A Multicenter, Randomized, Double-Blind, Controlled Study Evaluating the Efficacy and Safety of a Digital Therapeutic as an Adjunct to Treatment as Usual Among Women With Mild to Moderate Postpartum Depression
Phase: NA
Conditions: Postpartum Depression
Sponsor: Woebot Health

A Multicenter, Randomized, Double-Blind, Controlled Study Evaluating the Efficacy and Safety of
a Digital Therapeutic WB001 as an Adjunct to Treatment as Usual Among Women with Mild to
Moderate Postpartum Depression
NCT05551195
November 3, 2022

Woebot Health
Clinical Trial Protocol WB001-001
Protocol Number:
WB001-001
NCT Number:
[TBA]
Date; Version
03-Nov-2022
Clinical Trial Protocol WB001-001
A Multicenter, Randomized, Double-Blind, Controlled Study Evaluating the Efficacy and Safety of
a Digital Therapeutic WB001 as an Adjunct to Treatment as Usual Among Women with Mild to
Moderate Postpartum Depression
Document Type: Clinical Trial Protocol
Clinical Trial Phase: Pivotal
Version Number: 1.6
Property of Woebot Health
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Woebot Health

CONF DENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
CLINICAL STUDY PROTOCOL
Title:
A Multicenter, Randomized, Double-Blind, Controlled Study Evaluating the
Efficacy and Safety of a Digital Therapeutic WB001 as an Adjunct to
Treatment as Usual Among Women with Mild to Moderate Postpartum
Depression
Protocol Number:
WB001-001
Test Product:
WB001 (Class II Software Medical Device)
Regulatory Agency
Identifier Number(s):
[TBA]
Sponsor:
Contract Research
Organization:
Coordinating
Investigator:
[TBD]
Protocol Version and
Date:
v.1.6 03-Nov-2022
This study will be performed in compliance with the principles of Good Clinical Practice.
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
AMENDMENTS FROM PREVIOUS VERSIONS
Date
Version
Brief Summary of Changes
16-May-2022
1.0
Original version
03-Jun-2022
1.1
SCR/BL changed from Day 0 to Day 1
05-Jul-2022
1.2
Update to Study Title; Removal of CAGE-AID
assessment and clarification of planned SCID-5-CT
modules; Clarification of engagement data
monitoring; Exclusion #11 updated to “Previous
Woebot use” from “Previously participated in a
Woebot study”; Added section 5.4 for the collection of
Healthcare Utilization information
15-Jul-2022
1.3
Revised Section 9.1 (Model 3) per the Statistical
Analysis Plan; Protocol Title updated throughout for
consistency
09-Aug-2022
1.4
Addition of the ‘Program Assignment Assessment’
(Section 5.5); Updated the description of the
Secondary Objective/Endpoint, Interim Analysis, and
Blinding Analysis to be consistent with the current
SAP; Updated Figure 3; Update “Resources” to
“Helplines” to align directly to Product feature (pg 32,
pg 49)
14-Oct-2022
1.5
Updated Benefit/Risk Assessment; Addition of
minimum necessary operating system requirements to
Section 4.4; Updated screenshots in Appendix 2
03-Nov-2022
1.6
Sponsor address updated; Update to levels of clinical
concern being reported to DSMB and reporting
timeframe (10 to 5 day) in Section 7
This document is a confidential communication of Woebot Health. Acceptance of this document constitutes
agreement by the recipient that no unpublished information contained herein shall be published or disclosed
without prior written approval, except that this document will be disclosed to the appropriate Institutional
Review Board(s) under the condition that they keep it confidential.
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CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
PROTOCOL SIGNATURE PAGE – SPONSOR AND CRO
This protocol has been reviewed and approved by the representative(s) listed below. Any modification of the
protocol must be agreed upon by the Sponsor and the investigator and must be documented in writing.
Woebot Health representative(s):
Print Name
Title
Signature
Date
IQVIA representatives:
Print Name
Title
Signature
Date
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CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
PROTOCOL SIGNATURE PAGE – INVESTIGATOR
I have read this protocol, which has been agreed by Woebot Health, and given approval/favorable opinion by the
institutional review board, and I agree that it contains all necessary details for my staff and I to conduct this
study as described. I will provide copies of the protocol and any amendments to all study personnel under my
supervision and provide access to all information provided by Woebot Health or their specified designees. I will
discuss the material with the study personnel to ensure that they are fully informed about the study.
I understand that information contained in or pertaining to this protocol is confidential and should not be
disclosed, other than to those directly involved in the execution or the ethical review of the study, without
written authorization from Woebot Health. It is, however, permissible to provide information to a participant in
order to obtain consent.
I agree to conduct this study according to this protocol and to comply with its requirements, participant to ethical
and safety considerations and guidelines, and to conduct the study in accordance with the Declaration of
Helsinki, International Council for Harmonisation guidelines on Good Clinical Practice, and applicable regional
regulatory requirements.
I agree to comply with the procedures described for data recording and reporting and to permit monitoring and
auditing by Woebot Health and inspection by the appropriate regulatory authorities.
I agree to make my participants’ study records available to Woebot Health personnel, their representatives, and
relevant regulatory authorities in order to verify data that I have entered the case report forms. I will retain the
study-related essential documents until Woebot Health indicates that they are no longer needed. I am aware of
my responsibilities as an investigator as provided by Woebot Health.
I understand that Woebot Health may decide to suspend or prematurely terminate the study at any time for
whatever reason; such a decision will be communicated to me in writing. Conversely, should I decide to
withdraw from execution of the study, I will communicate my intention immediately in writing to Woebot
Health.
Investigator Name (Print)
Title
Institution:
Signature:
Date
PROTOCOL SYNOPSIS
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CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
Protocol Number: WB001-001
Full Title: A Multicenter, Randomized, Double-Blind, Controlled Study Evaluating the Efficacy and
Safety of a Digital Therapeutic WB001 as an Adjunct to Treatment as Usual Among Women with Mild
to Moderate Postpartum Depression
Abbreviated Title: [Study Evaluating the Efficacy and Safety of WB001 as an Adjunct to TAU in
Postpartum Depression]
Sponsor: Woebot Health
Coordinating Investigator: [TBA]
Study Type: Interventional
Planned Number of Subjects: 210, with interim analysis for sample size re-estimation
Study Sites: Up to 25 study centers within the U.S.
Primary Objectives: The purpose of the study is to determine whether, for women diagnosed with PPD,
WB001 with adjunctive Treatment as Usual (TAU; WB001+TAU) can reduce symptoms of depression
compared to an educational control with adjunctive TAU (Ed Control “ED001” +TAU), at the end of
treatment (EOT; 8 weeks) as measured by the HAM-D6.
Primary Aim: To evaluate the efficacy of [WB001+TAU] vs. [ED001+TAU] on depressive symptoms at
EOT as measured by a structured clinical interview with the 6-item Hamilton Rating Scale for
Depression (HAM-D6; Ruhe et al 2005) among women diagnosed with postpartum depression (PPD).
Secondary and Other Objectives:
Secondary Aims:
●
To evaluate the effectiveness of [WB001+TAU] vs. [ED001+TAU] at EOT on indices of clinical
interest (1) mother infant bonding (with the Mother-Infant Bonding Scale (MIBS)); (2)
Edinburgh Postnatal Depression Scale (EPDS), (3) Patient Health Questionnaire (PHQ-9); and
(4) Generalized Anxiety Disorder Questionnaire (GAD-7).
●
To evaluate the within-group differences on the HAM-D in the [WB001+TAU] and
[ED001+TAU] arms between BL and EOT.
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
Exploratory Aim: Investigate clinically significant between group differences of [WB001+TAU] vs.
[ED001+TAU] on the Clinical Global Impression (CGI) Scales and the Patient Global Impression (PGI)
Scales.
Study Design: This protocol comprises a randomized, double-blind, controlled trial to assess the
efficacy and safety of 8 weeks of treatment with either [WB001+TAU] or [ED001+TAU] in a population
of women with mild to moderate PPD. Patients will be referred by an obstetrician, pediatrician, or
other healthcare professional, or by other digital and site based recruitment methods and if interested,
will complete the pre-screening process. Those confirmed as eligible will be scheduled to attend a
screening/baseline onsite visit, at which they will complete an informed consent form and the Principal
Investigator (PI), or qualified site staff and Central Independent Rater (CIR) will conduct screening
assessments. The PI or sub-investigator will determine participant eligibility. Eligible participants will
be randomized to one of the two groups and will receive instructions on downloading and using the
smartphone application (app) to which they were randomized. Participants will use the app as
instructed and will attend telehealth visits with the CIR who will administer an assessment for the
primary endpoint (e.g., HAM-D6) and PI/qualified site staff who will administer key assessments for the
safety endpoints at Weeks 4 and 8 by video call (preferred) or telephone. Participants will also complete
several questionnaires (electronic patient-reported outcomes [ePROs]) on their own. All assessments
will be completed within 3 days prior to or 3 days (±3) after participants’ Week 4 and Week 8 key
assessment visit date.
Study Duration: 8 weeks
Target Population: Women with mild to moderate PPD who are ≤92 days postpartum
Key Inclusion Criteria:
●
Must have primary residence in the United States
●
Must be willing to comply with all study procedures and restrictions
●
Must be able to understand and willing to provide informed consent
●
Must be ≤92 days postpartum at the time of screening
●
Must be women aged 22-45 years who had onset of a major depressive episode any time during
pregnancy or within 4 weeks following delivery according to DSM-5 diagnostic criteria (Segre et al.,
2013)
●
Must own or have regular access to a smartphone (Android or iOS smartphone with a recent,
supported operating system), and has reliable Wi-Fi access or sufficient data plan to engage with
assigned treatment condition for the duration of the study
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ONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
●
Must have current mild-moderate depression as measured by the HAM-D6 score > 7 and < 13 (i.e.,
between 8-12, inclusive) at screening (Bech et al., 2007; Pridmore et al., 2020)
●
Participant must confirm having a form of TAU, defined as clinician supervised outpatient care
management and includes follow-up visits, medication, psychotherapy, or some combination thereof
●
As part of TAU during the study, any confirmed concomitant medications and/or psychotherapy are
permissible and must be regularly scheduled or stable (dose and frequency) for over 4 weeks prior
to baseline (BL) visit
Key Exclusion Criteria:
●
Gestation less than 28 weeks
●
HAM-D6 score ≤7 or ≥13 (severe depression) at Screening
●
Currently pregnant or plans to become pregnant within the next 8 weeks
●
History of drug and/or alcohol use disorder within the past 12 months measured by the SCID-5-CT
(Williams JB, 2015)
●
Lifetime history of suicide attempt or ideation with a plan and intent to harm oneself during the
current episode of PPD
●
Current or lifetime psychosis, including history of post- and peri-partum psychosis as measured by
the SCID-5-CT (Williams JB, 2015)
●
Current or lifetime history of schizophrenia, schizoaffective disorder, bipolar disorder, and/or
homicidal or infanticidal ideation as measured by the SCID-5-CT (Williams JB, 2015)
●
History of antidepressant treatment with ketamine/esketamine, electroconvulsive therapy, vagal
nerve stimulation, or a deep brain stimulation device
Fetal demise within the past 18 months
●
Previous Woebot use
Study Conditions: 1:1 randomization to either [WB001+TAU] or [ED001+TAU]
Control Device: The educational control application is an educational app named ED001.
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
Treatment as Usual (TAU): Participants will receive TAU, which is clinician supervised outpatient care
including follow-up visit(s), psychotropic medication, psychotherapy, or some combination thereof.
Primary Endpoint: Difference in HAM-D6 scores between groups at EOT, controlling for baseline (BL)
and other covariates
Secondary Endpoints:
1.
Difference between arms in the following assessments at EOT, controlling for BL and other
covariates:
●
Edinburgh Postnatal Depression Scale (EPDS)
●
Maternal-Infant Bonding Scale (MIBS)
●
Patient Health Questionnaire-9 (PHQ-9)
●
Generalized Anxiety Disorder-7 (GAD-7)
2.
Difference in HAM-D6 scores within arms between BL and EOT
Exploratory Endpoints:
●
Change from baseline in Clinical Global Impression-Improvement (CGI-I) the CGI-Severity
(CGI-S) at Week 4 and Week 8
●
Change from baseline in Patient Global Impression-Change (PGI-C) and Patient Global
Impression-Severity (PGI-S) at Week 4 and Week 8
●
Client Satisfaction Questionnaire-8 at Week 8
Safety Endpoints: C-SSRS and Adverse Events (AEs), Serious Adverse Events (SAEs)
Safety Aim: To evaluate the safety of [WB001+TAU] versus [ED001+TAU] based on PI and Sponsor
determined AE and SAEs. The study will use the Columbia-Suicide Severity Rating Scale (C-SSRS), the
PHQ-9 item #9, and the EPDS item #10, and the HAM-D17 item #3 to facilitate identification of AEs
and SAEs. It would be separately determined whether identified AEs or SAEs are related to the device.
Statistical Methods: The primary efficacy endpoint is the difference between treatment arms in the
HAM-D6 score at Visit Week 8 after controlling for baseline and other covariates. For the ITT
population, a restricted maximum likelihood (REML) based linear MMRM approach will be used to
test for systematic differences in change between arms over time, after accounting for
participant-specific heterogeneity in HAM-D6 scores residual error structure. The MMRM will be
parameterized to include random effects for site and repeated measures for post-baseline visits using an
unstructured residual covariance structure (3 parameters); in the unlikely event that the unstructured
covariance matrix fails to converge, the model will be refit with a first order autoregressive covariance
matrix (2 parameters).
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
This test will be performed using the final, MMRM model-based t-test with a two-sided significance
level of 5%. Estimated least squares means for change from baseline and the observed absolute values
(± SE) at each visit by treatment group will be plotted over time.
No explicit imputation will be performed; the MMRM model described above will be run on this
population, which implicitly imputes missing data under a missing at random (MAR) assumption.
As a sensitivity analysis for the primary analysis using ITT population, MMRM model in the same
manner as described above will be conducted in the PP population.
The treatment effectiveness on MIBS, EPDS, PHQ-9, and GAD-7 (difference between arms at Week 8,
controlling for baseline) will be evaluated using the same analysis plan proposed for the analysis of the
primary endpoint (HAM-D6).
Subgroup analyses will be accounted for by including potential subgroups as covariates in the primary
analysis model.
