much as possible, the 
events surrounding any premature removal of the patch and contact the site immediately. 
Although a given patch generally should indeed be applied for a full 7 days, in some 
cases a patch might end up being replaced before the 7 days is up (eg, if a previous patch 
falls off prematurely or if a subject removes a patch because of local skin 
irritation/inflammation). Instances of patch removal (unintentional or intentional) less 
than 7 days after the patch has been applied will constitute premature patch removal. 
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A reason must be recorded for every patch removal, including reasons for premature 
patch removal. 
Each time a previous (“old”) patch is removed (or inadvertently falls off), a new patch 
should be paired and applied immediately. 
Subjects are free to replace a patch offsite using dispensed trial supplies. A subject will 
then pair the new patch with the smartphone, prepare the skin for placement of the patch, 
remove the backings of the new patch to expose the adhesive layer, and then attach the 
patch to the skin at the proper position on the torso. 
Each subject will return all supplies, including all used patches and associated labels, to 
the trial site. At the end of the trial (Week 8/ET visit), all returned patches and associated 
labels will be destroyed at the trial site(s) or by a designated agent.
3.2.1.3
Digital Medicine System Versions
Different versions of the DMS have been developed. 
The version of the DMS that will be evaluated is the Archer IEM and DW5 patch 
combination (Archer/DW5) with Digital Medicine software application Version 2.1 (iOS 
and Android).
3.3
Trial Population
Adult subjects with SCH, or schizoaffective disorder, or first episode psychosis, who are 
prescribed either aripiprazole, olanzapine, quetiapine, or risperidone and meet eligibility 
criteria will be enroled in this trial.
3.3.1
Number of Subjects and Description of Population
The trial will enrol approximately 60 male and female adult subjects between 18 and 
65 years of age, inclusive, with a confirmed clinical diagnosis of SCH or schizoaffective 
disorder (defined by International Classification of Disease [ICD]-10 codes F20 and 
F25), or first episode psychosis using case note review. There is no limit on the duration 
of illness for those with SCH or schizoaffective disorder but first episode psychosis is 
defined as less than 3 years since presentation to the mental health team or first 
antipsychotic prescription. Subjects will receive care under at least one of the following 
care settings:

Discharge from a hospital admission (within 7 days) to an acute intervention team;

Referral to an acute intervention team, prior to any hospital admission;

Referral from an acute intervention team to a community mental health team;
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
Managed by community services (inclusive of patients on Care Programme
Approach);

Inclusion within early intervention caseload (< 3 years from initial symptoms);

HCP determines the subject would benefit from using the DMS.
3.3.2
Subject Selection and Numbering
All subjects will be given a unique 5-digit subject ID number. 
3.4
Eligibility Criteria
3.4.1
Informed Consent
Written informed consent will be freely obtained from all subjects (or their guardian or 
legally acceptable representative, as applicable for local laws). Consent will be 
documented on a written informed consent form (ICF). Caregivers/support persons (if 
applicable) will also be required to sign an ICF. The ICF will be approved by the same 
independent ethics committee (IEC) that approves this protocol. Additionally, the 
informed consent will cover the retrospective and prospective aspects of the trial.
Each ICF will comply with the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline23 and local regulatory requirements. The HCP will 
ensure that the sponsor reviews and authorises any written site-specific ICF used in the 
trial before submission to the IEC. 
HCPs may discuss trial availability and the possibility for entry with a potential subject 
without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the HCP (or designee), and it has been documented 
that the subject has had the opportunity to ask questions, the IEC-approved written ICF 
will be signed and dated by both the subject and the person obtaining consent (HCP or 
designee), as well as by any other parties required by the IEC. The subject will receive a 
copy of the signed ICF; the original shall be kept on file by the HCP.
Subjects may be asked to sign additional ICFs if the protocol is amended to significantly 
add or change procedures.
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3.4.2
Inclusion Criteria
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1.
Table 3.4.2-1
Inclusion Criteria
1.
Subject must be willing and able to give written (signed and dated) informed consent, which 
includes adherence to trial requirements and restrictions before enroling in the trial. Subject must 
be willing to adhere to trial procedures, including troubleshooting of the DMS by a third party if 
needed.
2.
Subject must be able to read and understand English.
3.
Male and female subjects 18 to 65 years of age, inclusive, at the time of informed consent.
4.
Subject possessing  their own smartphone or a smartphone provided by the Sponsor, and being 
familiar with its use and willing to download and interact with the DMS app, completing all tasks 
as well as adequately operate all devices, as applicable. Caregiver/support person or other third
party assistance can be utilised, if needed, although all subjects should be encouraged to attempt all 
tasks themselves.
5.
Subject possesses the capacity to utilise the technology interfaces (eg, open and navigate software 
applications using the touch screen) and telephone features of a smartphone. The subject has 
satisfactory mobile phone reception (preferably 3 bars or more, or have Wi-Fi) at home and/or at 
work for trial-designated wireless carrier.
6.
Subject is cooperative, able to ingest oral medication, willing to complete all aspects of trial, and 
capable of reporting AEs.
7.
Clinical diagnosis of SCH or schizoaffective disorder (defined by ICD-10 codes F20 and F25) or 
first episode psychosis using case note review.
8.
Subjects prescribed aripiprazole, olanzapine, quetiapine, or risperidone.
9.
Subject must fulfill at least one or more of the following: 

Discharge from a hospital admission (within 7 days of discharge) to an acute intervention 
team;

Referral to an acute intervention team, prior to any hospital admission;

Referral from an acute intervention team to a community team;

Managed by community services (inclusive of patients on Care Programme Approach);

Inclusion within early intervention caseload (< 3 years from initial symptoms);

HCP determines the subject would benefit from using the DMS.
10.
Subject’s general medical condition such that participation in the trial does not pose any additional 
risk as per HCP’s judgment.
11.
Skin on the anterior chest just above the lower edge of the rib cage that is free of any 
dermatological problems (eg, dermatosis or dermatitis, open wounds, or other skin disorders such 
as warts, rashes, atopic dermatitis, or irritations).
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3.4.3
Exclusion Criteria
Subjects will be excluded if they meet any of the exclusion criteria in Table 3.4.3-1.
Table 3.4.3-1
Exclusion Criteria
1.
Subject with any disorder including but not limited to intellectual developmental delay or disorder, 
major neurocognitive disorder or other condition that may impact the subject’s ability to participate 
in the trial or interact with the smartphone application.
2.
Subject who is likely to be incapable of using the DMS technology, even with assistance.
3.
Subject who has a history or evidence of a medical condition that would expose them to an undue 
risk of a significant AE or interfere with assessments of safety or usability during the course of the 
trial, including but not limited to, hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, 
hematologic, or immunologic disease as determined by the clinical judgment of the HCP.
4.
Subject with a known allergy to adhesive tape or any pertinent components of the patch or CoE 
product. 
5.
Prisoner must not be enroled into this trial.
6.
Subject who is hospitalised due to mental or physical illness (inpatient) at the time of 
screening/baseline must not be enroled into this trial.
7.
Any subject who, in the opinion of the HCP, should not participate in the trial.
8.
Any subject who, through religious or lifestyle choices, will not take gelatin capsules.
9.
Female (FOCBP) who is breast-feeding and/or who have a positive pregnancy test result prior to 
receiving trial enrolment, or who plans to become pregnant during the trial.
FOCBP = females of childbearing potential.
Individuals that are sectioned as part of the Mental Health Act (MHA), yet remain in the 
community (eg, community treatment orders) will be able to participate in the trial
providing all inclusion criteria are met. However, individuals that are sectioned as part of 
the MHA and are compulsory detained in a hospital or secure setting (eg, inpatient) will 
not be able to participate in the trial.
Individuals will be able to take two or more of the 4 DMs in the study, should the
HCP deem it necessary (eg, DM-Aripriprazole and DM-Quetiapine).
Individuals may be switched from their current medication to one of the 4 DMs prior to 
enrolment only if considered medically appropriate. No subject should be switched to one 
of the 4 DMs for the purpose of meeting trial entry criteria.
In respect to other examples of polypharmacy (eg, typical antipsychotics, atypical 
antipsychotics, mood stabilisers, antidepressants, or indeed other medication), individuals 
will be able to participate providing they are prescribed one of the four antipsychotics 
under investigation (eg, aripiprazole, olanzapine, quetiapine, or risperidone). 
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Subjects will be able to participate if they are taking a long-acting injectable/depot, 
providing that mediation is not the same as the oral equivalent in this trial:

Allowed (eg, flupentixol [Depixol®, Fluanxol®, flupenthixol] depot and DM);

