A Randomized, Sham-Controlled Study of PEAR-004 as an Adjunct to Standard-of-care Treatment for Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia
Sponsor: Novartis Pharmaceuticals

Novartis Institutes for BioMedical Research
PEA001
Clinical Trial Protocol CPEA001A12201
A Randomized, Sham-Controlled Study of PEAR-004 as an 
adjunct to standard-of-care treatment for schizophrenia
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
NA
Version number:
01 (Clean)
Clinical trial phase:
II
Release date:
12-Oct-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis

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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.

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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................8
Amendment 1 (October 2018)...........................................................................................10
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................14
1.1
Background............................................................................................................14
1.2
Purpose ..................................................................................................................15
2
Objectives and endpoints...................................................................................................15
3
Study design ......................................................................................................................17
4
Rationale............................................................................................................................17
4.1
Rationale for study design .....................................................................................18
4.2
Rationale for duration of treatment........................................................................18
4.3
Rationale for choice of control ..............................................................................18
4.4
Purpose and timing of interim analyses.................................................................18
4.5
Risks and benefits..................................................................................................18
5
Population..........................................................................................................................18
5.1
Inclusion criteria ....................................................................................................19
5.2
Exclusion criteria...................................................................................................19
6
Treatment...........................................................................................................................19
6.1
Study treatment......................................................................................................19
6.1.1
Treatment arms/group ...........................................................................20
6.2
Other treatment(s)..................................................................................................20
6.2.1
Concomitant therapy.............................................................................20
6.3
Subject numbering, treatment assignment, randomization....................................20
6.3.1
Subject numbering ................................................................................20
6.3.2
Treatment assignment, randomization ..................................................20
6.4
Treatment blinding.................................................................................................21
6.5
Dose escalation and dose modification..................................................................21
6.6
Additional treatment guidance...............................................................................22
6.6.1
Treatment compliance...........................................................................22
6.7
Treatment distribution ...........................................................................................22

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7
Informed consent procedures ............................................................................................22
8
Visit schedule and assessments .........................................................................................23
8.1
Screening ...............................................................................................................26
8.1.1
Eligibility screening ..............................................................................26
8.1.2
Information to be collected on screening failures.................................26
8.2
Subject demographics/other baseline characteristics.............................................26
8.3
Efficacy..................................................................................................................26
8.3.1
Positive and Negative Syndrome Scale (PANSS) ................................26
8.3.2
Brief Medication Questionnaire (BMQ) ...............................................26
8.3.3
Motivation and Pleasure-Self Report (MAP-SR) .................................26
8.3.4
World Health Organization Quality of Life (WHOQOL-BREF) 
Scale......................................................................................................26
8.3.5
Beck Depression Inventory, Second Edition (BDI-II)..........................27
8.3.6
Appropriateness of efficacy assessments..............................................27
8.4
Safety.....................................................................................................................27
8.4.1
InterSePT Scale for Suicidal Thinking-Plus (ISST-Plus).....................27
8.4.2
Appropriateness of safety measurements..............................................27
8.5
Additional assessments..........................................................................................28
8.5.3
Other Assessments ................................................................................29
9
Study discontinuation and completion ..............................................................................29
9.1
Discontinuation......................................................................................................29
9.1.1
Discontinuation of study treatment .......................................................29
9.1.2
Withdrawal of informed consent...........................................................30
9.1.3
Lost to follow-up...................................................................................30
9.1.4
Study stopping rules..............................................................................30
9.1.5
Early study termination by the sponsor.................................................31
9.2
Study completion and post-study treatment ..........................................................31
10 Safety monitoring and reporting........................................................................................31
10.1
Definition of adverse events and reporting requirements......................................31
10.1.1
Adverse events ......................................................................................31
10.1.2
Serious adverse events ..........................................................................32
10.1.3
SAE reporting........................................................................................33
10.2
Additional Safety Monitoring................................................................................34
10.2.1
Prospective suicidality assessment........................................................34
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11 Data Collection and Database management......................................................................34
11.1
Data collection.......................................................................................................34
11.2
Database management and quality control............................................................35
11.3
Site monitoring ......................................................................................................35
12 Data analysis and statistical methods ................................................................................36
12.1
Analysis sets ..........................................................................................................36
12.2
Subject demographics and other baseline characteristics......................................36
12.3
Treatments .............................................................................................................36
12.4
Analysis of the primary endpoint(s) ......................................................................37
12.4.1
Definition of primary endpoint(s).........................................................37
12.4.2
Statistical model, hypothesis, and method of analysis..........................37
12.4.3
Handling of missing values/censoring/discontinuations.......................37
12.4.4
Sensitivity and Supportive analyses......................................................37
12.5
Analysis of secondary endpoints ...........................................................................38
12.5.1
Efficacy endpoint(s)..............................................................................38
12.5.2
Safety endpoints....................................................................................39
12.6
Analysis of exploratory endpoints.........................................................................40
12.7
Interim analyses.....................................................................................................41
12.8
Sample size calculation..........................................................................................41
12.8.1
Primary endpoint(s)...............................................................................41
13 Ethical considerations and administrative procedures ......................................................41
13.1
Regulatory and ethical compliance........................................................................41
13.2
Responsibilities of the investigator and IRB/IEC..................................................41
13.3
Publication of study protocol and results...............................................................42
13.4
Quality Control and Quality Assurance.................................................................42
14 Protocol adherence ............................................................................................................42
14.1
Protocol Amendments ...........................................................................................43
15 References .........................................................................................................................44
List of tables
Table 2-1
Objectives and related endpoints ..........................................................15
Table 6-1
Blinding and unblinding plan................................................................21
Table 8-1
Assessment Schedule ............................................................................24
Table 8-2
Assessments and Specifications............................................................27
Table 12-1
Sensitivity of power to changes in assumptions for a design with 
N=102 evaluable subjects .....................................................................41
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List of figures
Figure 3-1
Study Design .........................................................................................17