Protocol Version and Date: [v1.6] [11.03.2022]
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
CONTENTS
CLINICAL STUDY PROTOCOL
1
AMENDMENTS FROM PREVIOUS VERSIONS
2
PROTOCOL SIGNATURE PAGE – SPONSOR AND CRO
3
PROTOCOL SIGNATURE PAGE – INVESTIGATOR
4
PROTOCOL SYNOPSIS
5
1. INTRODUCTION
14
1.1 Background
14
1.2 Study Rationale
14
1.3 Investigational Device
16
1.4 The WB001 Platform
16
A. Deep understanding of the lived experience of women with PPD
16
B.1
2. STUDY OBJECTIVES AND ENDPOINTS
24
Table 1
Study Objectives, Hypotheses, and Endpoints
25
3. STUDY DESIGN
26
3.1 Overall Study Design
26
3.2 Rationale for Duration of Treatment
28
3.3 Rationale for Choice of Control
28
3.4 Scientific Rationale for Study Design
29
3.5 Blinding
29
Table 2
Blinding Plan
32
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Protocol Number: WB001-001
3.6 Procedure for Breaking the Blind
33
4. STUDY POPULATION
33
4.1 Inclusion Criteria
33
4.2 Exclusion Criteria:
34
4.3 Rationale for ≤3 Months Postpartum
34
4.4 Minimum Technology Requirements
35
4.5 Screen Failures
35
4.6 Study Discontinuation or Withdrawal
35
4.7 Lost to Follow-up
36
5.
DESCRIPTION OF STUDY ASSESSMENTS
37
5.1 General Screening/Baseline Assessments
37
Demographics
37
Previous and Concomitant Medications and Therapy
37
Medical History
38
Pregnancy History And Pregnancy Status
38
5.2 Efficacy Assessments
39
5.3 Safety Assessments
42
Adverse Events
43
Suicidal Ideation and Behavior Risk Monitoring
43
C-SSRS
43
Pregnancy and Breastfeeding
45
12-lead Electrocardiogram, Vital Signs, and Physical Examinations
45
Unscheduled Visits
45
5.4 Healthcare Utilization
45
5.5 Blinding Assessment
45
6.
STUDY STOPPING RULES
46
6.1 Early Study Termination
46
7.
DATA AND SAFETY MONITORING
46
Table 3
Clinical Concerns Categorizations
47
7.1 Adverse Events
48
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Protocol Number: WB001-001
7.2 Assessment of Adverse Events
48
AE Severity
48
AE Causality
48
7.3 Serious Adverse Events
49
Unanticipated Adverse Device Effects
49
Documenting and Reporting Adverse Events and Serious Adverse Events
49
Reporting of Serious Adverse Events
50
AE and SAE Follow-up
50
Safety Reporting Oversight
51
7.4 Data Safety Monitoring Board (DSMB)
51
7.5 Data Collection and Database Management
52
7.6 Quality Control and Quality Assurance
52
8. STATISTICAL ANALYSIS
53
8.1 General methodology
53
8.2 Analysis Populations
53
Table 4. Summary of Analysis Sets
53
8.3 Sample Size Determination
54
9. STATISTICAL METHODS
55
9.1 Primary Endpoint
55
9.2 Secondary Endpoints
56
9.3 Exploratory Endpoint(s)
57
9.4 Safety Endpoint(s)
57
9.5 Analysis of Safety
57
9.6 Demographic and Baseline Characteristics
57
9.7 Subgroup Analyses
57
9.8 Handling of Missing Values
57
9.9 Interim Analysis
58
9.10 Blinding Analysis
58
10. ETHICS AND RESPONSIBILITIES
58
10.1 Good Clinical Practice
58
10.2 Institutional Review Board
58
10.3 Informed Consent
59
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
Contractual and Financial Details
60
Insurance, Indemnity, and Compensation
60
Financial Disclosure
60
11. RECORDS MANAGEMENT
60
11.1 Source Documentation
61
11.2 Case Report Form Completion and Data Management
61
11.3 Study Files and Record Retention
62
12. AUDITING AND MONITORING
62
12.1 Risk and Quality Tolerance Limits
63
12.2 Protocol Adherence and Deviations
63
13. AMENDMENTS
63
14. STUDY REPORT AND PUBLICATIONS
64
15. STUDY START AND TERMINATION
64
16. CONFIDENTIALITY
65
17. REFERENCES
66
Appendix 1: List of Abbreviations
75
Appendix 2: Design Integrity of Treatment arms
79
Appendix 3: Schedule of Events
80
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
1. INTRODUCTION
1.1 BACKGROUND
Childbirth is perhaps the most significant event and transition a woman may undergo in her lifetime. The period
following childbirth organically brings significant lifestyle, occupational, relational, and physical health changes
that may result in exhaustion, pain, anxiety, frustration, and guilt, as well as happiness and excitement.
Postpartum depression (PPD) is the occurrence of a major depressive episode with onset during pregnancy or
within the first four weeks following childbirth (American Psychiatric Association, 2013). In contrast to a major
depressive episode outside of the peripartum phase, in PPD, the pervasive negative thoughts are mainly related
to the infant and surrounding sequela. For example, extreme worry about the infant may present at clinically
significant levels (Norhayati et al., 2015) and intrusive thoughts about inadvertent and accidental potential harm
to the infant are ubiquitous (Pearlstein et al., 2009).
In the United States, as many as 1 in 5, up to 20%, of peripartum women experience PPD, although the actual
prevalence may be much higher because of limited screening and/or underreporting (Centers for Disease Control
and Prevention, 2020; Davey et al., 2011).
PPD presents an early risk to the infant, the mother-infant bond, and to the family unit as a whole (Hamdan &
Tamim, 2011).Specifically, PPD is associated with adverse maternal, infant, and child outcomes, such as lower
rates of breastfeeding initiation and shorter duration (Wouk et al., 2017),reduced or poor maternal-infant
bonding (Stein et al., 1991),and infant developmental disorders (Kingston et al., 2012).
Reducing maternal depression has been correlated with positive outcomes for both mother and child, including
mediating improvements in childhood behavioral problems among 3- to 4-year-old children (Shaw et al., 2009).
1.2 STUDY RATIONALE
Published recommendations from the American College of Obstetricians and Gynecologists (ACOG; The
American College of Obstetricians and Gynecologists, 2018), the United States Preventive Services Task Force
(USPSTF) (O’Connor et al., 2016; United States Preventative Services Taskforce, 2016), the American
Psychiatric Association (APA), and the National Institute for Health and Care Excellence (NICE) (National
Institute for Health and Care Excellence, 2020; Pilling et al., 2009) recommend early screening and treatment
for PPD, and some specifically recommend follow-up visits with the maternal care provider. Using the
Pregnancy Risk Assessment Monitoring System (PRAMS), CDC research shows that nationally, about 1 in 5
(20%) women experience symptoms of postpartum depression (CDC, 2020; Bauman et al., 2018). Depressive
symptoms in PPD can last more than 6 months among 25–50% of those affected (Anokye et al., 2018). Among
all postpartum women, approximately 50% have increased anxiety and depression symptoms (Whitton et al.,
1996), yet only 20% report these symptoms to their doctors (Palladino et al., 2011).Almost 60% of peri- and
postpartum women with depressive symptoms do not receive a clinical diagnosis and among those who are
diagnosed, an estimated 50% receive no treatment (Ko et al., 2012).
APA, USPSTF, and NICE recommend evidence-based psychotherapy, specifically cognitive behavioral therapy
(CBT), interpersonal psychotherapy (IPT), and more recently, computerized CBT (cCBT) without medication as
first-line treatment for patients with PPD (National Institute for Health and Care Excellence, 2020; Gelenberg et
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Protocol Number: WB001-001
al., 2010; Yonkers et al., 2009). Psychotherapeutic interventions are also attractive to providers and patients
because they do not involve the risk of exposure to medications that would be present in breast milk (Fitelson et
al., 2010). If psychotherapy and counseling are unavailable or unacceptable to the patient, or if depressive
symptoms become more severe, a trial of an antidepressant can be considered (Sriraman et al., 2015).These
recommendations apply to women with mild to moderate PPD, regardless to if they are breastfeeding. In terms
of specific evidence-based psychotherapeutic approaches, psychological interventions founded in CBT and IPT
have demonstrated substantive evidence and are recommended for PPD specifically (Stamou et al., 2018).
●
CBT
CBT is a manualized psychotherapeutic intervention validated for the treatment of depression based on decades’
worth of rigorous research and has been recommended as a primary line of treatment for depression (David et
al., 2018) including PPD (Huang et al., 2018; Mu et al., 2021. The CBT model postulates a direct and reciprocal
interaction between thoughts, feelings, and behaviors that both helps illuminate understanding of one's overall
emotional distress and situational responses as well as simultaneously highlight areas for intervention.
Specifically, CBT intervenes on cognitions, primarily through challenging and changing automatic thinking
patterns, and behaviors, primarily through behavioral activation (Beck et al., 2011). CBT is a psychosocial
intervention that aims to help the patient challenge their thinking and change maladaptive patterns of behavior,
and it has proven effective, across multiple systematic reviews and meta-analyses, in treating certain psychiatric
disorders such as major depression disorder and anxiety disorders (Barlow et al., 2017; Driessen & Hollon,
2010; Gilson et al., 2009; Knaus, et al., 2014).
●
IPT
IPT has demonstrated efficacy for and is a recommended intervention for depression as well as PPD
(Grigoriadis, et al., 2007). IPT for depression is based in attachment and interpersonal theory and postulates that
the depressive symptomatology has biopsychosocial roots and are therefore in part, consequences of
interpersonal distress in one of four IPT defined problem areas including: role disputes, role transitions, grief,
and interpersonal deficits. IPT for PPD mirrors this theoretical foundation and primarily focuses on role
disputes, role transitions, and grief and loss.IPT targets interpersonal functioning towards the reduction of
clinical symptomatology (Weissman et al., 2008),and it is an efficacious and recommended intervention for
depression (Pilling et al., 2009)as well as PPD (Stuart et al., 2012).
Woebot Health (hereafter noted as the Sponsor) developed WB001 as a digital therapy intended to deliver CBT
and some elements of IPT, to women who have recently given birth, to reduce the symptoms associated with
PPD. As a mobile patient application WB001 is a treatment modality that may fill an unmet need for patients
with PPD to access psychotherapeutic tools, under clinical supervision and as an adjunct to treatment-as-usual
(TAU) which includes follow-up visits, psychotherapy, or medication (or some combination thereof).
This study is being conducted to evaluate and compare the efficacy of [WB001+TAU] and an educational
control (ED001) [ED001+TAU] on reducing symptoms of PPD as measured by the 6-item Hamilton Rating
Scale for Depression (HAM-D6) among women diagnosed with mild to moderate PPD.
1.3 INVESTIGATIONAL DEVICE
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DENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
WB001 is a smartphone application designed for an 8-week treatment period, as an adjunct to TAU for women
aged 22-45 years with mild to moderate postpartum depression. Specifically, women must have given birth in
the previous 92 days and have no active or recent history with substance(s) abuse, not be currently psychotic,
have no lifetime occurrence of psychosis, schizophrenia or bipolar disorder, or a history of suicide attempt or
suicidal ideation or a plan or intent to harm oneself during the current episode of postpartum depression, or
history of homicidal or infanticidal ideation via self-report. WB001 is intended as a prescription-only adjunctive
treatment under the supervision of a clinician.
WB001 was developed based on evidence for mobile mental health applications, and factors associated with
positive outcomes in the literature proposed by Bakker and colleagues (2016), including the following:
●
Built on a CBT framework
●
Incorporates automated tailoring
●
Provides mental health information
●
●
Addresses both anxiety and depressed mood
●
Simple and intuitive interface and interactions
●
Real-time patient engagement and check-in reminders
1.4 THE WB001 PLATFORM
A. DEEP UNDERSTANDING OF THE LIVED EXPERIENCE OF WOMEN WITH PPD
This device was developed through a multi-phased design process to imbue a deep understanding of the lived
experience of women with PPD as well as an understanding of the day to day lives of women who have recently
given birth. Women, as well as clinicians, including psychologists, psychiatrists, and obstetricians, who
specialize in the treatment of women with PPD were interviewed about their experience to understand the
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
breadth and nuance of clinical presentation.
   
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Protocol Number: WB001-001
Therapeutic working alliance is a construct long recognized as meaningful and predictive of outcomes in
psychotherapeutic research (Ardito et al., 2011). The Sponsor has completed a series of studies to understand if
Woebot establishes a working alliance, as measured by the Working Alliance Inventory short form (WAI-SR), a
widely accepted and psychometrically valid assessment tool (Darcy et al., 2021). Published results from a
cross-sectional, retrospective analysis with more than 36,000 Woebot users indicated a working alliance with
Woebot was established within 5 days of initial app use and that the level of alliance was sustained through 8
weeks of application use (https://formative.jmir.org/2021). Moreover, the level of working alliance endorsed was
analogous to those from recent literature on traditionally delivered outpatient CBT.
results from an RCT of adult women (n =192; 46% White) who had recently given birth indicated that women
randomized to the WB001 established a working alliance with Woebot (Ramachandran et al., 2020).
C. OPTIMIZES TREATMENT EXPOSURE THROUGH A TRULY SCALABLE TECHNOLOGY
Despite the evidence base of efficacious therapies for PPD, there are several individual and systemic barriers to
treatment access that are specific to this population and underserved populations. These barriers include lack of
time, childcare issues, stigma, and fear of loss of parental rights, plus the lack of available psychotherapy and a
desire to avoid pharmacological interventions (Manso-Córdoba et al., 2020).
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BENEFIT/RISK ASSESSMENT
Potential benefits of participating in this study include improved mood, improved mother-infant bonding and
wellbeing of the infant, the acquisition of practical psychotherapeutic skills and increased knowledge of mental
health. Improved mood could lead to other benefits such as improved interpersonal functioning, ability to return
to work (if applicable), and improved performance at work.
Overall, there is also a low risk associated with participation in the study due to the study’s
due diligence to screen and exclude patients with severe depression and other psychosis history or substance
abuse. The primary potential risk to the participant that could lead to AEs is the worsening of negative
symptoms of PPD. These and other potential risks may be considered minimal, and no greater than those
associated with depression behavioral therapies for the treatment of PPD. The participants may experience some
AEs due to their underlying condition and/or with the use of adjunctive treatment. The risk profile of standard of
care used in clinical practice is well understood and is detailed in their respective package inserts.