Not allowed (eg, Risperdal Consta® and DM-Risperidone, Abilify Maintena® and 
DM-Aripiprazole).
Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects 
who have undergone bilateral oophorectomy and/or hysterectomy) and female subjects 
who have been postmenopausal for at least 12 consecutive months.
Subjects must agree to restrictions to medications and lifestyle as described in Section 4. 
3.5
Endpoints
3.5.1
Primary Endpoint
The primary endpoint is the proportion of days with good patch coverage during the trial, 
which is calculated by the number of days with good patch coverage divided by the total 
number of trial days for each subject. The good patch coverage will be defined as having 
at least 80% patch data available or MITs detected within the 24-hour period for each day 
while the subject is on the trial.
3.5.2
Secondary Endpoint
The secondary endpoint is subject’s adherence metric, which is the proportion of detected 
MITs over the expected MITs ingested during the trial days with good patch coverage.
3.5.3
Exploratory Endpoints
The exploratory endpoints are as follows:
1) To explore the acceptance and performance of the DMS with HCPs and adult 
subjects with SCH, schizoaffective disorder, or first episode psychosis as 
measured by:
The proportion of time during the trial period when the subject wears their 
patch. 
The engagement and satisfaction of subjects, HCPs, and caregivers/support 
persons (if applicable), as determined by the surveys (Subject Usability and 
Satisfaction Scale, HCP Utility Survey, and Caregiver/Support Person 
Involvement Scale [if applicable]).
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The proportion of days subjects are using the application and the proportion of 
days that HCP are using the HCP dashboard during the trial.
The proportion of ingested MITs registered on the digital health data server 
versus expected MITs ingested.
2) Additional variables will be captured to better understand outcomes that may 
impact use of the DMS or be impacted by the use of the DMS including: 
Change from baseline to Week 8/ET in Clinical Global Impression-Severity of 
Illness Scale (CGI-S);
HCP visits and associated setting of care;
Details surrounding any hospitalisations; 
Occurrence and timing of community/home visits; 
Any referrals during the observation period. 
3.5.4
Safety Variables
The safety variables are as follows:
Evaluate the safety and tolerability of the DMS, as assessed by the frequency 
and severity of SAEs, and device-related nonserious AEs;
Evaluate suicidality;
Evaluate any product quality complaints that arise.
3.6
Measures to Minimize/Avoid Bias
This trial is open-label.
3.7
Trial Procedures
Eligible subjects will enter the screening period for up to 1 week (7 days). Screening and 
baseline may occur at a single visit or may occur over 2 visits up to 7 days apart. The 
screening period may be extended at the discretion of the HCP. At the screening/baseline
visit, informed consent will be obtained before any trial-related assessments or 
procedures are performed. Initiation of the DMS will commence at the baseline visit for 
the subjects who meet all applicable eligibility criteria (Section 3.4), based on a series of 
assessments conducted at the screening/baseline visit.
During screening/baseline visit, the HCP will provide training on the correct use and 
required procedures associated with the DMS. The subject will be provided with patches, 
CoE product, other supplies, and instructions on the procedures to be followed over the 
coming weeks.
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Subjects will be monitored on the technology by the HCPs, who will review the HCP 
dashboard data at a minimum of every 2 weeks and make changes to current treatment 
plan and therapy at their discretion. The HCPs may request that a subject return to the site 
for unscheduled visits as deemed appropriate. In the event of an unscheduled visit, review 
of the DMS dashboard and safety events will be collected.
Subjects will visit the HCP for clinical evaluations at Week 4. During this visit, subjects 
will be dispensed patches, CoE product, and other supplies to last until the Week 8/ET 
visit. 
At the Week 8/ET visit, designated assessments and procedures will be conducted.
The Week 8/ET visit marks the end of the assessment period. The subject will stop taking 
CoE product and will restart his/her standard care (routine follow-up from care teams and 
continue non-DM medications). All trial materials will be returned to the trial site. Week 
8 assessments will be conducted. 
A follow-up telephone contact will be made 2 weeks (± 3 days) after the last dose of CoE 
product (for subjects who withdraw early and for those who complete the trial).
Furthermore, 24 weeks before and after the baseline visit (for a total of 48 weeks), all 
hospital admissions (psychiatric and non-psychiatric) would be recorded and assessed as 
either ‘planned’ or ‘unplanned’ and ‘related’ or ‘unrelated’ to the psychiatric illness.
Similarly, all encounters between any HCP (psychiatric and non-psychiatric) and the 
subject will be recorded to obtain the following information:

The nature of the contact (eg, home visit, inpatient, 
outpatient, HCP visit, day centre);

The HCP role (eg, community psychiatric nurse);

Whether the contact was planned or not;

Whether or not the contact was initiated as a result of data from the DMS;

Any medication titration, adherence counseling, education, and lifestyle coaching.
This data will be reported in the data collection tool at Week 24 (or up to 7 days after this 
time point).
Trial assessment time points are summarised in Table 3.7-1.
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Table 3.7-1
Schedule of Assessments
Assessment
Screening/Baselinea
Assessment Period
Follow-up
Post-treatment
Days - 7 to - 1
Week 2b
(± 3 days)
Week 4
(± 3 days) Week 6b
(± 3 days)
Week 8/ET
(± 3 days) 
Week 10
(± 3 days)
Week 24
(+ 7 days)
Trial site visit
X
X
X
Safety follow-up phone contact
X
Informed consent
X
Inclusion and exclusion criteria assessment
X
Smartphone (with means to communicate data [eg,
suitable data plan or wireless local area networking 
(Wi-Fi)] connectivity options) verification
X
Demographic information
X
Medical/psychiatric history
X
Urine pregnancy test for FOCBP
X
Training on DMSc
X
Suicidality assessment (face-to-face suicide risk 
assessment per trial site’s SOPs)d
X
X
X
Review of DMS dashboard datae
X
X
X
X
Subject pairs and applies patch at trial site
X
Subject Usability and Satisfaction Scale
X
HCP Utility Survey
X
Caregiver/Support Person Involvement Scale
(if applicable)
X
PAM-MH
X
X
CGI-S
X
X
PSP
X
Dispense drug originator tablet + CoE MIT, supplies, 
patches
X
X
Accountability for patches, and drug originator tablet
+ CoE MIT
X
X
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Table 3.7-1
Schedule of Assessments
Assessment
Screening/Baselinea
Assessment Period
Follow-up
Post-treatment
Days - 7 to - 1
Week 2b
(± 3 days)
Week 4
(± 3 days) Week 6b
(± 3 days)
Week 8/ET
(± 3 days) 
Week 10
(± 3 days)
Week 24
(+ 7 days)
Concomitant medication
X
X
X
Healthcare Utilisation Record Evaluationf
X
PAM-MH = Patient Activation Measure-mental Health; PSP = Personal and Social Performance Scale; SOPs = standard operating procedures.
aScreening/Baseline/Start may occur at a single visit or may occur over 2 visits up to 7 days apart.
bNot applicable to the subject. HCP must review dashboard only. 
cRefresher training on DMS will be given to the subject as required per judgment of the HCP.
dNumber of times will be determined by number of face-to-face visits at the HCPs discretion.
eDashboard data is reviewed and entered into the case report form every 2 weeks during the trial (4 in total) by the HCP whether or not the HCP has 
personally seen the subject.
fRecord in data collection tool all intervention data, including medical hospitalisations, psychiatric hospitalisations, accident and emergency (A and E) visits, 
and the number of crisis medications, from 24 weeks prior to baseline visit through Week 24 (total of 48 weeks).
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3.7.1
Schedule of Assessments
3.7.1.1
Screening/Baseline Visit
Eligible subjects will come to the trial site, on a day agreed upon by the subject (and his 
or her caregiver/support person, if applicable) and the HCP, to undergo 
screening/baseline assessments. 
At the screening/baseline visit, the following will be performed:

Informed consent;

The subject must provide documented informed consent before any other trial 
assessments or procedures are performed;

If the subject has a caregiver/support person, that caregiver/support person also 
must provide written informed consent.

Eligibility Assessment (Section 3.4);

All protocol inclusion and exclusion criteria will be reviewed by the HCP; only 
subjects who meet all of the inclusion criteria and none of exclusion criteria may 
be considered for further participation in the trial;

Smartphone verification: Each subject will be asked to confirm the availability of 
a suitable smartphone for the trial, in addition to confirming a suitable data plan 
or wireless local area networking (Wi-Fi) connectivity option is available to them.
Smartphones and associated data plans provided to subjects by the Sponsor will 
be suitable for the trial. 