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List of abbreviations
AE
Adverse Event
BDI-II
Beck Depression Inventory, Second Edition
BMQ
Brief Medication Questionnaire
CBT
Cognitive Behavioral Therapy
ClinRO
Clinician Reported Outcomes
COA
Clinical Outcome Assessment
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical Study Report
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISMT
Illness Self-Management Training
ISST-Plus
InterSePT Scale for Suicidal Thinking-Plus
MAP-SR
Motivation and Pleasure-Self Report
MedDRA
Medical dictionary for regulatory activities 
MMRM
Mixed-effects model for repeated measures
PANSS
Positive and Negative Syndrome Scale
PDT
Prescription Digital Therapeutic
PRO
Patient Reported Outcomes
SAE
Serious Adverse Event
SCID
Structured Clinical Interview for DSM-5
SD
standard deviation
SST
Social Skills Training
SOM
Site Operations Manual 
SUSAR
Suspected Unexpected Serious Adverse Reactions
WHO
World Health Organization 
WHOQOL-BREF
World Health Organization Quality of Life
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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject 
Cohort
A specific group of subjects fulfilling certain criteria and generally treated 
at the same time
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care.
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last subject or 
at a later point in time as defined by the protocol.
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained 
Mis-randomized 
subjects
Mis-randomized subjects are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose 
part and a multiple dose part, or a part in subjects with established 
disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study phases 
and will be used in clinical trial database setup and eventually in analysis
Personal data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned
Randomization number
A unique identifier assigned to each randomized subject
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study

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Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first subject.
Study treatment
Any single drug or combination of drugs or intervention administered to 
the subject as part of the required study procedures.
Study treatment 
discontinuation
When the subject permanently stops taking any of the study treatments
prior to the defined study treatment completion date (if any) for any 
reason; may or may not also be the point/time of study discontinuation 
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment arm/group
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the treatment being 
tested in the study
Withdrawal of study 
consent
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data.

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Protocol No. CPEA001A12201
Protocol summary
Protocol number
CPEA001A12201
Full Title
A Randomized, Sham-Controlled Study of PEAR-004 as an adjunct to 
standard-of-care treatment for schizophrenia
Brief title
Study of efficacy of PEAR-004 in schizophrenia
Sponsor and Clinical 
Phase
Novartis
Phase II
Investigation type
Device
Study type
Interventional
Purpose and rationale
The purpose of the study is to determine in patients currently being 
administered antipsychotic pharmacotherapy whether PEAR-004 can 
further reduce symptoms of schizophrenia as measured by the Positive 
and Negative Syndrome Scale (PANSS).
The overall rationale for the study is to assess the first prescription digital 
therapeutic (PDT) in schizophrenia using a form of proven psychosocial 
intervention, cognitive behavioral therapy (CBT), to supplement standard 
of care with antipsychotic medications.
Primary Objective(s) 
The primary objectives are to assess the efficacy of PEAR-004 as an 
adjunct to existing clinician-directed pharmacotherapy to reduce symptoms 
of schizophrenia by change in total PANSS score, and to evaluate retention 
to assigned study treatment by percent dropout rate at the end of the study
Secondary Objectives
Objective 1: To evaluate the efficacy of PEAR-004 as an adjunct to existing 
clinician-directed pharmacotherapy to reduce positive symptoms of 
schizophrenia by change in Positive and General Psychopathology PANSS 
scores
Objective 2: To evaluate the efficacy of PEAR-004 as an adjunct to existing 
clinician-directed pharmacotherapy to reduce negative symptoms of 
schizophrenia by change in Negative PANSS score and Motivation and 
Pleasure-Self Report (MAP-SR) score
Objective 3: To assess safety and tolerability of PEAR-004 by adverse 
event monitoring and InterSePT Scale for Suicidal Thinking-Plus (ISST-
Plus) score
Objective 4: To evaluate the efficacy of PEAR-004 as an adjunct to existing 
clinician-directed pharmacotherapy to improve psychosocial functioning in 
patients with schizophrenia by change in World Health Organization 
Quality of Life (WHOQOL-BREF) scale
Objective 5: To evaluate the efficacy of PEAR-004 as an adjunct to existing 
clinician-directed pharmacotherapy to reduce depression symptoms in 
patients with schizophrenia by change in Beck Depression Inventory, 
Second Edition (BDI-II) score
Objective 6: To evaluate the magnitude of the effect of PEAR-004 as an 
adjunct to existing clinician-directed pharmacotherapy to reduce symptoms 
of schizophrenia by percentage improvement in PANSS score
Objective 7: To evaluate the response to treatment by the proportion of 
responders

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Objective 8: To evaluate patient adherence to antipsychotic medication by 
change in Brief Medication Questionnaire (BMQ)
Study design
This is a randomized, sham controlled, rater-blinded, parallel group trial. 
Patients will be randomized 1:1 to receive PEAR-004 or a sham control. 
The study includes an up to 4-week screening period, a 12-week treatment 
period, and a 4-week follow-up period.
Population
The study will enroll approximately 102 male and female adults (18-65 
years of age, inclusive) with a diagnosis of schizophrenia
Key Inclusion criteria

Signed informed consent must be obtained prior to participation in the
study.