However, potential risks include the opportunity cost of seeking alternative treatment, device software failure,
leading to delayed access, information security breaches, and potentially brief emotional stress that may result
from attending key assessment visits, completing survey questions that cover sensitive topics, and discontinued
access to the assigned study intervention at the end of study (Week 8).
Several aspects of the study design will mitigate these potential risks of participating in the study:
●
adjunct.
●
The eligibility criteria will exclude patients with severe psychiatric diagnoses (e.g., psychosis, history of
attempted suicide or current suicidal ideation, substance use disorder).
●
Concomitant medications and psychotherapy are allowed during the study period per standard of care as
prescribed and administered by trained professionals, as long as the medication doses and frequency of
psychotherapy are stable for at least 4 weeks before the Baseline visit. The study will capture any
changes (e.g., starting or stopping a medication or any change in medication dose or frequency, as well
as changes in frequency of psychotherapy).
●
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Survey Questionnaires have been thoughtfully selected to minimize the risk of emotional upset due to
the topics covered.
●
Woebot performing appropriate software verification and validation testing to demonstrate that
the device’s behavioral therapy has been correctly implemented so that the participant can access it
when needed.
●
All study data will be gathered on a secure Health Insurance Portability and Accountability Act
(HIPAA)-compliant web platform and will be encrypted to minimize the risk of a data breach.
●
Participants will be informed that they may leave the study at any time and can receive appropriate
referrals for alternative treatment.
●
Participants will have contact with the investigator and/or designated clinical rater at each study
assessment time point, who will administer validated psychometric assessments to monitor for
worsening symptoms and/or the development of suicidal ideation.
●
Study withdrawal criteria are designed so that participants who experience worsening of symptoms can
withdraw from the study to receive additional treatment, per PI recommendation.
●
A Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC) will be established
with clear rules around study stopping criteria and appropriate assessment of participant safety.
Considering the measures taken to minimize the risks to participants participating in this study, the potential
risks identified in association with WB001 are justified by the anticipated benefits that may be afforded to
participants with PPD.
2. STUDY OBJECTIVES AND ENDPOINTS
The study objective is to determine if WB001 used adjunctively with TAU can further reduce symptoms of
depression for women with mild to moderate PPD beyond that of an educational control application and TAU, at
the end of the 8-week treatment period as measured by the change in HAM-D6. The endpoints to support the
study objectives are listed in Table 1.
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Protocol Number: WB001-001
TABLE 1
STUDY OBJECTIVES, HYPOTHESES, AND ENDPOINTS
Objective
Endpoint
Primary Objective: To evaluate the efficacy of
[WB001+TAU] vs [ED001+TAU] on depressive
symptoms as measured by a structured clinical
interview (with the Hamilton Depression Rating Scale
(HAM-D) among women diagnosed with PPD.
Difference in HAM-D6 scores between arms at
end of treatment (EOT) controlling for baseline
(BL) and other covariates
Secondary Objectives:
●
To evaluate the efficacy of [WB001+TAU] vs
[ED001+TAU] on indices of clinical interest
including (1) the Mother-Infant Bonding Scale
(MIBS), (2) Edinburgh Postnatal Depression
Scale (EPDS), (3) Patient Health Questionnaire
(PHQ), and (4) Generalized Anxiety Disorder
(GAD)
●
To evaluate the within-group differences on the
HAM-D in the [WB001+TAU] and
[ED001+TAU] arms
●
Difference between arms in indices
(MIBS; EPDS; PHQ; GAD) at EOT
controlling for BL and other covariates
●
Difference in HAM-D6 scores from BL to
EOT within each trial arm
Exploratory Objective: Investigate clinically significant
between group differences of [WB001+TAU] vs
[ED001+TAU] on the Clinical Global Impression
(CGI) scales and Patient Global Impression (PGI)
scales
Difference between arms on Clinical Global
Impression of Improvement and Severity
(Clinical Global Impression Improvement
(CGI-I) the CGI-Severity (CGI-S)) and Patient
Global Impression Scales (Patient Global
Impression Change (PGI-C) and Patient Global
Impression Severity (PGI-S)).
AE=adverse event; BL=baseline assessment; Clinical Global Impression - Improvement and Severity (CGI-I; CGI-S).
EOT=end of treatment assessment; EPDS= Edinburgh Postnatal Depression Scale; GAD=Generalized Anxiety Disorder
Questionnaire; MIBS=Mother-to-Infant Bonding Scale; Patient Global Impression – Change and Severity (PGI-C; PGI-S);
PHQ = Patient Health Questionnaire; SAE=serious adverse event
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
3. STUDY DESIGN
3.1 OVERALL STUDY DESIGN
This is a multicenter, double-blind, randomized, controlled trial to evaluate the efficacy and safety of WB001 in
adult women with mild to moderate PPD. Eligible participants must have diagnosis of mild to moderate PPD
and experience at least mild to moderate symptom severity as evidenced by a score of > 7 and < 13 (i.e.,
between 8-12, inclusive) on the HAM-D6.
The study will utilize referrals by an obstetrician, pediatrician, or other healthcare professional, or by other
digital and site based recruitment methods and direct participants to the closest study site, across up to 25 study
centers in the U.S., to schedule and complete a pre-screening/screening appointment. From there, the site staff
will schedule their first office visit, during which the site staff with oversight by the investigator, will obtain
informed consent and complete the screening and BL assessments. The CIR will be responsible for
administration of the HAM-D for the primary endpoint as outlined in Appendix 3: Schedule of Events. To
standardize and facilitate administration of the primary endpoint, the Structured Interview Guide for the
Hamilton Depression Rating Scale (SIGH-D) will be used (Williams, J.B. 2015).
Participants will then be randomized in a 1:1 manner to either [WB001+TAU] or [ED001+TAU] and will be
prompted to install the app on their smartphone. Study site personnel will help the participants with the app
installation to streamline enrollment. Participants in both groups will participate in a form of TAU, which is
clinician supervised outpatient care including, follow-up visit(s), psychotropic medication, psychotherapy, or
some combination thereof.
Both treatment arms will be presented as possibly helping to improve PPD and both will be
described as the study app so that there is no distinction made to the participants about WB001 or the digital
educational control app. Post-randomization, the 8-week treatment period begins when the participant
successfully downloads the study app and completes the integrated onboarding process.
Participants will attend a mid-study and EOT (at Week 4 and Week 8) telehealth visit with a CIR, to be assessed
based on the HAM-D, a validated standard clinician-rated and participant-rated outcome scales for PPD. Any
AE/SAE raised during CIR-administration of HAM-D, will be raised to the PI or qualified designee for final
determination on appropriate course of action. At Week 4 and Week 8 the PI or qualified site staff will
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administer the C-SSRS, evaluate for concomitant medications/therapy, pregnancy status, and safety throughout
the duration of the trial.
At Week 4 and 8, participants will be prompted to complete several online self-report assessments (e.g., EPDS,
PHQ-9, MIBS, GAD-7 and PGI) within 3-days prior to or 3-days after the visit date. The same assessment steps
in Week 4 will apply to Week 8 (EOT) visits, with the addition that at Week 8 participants will receive
instructions about how to uninstall the app and will go through other end-of-study procedures.
Not including the referral period and potential for participants to complete the last
self-reported assessments 3 days after the week 8 visit, the duration of study participation is 8 weeks. Figure 3
shows the overall Study Schematic.
Figure 3.
Study Schematic
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3.2 RATIONALE FOR DURATION OF TREATMENT
As discussed, CBT and IPT have robust efficacy for the treatment of depression in adults including PPD.
Although there is no exact standard length of treatment (cognitive behavioral therapy, 2011), flagship models of
CBT and IPT were delivered over the course of 12-20 sessions. However, briefer interventions, including guided
self-help adaptations of the therapies, have demonstrated meta-analytic level efficacy and durability of effect for
depression, including those which are six or fewer weekly sessions (Cuijpers, et al., 2019). Typically, CBT
guided self-help delivery ranges from 6 to 8 sessions total (Barth, et al., 2013). A 2021 meta-analysis of online
CBT guided self-help interventions found no significant differences on depression outcomes between groups
that were short (≤4 weeks), moderate (= 4-8 weeks), and greater (≥8 weeks) in length (Ma et al., 2021).
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3.4 SCIENTIFIC RATIONALE FOR STUDY DESIGN
To prevent bias in treatment allocation and assessment of treatment effect, the study is randomized.
The chosen efficacy objectives and endpoints represent standard assessments used in clinical studies of
treatments for depression and reflect clinically meaningful outcomes for patients with PPD and the clinicians
who treat them.
The safety data will also add to the Sponsor’s understanding of AEs that might be associated
with WB001.
The study is designed with telehealth visits, which are more convenient for study participants , and
accommodate the need to comply with recommended social distancing recommendations for reducing
transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
A participant is considered to have completed the study if she has completed at least BL and Week 4 or Week 8
for primary HAM-D6. The end of the study is defined as the date of the last visit or last procedure of the last
participant in the study.
3.5 BLINDING
This is a double-blind study. Participants will not be made aware to which intervention they are assigned and
will be randomized to receive the active treatment app (WB001) or the Educational Control (ED001). Thus,
participants, clinicians, and the clinical site study team will be blinded to treatment allocation to the extent
possible throughout the study period and database lock.
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TABLE 2 BLINDING PLAN
Role
Event
Randomization /
Treatment
Allocation
Week 4, 8
Assessments
Interim Analysis
Final Analysis
Participants
B
B
B
B
PI and Site staff to
administer assessments
B
B
B
B
One Site Coordinator
to assist with app
registration/download
UB
UB
UB
UB
Site/Central
Independent Rater
B
B
B
B
DSMB Statistician will
generate the
randomization
schedule and run
analysis queries
requested by DSMB
members
UB
UB
UB
UB
Independent (non
DSMB) statistician and
B
B
B
B
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programmer/data
analysts for Interim
Analysis and Final
Analysis (prespecified
in SAP)
B = Blinded; UB = Unblinded
3.6 PROCEDURE FOR BREAKING THE BLIND
In the event that a CIR, PI, or blinded site staff member is inadvertently unblinded, the site will be provided with
SOPs detailing the appropriate procedure for each of the following scenarios:
1.
Unblind a participant and or other study staff in an emergency situation
2.
Unblind data for the purpose of notification to the Data Safety Monitoring Board (DSMB)
3.
Manage and mitigate accidental unblinding
In the case of an emergency, the investigator has the sole responsibility for determining if unblinding of a
participants’ intervention assignment is warranted. Accidental unblinding, which may occur during discussions
between the participant and trial PI and site staff, would not impact the primary endpoint which will be collected
by CIRs. Any potential unblinding at the CIR level may trigger replacement of the rater. All instances of
unblinding will be recorded and assessed for comparability between the groups.
4. STUDY POPULATION
Eligible participants who are enrolled in the trial will be assigned a unique participant randomization number for
study app functionality assignment at baseline. Only participants who meet all the inclusion criteria and none of
the exclusion criteria will be eligible to participate in the study. Prospective approval of protocol deviations to
recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
4.1 INCLUSION CRITERIA
A participant will be eligible for entry into the study if all the following inclusion criteria are met:
1.
Participants must have primary residence in the United States
2.
Participant must be willing to comply with all study procedures and restrictions
3.
Participants must be able to understand and be willing to provide informed consent
4.
Participants must be ≤92 days postpartum at the time of screening
5.
Participants must be women aged 22-45 years who had onset of a major depressive episode during
pregnancy or within 4 weeks following delivery according to DSM-5 diagnostic criteria (Segre et al.,
2013)
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7.
Participants must own or have regular access to a smartphone (Android or iOS smartphone with a
recent, supported operating system), and has reliable Wi-Fi access or sufficient data plan to engage with
assigned treatment condition for the duration of the study
8.
Participants must have current mild-moderate depression as measured by the HAM-D6 score > 7 and
< 13 at Screening (Bech et al., 2007; Pridmore et al., 2020)
9.
Participants must confirm having a form of TAU, defined as clinician supervised outpatient care
management and includes follow-up visits, medication, psychotherapy, or some combination thereof.
10. As part of TAU during the study, any confirmed concomitant medications and psychotherapy are
permissible and must be regularly scheduled or stable (i.e., dose and frequency, respectively) for over 4
weeks prior to BL visit
4.2 EXCLUSION CRITERIA:
A participant will not be eligible for study entry if any of the following exclusion criteria are met:
1.
Gestation less than 28 weeks
2.
HAM-D6 score, ≤7 or ≥13 (severe depression) at Screening
3.
Currently pregnant or plans to become pregnant within the next 8 weeks
4.
History of drug and/or alcohol use disorder within the past 12 months as measured by the SCID-5-CT
5.
Lifetime history of suicide attempt or ideation with a plan and intent to harm oneself during the current
episode of PPD
6.
Current or lifetime psychosis, including history of post- or peri-partum psychosis as measured by the
SCID-5-CT (Williams JB, 2015)
7.
Current or lifetime history of schizophrenia, schizoaffective disorder, bipolar disorder, and/or homicidal
or infanticidal ideation as measured by the SCID-5-CT
8.
History of antidepressant treatment with ketamine/esketamine, electroconvulsive therapy, vagal nerve
stimulation, or a deep brain stimulation device
10. Fetal demise within the past 18 months
11. Previous Woebot use
4.3 RATIONALE FOR ≤3 MONTHS POSTPARTUM
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While timing of PPD indicates that the onset of a major depressive episode can occur anytime during pregnancy
or within the first 4 weeks after giving birth, the protocol has specified that a woman is potentially eligible to
participate in the proposed trial up to 3 months after giving birth. This 3-month period allows time for a woman
to be screened for depression at their initial postpartum physical examination with their
Obstetrician-Gynecologists, as recommended by ACOG and is the rational for stipulating ≤92 as an inclusion
criterion for this study. Specifically, this initial in-person, postpartum physical exam, which is recommended
standard of care practice, occurs soon after birth or within a few months after birth, depending on method of
delivery. ACOG and other professional guidelines recommend screening for PPD at these postpartum visits
(O’Connor et al., 2016; United States Preventative Services Taskforce, 2016). The 3-month period for the study
allows women to be screened for depression or present for treatment while still maintaining alignment with the
clinical definition for onset of PPD.
4.4 MINIMUM TECHNOLOGY REQUIREMENTS
Participants should have routine access to their smartphones for the duration of the trial. In order to support the
study application, participants’ smartphones must meet the minimum necessary operating system requirements
(Apple iOS 13 and Android OS 8). In addition, they should be able to attend in-clinic and remote telemedicine
visits during the trial as outlined in Appendix 3: Schedule of Events.