Interview the caregiver/support person (if applicable) to obtain demographic 
information;

Obtain demographic information and medical/psychiatric history from EHR and/or 
subject;

Obtain urine sample for pregnancy test (females of childbearing potential [FOCBP]);

Administer the suicidality assessment (face-to-face suicide risk assessment per trial 
site’s standard operating procedures [SOPs]);

Subject receives training on the DMS;

Subject attempts to pair and apply a patch;

Complete the Patient Activation Measure-Mental Health (PAM-MH)
(Section 3.7.2.2);

Complete the CGI-S (Section 3.7.2.3);

Administer the Personal and Social Performance Scale (PSP) (Section 3.7.3.4.1);

Concomitant medications review;
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
The following will be dispensed to the subject:

CoE products (drug originator tablet + MIT), supplies, and patches (prescribed 
dose is recorded) sufficient for 4 weeks (from Week 1 to Week 4). Containers 
(eg, baggies) will be included for the subject to collect and return used patches;

Instructions on how to install the DMS smartphone application;

User Guide for the DMS including introductory video and reference guides;

Contact information for the integrated call centre.
3.7.1.2
Assessment Period 
The assessment period is 8 weeks from baseline visit to Week 8/ET visit. Subjects will 
have their final assessment period visit at Week 8/ET.
In the event a scheduled assessment period visit is missed by a subject, the trial site will 
contact the subject immediately and reschedule another visit as close to the original visit 
schedule date as possible. After at least 2 phone calls are attempted, a certified letter will 
be sent to the subject. If a rescheduled visit falls outside of the allowable time window, 
then the HCP must be contacted for approval to continue the subject in the trial.
3.7.1.2.1
Week 1 Through Week 4 (Between HCP Visits)
After completion of the screening/baseline visit assessments and procedures, the subject 
will return home until the next visit (the Week 4 visit), which will be scheduled for 
approximately 4 weeks later.
During this time interval, the following will occur:

Subject wears a patch continuously;

Subject takes CoE product (drug originator tablet + MIT) daily;

The subject (and/or caregiver/support person, if applicable) may call the integrated 
call centre, if needed, for support regarding use of the DMS and its components (eg, 
CoE product [drug originator tablet + MIT], patch, or smartphone application).
3.7.1.2.1.1
Week 2
Week 2 (3 days) will not be a planned HCP visit for the subject; however, DMS 
dashboard data will be reviewed.
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3.7.1.2.1.2
Week 4
Week 4 (3 days) will be a HCP visit for the subject. At the Week 4 visit, the following 
will be performed:

Subject returns used and unused patches;

Accountability of patches and CoE product (drug originator tablet + MIT) supplies 
performed;

Dispense CoE product (drug originator tablet + MIT), supplies, and patches
(prescribed dose is recorded) for next 4 weeks until Week 8/ET visit. Containers (eg, 
baggies) will be included for the subject to collect and return used patches;

Review subject and HCP dashboards with the subject;

Remedial training provided, if needed;

Administer the suicidality assessment (face-to-face suicide risk assessment per trial 
site’s SOPs);

Monitor device-related nonserious AEs;

Review concomitant medications.
3.7.1.2.2
Week 5 Through Week 8 (Between HCP Visits)
After completion of Week 4 visit to trial site, the subject will return home until the next 
visit (the Week 8/ET visit), which will be scheduled for approximately 4 weeks later
(8 weeks after baseline visit).
During this time interval, the following will occur:

Subject wears a patch continuously;

Subject takes CoE product (drug originator tablet + MIT) daily;

The subject (and/or caregiver/support person, if applicable) may call the integrated 
call centre, if needed, for support regarding use of the DMS and its components (eg, 
CoE product [drug originator tablet + MIT], patch, or smartphone application).
3.7.1.2.2.1
Week 6
Week 6 (3 days) will not be a planned HCP visit for the subject; however, DMS 
dashboard data will be reviewed.
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3.7.1.2.2.2
Week 8/Early Termination Visit
Week 8/ET (3 days) will be a HCP visit for the subject. In addition, Week 8/ET visit 
evaluations are to be completed for any subject withdrawn from the trial at any time (for 
any reason other than full withdrawal of the consent). At the Week 8/ET visit, the 
following will be performed:

Subject returns used and unused patches;

Accountability of patches and CoE product (drug originator tablet + MIT) supplies 
performed;

Review subject and HCP dashboards with the subject;

Administer the suicidality assessment (face-to-face suicide risk assessment per trial 
site’s SOPs);

Administer the Subject Usability and Satisfaction Scale (Appendix 4);

Complete HCP Utility Survey (Appendix 5);

Administer the Caregiver/Support Person Involvement Scale (if applicable)
(Appendix 6);

Complete PAM-MH (Section 3.7.2.2);

Complete the CGI-S (Section 3.7.2.3);

Monitor device-related nonserious AEs;

Review concomitant medications;

Stop application of patches. Remove the final patch at the end of the visit (before the 
subject leaves the trial site) and retain it at the trial site;

Restart subject’s standard care (routine follow-up from care teams and continue 
non-DM medications). Subjects will not have access to their trial account or data in 
the smartphone app 30 days after the last subject’s Week 8/ET visit;

Instruct subject that they will be receiving a telephone call 2 weeks (± 3 days) later 
for a safety follow-up.
3.7.1.3
Safety and Safety Follow-up
A safety follow-up phone call will occur at 2 weeks (± 3 days) after the Week 8/ET visit, 
which will be the last official subject contact. At this time, the HCP will review SAEs
and device-related nonserious AEs.
3.7.1.4
Healthcare Utilisation Record Evaluation
Healthcare utilisation record evaluation will take place 24 weeks (+ 7 days) prior to and 
following the baseline visit (for a total of 48 weeks) to evaluate the subject health records 
and to examine subject interaction with the HCPs following the DMS usage. 
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Twenty-four weeks before and after the baseline visit (for a total of 48 weeks), all 
hospital admissions (psychiatric and non-psychiatric) would be recorded and assessed as 
either ‘planned’ or ‘unplanned’ and ‘related’ or ‘unrelated’ to the psychiatric illness. 
Similarly, all encounters between any HCP (psychiatric and non-psychiatric) and the 
subject will be recorded to obtain the following information:

The nature of the contact (eg, home visit);

The HCP role (eg, community psychiatric nurse);

Whether the contact was planned or not;

Whether or not the contact was initiated as a result of data from the DMS;

Any medication titration, adherence counseling, education, and lifestyle coaching.
Intervention data includes medical hospitalisations, psychiatric hospitalisations, A and E 
visits, outpatient visits, and the number of crisis interventions. This data will be recorded 
in the data collection tool at Week 24 or up to 7 days after this time point.
3.7.2
Outcome Assessments
This trial is designed primarily to explore the acceptance and performance of the DMS 
with HCPs and adult subjects with SCH, schizoaffective disorder, or first episode 
psychosis, who are on an oral atypical antipsychotic (aripiprazole, olanzapine, quetiapine, 
or risperidone).
The ability of subjects to interact with the DMS will be recorded in addition to recording 
the usability from different HCPs and caregivers/support persons (if applicable) since 
these make up the endpoint assessments.
Please refer to Section 3.5.
3.7.2.1
Scales to Evaluate Usability of the Digital Medicine System

Subject Usability and Satisfaction Scale (Appendix 4);

HCP Utility Survey (Appendix 5);

Caregiver/Support Person Involvement Scale (if applicable) (Appendix 6).
3.7.2.2
Patient Activation Measure-Mental Health Scale
The PAM-MH is a reliable and valid measure of subject activation among individuals 
with serious mental health problems.24 Subjects’ feeling of their mental health will be 
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rated using a series of questions at screening/baseline and Week 8/ET visit. The response 
choices include the following:

1 = Strongly Disagree

2 = Disagree

3 = Agree

4 = Strongly Agree
A sample of the PAM-MH is provided in Appendix 7.
3.7.2.3
Clinical Global Impression-Severity of Illness Scale
The severity of illness for each subject will be rated using the CGI-S at 
screening/baseline and Week 8/ET visit.25 To perform this assessment, the rater or HCP
will provide a response to the question “Considering your total clinical experience with 
this particular population, how mentally ill is the subject at this time?” Response choices 
include the following:

0 = not assessed

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 subjects  
A sample of the CGI-S is provided in Appendix 8.
3.7.3
Safety Assessments
Assessments for safety include SAEs, device-related nonserious AEs, pregnancy tests 
(FOCBP only), and the suicidality assessment (face-to-face suicide risk assessment per 
trial site’s SOPs).
3.7.3.1
Serious Adverse Events, Device-related Adverse Events, and 
Unanticipated Adverse Device Events
Refer to Section 5, Reporting of Serious Adverse Events.
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3.7.3.2
Clinical Laboratory Assessments
Urine pregnancy for FOCBP will be conducted at screening. If deemed appropriate, 
serum pregnancy test will be performed if positive urine screen is detected. Additional 
clinical laboratory assessments will be performed at the HCP’s discretion to ensure safety 
of the subject, but are not required as part of this trial.
3.7.3.3
Suicidality Assessment
Face-to-face suicide risk assessment will be conducted per trial site’s SOPs at 
screening/baseline, Week 4 and Week 8/ET visits, and at the discretion of HCP at 
any time during the trial. 
3.7.3.4
Other Assessments
3.7.3.4.1
Personal and Social Performance Scale
The PSP will be administered by a rater and measures the ability of the subject to perform 
socially useful activities, self-care, and engage in relationships. This scale will be 
measured at screening/baseline only. The scale also measures whether any disturbing or 
aggressive behaviours are present. A global score of general functioning is also obtained 
using this scale. A sample of the PSP is provided in Appendix 9.
3.7.4
End of Trial
The end of trial date is defined as the last date of contact or the date of final contact 
attempt for the last subject completing or withdrawing from the trial.
3.8
Stopping Rules, Withdrawal Criteria, and Procedures
3.8.1
Entire Trial 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to HCPs, IECs, and regulatory authorities in accordance with regulatory 
requirements.
3.8.2
Individual Trial Site
Individual trial site participation may be discontinued by the sponsor, the HCP, or the 
IEC if judged to be necessary for medical, safety, regulatory, ethical or other reasons 
consistent with applicable laws, regulations, and GCP. The HCP will notify the sponsor 
promptly if the trial is terminated by the HCP or the IEC at the site.
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3.8.3
Individual Subjects
3.8.3.1
Discontinuation of Digital Medicine System
After enrolment, a subject may stop the DMS permanently for a variety of reasons. The 
DMS discontinuations may be initiated by a subject who is not satisfied with treatment or 
may become medically necessary due to SAEs, and/or device-related nonserious AEs,
required treatment with a disallowed medication or therapy, or other issues, as 
determined by the HCP. However, each HCP must comprehensively review the 
circumstances and offer the subject options for continued treatment to the degree possible 
as described in Section 3.8.3.4.
If any subject discontinues the trial early (including subjects who are discontinued at the 
Week 4 visit), every effort should be made to complete the Week 8/ET evaluations (see 
Table 3.7-1) at that visit. All subjects (completers and early withdrawals) will be 
contacted to monitor for safety events via telephone or HCP visit at 2 weeks (± 3 days)
after the Week 8/ET visit.
3.8.3.2
Documenting Reasons for Treatment Discontinuation
A subject may discontinue the DMS for a number of reasons including those listed 
below:

Reasons related to SAE:

Subject decides to discontinue because of annoyance or discomfort due to a 
non-serious AE which is not otherwise determined to be an undue hazard.

Continuing DMS places the subject at undue risk as determined by the 
investigator (eg, a safety concern that is possibly, probably, or likely related to 
DMS).

SAEs.

Other potentially DMS-related safety concerns or AEs.

Death;

Reasons unrelated to medical condition (provide detail and review AE history with 
subject);

Withdrawal of informed consent (complete written withdrawal of consent form);

Lost to follow-up;

Pregnancy (see Section 5.5);

Termination of all or part of the trial by the sponsor.
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If the subject discontinues the DMS due to an AE, the investigator, or other trial 
personnel, will make every effort to follow the event until it has resolved or stabilised.
3.8.3.3
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The HCP can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the HCP confirming the subject’s verbal intent to completely withdraw 
from the trial, subjects should be followed for all protocol-specified evaluations and 
assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up (these methods of follow-up will also be noted in the trial ICF):

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol-specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and staff).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or HCP).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
Withdrawal of consent is a critical trial event and therefore should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to interrupt or discontinue the DMS
administration, which is not equivalent to a complete withdrawal of consent for further 
participation (see Section 3.8.3.1and Section 3.8.3.2). A subject may, however, indicate 
that further trial participation is creating a burden on their work or social schedule. 
Therefore, the HCP should follow the procedures outlined in Section 3.8.3.3 to determine 
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if the subject can continue participation in the trial if modifications to his/her treatment 
and/or schedule of assessments can be accommodated. Only subjects who withdraw their 
permission for all of the above degrees of follow-up are considered to have completely 
withdrawn their consent to participate in the trial.
3.8.3.4
Procedures to Encourage Continued Trial Participation
In all cases of impending the DMS discontinuation or consent withdrawal, HCP will be 
given instructions to meet and discuss with the subject their options of continuing in the
trial, preferably on the use of the DMS. The HCP should ensure understanding and 
documentation of the reasons for the subject’s desire to withdraw consent. 
3.9
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is 
documented in writing (ie, subject signs an ICF), but who is not started on the DMS.
Female subjects excluded for a positive urine pregnancy test (FOCBP) at screening are 
not eligible to be rescreened for participation in the trial. However, subjects excluded for 
any other reasons during the screening period may be rescreened at a later date. In the 
event that the subject is rescreened, a new ICF must be signed and a new screening 
number assigned.
3.10
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
the objectives of the trial irrespective of whether or not the subject actually administered 
all relevant supplies of the DMS. Subjects who are evaluated at the last scheduled visit 
during the assessment period will be defined as trial completers. For purposes of this trial, 
subjects who complete the Week 8/ET visit will be defined as trial completers.
3.11
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Week 8 visit during the assessment period
and who do not have a known reason for discontinuation (eg, withdrew consent or SAE) 
will be classified as “lost to follow-up” as the reason for discontinuation. Survival status 
can be determined from a variety of sources, either by obtaining acceptable 
documentation for death (eg, death certificate, medical records, public records, statement 
by a family member or primary care physician) or acceptable documentation for life (eg,
direct contact with the subject, medical records, successful telephone contact with the 
subject, statement by a family member or primary care physician, or public records).
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The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status. As such, subjects will have access to their trial
account or data in the smartphone app up until 30 days after recording the lost to 
follow-up status. After this duration, the subjects will no longer have access to their data
via the smartphone app.
3.12
Subject Compliance 
Subjects will be considered noncompliant if they lack adherence to the visit schedule or 
inappropriate or lack of the DMS use.
3.13
Protocol Deviations
This trial is intended to be conducted as described in this protocol. In the event of a 
significant deviation from the protocol due to an emergency, accident, or mistake (eg, 
violation of informed consent process, use of improved medical device, subject enroled in 
violation of eligibility criteria or concomitant medication criteria), the HCP or designee 
will contact the sponsor’s designees at the earliest possible time by telephone or e-mail. 
The HCP and sponsor will come as quickly as possible to a joint decision regarding the 
subject’s continuation in the trial. This decision will be documented by the HCP and the 
sponsor.
4
Restrictions
4.1
Prohibited Medications
Prohibited medications will be considered per approved label for each of the approved 
medication used in the trial.
4.2
Other Restrictions
4.2.1
Restricted Therapies and Precautions
Not applicable.
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4.2.2
Non-therapy Precautions and Restrictions
4.2.2.1
Precautions
Subjects should not undergo any elective medical procedure without prior consultation 
with the HCP. An elective procedure (minor surgery, dental surgery, orthopedic surgery, 
etc.) that might require hospitalisation or anaesthesia should be deferred until after the 
trial, whenever clinically appropriate.
4.2.2.2
Restrictions
Subjects will be encouraged to limit the drinking of alcoholic beverages and refrain from 
using illicit drugs during participation in this trial. 
5
Reporting of Adverse Events
In this phase 4 trial, all SAEs (ie, drug-related SAEs and device-related SAEs), device-
related nonserious AEs, potential hepatotoxicity cases and pregnancies will be monitored 
and collected.
5.1
Definitions
5.1.1
Drug-related Serious Adverse Events
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; eg, the subject was, in the opinion of the HCP, at immediate risk of 
death from the event as it occurred. It does not include an event that, had it occurred 
in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions.

Requires inpatient hospitalisation or prolongs hospitalisation.

Hospitalisation itself should not be reported as an SAE; whenever possible the 
reason for the hospitalisation should be reported.

Hospitalisations or prolonged hospitalisations for social admissions (eg, those 
required for reasons of convenience or other non-medical need) are not 
considered SAEs.

Congenital anomaly/birth defect.
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
Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalisation, or the development of drug dependency or drug 
abuse.
5.1.2
Device-related Serious Adverse Events
A device-related serious adverse event is defined as:

An event that reasonably suggests that a device has or may have caused or 
contributed to a death or serious injury. 

Contributed to is defined as a death or serious injury that was or may have been 
attributed to a medical device, or that a medical device was or may have been a 
factor in a death or serious injury, including events occurring as a result of any of 
the following: 

Failure;

Malfunction;

Improper or inadequate design;

Manufacture;

Labeling;

User error.

Serious injury means an injury or illness that includes any of the following:

Is life-threatening.

Results in permanent impairment of a body function or permanent damage to a 
body structure.

Necessitates medical or surgical intervention to preclude permanent impairment 
of a body function or permanent damage to a body structure. Permanent means 
irreversible impairment or damage to a body structure or function, excluding 
trivial impairment or damage.

Any of the following events that manufacturers or importers become aware of that 
reasonably suggests that one of their marketed devices:

May have caused or contributed to a death or serious injury.