Healthy male and female subjects 18 to 65 years of age, inclusive,
and in good health as determined by medical history, physical
examination, and vital signs at screening

SCID-based Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5) diagnosis of schizophrenia and a total PANSS
score > 60

Proficient in English at 5th grade reading level or higher, in the
judgement of the investigator

Capable of using a mobile device (compatible with PEAR-004) and
using common applications, in the judgement of the investigator
Key Exclusion criteria

Major change in primary antipsychotic medication in the prior 4 weeks
before screening (e.g., switching to a new agent or a major dose
adjustment within two weeks of randomization)

Planning to move out of the geographic area within 3 months

Unable to use English to participate in the consent process, the
interventions or assessments

Inability to comply with study procedures, due to severe medical
conditions or otherwise

Meet DSM-5 diagnosis for a current episode of major depression,
mania, or hypomania in the past month

Meet DSM-5 diagnosis for a current moderate or severe alcohol or
cannabis use disorder in the past 2 months

Meet DSM-5 diagnosis for a current substance use disorder (other
than alcohol or cannabis) in the past 2 months

Considered high risk for suicidal behavior based on ISST-Plus score
at screening, in the judgement of the investigator

Previously participated in a clinical study involving PEAR-004
Study treatment
PEAR-004
Sham control
Efficacy assessments

PANSS

BMQ

MAP-SR

WHOQOL-BREF

BDI-II
Key safety 
assessments

Adverse event monitoring

Vital signs

ISST-Plus

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Other assessments 
Data analysis
The change from baseline in total PANSS score will be analyzed using the 
mixed-effects model for repeated measures (MMRM), with fixed, 
categorical effects of treatment, visit, and treatment-by-visit interaction, as 
well as the continuous, fixed covariates of baseline score, baseline score-
by-visit interaction, and disease duration at baseline. An unstructured 
covariance structure will be used to model the within-patient errors. The 
Kenward-Roger method will be used to adjust the estimated covariance of 
the mean difference and the degrees of freedom. Several other covariance 
structures will be tested if there are convergence issues in the primary 
analysis.
The primary hypothesis to be tested is that mean change from baseline in 
PANSS is greater with PEAR-004 than with Sham at day 85 or last visit. 
The primary comparison will be the contrast between treatments on day 
85. The significance test will be carried out using 1-sided α=0.05. In
addition, two-sided 90% confidence intervals for the treatment mean
differences, as well as individual treatment mean change from baseline
values at each study visit will be constructed.
Two sensitivity analyses (the selection model and the pattern mixture 
model) will be performed to assess the robustness of the primary analysis 
to missing data results. The LOCF approach will also be performed to aid 
in the interpretation of the results from the primary analysis.
Key words
Schizophrenia, prescription digital therapeutic, cognitive behavioral 
therapy, smartphone app
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1
Introduction
1.1
Background
Schizophrenia is a common condition occurring in about 1% of the general population
Saha et al 2005. It is treated with antipsychotic medications, which can help acute exacerbations 
of delusions or hallucinations, but do not improve the long-term course of the illness. Functional 
impairment is severe and disabling, and not improved by medication. Most patients are unable 
to work or live independently.
Cognitive-behavioral therapy (CBT) has been shown to improve symptoms of schizophrenia 
somewhat, both for delusions and hallucinations (“positive” symptoms) as well as for apathy 
and flat affect (“negative” symptoms) and functional status (engagement with employment or 
social interactions) Rector and Beck 2001. Access to CBT can be difficult based on cost and 
availability of psychotherapists. PEAR-004 is being developed as a prescription digital 
therapeutic (PDT), delivered via mobile devices, that delivers coping skills from evidence-
based treatments such as CBT, Social Skills Training (STS), and Illness Self-Management
Training (ISMT). It is intended to be used by patients who are under the care of a qualified 
healthcare professional and are on antipsychotic pharmacotherapy. If efficacious, it would 
demonstrate that 24/7 access to evidence-based coping skills, which when added to medications, 
may improve symptom management and functional outcomes.
PEAR-004 is intended to deliver multimodal evidence-based neurobehavioral mechanisms of 
action which include Cognitive Restructuring, Behavioral Activation, ISMT, and SST.
Preliminary evidence has shown that patients with psychotic disorders can actively engage with 
software similar to PEAR-004, which suggests that PEAR-004 may improve both positive and 
depressive symptoms in patients with schizophrenia Ben-Zeev et al 2014; Ben-Zeev et al 2016
and serious mental illness Ben-Zeev et al 2018.
PEAR-004 is comprised of a patient-facing mobile-device application interface (via smartphone) 
and a clinician-facing web interface. The patient application delivers therapeutic content 
organized into multiple domains representing common symptoms or problem areas for patients 
with schizophrenia including: thoughts, voices, social functioning, medication, mood, sleep, 
and other coping skills for daily life. Patients are prompted to interact with PEAR-004 three 
times per day by automated notifications. Therapeutic content is delivered via a series of short 
interactions. Patients can select a therapeutic domain and choose what kind of skill they think 
would be most helpful. Patients then choose the specific skill and have the option of watching, 
reading, or listening to content about what the skill is and how they can give it a try. Patients 
then view tips for successful practice, and after they practice a skill are asked to provide 
feedback about whether the skill was helpful. Helpful skills are stored in the Toolbox to promote 
repeated practice and skill mastery.
PEAR-004’s academic precursor is FOCUS, a software-based intervention (delivered via 
mobile devices) designed with input from both treatment providers and patients to optimize 
both usability and engagement and developed to be used in conjunction with ongoing outpatient 
treatment Ben-Zeev et al 2013. The feasibility, acceptability, and initial efficacy of FOCUS for 
improving symptoms and treatment engagement in patients with schizophrenia was established 
in a one month open-label trial. In this trial, overall satisfaction (91%), retention (100%), and 