4.5 SCREEN FAILURES
Participants who consent to participate in the clinical study but fail screening are not subsequently entered in the
study. A minimal set of screen failure information is required to ensure transparent reporting of participants who
fail screening, to meet the Consolidated Standards of Reporting Trials publishing requirements (Bhatt, 2022),
and to respond to queries from regulatory authorities. Minimal information includes demographics, screen
failure details, eligibility criteria, and any AE/SAEs. Re-screens for medication or psychotherapy stability may
only be permitted with investigator approval, given all other inclusion/exclusion criteria are still met.
De-identified participant ID numbers assigned to participants who screen fail will not be reused.
4.6 STUDY DISCONTINUATION OR WITHDRAWAL
Discontinuation of study treatment for a participant occurs when study treatment is stopped earlier than the
protocol planned duration and can be initiated by either the participant or the investigator. The investigator must
discontinue study treatment for a given participant if he/she believes that continuation would negatively impact
the participant’s well-being. Involvement in the study is strictly voluntary. Participants have the right to
withdraw from the study at any time for any reason, without any reprisal.
Participants should be discontinued from the study if any of the following occur:
1.
The participant withdraws consent to participate in the study
2.
The participant develops an illness that would interfere with her continued participation in the study
3.
The participant has an SAE rated as Grade 3 (severe) or higher (see Table 3 Clinical Concerns
Categorizations)
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4.
The participant is noncompliant with treatment schedule, study procedures, in the opinion of the investigator
and per the protocol, where applicable
5.
The participant is confirmed to be pregnant (by self-report during scheduled assessment with the
investigator/qualified site staff at Week 4 and 8)
6.
The PI, Sponsor, IRB, or regulatory agency requests withdrawal of the participant
7.
Any other reason relating to the participant's safety or integrity of the study data as determined by the
DSMB
Participants who withdraw from the study may be replaced. Participants who withdraw or are withdrawn from
the study cannot subsequently rejoin the study.
If a participant withdraws or is withdrawn from the study, the study Sponsor, sites, and DSMB will be informed
immediately. If there is a medical reason for withdrawal, the participant will remain under the supervision of the
investigator until satisfactory health has returned or appropriate referrals have been made and executed upon.
Unless a participant withdraws consent for follow-up procedures, they should continue to attend all scheduled
study telehealth visits, including the EOT visit. Even if a participant declines to participate in the remaining
scheduled telehealth visits, she will be encouraged to attend an early withdrawal visit, with the same
assessments as the Week 8 EOS visit, as indicated in Appendix 3: SoE.
If the participant withdraws consent for disclosure of further information, the Sponsor may retain and continue
to use any collected data before such a withdrawal of consent.
Although a participant is not obliged to give a reason for withdrawing from a study, the investigator should
make a reasonable effort to ascertain the reason, while fully respecting the participant's rights.
4.7 LOST TO FOLLOW-UP
A participant will be considered lost to follow-up and withdrawn from the study if they fail to attend both
scheduled key assessments visits (Week 4 and Week 8) and are unresponsive to multiple reminders and
communication from the study site. Participants that miss one key assessment visit (Week 4 OR Week 8) will be
permitted to continue in the study.
The following actions must be taken if a participant fails to attend a required telehealth study visit:
●
The site must attempt to contact the participant and reschedule the missed visit as soon as possible, counsel
the participant on the importance of maintaining the assigned visit schedule and ascertain whether the
participant wishes to and/or should continue in the study.
●
Before a participant is deemed lost to follow-up, the investigator or site staff designee must make every
effort to regain contact with the participant, where possible. Sites will be instructed to complete at least 3
separate outreach attempts to participant via phone, text, or email (with 1 being a direct telephone call).
These contact attempts should be documented in the participant’s electronic case report form (eCRF) and in
the EDC system.
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5.
DESCRIPTION OF STUDY ASSESSMENTS
Study assessments and procedures, including their timing over the 8 weeks of treatment are outlined in the SoE
(see Appendix 3) and described in the subsequent subsections. Participants will be instructed to adhere to the
study design schedule and to complete all required assessments and procedures. The CIR-administered HAM-D
will be administered by clinical psychologists who have been appropriately trained. The Protocol Supplement
(separate document) provides more detail on the specific study assessments, including response options, scoring
etc.
5.1 GENERAL SCREENING/BASELINE ASSESSMENTS
After obtaining informed consent from the participant, the PI or site staff will assess the participant for eligibility
as outlined in the inclusion/exclusion criteria and administer screening/baseline assessments (see Appendix 3).
Some assessments are for screening purposes only, e.g., the Structured Clinical Interview for DSM-5 - Clinical
Trials Version (SCID-5-CT).
The SCID-5-CT (First, et al., 2016) is a structured diagnostic interview for diagnosing the major psychiatric
disorders found in DSM-5 that is tailored and streamlined to the primary inclusion criteria of the study. It is
administered by a clinician or trained mental health professional who is familiar with the DSM-5 classification
and diagnostic criteria. The interview participants may be either psychiatric or general medical patients—or
individuals who do not identify themselves as patients, such as participants in a community survey of mental
illness or family members of psychiatric patients. The SCID-5-CT is used in the research context to assess
common disorders in mental health and will be customized for this study to specifically assess the diagnoses of
major depressive disorder (MDD), current and lifetime diagnosis of a psychotic disorder including postpartum
psychosis and Schizophrenia. Participants will also be assessed for bipolar disorder, homicidal or infanticidal
ideation, and history of drug and/or alcohol use disorder within the past 12 months, in accordance with the
inclusion criteria.
DEMOGRAPHICS
Demographic data, including year of birth/age, sex, ethnicity, and race, will be recorded.
PREVIOUS AND CONCOMITANT MEDICATIONS AND THERAPY
Previous and concomitant medications and therapy will be recorded by self-report at the time of
screening/baseline visit and reconciled by study personnel. Any changes in medication and/or therapy would be
confirmed through the study period. For this study, concomitant medications are those being taken at the time of
screening or during the study.
At a minimum, concomitant medications will include all Rx drugs, standing or pro re nata (PRN) medication for
dose, route, and frequency. The study will allow for exceptions of collecting common over the counter (OTCs)
(e.g., ibuprofen, acetaminophen) and prescription medications (e.g., antibiotics) for minor transient ailments
(i.e., non-sedating antihistamines to treat seasonal allergies or a cold). The following details must be recorded:
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●
Medication name (generic name)
●
Reason for use
●
Start and end date of administration
●
The dose and frequency of administration
●
Participation in psychotherapy
●
The frequency of psychotherapy sessions
●
Primary reason for psychotherapy
The PI should be contacted if there are any questions regarding concomitant medication.
Any changes in concomitant medications meaning a change in dose or frequency of a medication or the
introduction of a new intervention or discontinuation of existing intervention will be recorded by site staff,
whether the medications are for PPD, MDD, or other conditions.
MEDICAL HISTORY
Medical history, including previous and ongoing illnesses (including psychiatric), will be recorded by site staff,
with the start date and end date (if applicable) of the illness or condition. Any pre-study procedures will be
recorded in the eCRF as part of the medical history assessment. Any AEs that begin between the time of
informed consent and the first use of the blinded study intervention will be recorded as an AE/SAE and
unrelated to the device.
PREGNANCY HISTORY AND PREGNANCY STATUS
Obstetrical medical history, including total number of previous pregnancies, will be recorded by site staff in the
eCRF, with applicable dates.
Although pregnancy is exclusionary and a participant who becomes pregnant during the study will be
withdrawn, there are no protocol-specific requirements for pregnancy testing or contraceptive use. Changes in
pregnancy status will be completed via self-report during key assessment visits. There are no precautions
regarding breastfeeding during the study because the intervention is not a medicinal product.
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5.2 EFFICACY ASSESSMENTS
The following table summarizes the efficacy and safety assessments that will be used for primary, secondary,
and exploratory endpoints during the study period.
Assessment
Endpoint Type
Definition
HAM-D
Primary
●
The HAM-D17 is a 17-item clinician-rated measure of
depression (Hamilton, 1960).
●
The HAM-D6 is a subset of the HAM-D17 that assesses 6 core
items associated with major depression: depressed mood (item
1), feeling of guilt (item 2), difficulty performing work and
activities (item 7), motor retardation (item 8), psychic anxiety
(item 10), and somatic symptoms (general, i.e., low energy and
bodily pain) (item 13)
●
Item 13 is scored 0 to 2 (0 = none/absent to 2 = most severe) and
all other items are scored 0 to 4 (0 = none/absent to 4 = most
severe).
●
Total score ranges from 0 to 22 and a higher score indicates
greater severity of depression.
●
The HAM-D is commonly used for diagnostic purposes in
research, and structured clinical interviews such as this are
recommended to formally diagnose clinical depression
(Norhayati et al., 2015).
●
The HAM-D17 will be administered at baseline via the
Structured Interview Guide for the Hamilton Depression
Rating Scale (SIGH-D 17-item HAM-D), at Week 4, and Week 8
to derive HAM-D6
EPDS
Secondary
●
A brief self-report questionnaire used as a screening tool to
identify patients who are at risk for perinatal depression (Cox
et al., 1987; Wisner et al., 1994).
●
The 10-item scale assesses depression criteria (including
anhedonia, anxiety, sleep disturbance, and suicidal ideation) in
the past seven days.
●
Each item has four ordinal response options, yielding a total
score of 0 to 30 where a higher score denotes greater depression
(values ≥10 denote possible depression).
●
The EPDS is a widely used measure with demonstrated
reliability and validity for the assessment of depression (Yawn
et al., 2009; Zhong et al., 2014), and is also routinely used in
clinical care practice for the assessment of patients with PPD.
●
The EPDS will be administered at baseline, Week 4, and Week
8.
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PHQ-9
Secondary
●
A 9-item, self-report questionnaire that evaluates frequency and
severity of depression symptoms within the previous 2 weeks.
●
The 9 items are based on the DSM-4 criteria for major
depressive disorders (American Psychiatric Association, 2000).
●
Each item is scored on a 4-point Likert scale from 0 (not at all)
to 3 (nearly every day).
●
It is a widely used self-report measure; it has demonstrated
reliability and sensitivity to clinical change.
●
Scores of 5, 10, 15, and 20 represent cut points for mild,
moderate, moderately severe, and severe depression,
respectively (Kroenke & Spitzer, 2002).
●
The PHQ-9 will be administered at baseline, Week 4, and Week
8.
GAD-7
Secondary
●
This is a 7-item, self-report questionnaire for assessing how
often respondents have been bothered by anxiety symptoms
over the last two weeks (Spitzer et al., 2006).
●
Each item has 4 ordinal response categories: Not at all (0);
Several days (1); More than half the days (2); Nearly every day
(3). Responses are summed to yield a score from 0-21, where
higher scores denote greater anxiety
●
Scores of 5, 10, and 15, represent cut points for mild, moderate,
and severe anxiety, respectively (Spitzer et al., 2006).
●
It has demonstrated reliability, validity, and responsiveness
(Dear et al., 2011).
●
The GAD-7 will be administered at baseline, Week 4, and Week
8.
MIBS
Secondary
●
A self-report questionnaire consisting of 8 words such as
‘‘loving,’’ “joyful,” or ‘‘disappointed.”
●
Mother’s rate each of the 8 words using a 4-point Likert scale
(very much, a lot, a little, or not at all) to indicate how they feel
about their baby in the first few weeks.
●
Five of the words describe negative emotional responses and are
reverse scored (Taylor et al., 2005).
●
Total scores can range from 0 to 24, with lower scores
indicating good bonding.
●
The MIBS will be administered at baseline, Week 4, and Week
8.
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CGI-S
Exploratory
●
A single item, 7-point Likert scale to measure the overall
severity of the patient’s current clinical presentation and
symptomatology. (Busner et al., 2007)
●
The investigator will rate the participant’s severity of illness
based on clinical interviews and assessments relative to their
experience with other patients with the same diagnosis.
●
Response choices include 0 (not assessed) and range from 1
(Normal, not at all ill) to 7 (Among the most extremely ill
patients).
●
The CGI-S will be administered at baseline, Week 4, and Week
8.
CGI-I
Exploratory
●
A single item, 7-point Likert scale to measure the overall
improvement in the patient’s condition at the end of treatment.
(Busner et al., 2007)
●
The investigator will rate whether the participant's total
improvement was due entirely to the intervention.
●
Response choices include 0 (not assessed) and range from 1
(very much improved) to 7 (very much worse).
●
The CGI-I will be administered at Week 4 and Week 8.
PGI
Exploratory
●
The Patient Global Impression scale (PGI), also known as
Subject Global Impression (SGI), is the PRO counterpart to the
Clinical Global Impressions scale, (CGI), which was published
in 1976 by the National Institute of Mental Health (US).
(Snyder et al., 2020)
●
Consists of one item based on the CGI and is adapted to the
patient.
●
The PGI mainly measures change in clinical status (PGI-C) but
can also measure disease severity (PGI-S) or disease
improvement (PGI-I).
●
PGI-S is administered at baseline, Week 4, and Week 8; PGI-C
is only administered at Week 4 and Week 8.
Client Satisfaction
Questionnaire
Other/
Exploratory
●
Participants will be prompted to complete an 8-question Client
Satisfaction Questionnaire (CSQ) to assess their level of
satisfaction with WB001 vs. ED001 applications.
●
The CSQ will be administered at Week 8.
5.3 SAFETY ASSESSMENTS
To further manage risk in this clinical trial of WB001, the study will incorporate validated psychometric
assessments conducted at regular intervals to monitor for worsening symptoms and/or the development of
suicidal ideation. The study population will only include participants with mild-moderate depression (inclusion
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criterion) and specifically excludes patients with severe depression and prior history of treatment-resistant
depression (exclusion criteria). The study will also appropriately monitor worsening of symptoms through the
following:
a.
Administering the C-SSRS at BL, Week 4, and Week 8
b.
Administering the PHQ-9 (item #9), EPDS (item #10), and HAM-D (item #3) at BL, Week 4, and Week
8
c.
This protocol continues to adhere to FDA guidance that appropriate assessments, such as assessing for
AE/SAEs and administering the C-SSRS, should occur at each planned visit wherein the other clinical
assessment will be administered. Thus, the assessment schedule for the C-SSRS mirrors that of the
HAM-D.
d.