Has malfunctioned and that the device or a similar device marketed by the 
manufacturer or importer would be likely to cause or contribute to a death or 
serious injury if the malfunction were to recur.
For the purpose of this trial, device-related serious adverse events include any event that 
is related to the IEM, patch, or the phone and application (reported to Otsuka).
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If an AE is related to the patch, then the Skin Irritation Scoring System (Appendix 10)
will be completed by the HCP. A photo of the affected area should also be taken using 
the trial provided data collection tool, if possible. Patch-related AEs grade 2 or above will 
be considered medically significant for purposes of this trial.
5.1.3
Device-related Nonserious Adverse Events
Device-related nonserious AEs are considered skin reactions caused by patch graded 
lower than grade 2.
5.1.4
Nonserious Adverse Events 
Nonserious AEs are all AEs that do not meet the criteria for a "serious" AE (Section 5.1.1
and Section 5.1.2) and device-related nonserious adverse events (Section 5.1.3).
5.1.5
Immediately Reportable Event
Immediately reportable events (IREs) include the events discussed in Section 5.1.1, 
Section 5.1.2, and any of the following outcomes:

Any SAEs;

Any device-related nonserious AEs related to occupational exposure;

Potential drug-induced liver injury (DILI) case (see Section 5.4);

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate DMS discontinuation and must be reported on an IRE form to the 
sponsor. Pregnancy will only be documented as an AE in the data collection tool, if 
there is an abnormality or complication.
5.1.6
Abnormal Clinical Laboratory Test Changes
Clinical laboratory assessments will be conducted at the HCPs’ discretion to ensure 
safety of the subject. However, aside from the urine pregnancy test at screening, ongoing 
clinical laboratory assessments are not required for this trial.  In the event that the HCP 
orders a laboratory test in the interest of subject safety, it is the HCP’s responsibility to 
review the results of all laboratory tests as they become available. This review will be 
documented by the HCP’s dated signature on the laboratory report. For each abnormal 
laboratory test result, the HCP needs to ascertain if this is abnormal (eg, clinically 
significant) for that individual subject. This determination, however, does not necessarily 
need to be made the first time an abnormal value is observed. The HCP may repeat the 
laboratory test or request additional tests to verify the results of the original laboratory 
tests. If this laboratory value is considered medically relevant by the HCP (subject is 
symptomatic, requiring corrective treatment or further evaluation), or if the laboratory 
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value leads to discontinuation, and/or fulfills a seriousness criterion, this is considered an 
AE. 
5.1.7
Severity
Adverse events will be graded on a 3-point scale and reported as indicated in the data 
collection tool. The intensity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
5.1.8
Digital Medicine System Causality
Assessment of causal relationship of an SAE or device-related nonserious AE to the use 
of the CoE product, patch, or smartphone is defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the DMS and the SAE or device-related 
nonserious AE.
Not Related: 
There is no temporal or causal relationship between the DMS and 
the SAE or device-related nonserious AE.
5.2
Eliciting and Reporting Serious Adverse Events
The HCP will periodically assess subjects for the occurrence of SAEs. To avoid bias in 
eliciting SAEs, subjects should be asked the non-leading question: “How have you felt 
since your last visit?” All SAEs reported by the subject must be recorded on the source 
documents and data collection tool provided by the sponsor. Serious AE collection is to 
begin after a subject has signed the ICF. All SAEs will be collected starting from the 
signing of the ICF until 2 weeks following the last dose of CoE product.
Use medical terminology in SAE reporting. Serious adverse events should be reported as 
a single unifying diagnosis whenever possible or, in the absence of a unifying diagnosis, 
as individual signs or symptoms. Exacerbation or disease progression should be reported 
as an SAE only if there are unusual or severe clinical features that were not present, or 
experienced earlier, or not expected based on the course of the condition. An SAE that 
undergoes a change in severity, seriousness, or toxicity should be reported as a new SAE.
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In addition, Clinical Safety and Pharmacovigilance must be notified immediately by 
telephone, fax, or e-mail of any IREs according to the procedure outlined below, in 
Section 5.3. Special attention should be paid to recording hospitalisation and concomitant 
medications.
5.3
Immediately Reportable Events 
The HCP must immediately report after becoming aware of any SAE, potential DILI,
confirmed pregnancy, or device-related nonserious AE requiring discontinuation of the 
DMS, by telephone, fax, or e-mail to Clinical Safety and Pharmacovigilance using the 
contact information on the cover page of this protocol (see also Appendix 2). An IRE 
form must be completed and sent by e-mail, fax, or overnight courier to Clinical Safety 
and Pharmacovigilance. (Please note that the IRE form is NOT the SAE form.)
Subjects experiencing SAEs should be followed clinically until their health has returned 
to baseline status, or until all parameters have returned to normal or have otherwise been 
explained. It is expected that the HCP will provide or arrange appropriate supportive care 
for the subject and will provide prompt updates on the subject’s status to Clinical Safety 
and Pharmacovigilance.
5.4
Potential Drug-induced Liver Injury
For a subject who experiences an elevation in aspartate aminotransferase or alanine 
aminotransferase that is 3 times the upper limit of normal (ULN), a total bilirubin level 
should also be evaluated. If the total bilirubin is 2 times the ULN, complete an IRE 
form with all values listed and also report as an AE in the data collection tool.
5.5
Pregnancy
Females of childbearing potential are defined as female subjects or female partners of the 
male subjects for whom menstruation has started and who are not documented as sterile 
(eg, have had a bilateral oophorectomy and/or hysterectomy or who have been 
postmenopausal for at least 12 months).
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For FOCBP and for men who are sexually active, there must be a documented agreement 
that the subject and/or their partner will take effective measures to prevent pregnancy 
during the course of the trial and for 30 days after the last use of the DMS for females, 
and 90 days after the last use of the DMS for males. Unless the subject is sterile 
(eg, females who have had a bilateral oophorectomy and/or hysterectomy or who have 
been postmenopausal for at least 12 consecutive months; or men who have had a bilateral 
orchidectomy) or remains abstinent, 2 of the following precautions must be used: 
vasectomy, tubal ligation, vaginal diaphragm (barrier method), intrauterine device
(barrier method), birth control pills, birth control depot injection, birth control implant, 
condom with spermicide (barrier method), or sponge with spermicide (barrier method). 
Any single method of birth control, including vasectomy and tubal ligation, may fail, 
leading to pregnancy. The contraceptive method will be documented at each HCP visit.
Before enroling FOCBP in this clinical trial, HCPs must review the guidelines about trial 
participation with all FOCBP. The topics should generally include:

General information;

Informed consent form;

Pregnancy prevention information;

Drug interactions with hormonal contraceptives;

Contraceptives in current use;

Guidelines for the follow-up of a reported pregnancy.
Before trial enrolment, FOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy. 
The subject must sign an ICF stating that the above-mentioned risk factors and the 
consequences were discussed with her.
A urine pregnancy test for human chorionic gonadotropin will be performed at screening 
on all FOCBP. If a urine test is performed and is positive, the HCP will follow-up with a 
confirmatory serum test.
During the trial, all FOCBP should be instructed to contact the HCP immediately if they 
suspect they might be pregnant (eg, missed or late menstrual cycle).
If a female subject is suspected to be pregnant before the subject receives DMS, the DMS 
administration must be withheld until the results of serum pregnancy tests are available. 
If the pregnancy is confirmed, the subject must not receive the DMS and must not be 
enroled in the trial. If pregnancy is suspected while the subject is taking DMS, the DMS 
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may be continued at HCP discretion until the result of the pregnancy test is known. If 
pregnancy is confirmed, the DMS may be continued at HCP discretion based on 
treatment guidelines for the medication administered. If the HCP discontinues the subject 
from DMS, it must be performed in an appropriate manner (eg, dose tapering if necessary 
for subject safety) and the subject will be withdrawn from the trial. (Exceptions to trial 
discontinuation may be considered for life-threatening conditions only after consultations 
with the Clinical Safety and Pharmacovigilance department [see the cover page of this 
protocol for contact information]).
The HCP must immediately notify the sponsor of any pregnancy associated with DMS 
exposure during the trial and for 30 days for a female subject, 90 days for female partner 
of a male subject, after the last dose of the DMS, and record the event on the IRE form 
and forward it to the sponsor. Pregnancies of subjects or their partners will be followed to 
term. In the event of pregnancy of a subject’s partner, consent to follow the pregnancy 
will be obtained. The sponsor will forward Pregnancy Surveillance Form(s) for 
monitoring the outcome of the pregnancy.
Protocol-required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered, if indicated. In addition, the HCP
must report to the sponsor, on appropriate Pregnancy Surveillance Form(s), follow-up 
information regarding the course of the pregnancy, including perinatal and neonatal 
outcome. Infants will be followed for a minimum of 6 months from the date of birth.  
5.6
Follow-up of Serious Adverse Events
This trial requires that subjects be actively monitored for SAEs up to 14 days after the 
last use of the DMS is administered.
Serious AEs that are identified or ongoing at the last scheduled contact must be 
recorded in the data collection tool and reported to the Clinical Safety and 
Pharmacovigilance department according to the reporting procedures outlined in 
Section 5.3. This may include unresolved previously reported SAEs, or new SAEs. 
The HCP will follow SAEs until the events are resolved, stabilised, or the subject is lost 
to follow-up. Resolution means that the subject has returned to the baseline state of health 
and stabilised means that the HCP does not expect any further improvement or worsening 
of the subject’s condition. The HCP will continue to report any significant follow-up 
information to Clinical Safety and Pharmacovigilance up to the point the event has been 
resolved.
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5.6.1
Follow-up and Reporting of Serious Adverse Events Occurring 
after Last Scheduled Contact
Any new SAEs reported by the subject to the HCP that occur after the last scheduled 
contact, and are determined by the HCP to be reasonably associated with the use of the 
DMS, should be reported to Otsuka Pharmaceutical Development and
Commercialization, Inc (OPDC). 
This may include SAEs that are captured on follow-up telephone contact or at any other 
time point after the defined trial period (eg, up to last scheduled contact). The HCP
should follow SAEs identified after the last scheduled contact until the events are 
resolved, stabilised, or the subject is lost to follow-up. The HCP should continue to report 
any significant follow-up information to OPDC up to the point the event has been 
resolved or stabilised.
6
Statistical Analysis
Descriptive statistics will be presented for primary, secondary, and exploratory endpoints 
and safety variables.
Complete details of the planned statistical analysis will be presented in the statistical 
analysis plan (SAP).
6.1
Sample Size
The trial is exploratory in nature. 
The sample size was determined from practical considerations. Approximately 
60 subjects will be enroled in the trial. With an approximate 25% discontinuation rate, it 
is expected that at least 45 subjects will complete the 8-week assessment period of the 
trial.
6.2
Datasets for Analysis
The following analysis samples are defined for this trial:

Enroled sample: All subjects who sign an ICF and enter the trial;  

Intent-to-treat (ITT) sample: All subjects who enter the trial and use the DMS;

Safety sample: All subjects who enter the trial and use the DMS;
For the primary variable, the analysis will be conducted based on the ITT sample.
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6.3
Handling of Missing Data
For the primary variable, the analysis will be based on the proportion of days with good 
patch coverage during the trial and no imputation will be performed for missing data. For 
analysis of change from baseline, last-observation-carried-forward and observed-cases 
methods will be used, as considered applicable.  No imputation will be performed for 
other missing data, unless specified otherwise.
6.4
Primary, Secondary, and Exploratory Endpoint Analyses
The analysis will be conducted based on the ITT sample (ie, all subjects who enter the 
trial and use the DMS). 
Descriptive statistics will be provided for all primary, secondary, and exploratory 
endpoints and safety variables in general. Continuous variables will be summarised by 
tabulations of mean, median, range, and SD. Tabulations of frequency distributions will 
be provided for categorical variables.
6.4.1
Primary Endpoint Analysis
The primary endpoint is the proportion of days with good patch coverage during the trial, 
which will be calculated by the number of days with good patch coverage divided by the 
total number of trial days for each subject. 
The proportion of days with good patch coverage will be summarised by week and for 
overall trial period and the descriptive statistics include mean, SD, median, minimum, 
maximum, first quartile and third quartile.
6.4.2
Secondary Endpoint Analysis
The secondary endpoint is subject’s adherence metric, which is the proportion of detected 
MITs over the expected MITs ingested during the trial days with good patch coverage
and calculated as the number of ingested MITs detected divided by the number of 
expected MITs ingested during the trial days with good patch coverage for each subject.
The adherence metric will be summarised by week and for overall trial period and the 
descriptive statistics including mean, SD, median, minimum, maximum, and first quartile 
and third quartile.
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6.4.3
Exploratory Endpoint Analyses
The exploratory endpoints are as follows:
1) To explore the acceptance and performance of the DMS with HCPs and adult 
subjects with SCH, schizoaffective disorder, or first episode psychosis as 
measured by:
The proportion of time during the trial period when the subject wears their 
patch. The time duration of patch wearing will be calculated based on the 
digital health data.
The level of engagement and satisfaction of subjects, HCPs, and 
caregivers/support persons (if applicable), as determined by surveys Subject 
Usability and Satisfaction Scale, HCP Utility Survey, and Caregiver/Support 
Person Involvement Scale [if applicable]) will be summarised using descriptive 
statistics, respectively. Tabulations of frequency distributions will be provided 
for all these categorical variables.
The proportion of days subjects are using the application and the proportion of 
days that HCP are using the HCP dashboard during the trial will be 
summarised using descriptive statistics.
The proportion of ingested MIT registered on the digital health data server 
versus expected MIT ingested will be summarised using descriptive statistics. 
The proportion is calculated as the number of MITs detected divided by the 
number of expected MITS ingested during the treatment period.
2) Additional variables will be captured to better understand outcomes that may 
impact use of the DMS or be impacted by the use of the DMS including: 
Change from baseline to Week 8 in CGI-S will be summarised using 
descriptive statistics;
HCP visits and associated setting of care;
Details surrounding any hospitalisations; 
Occurrence and timing of community/home visits; 
Any referrals during the observation period. 
Details of exploratory analysis will be included in SAP.
6.5
Analysis of Demographic and Baseline Characteristics
Demographic and baseline characteristics for enroled subjects will be summarised and 
listed by subject.
6.6
Safety Analysis
Safety analysis will be conducted based on the safety sample. 
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Safety variables to be analysed include SAEs, device-related nonserious AEs, and the 
suicidality assessment. Any product quality complaints will be analysed as required.
6.6.1
Adverse Events
All collected AEs will be coded by system organ class and Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term. The incidence of the following events 
will be summarised:

Treatment-emergent AEs (TEAEs)

TEAEs by severity

TEAEs potentially causally related to the DMS

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the DMS 
Adverse event data will also be present in listings.
6.6.2
Clinical Laboratory Data
The urine pregnancy test and confirmatory serum test (if applicable) at screening on all 
FOCBP will be provided in a listing.
6.6.3
Physical Examination and Vital Signs Data
Not applicable.  
6.6.4
Electrocardiogram Data 
Not applicable.
6.6.5
Other Safety Data
6.6.5.1
Suicidality Assessment
The suicidality assessment data will be analysed for evidence of any treatment-emergent 
issues related to suicidal ideation or behaviour.
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7
Management of Digital Medicine System
7.1
Packaging and Labeling
The DMS will be provided to the HCPs and the persons designated by the HCP(s) or 
institution(s) by the sponsor or designated agent. The CoE products will be supplied in
bottles. Each bottle used in the dosing period will be labeled to clearly disclose the 
subject ID, compound ID, trial number, sponsor’s name and address, instructions for use, 
route of administration, appropriate precautionary statements, and other information as 
required by local regulatory authorities.
The details of the contents of the DMS are provided in Appendix 3.
7.2
Storage
The CoE products and patches will be stored in a securely locked cabinet or enclosure. 
Access will be limited to HCPs and their designees. Neither HCPs nor any designees may 
provide medical device to any subject not participating in this protocol.
The medical device should be stored according to conditions specified in the label of the 
DMS. The HCP or designee will maintain a temperature log in the storage area recording 
the temperature at least once each working day.
7.3
Accountability
The HCP or designee must maintain an inventory record of the DMS (patches and drug 
originator tablet + CoE MIT) received, dispensed, administered, and returned.
7.4
Returns and Destruction
Upon completion or termination of the trial all unused and/or partially used CoE products 
and patches must be destroyed at the trial site(s) or designated agent. 
The assigned HCP or designate will facilitate the destruction of unused and/or partially 
used CoE products and patches.
7.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a HCP, consumer, subject, medical representative, Competent Authority, regulatory 
agency, partner, affiliate or other third party that alleges deficiencies or dissatisfaction 
related to identity, quality, labeling, packaging, reliability, safety, durability, tampering, 
counterfeiting, theft, effectiveness or performance of a drug product or medical device 
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after it is released for distribution. Examples include, but are not limited to, 
communications involving:
•
Failure/malfunction of a product to meet any of its specifications;
•
Incorrect or missing labeling;
•
Packaging issues (eg, damaged, dirty, crushed, missing product);
•
Blister defects (eg, missing, empty blisters);
•
Bottle defects (eg, under/over-fill, no safety seal);
•
Vial defects;
•
Product defect (eg, odor, chipped, broken, embossing illegible);
•
Loss or theft of product.
7.5.1
Eliciting and Reporting Product Quality Complaints
The HCP or designee must record all PQCs identified through any means from the receipt 
of the DMS from the sponsor, or sponsor’s designee, through and including reconciliation 
and up to destruction, including subject dosing. The HCP or designee must notify the 
sponsor (or sponsor’s designee) by e-mail or telephone within 24 hours of becoming 
aware of the PQC according to the procedure outlined below to Otsuka Pharmaceutical 
Europe Ltd. Quality Assurance (OPEL QA):
•
Online - Send information required for reporting purposes to 
Identification of a PQC by the subject should be reported to the HCP, who should then 
follow one of the reporting mechanisms above.
7.5.2
Information Required for Reporting Purposes
•
Description of complaint;
•
Reporter identification (eg, subject, HCP, site, etc.);
•
Reporter contact information (eg, address, phone number, e-mail address);
•
ID of material (product/compound name, coding);
•
Clinical protocol reference (number and/or trial name);
•
Dosage form/strength (if known);
•
Pictures (if available);
•
Availability for return.
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7.5.3
Return Process
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, return it in the product retrieval package, 
which will be provided by OPEL-PQC.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
7.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
8
Records Management
8.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to progress 
notes, electronic data, screening logs, and recorded data from automated instruments. All 
source documents pertaining to this trial will be maintained by the HCPs and made 
available for direct inspection by authorised persons.
Healthcare professionals will permit trial-related monitoring, audits, IEC review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorised persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.
8.2
Data Collection
During each subject’s visit to the HCP, a clinician participating in the trial will record 
progress notes to document all significant observations. At a minimum, these notes will 
contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the HCP’s decision to enrol the subject into the trial, the review of 
all inclusion/exclusion criteria prior to the use of the DMS, and confirmation of the 
subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any SAEs and the HCP's 
assessment of relationship to the DMS must also be recorded;
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
Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of each clinician (or designee) who made an entry 
in the progress notes.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. Any changes to information in the trial progress notes and other source 
documents will be initialed and dated on the day the change is made by the HCP 
authorised to make the change. Changes will be made by striking a single line through 
erroneous data (so as not to obliterate the original data), and clearly entering the correct 
data (eg, wrong data right data). If the reason for the change is not apparent, a brief 
explanation for the change will be written in the source documentation by the clinician. If 
electronic data systems are being utilised, a full audit trail of changes must be maintained.
Data will be entered by the HCP into a data collection tool specific for this trial.
8.3
File Management at the Trial Site
The HCP will ensure that the trial site file is maintained in accordance with Section 8 of 
the ICH GCP Guideline E6 and as required by applicable local regulations. The 
HCP/institution will take measures to prevent accidental or premature destruction of 
these documents.
8.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating HCPs maintain detailed clinical data for the longest of the following 
periods:

A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if DMS development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the HCP that the final report has 
been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable. 
The HCP must not dispose of any records relevant to this trial without either (1) written 
permission from the sponsor or (2) provision of an opportunity for sponsor to collect such 
records. The HCP will be responsible to maintain adequate and accurate electronic or 
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hard copy source documents of all observations and data generated during this trial 
including any data clarification forms received from the sponsor. Such documentation is 
subject to inspection by the sponsor and relevant regulatory authorities. If the HCP
withdraws from the trial (eg, due to relocation or retirement), all trial-related records 
should be transferred to a mutually agreed-upon designee within a sponsor-specified 
timeframe. Notice of such transfer will be given to the sponsor in writing.
9
Quality Control and Quality Assurance 
9.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP: Consolidated Guidance, and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all HCPs and trial site 
personnel will undergo initial and ongoing training for this particular trial, and this 
training will be clearly documented.
9.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, the DMS supply, presence of required 
documents, the informed consent process, and comparison of the data collection tool with 
source documents. The HCP agrees to participate with audits.
Regulatory authorities may inspect the trial site during or after the trial. The HCP will 
cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs.
10
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, ICH GCP Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki and Council for 
International Organizations of Medical Science (CIOMS) guidelines, and applicable local 
laws and regulations. Each trial site will seek approval/favorable opinion by an IEC
according to regional requirements, and the HCP will provide that documentation to the 
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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sponsor. The IEC will evaluate the ethical, scientific and medical appropriateness of the 
trial. Further, in preparing and handling the data collection tool, the HCP and their staff 
will take measures to ensure adequate care in protecting subject privacy. To this end, a 
subject number and subject ID code will be used to identify each subject.
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the HCP.
11
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorised regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. 
Subjects will be identified only by unique subject numbers in the data collection tool. If 
further subject ID is required, subjects’ full names may be made known to a regulatory 
agency or other authorised officials if necessary, subject to local regulations.
12
Amendment Policy
The HCP will not make any changes to this protocol without the sponsor’s prior written 
consent and subsequent approval/favorable opinion by the IEC. Any permanent change to 
the protocol, whether an overall change or a change for specific trial site(s), must be 
handled as a protocol amendment. Any amendment will be written by the sponsor. Each 
amendment will be submitted to the IEC, as required by local regulations. Except for 
“administrative” or “non-substantial” amendments, HCPs will wait for IEC 
approval/favorable opinion of the amended protocol before implementing the change(s). 
Administrative amendments are defined as having no effect on the safety of subjects, 
conduct or management of the trial, trial design, or the quality or safety of the DMS used 
in the trial. A protocol change intended to eliminate an apparent immediate hazard to 
subjects should be implemented immediately after agreement by the sponsor and HCP, 
followed by IEC notification within local applicable timelines. The sponsor will submit 
protocol amendments to the applicable regulatory agencies within local applicable 
timelines.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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When the IEC, HCP, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval/favorable opinion of the new ICF by the IEC, repeat written informed consent 
will be obtained from subjects enroled in the trial before expecting continued 
participation and before the amendment-specified changes in the trial are implemented.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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13
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2. Drafting the work or revising it critically for important intellectual content; AND
3. Final approval of the version to be published; AND
4. Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Healthcare professionals or other trial participants who do not qualify for authorship may 
be acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, HCPs or other trial participants consent to such acknowledgement in any 
publications resulting from its conduct.
14
References
1
Kimhy D, Delespaul P, Corcoran C, Ahn H, Yale S, Malaspinaa D. Computerized 
experience sampling method (ESMc): Assessing feasibility and validity among 
individuals with schizophrenia. J Psychiatr Res. 2006;40(3):221–30.
2
Granholm E, Ben-Zeev D, Link PC, Bradshaw KR, Holden JL. Mobile Assessment 
and Treatment for Schizophrenia (MATS): a pilot trial of an interactive text-
messaging intervention for medication adherence, socialization, and auditory 
hallucinations. Schizophr Bull. 2012;38:414-25.
3
Oorschot M, Lataster T, Thewissen V, Wichers M, Myin-Germeys I. Mobile 
assessment in schizophrenia: a data-driven momentary approach. Schizophr Bull. 
2012;38:405-13.
4
Swendsen J, Ben-Zeev D, Granholm E. Real-time electronic ambulatory monitoring 
of substance use and symptom expression in schizophrenia. Am J Psychiatry. 
2011;168:202-9.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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5
Ben-Zeev D, McHugo GJ, Xie H, Dobbins K, Young MA. Comparing retrospective 
reports to real-time/real-place mobile assessments in individuals with schizophrenia 
and a nonclinical comparison group. Schizophr Bull. 2012; 38:396-404.
6
Ainsworth J, Palmier Claus JE, Machin M, Barrowclough C, Dunn G, Rogers A, et 
al. A comparison of two delivery modalities of mobile-phone based assessment for 
serious mental illness: native smartphone application vs text–messaging only 
implementations. J Med Internet Res. 2013;15:e60.
7
Eysenbach G.  The law of attrition. J Med Internet Res. 2005;7(1):e11.
8
Feinstein AR. On white-coat effects and the electronic monitoring of compliance. 
Arch Intern Med. 1990;150:1377-8.
9
Firth J, Cotter J, Torous J, Bucci S, Firth JA, Yung AR. Mobile phone ownership and 
endorsement of “mhealth” among people with psychosis: a meta-analysis of cross-
sectional studies. Schizophr Bull. 2016;42(2):448-55.
10 Granholm E, Loh C, Swendsen J. Feasibility and validity of computerized ecological 
momentary assessment in schizophrenia. Schizophr Bull. 2008;34(3):507-14.
11 Palmier-Claus JE, Rogers A, Ainsworth J, Machin M, Barrowclough C, Laverty L, et 
al. Integrating mobile-phone based assessment for psychosis into people’s everyday 
lives and clinical care: a qualitative study. BMC Psychiatry. 2013;13:34.
12 Kane JM, Perlis RH, DiCarlo LA, Au-Yeung K, Duong J, Petrides G. First 
experience with a wireless system incorporating physiological assessments and direct 
confirmation of digital tablet ingestions in ambulatory patients with schizophrenia or 
bipolar disorder. J Clin Psychiatry. 2013;74(6):e533-40.
13 Otsuka Pharmaceutical Co., Ltd. OPC-14597 Digital (Digital Medicine 1) 
Investigator’s Brochure, Edition 5. Otsuka Report, Issued 11 Sep 2017.
14 Abilify [Summary of Product Characteristics]. United Kingdom, Otsuka 
Pharmaceuticals (UK) Ltd; 10 November 2016.
15 Risperdal [Summary of Product Characteristics]. United Kingdom, Janssen-Cilag Ltd; 
16 June 2015.
16 Zyprexa [Summary of Product Characteristics]. United Kingdom, Eli Lily and 
Company Limited; 23 February 2017.
17 Seroquel [Summary of Product Characteristics]. United Kingdom, AstraZeneca UK 
Limited; 09 August 2016.
18 Velligan DI, Weiden PJ, Sajatovic M, Scott J, Carpenter D, Ross R, et al. Strategies 
for addressing adherence problems in patients with serious and persistent mental 
illness: recommendations from the expert consensus guidelines. J Psychiatr Pract. 
2010;16(5):306-24.
19 Byerly MJ, Thompson A, Carmody T, Bugno R, Erwin T, Kashner M, et al. Validity 
of electronically monitored medication adherence and conventional adherence 
measures in schizophrenia. Psychiatr Serv. 2007;58:844–7.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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20 Velligan D, Mintz J, Maples N, Xueying L, Gajewski S, Carr H, et al. A randomized 
trial comparing in person and electronic interventions for improving adherence to oral 
medications in schizophrenia. Schizophr Bull. 2013;39:999-1007.
21 Baldessarini RJ, Perry R, Pike J. Factors associated with treatment nonadherence 
among US bipolar disorder patients. Hum Psychopharmacol. 2008;23:95–105.
22 Velligan DI, Wang M, Diamond P, Glahn DC, Castillo D, Bendle S, et al. 
Relationships among subjective and objective measures of adherence to oral 
antipsychotic medications. Psychiatr Serv. 2007;58:1187–92.
23 International Conference on Harmonisation (ICH) [homepage on the Internet]. E6: 
Good Clinical Practice:  Consolidated Guideline [finalised 1996 May, corrected 1996 
Jun 10; cited 2014 Dec 5].  Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E
6/E6_R1_Guideline.pdf.
24 Administration and Policy in Mental Health and Mental Health Services Research.  
2010 Jul; 37(4): 327-333.
25 Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of 
Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: National 
Institute of Mental Health; 1976.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 1
Sponsor Personnel
Phone:  
E-mail: 
 