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engagement (patients active 87.5% of trial days) were very high. Participants in this trial had 
significant reductions in both overall symptoms of schizophrenia and depression from baseline 
to end of trial Ben-Zeev et al 2014.
In a separate study Ben-Zeev et al 2016, engagement with FOCUS among patients with 
schizophrenia was measured during a 6-month period following psychiatric hospitalization 
discharge. Similar to findings from the one-month feasibility trial, patients with schizophrenia 
were highly engaged over the course of 6 months (active use on 82% of the weeks during which 
they had access to the intervention). Taken together, these preliminary findings show the 
promise of PEAR-004 (developed based on the academic version of FOCUS software) as a 
PDT for improving symptoms and treatment outcomes in patients with schizophrenia.
1.2
Purpose
The purpose of the study is to determine in patients currently being administered antipsychotic
pharmacotherapy whether PEAR-004 can further reduce symptoms of schizophrenia as 
measured by the total score on the Positive and Negative Syndrome Scale (PANSS).
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints 
Objectives and endpoints
Primary Objective
Objective

To assess the efficacy of PEAR-004 as an
adjunct to existing clinician-directed
pharmacotherapy to reduce symptoms of
schizophrenia
Endpoint 

Change in total PANSS score from
baseline to day 85 or last visit

To evaluate retention to assigned study
treatment

Percent dropout rate
Secondary Objectives
Objectives
Endpoints

To evaluate the efficacy of PEAR-004 as an
adjunct to existing clinician-directed
pharmacotherapy to reduce positive symptoms
of schizophrenia

Change in the Positive PANSS score
from baseline to day 29, day 57, and day
85 or last visit

Change in the General Psychopathology
PANSS score from baseline to day 29,
day 57 and day 85 or last visit

To evaluate the efficacy of PEAR-004 as an
adjunct to existing clinician-directed
pharmacotherapy to reduce negative symptoms
of schizophrenia

Change in the Negative PANSS score
from baseline to day 29, day 57, and day
85 or last visit

Change in the Motivation and Pleasure
self-report (MAP-SR) score from
baseline to day 29, day 57, and day 85
or last visit

To assess safety and tolerability of PEAR-004

Adverse events, serious adverse events,
and adverse events leading to
discontinuation throughout the study

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
Vital signs at baseline, day 85 or last visit

InterSePT Scale for Suicidal Thinking-
Plus (ISST-Plus) score at baseline, day
29, day 57, day 85, and day 115 or last
visit

To evaluate the efficacy of PEAR-004 as an
adjunct to existing clinician-directed
pharmacotherapy to improve psychosocial
functioning in patients with schizophrenia

Change on the World Health
Organization Quality of Life (WHOQOL-
BREF) scale from baseline to day 29,
day 57, and day 85 or last visit

To evaluate the efficacy of PEAR-004 as an
adjunct to existing clinician-directed
pharmacotherapy to reduce depression
symptoms in patients with schizophrenia

Change in the Beck Depression
Inventory, Second Edition (BDI-II) total
score from baseline to day 29, day 57,
and day 85 or last visit

To evaluate the magnitude of the effect of
PEAR-004 as an adjunct to existing clinician-
directed pharmacotherapy to reduce symptoms
of schizophrenia

Percentage change in PANSS score
(within assigned group) from baseline to
day 29, day 57, and day 85 or last visit

To evaluate the response to treatment

Proportion of responders, defined as a
reduction of at least 20% at day 85 or
last visit in total PANSS score relative to
baseline

To evaluate patient adherence to antipsychotic
medication

Change in antipsychotic
pharmacotherapy use as measured by
the Brief Medication Questionnaire
(BMQ) at day 29, day 57, and day 85 or
last visit
Exploratory Objectives
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3
Study design
This is a randomized, sham controlled, rater-blinded, parallel group trial. Approximately 102 
subjects will be randomized 1:1 in to the following groups: 

Group A: Clinician-directed pharmacotherapy + PEAR-004

Group B: Clinician-directed pharmacotherapy + Sham application
An up to 28-day screening period will include standard screening assessments as defined in the 
assessment schedule. Eligible subjects will be randomized on day 1 into one of the treatment 
groups.
Subjects in both groups will continue to receive their clinician-directed standard of care
treatment for schizophrenia, including pharmacotherapy. Subjects in Group A will use PEAR-
004 for a period of 12 weeks. Subjects in Group B will use a sham for a period of 12 weeks. 
Subjects will return to the clinic for outpatient visits at week 4 (day 29), week 8 (day 57), and 
week 12 (day 85). At each visit, standard assessments will be performed according to the 
assessment schedule, including PANSS, ISST-Plus, CGI, BMQ, MAP-SR, WHOQOL-BREF, 
BDI-II, ISI, and Adverse Events (AEs). A final follow-up visit will be performed at week 16 
(day 115), including the assessments as detailed in the assessment schedule.
Figure 3-1
Study Design
4
Rationale
The overall rationale for the study is to assess the first PDT in schizophrenia using evidence-
based coping skills to supplement standard of care with antipsychotic medications.
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4.1
Rationale for study design

The design of this study addresses the primary objective of assessing the efficacy of
PEAR-004 in subjects with schizophrenia and takes into account the novel use of a
digital therapeutic to treat disease.