Study participants are welcome to initiate contact anytime throughout the duration of the study with
their site. If the contact is attributable to safety reasons, then an Unplanned Visit would ensue, wherein
qualified study personnel would follow-up with the participant in a timely manner, and if needed
administer the C-SSRS.
Scenarios that would trigger an escalation for an Unplanned Visit include:
●
ADVERSE EVENTS
At each telehealth visit, the PI and site staff will evaluate participants for any changes that could indicate AEs.
Participants with AEs will be followed, recorded in the EDC and reported in line with the procedures described
in Section 7. Participants will be instructed to contact the study site if any new symptoms occur in between the
weeks of telehealth visits. The CIR is responsible for detecting, documenting, and recording any potential safety
events based on the administered HAM-D (i.e., score of ≥2 on HAM-D17 item #3) that may meet the definition
of an AE or SAE, but the investigator will remain responsible for following up on all safety events to confirm if
an AE/SAE has occurred and determine the appropriate course of action. The method of recording, evaluating,
and assessing causality of AEs and SAEs and the procedures for completing and transmitting SAE reports are
provided in Section 7.
SUICIDAL IDEATION AND BEHAVIOR RISK MONITORING
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The study design includes assessment of suicidal ideation as described. All participants will meet with the
investigator or qualified site staff at Baseline, Week 4, and Week 8 during a telehealth visit, and will be
administered psychometric tests (i.e., C-SSRS and HAM-D item #3) to assess suicidal ideation.
C-SSRS
The clinician-administered C-SSRS is a measure used to identity and assess individuals at risk for suicide (The
Columbia Lighthouse Project/Center for Suicide Risk Assessment, 2019). The C-SSRS measures four
constructs: the severity of ideation, the intensity of ideation, behavior, and lethality. The C-SSRS is made up of
ten categories, with binary responses (Yes or No) to indicate presence or absence of the behavior, and the
outcome is a numerical score obtained from these categories. The C-SSRS will be administered by the
investigator or qualified site staff during telehealth visits at baseline, Week 4, and Week 8 to monitor for
potential onset of suicidal ideation. If a score on the C-SSRS raises a safety concern, i.e., ‘yes’ on questions 4 or
5, or answer ‘yes’ to “actual attempt” question in “Suicidal Behavior” section the site-based rater will
immediately contact the PI/sub-investigator to ensure that the investigator urgently conducts an assessment of
this participant to determine the appropriate actions to take and disposition of the participant. Similarly, if a
safety concern is raised due to a score submitted through a CIR administered structured clinical interview (a
score of ≥2 on the HAM-D17 item #3) or self-report ePROs (a score of ≥2 on item #9 of PHQ-9 and/or score of
>2 on item #10 of EPDS), an electronic system at the sites will notify the investigator to review each incident
and follow up with the participant within 24 hours to determine if any action is required. If so, the investigator
will be responsible for administering a formal assessment using the C-SSRS, if deemed necessary.
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PREGNANCY AND BREASTFEEDING
Although pregnancy is exclusionary and a participant who becomes pregnant during the study will be
withdrawn, there are no protocol-specific requirements for pregnancy testing or contraceptive use. Changes in
pregnancy status will be completed via self-report during key assessment visits. There are no precautions
regarding breastfeeding during the study because the intervention is not a medicinal product.
Details of all pregnancies in female participants will be collected after the start of study intervention and until
end of Week 8.
If a pregnancy is reported, the site staff and/or investigator will record pregnancy information in the EDC and
submit it to the Sponsor within 24 hours of learning of the female participant's pregnancy and initiate
withdrawal from the study.
12-LEAD ELECTROCARDIOGRAM, VITAL SIGNS, AND PHYSICAL EXAMINATIONS
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These assessments are not scheduled as part of the study; however, if deemed necessary, the investigator may
arrange for participants to be referred for medical evaluation.
UNSCHEDULED VISITS
Study participants are welcome to initiate contact anytime throughout the duration of the study with their site. If
the contact is attributable to safety reasons, then an Unscheduled Visit would ensue, wherein the qualified study
personnel would follow-up with the participant, and if needed administer the C-SSRS.
5.4 HEALTHCARE UTILIZATION
Healthcare service utilization will be assessed via participant reports. At Day 1 and at each subsequent
assessment, participants will be asked to indicate the number of all-cause and (separately) mental health-related
encounters or visits they had for themselves in the previous month/4 weeks within the following categories of
service: inpatient (hospital), emergency department, and outpatient medical; outpatient psychotherapy and
psychotropic prescription utilization will also be assessed. Additionally, participants will be asked at each
assessment (Weeks 4 and 8) to report the healthcare service utilization (i.e., inpatient/hospital, emergency
department, and outpatient services) of their new babies during the previous month/4 weeks.
5.5 BLINDING ASSESSMENT
The success of maintaining the participant blind will be evaluated by the ‘Program Assignment Assessment’.
This two question patient reported scale will be administered at Week 8 and ask participants to select the
treatment group which they believe they were assigned to (see additional details in the SAP).
6.
STUDY STOPPING RULES
Study procedures will be stopped if the Sponsor in discussion with the DSMB, IRB, and/or investigator(s), as
applicable, determines that the number and/or severity of AEs or abnormal safety monitoring tests justify putting
the study on hold. See Section 7.4 Data Safety Monitoring Board (DSMB).
The investigator may initiate study-site closure at any time, provided there is reasonable cause and sufficient
notice is given in advance of the intended termination.
The study may resume following the safety review, if the PI and Sponsor agree it is safe to proceed.
Study sites will be closed upon study completion. A study site is considered closed when all required documents
and study supplies have been collected and a study-site closure visit has been performed.
6.1 EARLY STUDY TERMINATION
The study can be terminated by the Sponsor at any time. Reasons for early termination include:
●
Study recruitment or retention is too low for the study to provide meaningful results
●
Unanticipated, significant, or unacceptable safety risk to participants enrolled in the study
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Decision based on recommendations from PI and DSMB after review of safety and efficacy data
●
Discontinuation of study if PIs, in collaboration with study clinicians and DSMB, determine from
planned analyses that the app is not efficacious or if there are safety concerns.
In taking the decision to terminate, the Sponsor and DSMB will always consider the participants’ welfare and
safety. Should early termination be necessary, participants must be seen as soon as possible to conduct a formal
assessment and treated as a prematurely withdrawn participant. The investigator may be informed of additional
procedures to be followed to ensure that adequate consideration is given to the protection of the participant’s
interests. The investigator or Sponsor depending on the local regulation will be responsible for informing
Institutional Review Boards (IRB) of the early termination of the trial.
7.
DATA AND SAFETY MONITORING
Data monitoring will be conducted by the research coordinator and site staff (research team) and overseen by
project PIs.
During data collection and monitoring, study coordinators will follow an internal safety protocol and alert a
study PI of any clinical concerns. A clinical concern is defined here as any negative experience or symptom that
occurs during baseline or post randomization sessions that are raised via email/text/phone correspondence
directly by the patient, or in key assessment visits to the CIR, whether it is associated with participation in the
study.
The PIs in consultation with study site staff will be responsible for monitoring participant safety during the study
and will review relevant data/information to determine whether it is appropriate for the participant to continue
study participation and whether further action to ensure the safety and wellbeing of the participant is warranted.
Given this study will be conducted among women with PPD, there are clinical concerns that may be anticipated
in the target patient population due to the natural course of disease. Anticipated clinical concerns may include
suicidal ideation, clinically significant deterioration in depressive symptoms, self-injurious behavior, suicide
attempts, and completed suicide. These events will be recorded and will be elevated to AE or SAE status if
deemed appropriate by the investigator, and promptly reported to the Sponsor. As part of a Safety Monitoring
process, all AEs/SAEs will require DSMB review, and the Sponsor can query any PI-determined AEs/SAEs.
TABLE 3 CLINICAL CONCERNS CATEGORIZATIONS
Clinical Concern
Definition
0 - Not a clinical concern:
Qualified research personnel determined that triggering event was not a
clinical concern
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1- Mild clinical concern:
Qualified research personnel determined that triggering event doesn’t
require investigator input and will continue to monitor participant’s
responses
2- Moderate clinical concern:
Qualified research personnel determined that triggering event requires
investigator input. PI/Clinician determined that the research team
should continue to monitor participant’s responses but that no follow-up
was needed.
3- Elevated clinical concern:
Qualified research personnel determined that triggering event requires
clinician input. PI/Clinician determined follow-up was indicated and
confirmed participant safety (participant did not endorse intent to
self-harm) via email or phone communication with participant or their
provider.
4- Significant clinical
concern:
Qualified research personnel determined that triggering event requires
clinician input. PI/Clinician determined that follow-up was indicated
and after follow-up with participant, parent/guardian, or provider
determined that participant should be withdrawn from study (e.g., due
to suicide attempt, self-harm or self-harm attempt, suicidal ideation with
intent, reported hospitalization for self-harm or suicide attempt while
enrolled in study).
All clinical concerns documented as level 4 of concern will be reported to the DSMB for review and oversight
within 5 working days to ensure patient safety and efficient monitoring. In addition, appropriate reporting will
be done to notify the Sponsor and IRB per details in Section 10.2 Institutional Review Board.
7.1 ADVERSE EVENTS
An AE is any unanticipated medical occurrence in a participant or clinical study participant using an
investigational product that does not necessarily have a causal relationship with this product. An AE can
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or
disease temporally associated with the use of an investigational product, whether or not related to the
investigational product.
All AEs recorded during the study period will be assessed for: severity grade (mild, moderate, severe,
fatal/life-threatening, relationship to the study treatment or conduct, duration, and whether it is deemed an SAE
as defined by Sponsor and requires an action taken regarding study treatment to avoid a negative outcome(s).
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7.2 ASSESSMENT OF ADVERSE EVENTS
AE SEVERITY
Investigators will grade the severity of all AEs using the Common Terminology Criteria for Adverse Events
(CTCAE). If possible, investigators should report event terms that reflect a single, unifying diagnosis rather than
individual signs or symptoms (e.g., “influenza” instead of “coughing, body aches, fever;” and “anemia” rather
than “low hemoglobin”).
If an AE term is not listed in the CTCAE criteria, a corresponding grading is to be performed by the investigator
based on his/her best medical judgment as follows:
●
Mild (Grade 1): asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not
indicated
●
Moderate (Grade 2): minimal, local, or noninvasive intervention indicated; limited age-appropriate
instrumental activities of daily living (ADL)
●
Severe (Grade 3): medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; or limiting self-care ADL
●
Life-threatening (Grade 4): life-threatening consequences; urgent intervention indicated
●
Fatal (Grade 5): death related to an AE
AE CAUSALITY
Investigators are required to systematically assess the causal relationship between the AEs and SAEs and the
treatment using the following definitions:
An event should be reported as related to the study treatment if it follows a reasonable temporal sequence to use
of the investigational device and cannot be reasonably explained by the participant’s clinical state or other
factors (e.g., disease under study, concurrent diseases, or concomitant medications); OR the AE follows a
reasonable temporal sequence to use of the investigational device and is a known reaction to the investigational
device.
An event should be reported as unrelated to study treatment if it does not follow a reasonable sequence from an
investigational device, or it can be reasonably explained by the participant’s clinical state or other factors (e.g.,
disease under study, concurrent diseases, and concomitant medications).
7.3 SERIOUS ADVERSE EVENTS
An SAE is any AE that meets any of the following criteria:
●
Results in death
●
Is life-threatening
●
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Results in persistent or significant disability/incapacity
●
Is an important medical event
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UNANTICIPATED ADVERSE DEVICE EFFECTS
A suspected unanticipated adverse device effect (UADE) is defined as an untoward and unintended response to a
study treatment, which is not listed in the applicable product information, and meets at least one AE or SAE
criterion, and is assessed as causally related to the study treatment. The Sponsor or designee will be responsible
for carrying out required reporting to investigators, health authorities, and other entities as required by law.
DOCUMENTING AND REPORTING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
Reporting of non-serious AEs and SAEs will begin at the time of first interaction with the app and will continue
through EOT. Any new clinical condition or worsening of existing conditions between the time the informed
consent form (ICF) is signed, and the first use of the study intervention will be recorded as AE/SAEs unrelated
to the device.
AEs and SAEs may be reported spontaneously by participants, discovered as a result of general, non-leading
verbal questioning by the study staff, or determined by assessments. As needed, qualified study staff will inform
investigators to inquire about any new symptoms or worsening of symptoms during the telehealth visits at
Weeks 4 and 8. In the interim, participants will be instructed to contact the investigator if new or worsening
symptoms develop outside of key assessment visits. All incidences confirmed as AEs or SAEs will be monitored
and recorded in the eCRF throughout the entire study.
The investigator must pursue and obtain adequate information about all incidences they deem as AEs and SAEs.
At minimum this includes a description of the event, severity, device relatedness, start and stop times, duration,
outcome, and any action (e.g., treatment/follow-up tests). The investigator must also assess whether the event
meets the criteria for classification as an SAE.
It is the investigator’s responsibility to review all documentation (e.g., hospital notes, laboratory reports, and
diagnostic reports) related to an AE or SAE. Whenever possible, a single unifying diagnosis should be reported
as the event term, and not the individual signs and symptoms.
Investigators are not obligated to actively seek AEs or SAEs after the participant’s conclusion of study
participation. However, if the investigator learns of any SAE, including death, at any time after a participant has
been discharged from the study, and he/she considers the event to be reasonably related to the investigational
device or study participation, the investigator must promptly notify the Sponsor.
REPORTING OF SERIOUS ADVERSE EVENTS
The investigator must immediately report SAEs to the Sponsor or designee (no later than 24 hours after
becoming aware of the event) using the SAE report form.
The investigator is obliged to promptly respond to any request for follow-up information (e.g., additional
information, event outcome, final evaluation, or other records if needed) and to any question from the Sponsor
or designee. This timely reporting is necessary to ensure prompt assessment of the event by the Sponsor or
designee and to allow them to meet strict regulatory timelines associated with expedited reporting obligations
for SAEs.
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The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies
about the safety of a study intervention under clinical investigation. The Sponsor will comply with
country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRB, and
investigators.
An investigator who receives an investigator safety report describing an SAE or other specific safety
information (e.g., summary or listing of SAEs) from the Sponsor will review and then file it along with the
Investigator’s Brochure and will notify the IRB, if appropriate according to local requirements.