Phone: 
E-mail:
Phone: 
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FRQILGHQWLDOLQIRUPDWLRQDQGVKRXOGQRWEHGXSOLFDWHGRUUHGLVWULEXWHGZLWKRXWSULRUZULWWHQFRQVHQWRI2WVXND
&OLQLFDO6WXG\5HSRUW
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Appendix 2
Safety Reporting
For medical emergencies, the investigator can contact the Global Safety and 
Pharmacovigilance department via a 24-hour telephone number: 
. A 
call to this telephone number does not alleviate the investigator’s responsibility to report 
an SAE in writing, via fax. 
Report Immediately Reportable Events (SAEs, potential DILI, confirmed pregnancies,
and any device-related nonserious AEs) to the Global Safety and Pharmacovigilance 
department as follows:
Global Safety and Pharmacovigilance
Phone: 
 
Global Fax: 
Global E-mail: 
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Appendix 3
Digital Medicine System Contents
Digital Medicine System Contents
Digital Medicine System 
Component
Description
CoE product
CoE product will be dispensed to the subjects during the trial. Capsules 
will be taken as prescribed by the healthcare professional, with 
approximately 120 mL of water.
Patch
Patches will be dispensed to a subject for use. Each patch is designed
for 7-day wear; extra devices are provided should the subjects desire to 
change the patch more frequently during the period of familiarization 
or in case of sensor malfunction.
Computing Device & 
Accessories
Subjects will use their own smartphone and required accessories or the 
smartphone provided by the Sponsor. Subjects will be requested to 
carry their smartphone with them as much as possible and to plug in 
the device at a dedicated location at home where they could have easy 
and frequent access when not being carried. The preferred location is 
on a nightstand or a location immediately adjacent to where the subject 
sleeps.
Digital Medicine System
Reference Guide
A printed reference guide will provide explicit directions for normal 
use and troubleshooting.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 6
Caregiver/Support Person Involvement Scale
DMS Caregiver/Support Person Involvement Scale
1. Are you aware that the study participant/subject is currently participating in the 
Digital Medicine study (check one)?
Yes
No *
*if no, stop here and do not answer the rest of the questions on this form.
2. Indicate your relationship to the study participant/subject by placing a √ 
(check).
Friend
Hired Caregiver
Relative*
Other**
*If you are a relative, please specify relationship to the study participant/subject, eg., 
wife, father: 
**If you selected “Other”, please specify your relationship to the study 
participant/subject: 
________________________________________________________________________
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 7
Patient Activation Measure-Mental Health Scale
PAM-MH 13
The following questions ask about your feelings regarding your mental healthcare.
When you think about for mental health and mental health care, how much do you agree 
or disagree with the following statements? Please circle the answer that you most agree 
with:
1.   When all is said and done, I am the person who is responsible for managing my 
mental health.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
2.   Taking an active role in my own mental health is the most important factor in 
determining my mental health and ability to function.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
3.   I am confident that I can take actions that will help prevent or minimize some 
symptoms or problems associated with my mental health condition.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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4.   I know what each of my prescribed mental health medications does.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
5.   I am confident that I can tell when I need to go get mental health care, and when I can 
handle a mental health problem myself.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
6.   I am confident I can tell my mental health clinician about concerns I have, even when 
he or she does not ask.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
7.   I am confident that I can follow through on mental health treatments I need to do at 
home.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
8.   I understand the nature and causes of my mental health condition(s).
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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9.   I know the different treatment options available for my mental health condition(s).
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
10.   I am able to maintain the lifestyle changes I have made for my mental health.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
11.   I know how to prevent further mental health problems.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
12.   I am confident I can figure out solutions when new situations or problems arise with 
my mental health.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
13.   I am confident that I can maintain lifestyle changes, like diet and exercise, even 
during times of stress.
1
2
3
4
Strongly Disagree
Disagree
Agree
Strongly Agree
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 8
Clinical Global Impression-Severity of Illness Scale
Considering your total clinical experience with this particular population, how mentally 
ill is the subject at this time? 
0 = Not assessed
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 subjects
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 9
Personal and Social Performance Scale
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Appendix 10
Skin Irritation Scoring System
Dermal Response:
Grade
Skin Event
0
No evidence of irritation
1
Minimal erythema, barely perceptible
2
Definite erythema, readily visible; minimal edema or minimal papular response
3
Erythema and papules
4
Definite edema
5
Erythema, edema, and papules
6
Vesicular eruption
7
Strong reaction spreading beyond the test site
Source: US Department of Health and Human Services, FDA Center for Drug Evaluation and Research, 
December 1999.
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the Digital Medicine System, the concurrent medications, the 
efficacy and safety parameters and the conduct of the trial in general. I am aware that this 
protocol must receive a favorable opinion by the Independent Ethics Committee (IEC) responsible 
for such matters in the clinical trial facility where Digital Medicine System will be tested prior to 
commencement of this trial. I agree to adhere strictly to the attached protocol (unless amended in 
the manner set forth in the sponsor's Clinical Trial Agreement, at which time I agree to adhere 
strictly to the protocol as amended).
I understand that this IEC-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on case report forms by me and my 
staff will be utilised by the sponsor in various ways, such as for submission to governmental 
regulatory authorities and/or in combination with clinical data gathered from other research sites, 
whenever applicable. I agree to allow sponsor and designee monitors and auditors full access to 
all medical records at the research facility for subjects screened or enroled in the trial.
I agree to await IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IEC within the required local applicable timelines. 
Administrative changes to the protocol will be transmitted to the IEC for informational purposes 
only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable 
regulations and by ICH guidelines. I agree to report to the sponsor any adverse experiences in 
accordance with the terms of the sponsor's Clinical Trial Agreement and the relevant regional 
regulation(s) and guideline(s). I further agree to provide all required information regarding 
financial certification or disclosure to the sponsor for all investigators and sub-investigators in 
accordance with the terms of the relevant regional regulation(s). I understand that participation in 
the protocol involves a commitment to publish the data from this trial in a cooperative publication 
before publication of efficacy and safety results on an individual basis may occur, and I consent to 
be acknowledged in any such cooperative publications that result.
____________________________
_____________________________
___________
Healthcare Professional Print Name
Signature
Date
Until the information herein is released by Otsuka to the public domain, the contents of this document are Otsuka 
confidential information and should not be duplicated or re-distributed without prior written consent of Otsuka.
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T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: Pr ot o c ol 0 3 1- 2 0 1- 0 0 1 8 6
D o c u m e nt N u m b er: 0 0 0 1 2 7 8 0 9 3
D o c u m e nt V er si o n: 3. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Bi o st ati sti c s A p pr o v al
0 4- J a n- 2 0 1 9
1 9: 3 2: 2 2
Cli ni c al A p pr o v al
0 4- J a n- 2 0 1 9
2 1: 2 4: 3 3
U ntil t he i nf or m ati o n herei n is rele ase d b y Ots u k a t o t he p u bl ic d o m ai n, t he c o nte nts of t his d oc u me nt are Ots u k a 
c o nfi de nti al i nf or m ati o n a n d s h o ul d n ot be d u plic ate d or re- distri b ute d wit h o ut pri or writte n c o nse nt of Ots u k a.
Cli nic al St u d y Re p ort 0 3 1- 2 0 1- 0 0 1 8 6
1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
1 0 9
P P D
P P D

T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
SI G N A T U R E P A G E
D o c u m e nt N a m e: 0 3 1- 2 0 1- 0 0 1 8 6- pr ot o c ol- or- a m e n d m e nt
D o c u m e nt N u m b er: 1 0 0 0 0 6 3 8 2 7
D o c u m e nt V er si o n: 2. 0
Si g n e d b y
M e a ni n g of Si g n at ur e
S er v er D at e
( d d- M M M-
y y y y h h: mi n) -
U T C ti m e z o n e
Bi o st ati sti c s A p pr o v al
2 7- F e b- 2 0 2 0
0 0: 3 6: 2 0
Cli ni c al A p pr o v al
2 7- F e b- 2 0 2 0
0 0: 1 8: 1 3
P P D
P P D