Bias will be reduced by randomizing subjects to PEAR-004 or sham. Only subjects
randomized to Group A will have access to the full clinical content and treatment logic
of PEAR-004 and its therapeutic components.

Raters will be blinded to randomization assignment.
4.2
Rationale for duration of treatment
No investigational medicinal product will be provided in this study; subjects will continue on 
their prescribed clinician-directed pharmacotherapy.
PEAR-004 is an investigational medical device, which is a prescription digital therapeutic.
The duration of treatment of 12 weeks with PEAR-004 or sham was selected based on the 
standard treatment duration for antipsychotic drug trials in schizophrenia to assess short-term 
benefit.
4.3
Rationale for choice of control
Digital therapy with PEAR-004 involves interaction with an application on a smartphone. To 
control for nonspecific effects of engagement with a smartphone, a sham application will be
provided which does not deliver active coping skills derived from evidence-based psychosocial 
interventions. The sham app will include notifications 3 times per day, and when the app is 
opened it will display a prescription timer for the remaining duration of app availability. 
4.4
Purpose and timing of interim analyses
Interim analyses may be conducted to support decision making concerning the current clinical 
study, the sponsor’s clinical development projects in general, or in case of any safety concerns.
4.5
Risks and benefits
There is no benefit expected for subjects participating in this study.
Appropriate eligibility criteria and stopping rules are included in this protocol. 
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring.
5
Population
Approximately 102 subjects will be enrolled in the study and randomized.
The investigator must ensure that all subjects being considered for the study meet the following 
eligibility criteria. No additional criteria should be applied by the investigator, in order that the 
study population will be representative of all eligible subjects.

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Subject selection is to be established by checking through all eligibility criteria at screening. A 
relevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Healthy male and female subjects 18 to 65 years of age, inclusive, and in good health as 
determined by medical history, physical examination, and vital signs at screening
3. SCID-based DSM-5 diagnosis of schizophrenia and a total PANSS score > 60 
Kay et al 1987
4. Proficient in English at 5th grade reading level or higher, in the judgement of the 
investigator
5. Capable of using a mobile device (compatible with PEAR-004) and using common 
applications, in the judgement of the investigator
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Major change in primary antipsychotic medication in the prior 4 weeks before screening 
(e.g., switching to a new agent or a dose adjustment within two weeks of randomization)  
2. Planning to move out of the geographic area within 3 months
3. Unable to use English to participate in the consent process, the interventions or 
assessments
4. Inability to comply with study procedures, due to severe medical conditions or otherwise
5. Meet DSM-5 diagnosis for a current episode of major depression, mania, or hypomania in 
the past month
6. Meet DSM-5 diagnosis for a current moderate or severe alcohol or cannabis use disorder 
in the past 2 months
7. Meet DSM-5 diagnosis for a current substance use disorder (other than alcohol or 
cannabis) in the past 2 months
8. Considered high risk for suicidal behavior based on ISST-Plus score at screening, or in the 
judgement of the investigator
9. Previously participated in a clinical study involving PEAR-004
6
Treatment
6.1
Study treatment
Details on the requirements for management of study treatment, and instructions to be followed 
for subject numbering, providing and utilizing study treatment are outlined in the SOM.
PEAR-004 is an investigational digital therapeutic, currently available on a mobile device (iOS 
and Android based). It is designed to serve as an illness self-management tool. Subjects can 

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access PEAR-004 as needed to receive suggestions about coping strategies to overcome 
difficulties in daily life.
A control sham will be available to the control group. The sham will be downloaded to the 
subject’s phone, but will not deliver the active therapeutic content of PEAR-004. It will deliver 
notifications prompting the subject to open the sham app, and will then display a prescription 
timer for the remaining duration of app availability.
Eligible subjects will gain access to either PEAR-004 or sham according to their randomization 
assignment via a digital prescription access code provided to the site. Study site staff will 
receive training on how to download PEAR-004 or sham to the assigned subject’s phone as part 
of site initiation activities.
6.1.1
Treatment arms/group
Subjects will be assigned on Day 1 to one of the following two treatment arms/groups in a ratio 
of 1:1

PEAR-004

Sham
6.2
Other treatment(s)
6.2.1
Concomitant therapy
Subjects are expected to maintain their physician prescribed pharmacotherapy during the study, 
as specified in the exclusion criteria.
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject is enrolled into the study must be recorded on 
the appropriate Case Report Forms.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see ‘Subject 
numbering’ section in the Site Operations Manual.
6.3.2
Treatment assignment, randomization
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from raters at the site. A subject randomization 
list will be produced by the IRT provider, or by a delegate under Novartis supervision, using a 
validated system that automates the random assignment of subject numbers to randomization 
numbers. These randomization numbers are linked to the different treatment arms, which in 
turn are linked to treatment numbers. A separate treatment list will be produced using a 
validated system that automates the random assignment of treatment numbers.