All serious and/or possibly related or related (to the device or study procedure) AEs will be reported to the
DSMB and reviewed on an on-going basis throughout the participant enrollment and follow-up period as
specified in the DSMB charter to ensure the safety of participants enrolled in this study. The DSMB may request
additional information as needed. Based on safety data, the DSMB may recommend that the Sponsor modify or
discontinue the study; however, all final decisions regarding study modifications rest with the Sponsor.
AE AND SAE FOLLOW-UP
During the study (and after the EOT visit), all AEs and SAEs should be followed proactively by the investigator
or qualified designee until the event resolves, or the condition stabilizes to a level acceptable to the investigator,
until the event is otherwise explained, or until the participant is lost to follow-up. New or updated information
will be recorded in the originally completed eCRF and the investigator will submit any updated SAE
information to the sponsor within 24 hours of receipt of the information.
SAFETY REPORTING OVERSIGHT
In accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), the Sponsor or
designee will inform investigators of findings that could adversely affect participant safety, impact the conduct
of the trial, or alter the IRB’s approval/favorable opinion to continue the trial.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies
about the safety of an investigational treatment. The Sponsor will comply with country-specific regulatory
requirements relating to safety reporting to the regulatory authority, IRB, and investigators.
An investigator who receives an investigator safety report describing SAEs or other specific safety information
(e.g., summary or listing of SAEs) from the Sponsor will file it along with the Investigator’s Brochure (IB) and
will notify the IRB, if appropriate, according to local requirements.
7.4 DATA SAFETY MONITORING BOARD (DSMB)
The Data Safety Monitoring Board is co-responsible for the oversight and safety monitoring of the study. The
DSMB advises the Sponsor regarding the continuing safety of the trial participants and those yet to be recruited
to the trial, as well as the continuing validity and scientific merit of the trial. The team assembled for the DSMB
will have relevant and complementary expertise in psychiatry, obstetrics and gynecology, clinical trial design,
digital health, and statistics. This DSMB should include members from academic sites independent of the study
sites and should consist of at least one non-study, board-certified psychiatrist and one biostatistician.
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Importantly, none of these individuals will be involved in any other capacity with this study or have any
potential conflicts of interest in study-related outcomes.
The DSMB will review and evaluate information relevant to the safety of this study before the implementation
of the protocol. Activities of the DSMB will include:
1.
Developing the DSMB Charter that will be approved by the Sponsor (including study stopping criteria
and final interim analyses being conducted by the independent statistician etc.)
2.
Reviewing the study protocol at the start of the study and any proposed amendments related to changes
in study design, safety monitoring, or analytic plan
3.
Recommending alterations to the study design
4.
Approving the study protocol before commencement
5.
Performing expedited monitoring of unanticipated serious adverse device effects at the time of their
occurrence and providing recommendations accordingly
6.
Performing quarterly review of all clinical concerns
7.
Performing ongoing quarterly review of study progress
8.
Reviewing any data that may reflect differences in safety between treatment groups
9.
Determining whether study procedures should be changed, or the study should be halted for reasons
related to the safety of study participants
10. Performing quarterly review of the completeness and validity of data to be used for analysis of safety
and efficacy.
7.5 DATA COLLECTION AND DATABASE MANAGEMENT
The study will leverage an Electronic Data Capture (EDC) for data collection. Designated full trained site staff
will be responsible for handling and entry of all patient-level data into the eCRF as outlined in the protocol.
Each eCRF have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 11
requirements. The investigator is responsible for assuring that the data entered into the eCRF is complete,
accurate and that the entry and updates are performed in a timely manner.
The EDC system in place will run automatic validation program checks to identify any data discrepancies in the
eCRFs for efficient query resolution. In the event that a query is flagged, the system allows for modification and
or verification of the entered data by designated staff if needed. 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 for prompt review and resolution by site staff.
After final database lock, the investigator will receive copies of the participant data for archiving at the
investigational site.
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All data should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and
verification.
Additional security measures, data validation steps etc. during and post database lock will be outlined in a Data
Management Plan (DMP) which will describe how to handle the data under foreseeable circumstances (e.g.,
how data will be recorded, tracked, verified for quality control, transferred, and extracted according to FDA
guidelines). Along with the DMP, a Data Validation Plan (DVP) containing all edit‑checks to be performed and
the calculations for derived variables are also prepared.
7.6 QUALITY CONTROL AND QUALITY ASSURANCE
The Sponsor maintains a robust Quality Management System (QMS) that includes all activities involved in
quality assurance and quality control per 21 CFR 820, to ensure compliance with written SOPs as well as
applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Sponsor 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 21 CFR 820 and GCP compliance with global and local regulatory requirements,
protocols and internal SOPs and are performed according to specified Sponsor processes.
8. STATISTICAL ANALYSIS
8.1 GENERAL METHODOLOGY
Analyses will be performed using SAS® (SAS Institute, Cary, NC, US) and R (R Core Team (2021). R
Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/). Each analysis will be
conducted by a blinded statistician, and the statisticians will not confer until QC. The DSMB statistician will be
unblinded and generate the randomization schedule. The interim re-estimation of sample size will be conducted
by blinded pair programming, as with the main analysis. All personnel involved with the analysis of the study
will remain blinded until database lock and identification of protocol deviations, unless otherwise mentioned in
the protocol (e.g., DSMB statistician performing randomization and analysis requested by DSMB members).
The statistical analysis plan (SAP) will be approved prior to the interim analysis performed by the blinded
independent statistician, and otherwise prior to any lock of the study database and unblinding of the study data.
The SAP will provide a detailed description of the statistical methods and expand on the details provided in the
protocol.
All data will be presented by treatment group. Descriptive statistics (number of observations, mean, standard
deviation [SD], median, interquartile range [q25 and q75], and range [minimum and maximum]) will be
provided for continuous variables, and counts and percentages will be presented for categorical variables.
Baseline is defined as the last non-missing measurement before or on the date of first use of the investigational
device.
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All statistical tests will be 2-sided and performed at the 0.05 level of significance unless stated otherwise.
Descriptive analyses and p-values will be presented for exploratory endpoints.
Checks of assumptions (e.g., normality) underlying statistical procedures will be performed and appropriate
corrective procedures will be applied (e.g., transformation or nonparametric tests) prior to statistical testing.
8.2 ANALYSIS POPULATIONS
For the purposes of analysis, the following analysis sets are defined in Table 4 below.
TABLE 4. SUMMARY OF ANALYSIS SETS
Analysis Set
Description
Enrolled
All participants who signed the ICF
Intention-To-Treat (ITT)
All randomized participants with HAM-D6 measured at
baseline. Participants will be included in the ITT
population regardless of how often they engage with
WB001 or ED001. This analysis set will be the primary
set used for analyses/summaries of the primary efficacy
endpoint, as well as for all secondary and exploratory
efficacy endpoints.
Per-Protocol (PP)
All randomized participants also in the ITT population
who complete 8 weeks of treatment and have at least
75% compliance on engaging with the Woebot
application at least 1 day per week, and who have
HAM-D measured at baseline, Week 4, and Week 8,
with no other major protocol deviation that could affect
the interpretability of the efficacy outcome. This
analysis set will be used for sensitivity analyses.
Safety
All randomized participants who used WB001 or ED001
and who have at least one post-baseline safety
assessment (i.e., C-SSRS). This analysis set will be used
for summaries of safety data.
*Note: Inclusion criteria at screening will assess for participants engagement in TAU. If participant is
confirmed as not having completed TAU by EOT, the data from these patients will be excluded from the
primary analysis; however, their data will be retained for the purpose of conducting exploratory analysis.
8.3 SAMPLE SIZE DETERMINATION
The concept of a minimally important difference (MID) for depression rating scales are not yet widely
established. However, both researchers and a growing number of clinicians who are using measurement-based
care employ standardized symptom rating scales to determine whether treatments for depression and other
conditions are working effectively (Rush et al., 2021). The degree of symptom improvement that is meaningful
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to patients remains unclear. However, a recent analysis based on Brexanolone, an FDA-approved PPD-specific
treatment based on HAM-D, provided the first estimates of PPD-specific MID and meaningful change threshold
(MCTs) for the HAM-D in this clinically important outcome. It concluded that a 2–3 point change in the
HAM-D6 is clinically meaningful and a 4–7 point change is clinically substantial (Rush et al., 2021). A second
analysis based on two randomized controlled trials in 482 adult patients with MDD suggested a 2-point
difference on the HAM-D6 will allow detection of a change in depression category as mild and moderate and
defined as a scores of 8-9 and 10-12, respectively (Ruhe et al., 2005). Thus, as an adjunct to TAU, a 3-point
change was identified as an a priori clinically meaningful difference for WB001 to demonstrate a reduction of
depression for mild and moderate PPD (for additional justification for use of the HAM-D6 as the primary
endpoint see Section 9.1 Primary Endpoint).
Simulations using this RCT study data were conducted to determine the power of various sample
sizes to detect a 3-point difference in HAM-D6 score between the treatment and control groups at Week 8,
controlling for relevant baseline factors and considering potential for additional variability within the study.
9. STATISTICAL METHODS
9.1 PRIMARY ENDPOINT
The HAM-D is considered the gold standard assessment in clinical trials of major depression, including
pharmacotherapy trials in post-partum depression (Hantsoo, et al., 2014). Consequently, as PPD is considered a
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subtype of major depression in the DSM-5, the HAM-D was considered the most appropriate primary endpoint.
A recent comparative, post hoc analysis of the HAM-D17 and the abbreviated HAM-D6 in the GUIDED trial
for MDD treatment found greater sensitivity differences in the treatment effects using the HAM-D6 scale
(Dunlap et al., 2019). It was noted that as a multidimensional (or multifactorial) scale the HAM-D17 is good for
detecting a broad array of clinical features, it also may reduce the ability to detect change over time, because
some factors may not adequately distinguish groups when valid differences exist (Ruhe et al., 2005).
The importance of maximizing signal detection through use of the most sensitive scale to detect treatment
effects is of great importance for comparative effectiveness studies. Particularly in a PPD population this
provided justification for using the HAM-D6 scale (over the HAM-D17) that more narrowly and precisely
measures the “core symptoms” of major depressive disorder according to DSM-5 criteria. The structural validity
(unidimensionality) and measurement properties of the HAM-D6 have been well validated (e.g., O'Sullivan et
al., 1997; Licht et al., 2005; Bech et al., 2009; Timmerby et al., 2017) and studies comparing the responsiveness
of the HAM-D6 and HAM-D17 generally showed that the effect size of treatments was substantially larger
according to HAM-D6 versus the HAM-D17 (Timmerby et al., 2017). Further, in studies where symptom
reduction was used as an outcome measure, the HAM-D6 detected statistically significant differences between
treatment groups more often than HAM-D17 (e.g., Feiger et al., 2006; Bech et al., 2022). Similarly, when
remission or relapse rates constituted the outcome measure, HAM-D6 was generally found to be more sensitive
than HAM-D17 in detecting differences between treatment groups (e.g., Rasmussen et AL., 2003; Thase et al.,
2011).
Thus, for this study, the primary efficacy endpoint is the difference between treatment arms in the HAM-D6
score at Week 8 after controlling for baseline and other covariates. For the ITT population, a restricted
maximum likelihood (REML) based linear mixed-effects model for repeated measures (MMRM) approach will
be used to test for systematic differences in change between arms over time, after accounting for participant
-specific heterogeneity in HAM-D scores residual error structure. The MMRM will be parameterized to include
random effects for site and repeated measures for post-baseline visits using an unstructured residual covariance
structure (3 parameters); in the unlikely event that the unstructured covariance matrix fails to converge, the
model will be refit with a first order autoregressive covariance matrix (2 parameters).
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9.2 SECONDARY ENDPOINTS
The treatment efficacy of MIBS, EPDS, PHQ-9, and GAD-7 (difference between arms at Week 8, controlling
for baseline) will be evaluated using the same analysis plan proposed for the analysis of the primary endpoint
(HAM-D). In addition, the differences in HAM-D6 scores between baseline and week 8 within each treatment
arm will be calculated. Secondary endpoints are not powered to detect a significant difference between treatment
groups and no sequential testing will be applied.
9.3 EXPLORATORY ENDPOINT(S)
Exploratory analyses will be conducted in the ITT population. Given the ordinal nature of the remaining efficacy
endpoints (CGI-I; CGI-S; PGI-C; PGI-S), the analysis plan for HAM-D will be modified to compare treatment
arms by the odds selecting a given ordinal category at Week 8 controlling for other factors in the model. Models
will be fit via PROC GLIMMIX.
Additionally, the MMRM approach to analyzing the difference between arms will be supplemented via a latent
class analysis approach that uses a multiple indicator linear growth model (LGM) for categorical outcomes.
More details about the analyses can be found in the SAP.
9.4 SAFETY ENDPOINT(S)
AEs and SAEs that may be reported by the participant or detected by the investigator through the C-SSRS will
be compared between treatment groups. All safety variables will be summarized descriptively by randomized
treatment.
9.5 ANALYSIS OF SAFETY
The Safety Analysis Set will be used for the analysis of AE data.
AEs will be coded with MedDRA. All AEs with an onset date on or after the date of first use of the
investigational product and before the date of last use of the investigational device will be collected and
presented by system organ class and preferred term in frequency tables. Participants with multiple AEs will be
counted only once within each preferred term and system organ class. Key participant information for
participants with an AE with an outcome of death, participants with SAEs, and participants with an AE leading
to withdrawal from the study will be listed.
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9.6 DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographic and baseline characteristics will be presented descriptively.
9.7 SUBGROUP ANALYSES
The study will encourage participant enrollment to be inclusive of all populations as defined by demographic
factors such as race, ethnicity, gender identity, age, and by the presence of certain clinical characteristics such as
multiple comorbidities. Subgroup analyses will be accounted for by including potential subgroups as covariates
in Model 3 (see Section 9.1 Primary Endpoint).
9.8 HANDLING OF MISSING VALUES
According to the schedule of events, patients are expected to attend visits at baseline, Week 4, and Week 8. No
explicit imputation will be performed; the MMRM model described above will be run on the ITT population,
which implicitly imputes missing data under a missing at random (MAR) assumption.
To examine the impact of intermediate missing values and missing values after early withdrawal from the study,
sensitivity analyses including multiple imputations will be performed. Missing safety data will not be imputed.
9.9 INTERIM ANALYSIS
After 50% of the planned participants have completed the study (been evaluated after 8 weeks on treatment) an
interim analysis will be conducted on blinded data by an independent statistician to verify that the effect size
estimates used to plan the study sample remain reasonable and, if needed, calculate a new required sample given
the updated effect size estimates. Specifically, the clinically important difference (CID) analyses (described in
section 7.2 of the SAP) will be performed on the interim HAM-D6 data to determine whether clinician
judgments of category differences in the HAM-D6 in the context of use of PPD (Δ) are consistent with a
priori expectations of a 3-point CID for MDD. Additionally, the SD of the difference between baseline and
Week 8 will be calculated to determine whether is it is in line with expectations for detecting a 3-point (or
Δ) difference between arms with α = .05, two-tailed and 1-β = .80, i.e., n /arm ≥2*(zα/2 + z1-β)^2*SD/Δ =
2*2.8^2*SD/Δ = 15.68* SD/Δ.
9.10 BLINDING ANALYSIS
The success of blinding will be assessed at EOT by providing participants with a questionnaire on which
treatment arm they believe they were assigned to. Response categories are “active”, “control/placebo”, or “do
not know”. Formal analysis will be performed using the James’ Blinding Index (Kolahi et al., 2011), which is a
variation of the kappa coefficient that is sensitive not to the degree of agreement but to the degree of
disagreement, by placing the highest weight on the “do not know” responses. The index ranges from 0 (total
lack of blinding) to 1 (complete blinding).
10. ETHICS AND RESPONSIBILITIES
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10.1 GOOD CLINICAL PRACTICE
This study will be conducted in accordance with the Note for Guidance on GCP ICH Harmonised Tripartite
Guideline E6 (R1)/Integrated Addendum E6 (R2); US FDA Code of Federal Regulation (CFR) (Title 21 Parts
50, 56, 312), requirements for the conduct of clinical studies as provided in the EU Directive 2001/20/EC; the
general guidelines indicated in the Declaration of Helsinki; and all applicable regulatory requirements.
10.2 INSTITUTIONAL REVIEW BOARD
The final study protocol, including the final version of the ICF, must be approved, or given a favorable opinion
in writing from the IRBs as appropriate. A written approval from the IRB is required for any study protocol
amendment(s), ICF updates, participant recruitment procedures (e.g., advertisements), and any written
information to be provided to participants and a statement from IRB to ensure compliance with GCP
requirements (if applicable). A current copy of the Investigator’s Brochure should be included as part of the
written application to the IRB. The investigator is required to sign a protocol signature page confirming
his/her/their agreement to conduct the study in accordance with the document and all of the instructions and
procedures found in this protocol and to give access to all relevant data and records to Sponsor monitors,
auditors, Sponsor Quality assurance representatives, designated agents of Sponsor, IRBs, and regulatory
authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the investigator
must inform the Sponsor immediately that this request has been made.
The IRB approval(s) must identify the protocol version as well as the documents reviewed. Any amendments to
the protocol will require IRB approval before the implementation of the changes made to the study, except for
changes necessary to eliminate an immediate hazard to the study participants.
The investigator will be responsible for the following:
●
Providing written summaries of the status of the study to the IRB annually or more frequently in accordance
with the requirements, policies, and procedures established by the IRB
●
Notifying the IRB of SAEs or other significant safety findings, including adverse drug reactions (both
serious and unanticipated), as required by IRB procedures
●
Providing oversight of the conduct of the study at the site and adherence to the requirements of all
applicable regulations
●
Promptly reporting deviations from, or changes to, the protocol to eliminate immediate hazards to the study
participants
10.3 INFORMED CONSENT
In obtaining and documenting consent via an Electronic Informed Consent Form (eICF), the investigator should
comply with the applicable regulatory requirement(s) and should adhere to GCP and to the ethical principles that
have their origin in the Declaration of Helsinki. Prior to the beginning of the study, the investigator should have
the IRB’s written approval/favorable opinion of the eICF and any other pertinent information to be provided to
participants.
●
The investigator or his/her representative will explain the purpose and nature of the study as well as possible
AEs to the participant or their legally acceptable representative and answer all questions regarding the study.
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Participants must be informed that their participation is voluntary, and consent can be withdrawn at any
point.
●
Participants or their legally acceptable representative will be required to sign a statement of informed
consent that meets the requirements of US FDA CFR Title 21 Part 50, local regulations, ICH guidelines,
HIPAA requirements in the US, and the IRB or study site.
●
Prior to a participant’s participation in the study, the eICF should be signed and personally dated by the
participant or by the participant's legally acceptable representative, and by the person who conducted the
informed consent discussion.
●
An electronic copy of the signed eICF will be retained at the study site.
●
A copy of the eICF and any other pertinent information must be provided to the participant or the
participant’s legally acceptable representative.
●
If the eICF is revised, the revised eICF must have received the IRB's approval/favorable opinion in advance
of its use. Participants must be informed of the changes to the eICF and must re-consent to the most current
version during their participation in the study if the DSMB confirms the change requires reconsent. The
participant or the participant’s legally acceptable representative should be informed in a timely manner if
new information becomes available that may be relevant to the participant’s willingness to continue
participation in the study. The communication of this information should be documented.
Note: Any study sites that do not have electronic consent capabilities will be permitted to use paper or written
copy of the ICF.10.4 Financing and Insurance
CONTRACTUAL AND FINANCIAL DETAILS
The investigator (and/or, as appropriate, the hospital administrative representative) and the Sponsor will sign a
clinical study agreement prior to the start of the study, outlining overall Sponsor and investigator responsibilities
in relation to the study. The contract should describe whether costs for pharmacy, laboratory, and other
protocol-required services are being paid directly or indirectly.
INSURANCE, INDEMNITY, AND COMPENSATION
The sponsor will maintain an appropriate clinical study insurance policy.
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial information as
requested to allow the Sponsor to submit complete and accurate financial certification or disclosure statements
to the appropriate regulatory authorities.
11. RECORDS MANAGEMENT
All clinical study information should be recorded, handled, and stored in a way that allows its accurate
reporting, interpretation, and verification. This principle applies to all records referenced in this protocol,
irrespective of the type of media used.
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Details regarding eCRF access and handling are detailed in the “Electronic Case Report Form Completion and
Data Management” section.
During each study visit, a physician participating in the study will maintain progress notes in the participant’s
medical records to document all significant observations. At a minimum, these notes are to contain:
●
The date of the visit and the corresponding day or visit in the study schedule
●
General condition and status remarks by the participant, including any significant medical findings. The
severity, frequency, duration, and resolution of any reported AE, and the investigator's assessment as to
whether the reported AE is related to the investigational device
●
Changes (including dosages) in concomitant medications/therapies or procedures
●
A general reference to the procedures completed
●
The signature or initials of all physicians making an entry in the medical record (progress notes)
In addition, any contact with the participant via telephone or other means that provides significant clinical
information is to also be documented in the medical record (progress notes), as described above.
Information from the medical records (progress notes) and other source documents is to be promptly entered
into the appropriate section of the eCRF.
Changes to information in the medical record (progress notes) and other source documents are to be initiated and
dated on the day the change is made by the investigator (or designee). If the reason for the change is not
apparent, a brief explanation for the change is to be written adjacent to the change. Changes to the eCRF will be
electronically tracked.
The IQVIA data management department will write a data management plan, which will be finalized prior to
performing any data validation.
11.1 SOURCE DOCUMENTATION
Source documents contain the results of original observations and activities of a clinical investigation. They are
the original records in which raw data are first recorded. Source documents include, but are not limited to,
medical records (progress notes), central rating results reports, screening logs, completed scales, quality of life
questionnaires, and recorded data from automated instruments.
The investigator/site personnel should maintain adequate and accurate source documents and study records that
include all pertinent observations on each of the site’s study participants. Source data should be attributable,
legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should
not obscure the original entry, and should be explained if necessary (e.g., via an audit trail).
All source documents from this study are to be maintained by the investigator and made available for inspection
by authorized persons. The investigator will provide direct access to source documents/data for study-related
monitoring, audits, IRB review, and regulatory inspections. The Sponsor should verify that each participant has
consented, in writing, to direct access to his/her original medical records for study-related monitoring, audit,
IRB review, and regulatory inspection.
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11.2 CASE REPORT FORM COMPLETION AND DATA MANAGEMENT
An eCRF will be used to store and transmit participant information. The file structure and format for the eCRF
will be provided by the Sponsor or its representative and should be handled in accordance with instructions
provided.
The eCRF must be reviewed and electronically signed and dated by the investigator.
Access to the eCRF will be strictly password protected and limited to personnel directly participating in the
study. Data should be entered into the eCRF completely by authorized site personnel (e.g., investigators and the
study coordinator). The eCRF must be completed as soon as possible (no later than 5 business days) after any
participant evaluation or communication. If data are to be changed due to erroneous input or other reason, an
electronic audit trail will track the changes. The eCRFs and computers that store them must be accessible to
study monitors and other regulatory auditors. Changes to the eCRF will be electronically tracked.
Data will be entered/loaded into a validated electronic database using a clinical data management system.
Computerized data cleaning checks will be used in addition to manual review to check for discrepancies and to
ensure consistency of the data.
11.3 STUDY FILES AND RECORD RETENTION
All data derived from the study will remain the property of the Sponsor. The Sponsor assumes accountability for
actions delegated to other individuals, e.g., the CRO.
Records must be retained in accordance with the current ICH Guidelines on GCP. All essential study documents,
including records of participants, source documents, and eCRFs must be kept on file.
Essential documents should be retained until at least 2 years after the last approval of a marketing application in
an ICH region and until there are no pending or contemplated marketing applications in an ICH region, or until
at least 2 years have elapsed since the formal discontinuation of clinical development of WB001. However,
essential documents may be retained for a longer period if required by the applicable regulatory requirements or
by agreement with the Sponsor. The Sponsor is responsible for informing the investigator when these documents
need no longer be retained.
The investigator is not to dispose of any records relevant to this study without written permission from the
Sponsor and is to provide the Sponsor the opportunity to collect such records. The investigator shall take
responsibility for maintaining adequate and accurate hard copy source documents of all observations and data
generated during this study. Such documentation is participant to inspection by the Sponsor, its representatives,
and regulatory authorities.
If an investigator moves, withdraws from a study, or retires, the responsibility for maintaining the records may
be transferred to another person who will accept responsibility. Notice of transfer must be made to and agreed by
the Sponsor.
12. AUDITING AND MONITORING
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Sponsor-assigned monitors will conduct regular site visits to the investigational facilities for the purpose of
monitoring various aspects of the study, such as assessing participant enrollment, compliance with protocol
procedures, completeness and accuracy of data entered into the eCRFs, verification of eCRF data against
original source documents, and occurrence of AEs. The investigator must agree to Sponsor-authorized personnel
having direct access to the clinical (or associated) files and clinical study supplies (dispensing and storage areas)
to ensure compliance with applicable regulations, and the investigator will assist with the Sponsor’s monitoring
activities.
Quality control will occur at each stage of data handling to ensure that all data are reliable and have been
processed correctly. The Sponsor should ensure oversight of any study-related duties and functions carried out
on its behalf, including study-related duties and functions that are subcontracted to another party by the
Sponsor’s contracted CRO(s).
The eCRFs should be completed in a timely manner and on an ongoing basis to allow regular review by the
study monitor.
Details describing the strategy, responsibilities, and requirements of the study monitoring are provided in the
study monitoring plan.
The purpose of an audit is to assess whether ethics, regulatory, and quality requirements are being fulfilled. The
Sponsor or its representative may conduct audits at the investigative sites including, but not limited to, presence
of required documents, the informed consent process, and comparison of eCRFs with source documents.
Government regulatory authorities may also inspect the investigator during or after the study. The investigator
(or designee) should contact the Sponsor/CRO immediately if this occurs. All medical records (progress notes)
must be available for audit. The investigator must agree to participate with audits conducted at a convenient time
in a reasonable manner.
12.1 RISK AND QUALITY TOLERANCE LIMITS
Perceived risks and quality tolerance limits (QTLs) will be identified and documented before the study start.
The Sponsor will review risk control measures periodically to ascertain whether the implemented quality
management activities remain effective and relevant. The quality management approach and any important
deviations from the predefined QTLs (and remedial actions adopted) will be described in the clinical study
report (CSR).
12.2 PROTOCOL ADHERENCE AND DEVIATIONS
The investigator and site personnel should conduct the study in compliance with the protocol and should use
continuous vigilance to identify and report protocol deviations.
A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the
protocol that may be on the part of the investigator, site personnel, or the participant.
Important protocol deviations are a subset of protocol deviations that may significantly impact the completeness,
accuracy, and/or reliability of the study data or that may significantly affect a participant's rights, safety, or
well-being. For example, important protocol deviations may include enrolling participants in violation of key
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eligibility criteria designed to ensure a specific participant population or failing to collect data necessary to
interpret primary endpoints, as this may compromise the scientific value of the study.
The investigator should not implement any deviation from the protocol without agreement from the Sponsor and
prior review and approval from the IRB of an amendment, except where necessary to eliminate an immediate
hazard to a study participant, or when the change involves only logistical or administrative aspects of the study,
such as a change in a monitor or telephone number.
In the event of an important protocol deviation, the investigator will discuss the deviation with the Sponsor’s
medical monitor and will come to an agreement as to whether the participant should be withdrawn from the
study due to the important protocol deviation.
13. AMENDMENTS
Protocol modifications, except those intended to reduce immediate risk to study participants, may be made only
by the Sponsor. A protocol change intended to eliminate an apparent immediate hazard to participant s should be
implemented immediately.
Any permanent change to the protocol must be handled as a protocol amendment. The written amendment must
be submitted to the IRB, and the investigator must await approval before implementing the changes. The
Sponsor will submit protocol amendments to the appropriate regulatory authorities for approval.
The current version of the ICF will require similar modification if the IRB, investigator, and/or Sponsor, judge
the amendment to the protocol to substantially change the study design and/or increase the potential risk to the
participant and/or impact the participant's involvement as a study participant. In such cases, the ICF will be
renewed for enrolled participants before their continued participation in the study.
14. STUDY REPORT AND PUBLICATIONS
This study will be registered on ClinicalTrials.gov in accordance with applicable laws or publication policy and
may also be registered on other publicly accessible websites as necessary.
The Sponsor is responsible for preparing and providing the appropriate regulatory authorities with the CSR
according to the applicable regulatory requirements. The Sponsor should ensure that the CSR meets the
standards of the ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3).
The publication policy of the Sponsor is discussed in the investigator's clinical research agreement.
The results of this study may be published or presented at scientific meetings. If this is foreseen, the investigator
agrees to submit all manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to
protect proprietary information and to provide comments.