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The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects.
6.4
Treatment blinding
This is a rater-blinded study. Raters will remain blinded to study treatment throughout the study.
The identity of the treatments will be concealed by limiting rater access to the randomization 
list, subject-specific phone, and web portal. Raters will be independent of other aspects of study 
conduct, and subjects will be instructed not to provide specific details about the content they 
are viewing on their phone to the rater. 
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind the rater confidential and secure until clinical database lock.
Following final database lock all roles may be considered unblinded. See the 
blinding/unblinding table for an overview of the blinding/unblinding plan.
Table 6-1
Blinding and unblinding plan
Role
Time or Event
Randomization 
list generated
Treatment 
allocation
Safety event 
(single subject 
unblinded)
Interim 
Analysis
Subjects
UI
UI
UI
UI
Site staff
UI
UI
UI
UI
Raters (independent of other aspects of 
study conduct)
B
B
B
B
Randomization Office
UI
UI
UI
UI
Unblinded sponsor staff
UI
UI
UI
UI
Unblinded Pharmacovigilance sponsor 
staff
NA
NA
NA
NA
Statistician/statistical programmer/ data 
analysts (e.g. biomarker)
UI
UI
UI
UI
Independent committees used for 
assessing interim results, if required 
(e.g. DMC)
NA
NA
NA
NA
All other sponsor staff not identified 
above (trial team, project team, 
management & decision boards, 
support functions)
UI
UI
UI
UI
UI: Allowed to be unblinded on individual subject level
B: Remains blinded
NA: Not applicable to this study
6.5
Dose escalation and dose modification
Not applicable.

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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Treatment compliance here refers to subject use of PEAR-004. Data will be collected to assess 
frequency of subject use of PEAR-004, including whether use was prompted by a notification 
or subject-initiated.
Self-reported compliance with the subject’s ongoing clinician-directed pharmacotherapy will 
additionally be assessed via the BMQ.
6.7
Treatment distribution
Each study site will be provided with access to study treatment as described under the 
investigational and control treatment section. See the Site Operations Manual for further details.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational treatment will 
be included in the subject informed consent and should be discussed with the subject during the 
study as needed. Any new information regarding the safety profile of the investigational 
treatment will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
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A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
Refer to the Site Operations Manual for a complete list of ICFs included in this study.
8
Visit schedule and assessments
The Assessment schedule (Table 8-1) lists all of the assessments and when they are performed. 
All data obtained from these assessments must be supported in the subject’s source 
documentation.
Subjects should be seen for all visits/assessments as outlined in the Assessment schedule 
(Table 8-1) or as close to the designated day as possible. Missed or rescheduled visits should 
not lead to automatic discontinuation. Subjects who prematurely discontinue the study for any 
reason should be scheduled for a visit as soon as possible, at which time all of the assessments 
listed for the final visit will be performed. At this final visit the adverse event and concomitant 
medications should be recorded on the CRF.

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Table 8-1
Assessment Schedule
Epochs
SCREENING 
(Non-Treatment)
Treatment
EOS
Visit Name
Screening
Treatment
EOS
Weeks
1
4
8
12
16
Days
-28 to -1
1
29
57
85
115
Obtain informed consent
X
Inclusion /Exclusion criteria 
S
Relevant med history / current medical conditions
X
Demography
X
Physical examination
S
S*
Randomization
X
PEAR-004/Sham distribution and data collection1
X
X
X
X
X
Body height
X
Body weight
X
X3
X*
Vital signs (Body temp, blood pressure, pulse rate)
X
X3
X
X*
Concomitant meds/Therapies
X
X
X
X
X
X*
PANSS
X
X3
X
X
X
X*
ISST-Plus
X
X3
X
X
X
X*
BMQ
X3
X
X
X
X*
MAP-SR
X3
X
X
X
X*
WHOQOL-BREF
X3
X
X
X
X*
BDI-II
X3
X
X
X
X*
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Epochs
SCREENING 
(Non-Treatment)
Treatment
EOS
Visit Name
Screening
Treatment
EOS
Weeks
1
4
8
12
16
Days
-28 to -1
1
29
57
85
115
Adverse Events
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
Note: If several assessments are scheduled at the same time point, please see the SOM for guidance on recommended sequence of assessments
X = assessment to be recorded in clinical database
S = assessment to be recorded in source documentation only and will not be entered into the CRF
*These assessments are also to be conducted for subjects who discontinue study treatment
1 Data collection from day 1 through day 85.
3 Assessment performed on day 1 prior to PEAR-004/Sham distribution is considered baseline.
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8.1
Screening
Re-screening of potential subjects is allowed if the subject fails an initial screening. 
Re-consenting is required.
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the Site Operations Manual.
8.1.1
Eligibility screening
DSM-5 will be used to assess eligibility. SCID-based diagnosis of schizophrenia will be a 
paper-based assessment administered by a clinician at the screening visit. 
8.1.2
Information to be collected on screening failures
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the Site Operations Manual.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data are to be collected on all subjects. 
Relevant medical history/current medical condition present before signing the informed consent 
will be recorded. Details are outlined in the Site Operations Manual. 
8.3
Efficacy
8.3.1
Positive and Negative Syndrome Scale (PANSS)
The PANSS is a 30-item clinician-administered semi-structured interview of schizophrenia 
symptoms. The PANSS total score can be further broken down to subscales for positive, 
negative, and general symptoms.
8.3.2
Brief Medication Questionnaire (BMQ)
The BMQ is a self-report of medication usage, including what medications the patient is 
currently taking, how they took each medication in the past week, drug effects and bothersome 
features, and difficulties remembering to take their medication.
8.3.3
Motivation and Pleasure-Self Report (MAP-SR)
The MAP-SR is a 15-item self-report measure that provides a total score index of current 
motivation/pleasure negative symptoms.
8.3.4
World Health Organization Quality of Life (WHOQOL-BREF) Scale
The WHOQOL-BREF is a 26-item clinician-administered structured interview that assesses 
psychological functioning and quality of life in four primary domains: social relationships, 
psychological, physical, and environment.

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8.3.5
Beck Depression Inventory, Second Edition (BDI-II)
The BDI-II is a 21-item self-report measure that provides a total score index of current 
depression symptom severity.
8.3.6
Appropriateness of efficacy assessments
These assessments are considered standard for schizophrenia, and for the specific outcomes 
being measured, such as depression and quality of life.
8.4
Safety
Safety assessments are specified below with the Assessment schedule (Table 8-1) detailing
when each assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
Table 8-2
Assessments and Specifications
Assessment
Specification
Physical 
examination
A short physical exam will include the examination of general appearance and 
vital signs (blood pressure [SBP and DBP] and pulse). 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior 
to signing informed consent must be recorded on the appropriate CRF that 
captures medical history. Significant findings made after signing informed consent 
which meet the definition of an Adverse Event must be recorded as an adverse 
event.
Vital sign
Vital signs include BP and pulse measurements. After the subject has been sitting 
for five minutes, with back supported and both feet placed on the floor, systolic 
and diastolic blood pressure will be measured three times using an automated 
validated device, e.g. OMRON, with an appropriately sized cuff. The repeat sitting 
measurements will be made at 1 - 2 minute intervals and the mean of the three 
measurements will be used. In case the cuff sizes available are not large enough
for the subject's arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured.
The methods for each assessment and data recording details are specified in the SOM.
8.4.1
InterSePT Scale for Suicidal Thinking-Plus (ISST-Plus) 
Prospective suicidality will be assessed by the ISST-Plus, a clinician-administered semi-
structured interview. The ISST-Plus is an updated version of the scale used in the InterSePT 
trial Ayer et al 2008, which was a Novartis-sponsored Phase III trial of treatment of suicidality 
with clozapine. The ISST-Plus is specifically designed for use in schizophrenia
Sheehan et al 2014, and meets Health Authority criteria for suicidality assessments CDER 2012.
8.4.2
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.

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8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
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8.5.3
Other Assessments
No additional tests will be performed on subjects entered into this study.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.

Study treatment must be discontinued if the subject withdraws consent.
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the Assessment schedule (Table 8-1), especially the day 85
and EOS (day 115) visits. If they fail to return for these assessments for unknown reasons, every 
effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-designated 
contact as specified in the lost to follow-up section. This contact should preferably be done 
according to the study visit schedule.
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If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent form.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
In order to better adhere to the intent-to-treat principle, subjects will be encouraged to 
continue in the trial even if they discontinue treatment (often referred to as “retrieved 
dropout”).
9.1.4
Study stopping rules
Study procedures will be stopped if the Sponsor considers that the number and/or severity of 
AEs or abnormal safety monitoring tests justify putting the study on hold.
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed.

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9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and
efficacy data

Discontinuation of study digital therapeutic development
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on the local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion (EOS) 
visit, and any repeat assessments associated with this visit have been documented and followed-
up appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision. Each subject will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subjects and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings or other 
assessments.

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Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to
Section 10.1.2):
1. The severity grade.

mild: usually transient in nature and generally not interfering with normal
activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment or conduct. If the event is due to lack of efficacy or
progression of underlying illness (i.e. progression of the study indication) the assessment
of causality will usually be ‘Not suspected’. The rationale for this guidance is that the
symptoms of a lack of efficacy or progression of underlying illness are not caused by the
trial treatment, they happen in spite of its administration and/or both lack of efficacy and
progression of underlying disease can only be evaluated meaningfully by an analysis of
cohorts, not on a single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which
seriousness criteria have been met
5. action taken regarding study treatment
6. its outcome i.e., its recovery status or whether it was fatal
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Follow the instructions found in the Site Operations Manual for data capture methodology 
regarding AE collection for subjects that fail screening.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening

Life-threatening in the context of a SAE refers to a reaction in which the subject was
at risk of death at the time of the reaction; it does not refer to a reaction that

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hypothetically might have caused death if it were more severe (please refer to the 
ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
10.1.3.1 Screen Failures
SAEs occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.

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Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period (following the last administration of study 
treatment) should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.2
Additional Safety Monitoring 
10.2.1
Prospective suicidality assessment
The ISST-Plus is a questionnaire that prospectively assesses suicidal ideation and suicidal 
behavior. The ISST-Plus must be administered at each visit, including unplanned visits.
The ISST-Plus, which uses a semi-structured interview to probe subject responses, will be 
administered by an individual who has received training and certification in its administration. 
If, at any time after screening and/or baseline, there is a notable clinical worsening in suicidal 
ideation or behavior, the subject should be evaluated by a mental health care professional for 
further assessment and/or treatment, if not already under active clinical care. The decision on 
whether the study treatment should be discontinued is to be taken by the investigator in 
collaboration with the treating mental health professionals.
In addition, all life-threatening events must be reported as SAEs. All events of “Non-Suicidal 
Self-Injurious Behavior” should be reported as AEs and assigned the appropriate severity grade.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, and allow modification and/or verification of the 
entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.

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11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Randomization codes and data about all study treatment(s) dispensed to the subject will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis (or 
a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis/
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being distributed and accounted 
for according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis/delegated CRO/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).

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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Full Analysis Set (FAS) population will serve as the primary population for the analysis of 
efficacy data in this trial.
The FAS comprises all subjects to whom study treatment has been assigned by randomization 
and who have a baseline observation and at least one post-randomization observation for the 
analysis endpoint. According to the intent-to-treat principle, subjects will be analyzed according 
to the treatment they have been assigned to during the randomization procedure.
The Safety Set includes all randomized subjects who received the study treatment, with subjects 
included in the treatment group corresponding to the treatment they actually received.
While no per-protocol analysis is planned, a list of protocol violators (e.g. subjects with lack of 
study treatment compliance, change in background therapy during the trial) will be finalized 
prior to unblinding.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data will be listed and summarized descriptively by treatment 
group for the FAS and the Safety Set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group.
12.3
Treatments
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure to the study treatment will be summarized using descriptive statistics.

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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
Reasons for discontinuation for all patients will be listed and tabulated for both treatment groups. 
The median time to all-cause discontinuation will be compared between the treatment groups. 
The log-rank test will be used to test the null hypothesis against the alternate hypothesis that 
the median time to discontinuation is not the same between the groups.
12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
The primary efficacy endpoint in the study is change in total PANSS score from baseline to day 
85 or last visit, analyzed using the FAS.
12.4.2
Statistical model, hypothesis, and method of analysis
The change from baseline in total PANSS score will be analyzed using the mixed-effects model 
for repeated measures (MMRM) Mallinckrodt et al 2001, including the fixed, categorical 
effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous, fixed 
covariates of baseline score, baseline score-by-visit interaction, and disease duration at baseline. 
An unstructured (UN) covariance structure will be used to model the within-patient errors. The 
Kenward-Roger (KR) method will be used to adjust the estimated covariance of the mean 
difference and the degrees of freedom.
12.4.3
Handling of missing values/censoring/discontinuations
The primary MMRM model implicitly imputes missing data under a missing at random (MAR) 
assumption. Therefore, no explicit imputation of missing data will be done for the primary 
analysis approach.
12.4.4
Sensitivity and Supportive analyses
12.4.4.1 Sensitivity analyses
Two sensitivity analyses to assess the robustness of the primary analysis to missing data results 
will be performed.
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12.4.4.2 Supportive analyses
The last-observation-carried-forward (LOCF) approach will be applied to analyze the change 
from baseline in the total PANSS score. These results will only be used to aid in the 
interpretation of the results from the primary analysis.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy endpoint(s)
The secondary efficacy endpoints listed below will be analyzed separately using an MMRM 
analysis. The change from baseline to each post-baseline visit will be the dependent variable. 
The model will include the fixed, categorical effects of treatment, visit, and treatment-by-visit 
interaction, as well as the continuous, fixed covariates of baseline score, baseline score-by-visit 
interaction, and disease duration at baseline (in years). The analysis strategy will be the same 
as for the primary outcome (Section 12.4.2). The outcomes to be analyzed are:
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
change from baseline in the positive PANSS score;

change from baseline in the General Psychopathology PANSS score;

change from baseline in the negative PANSS score;

change from baseline in the MAP-SR score;

change from baseline in the WHOQOL-BREF scale;

change from baseline in the BDI-II total score
In addition, the percentage change from baseline in the total PANSS score will be analyzed 
using an MMRM approach, as described in Section 12.4.2. Estimates of mean percentage 
change from baseline to each study visit with (90% CIs) will be obtained for each treatment 
group.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
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The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment.
Adverse events
All information obtained on AEs will be displayed by treatment group and subject.
The number (and percentage) of subjects with AEs will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related AEs, death, SAEs, and other
significant AEs leading to discontinuation.
A subject with multiple AEs within a primary system organ class is only counted once towards
the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available, abnormalities as well as clinically notable values will be flagged. Summary statistics 
will be provided by treatment and visit/time.
Other safety evaluations
ISST-Plus score data will be listed by treatment, subject and visit/time; abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time as appropriate.
12.6
Analysis of exploratory endpoints
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12.7
Interim analyses
Not applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Approximately 102 subjects will be randomized in a 1:1 ratio to one of two treatment groups: 
Sham and PEAR-004. This sample size will provide 80% power to detect a statistically 
significant difference between the two groups at a 1-sided alpha=0.05 when the true mean 
difference is 8 points assuming SD =16 (common to the two groups). This difference is 
equivalent to a standardized effect size of 0.5, which is considered a moderate effect size, and 
is consistent with prior randomized controlled trials (RCTs) of cognitive behavioral therapy 
(CBT) in schizophrenia.
Table 12-1 shows the values of power for the true mean treatment difference in the range from 
-4 to -10.
Table 12-1
Sensitivity of power to changes in assumptions for a design with 
N=102 evaluable subjects
Allocation 
ratio
SD (common 
to 2 arms)
True mean 
difference (#)
True effect 
size (#/SD)
$ (1-sided)
Power
1:1
16
-4
-0.25
0.05
35%
1:1
16
-6
-0.375
0.05
59%
1:1
16
-8
-0.5
0.05
81%
1:1
16
-10
-0.625
0.05
93%
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
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written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meeting or site initiation visit.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational treatments under the 
protocol, other than the purpose of the study. If despite this interdiction prohibition, data, 
information, observation would be incidentally collected, the investigator shall immediately 
disclose it to Novartis and not use it for any purpose other than the study, except for the 
appropriate monitoring on study participants.

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Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
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