The Sponsor will comply with the requirements for publication of study results. In accordance with standard
editorial and ethical practice, the Sponsor will generally support publication of multicenter studies only in their
entirety and not as individual site data. In this case, a coordinating investigator will be designated by mutual
agreement.
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Authorship will be determined by mutual agreement and in line with International Committee of Medical
Journal Editors authorship requirements.
15. STUDY START AND TERMINATION
The study start date is the date on which the first participant provides informed consent.
The end of the study is defined as the last participant’s last assessment.
Both the Sponsor and the investigator reserve the right to terminate the study or the participation in the study at
an investigator’s site at any time. In terminating the study, the Sponsor and the investigator will assure that
adequate consideration is given to the protection of the participants’ interests.
If the study is prematurely terminated or suspended for any reason, the Sponsor/investigator/site personnel
should promptly inform the study participants and should assure appropriate therapy and follow-up for the
participants. Where required by the applicable regulatory requirements, the IRB, DSMB, and other entities
involved in the study should be informed promptly and be provided with a detailed written explanation of the
termination or suspension.
If the investigator terminates or suspends a study without prior agreement of the Sponsor, the investigator should
inform the site personnel. The investigator/site personnel should promptly inform the Sponsor and the IRB. The
investigator/site personnel should also provide the Sponsor and the IRB a detailed written explanation of the
termination or suspension.
16. CONFIDENTIALITY
All information generated in this study is considered highly confidential and must not be disclosed to any person
or entity not directly involved with the study unless prior written consent is gained from the Sponsor. However,
authorized regulatory officials, IRB personnel, the Sponsor and its authorized representatives are allowed full
access to the records.
All study participants must be informed that their personal study-related data will be used by the Sponsor in
accordance with local data protection law. The level of disclosure must also be explained to the participant, who
will be required to give consent for their data to be used as described in the ICF. Participants must be informed
that their medical records may be examined by auditors or other authorized personnel appointed by the Sponsor,
by appropriate IRB members, and by inspectors from regulatory authorities.
Identification of participants and eCRFs shall be by unique participant identification numbers (such as screening
or randomization number) only. All personal identifiers according to applicable regulations (e.g., name, phone
number) must be redacted permanently by the site personnel and replaced with the participant ’s unique
identification number in all records and data before transfer to the Sponsor (or designee).
All personal details will be treated as confidential by the investigator and staff at IQVIA.
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17. REFERENCES
1. Anokye, R., Acheampong, E., Budu-Ainooson, A., Obeng, E. I., & Akwasi, A. G. (2018). Prevalence of postpartum
depression and interventions utilized for its management. Annals of general psychiatry, 17, 18.
https://doi.org/10.1186/s12991-018-0188-0Washington, DC: Author. (5th ed.).
https://doi.org/10.1176/appi.books.9780890425596
2. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed.).
3. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).
4. Bhatt A. (2022). Clinical trials and Consolidated Standards of Reporting Trials: Continuing concerns of compliance in
COVID-19 era. Perspectives in clinical research, 13(1), 1–2. https://doi.org/10.4103/picr.picr_259_21
5. Bakker, D., Kazantzis, N., Rickwood, D., & Rickard, N. (2016). Mental Health Smartphone Apps: Review and
Evidence-Based Recommendations for Future Developments. JMIR Mental Health, 3(1), e7.
https://doi.org/10.2196/mental.4984
6. Barth, J., Munder, T., Gerger, H., Nüesch, E., Trelle, S., Znoj, H., Jüni, P., & Cuijpers, P. (2013). Comparative efficacy of
seven psychotherapeutic interventions for patients with depression: a network meta-analysis. PLoS medicine,
10(5), e1001454. https://doi.org/10.1371/journal.pmed.1001454
7. Barlow, D. H., Farchione, T. J., Bullis, J. R., Gallagher, M. W., Murray-Latin, H., Sauer-Zavala, S., Bentley, K. H.,
Thompson-Hollands, J., Conklin, L. R., Boswell, J. F., Ametaj, A., Carl, J. R., Boettcher, H. T., &
Cassiello-Robbins, C. (2017). The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders
Compared With Diagnosis-Specific Protocols for Anxiety Disorders. JAMA Psychiatry, 74(9), 875–884.
https://doi.org/10.1001/jamapsychiatry.2017.2164
8. Bauman BL, Ko JY, Cox S, et al. Vital Signs: Postpartum Depressive Symptoms and Provider Discussions About
Perinatal Depression — United States, 2018. MMWR Morb Mortal Wkly Rep 2020;69:575–581. DOI:
http://dx.doi.org/10.15585/mmwr.mm6919a2external icon.
9. Bech P, Lunde M, Bech-Andersen G, et al. (2007) Psychiatric outcome studies (POS): Does treatment help the patients?
Version 1.6
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Page 65 of 82

CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
A Popperian approach to research in clinical psychiatry. Nord J Psychiatry 61 Suppl 46
10. Bech, P., Wilson, P., Wessel, T., Lunde, M., & Fava, M. (2009). A validation analysis of two self‐reported HAM‐D6
versions. Acta Psychiatrica Scandinavica, 119(4), 298-303.
11. Bech, P., Fava, M., Trivedi, M. H., Wisniewski, S. R., & Rush, A. J. (2012). Outcomes on the pharmacopsychometric
triangle in bupropion‐SR vs. buspirone augmentation of citalopram in the STAR* D trial. Acta Psychiatrica
Scandinavica, 125(4), 342-348
12. Busner, J., & Targum, S. D. (2007). The Clinical Global Impressions Scale. Psychiatry (Edgmont), 4(7), 28–37.
13. Centers for Disease Control and Prevention. (2020, May 14). Depression Among Women. Reproductive Health.
https://www.cdc.gov/reproductivehealth/depression/index.htm
14. Chawla, N. V., Bowyer, K. W., Hall, L. O., & Kegelmeyer, W. P. (2002). SMOTE: synthetic minority over-sampling
technique. Journal of Artificial Intelligence Research, 16, 321–357.Clarke, J., Proudfoot, J., Birch, M.-R., Whitton,
A. E., Parker, G., Manicavasagar, V., Harrison, V., Christensen, H., & Hadzi-Pavlovic, D. (2014). Effects of mental
health self-efficacy on outcomes of a mobile phone and web intervention for mild-to-moderate depression, anxiety
and stress: Secondary analysis of a randomised controlled trial. BMC Psychiatry, 14, 272.
https://doi.org/10.1186/s12888-014-0272-1
15. Overview | Common mental health problems: identification and pathways to care | Guidance | NICE. 2011
16. Cox, J. L., Holden, J. M., & Sagovsky, R. (1987). Detection of postnatal depression. Development of the 10-item
Edinburgh Postnatal Depression Scale. The British Journal of Psychiatry: The Journal of Mental Science, 150,
782–786. https://doi.org/10.1192/bjp.150.6.782
17. Darcy, A., Daniels, J., Salinger, D., Wicks, P., & Robinson, A. (2021). Evidence of Human-Level Bonds Established
With a Digital Conversational Agent: Cross-sectional, Retrospective Observational Study. JMIR Formative
Research, 5(5), e27868. https://doi.org/10.2196/27868
18. Davé, S., Petersen, I., Sherr, L., & Nazareth, I. (2010). Incidence of maternal and paternal depression in primary care: A
cohort study using a primary care database. Archives of Pediatrics & Adolescent Medicine, 164(11), 1038–1044.
Version 1.6
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Page 66 of 82

CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
https://doi.org/10.1001/archpediatrics.2010.184
19. Davey, H. L., Tough, S. C., Adair, C. E., & Benzies, K. M. (2011). Risk factors for sub-clinical and major postpartum
depression among a community cohort of Canadian women. Maternal and Child Health Journal, 15(7), 866–875.
https://doi.org/10.1007/s10995-008-0314-8
20. Dear, B. F., Titov, N., Sunderland, M., McMillan, D., Anderson, T., Lorian, C., & Robinson, E. (2011). Psychometric
comparison of the generalized anxiety disorder scale-7 and the Penn State Worry Questionnaire for measuring
response during treatment of generalised anxiety disorder. Cognitive Behaviour Therapy, 40(3), 216–227.
21. Driessen, E., & Hollon, S. D. (2010). Cognitive Behavioral Therapy for Mood Disorders: Efficacy, Moderators and
Mediators. The Psychiatric Clinics of North America, 33(3), 537–555. https://doi.org/10.1016/j.psc.2010.04.005
22. Dunlop BW, Parikh SV, Rothschild AJ, Thase ME, DeBattista C, Conway CR, Forester BP, Mondimore FM, Shelton
RC, Macaluso M, Logan J, Traxler P, Li J, Johnson H, Greden JF. (2019). Comparing sensitivity to change using
the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial. Open
Access Publications by UMMS Authors. https://doi.org/10.1186/ s12888-019-2410-2
23. Feiger, A. D., Rickels, K., Rynn, M. A., Zimbroff, D. L., & Robinson, D. S. (2006). Selegiline transdermal system for
the treatment of major depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration
trial. The Journal of clinical psychiatry, 67(9), 1354-1361.Gibbons, R. D., Clark, D. C., & Kupfer, D. J. (1993).
Exactly what does the Hamilton depression rating scale measure?. Journal of psychiatric research, 27(3), 259-273
24. Fitelson, E., Kim, S., Baker, A. S., & Leight, K. (2010). Treatment of postpartum depression: Clinical, psychological
and pharmacological options. International Journal of Women’s Health, 3, 1–14.
https://doi.org/10.2147/IJWH.S6938
25. Gelenberg, A. J., Freeman, M. P., Markowitz, J. C., Rosenbaum, J. F., Thase, M. E., Trivedi, M. H., Rhoads, R. S. V.,
Reus, V. I., DePaulo, J. R., Fawcett, J. A., Schneck, C. D., & Silbersweig, D. A. (2010). APA Practice Guidelines
for the Treatment of Patients with Major Depressive Disorder. 152.
26. Gilson, M., Freeman, A., Yates, M. J., & Freeman, S. M. (2009). Overcoming Depression: A Cognitive Therapy
Version 1.6
Confidential
Page 67 of 82

CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
Approach: Therapist Guide. In Overcoming Depression: A Cognitive Therapy Approach. Oxford University Press.
https://www.oxfordclinicalpsych.com/view/10.1093/med:psych/9780195300000.001.0001/med-9780195300000
27. Grigoriadis, S., & Ravitz, P. (2007). An approach to interpersonal psychotherapy for postpartum depression: focusing
on interpersonal changes. Canadian family physician Medecin de famille canadien, 53(9), 1469–1475.
28. Hamdan, A., & Tamim, H. (2011). Psychosocial risk and protective factors for postpartum depression in the United
Arab Emirates. Archives of Women’s Mental Health, 14(2), 125–133. https://doi.org/10.1007/s00737-010-0189-8
29. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56–62.
https://doi.org/10.1136/jnnp.23.1.56
30. Hantsoo L, Ward-O’Brien D, Czarkowski KA, Gueorguieva R, Price LH, Epperson CN. A randomized,
placebo-controlled, double-blind trial of sertraline for postpartum depression. Psychopharmacology 2014; 231:
939–48.
31. Huang, L., Zhao, Y., Qiang, C., & Fan, B. (2018). Is cognitive behavioral therapy a better choice for women with
postnatal depression? A systematic review and meta-analysis. PloS one, 13(10), e0205243.
https://doi.org/10.1371/journal.pone.0205243
32. InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-.
Cognitive behavioral therapy. 2013 Aug 7 [Updated 2016 Sep 8]. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK279297/
33. Kim DR, Epperson CN, Weiss AR, Wisner KL. Pharmacotherapy of postpartum depression: an update. Expert Opin
Pharmacother 2014; 15: 1223–34
34. Kingston, D., Tough, S., & Whitfield, H. (2012). Prenatal and postpartum maternal psychological distress and infant
development: A  systematic review. Child Psychiatry and Human Development, 43(5), 683–714.
https://doi.org/10.1007/s10578-012-0291-4
35. Knaus, W. J. (2014). The Cognitive Behavioral Workbook for Anxiety: A Step-By-Step Program. New Harbinger
Publications, Inc. https://www.amazon.com/Cognitive-Behavioral-Workbook-Anxiety-Step/dp/1626250154
Version 1.6
Confidential
Page 68 of 82

CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
36. Ko, J. Y., Farr, S. L., Dietz, P. M., & Robbins, C. L. (2012). Depression and treatment among U.S. pregnant and
nonpregnant women of reproductive age, 2005-2009. Journal of Women’s Health (2002), 21(8), 830–836.
https://doi.org/10.1089/jwh.2011.3466
37. Kolahi, J., Bang, H., & Park, J. (2009). Towards a proposal for assessment of blinding success in clinical trials:
up-to-date review. Community Dentistry and Oral Epidemiology (2009) December; 37(6): 477–484.
https://doi.org/10.1111/j.1600-0528.2009.00494.x
Korja, R., Savonlahti, E., Ahlqvist-Björkroth, S., Stolt, S., Haataja, L., Lapinleimu, H., Piha, J., Lehtonen, L., & PIPARI
study group. (2008). Maternal depression is associated with mother-infant interaction in preterm infants. Acta
Paediatrica (Oslo, Norway: 1992), 97(6), 724–730. https://doi.org/10.1111/j.1651-2227.2008.00733.x
38. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener.
Med Care. 2003 Nov;41(11):1284-92. doi: 10.1097/01.MLR.0000093487.78664.3C. PMID: 14583691.
39. Kroenke, K., Spitzer, R. L., & Williams, J. B. (2001). The PHQ-9: validity of a brief depression severity measure.
Journal of general internal medicine, 16(9), 606–613. https://doi.org/10.1046/j.1525-1497.2001.016009606.x
40. Ma, L., Huang, C., Tao, R., Cui, Z., & Schluter, P. (2021). Meta-analytic review of online guided self-help interventions
for depressive symptoms among college students. Internet interventions, 25, 100427.
https://doi.org/10.1016/j.invent.2021.100427
41. Manso-Córdoba, S., Pickering, S., Ortega, M. A., Asúnsolo, Á., & Romero, D. (2020). Factors Related to Seeking Help
for Postpartum Depression: A Secondary Analysis of New York City PRAMS Data. International journal of
environmental research and public health, 17(24), 9328. https://doi.org/10.3390/ijerph17249328
42. Mu, T. Y., Li, Y. H., Xu, R. X., Chen, J., Wang, Y. Y., & Shen, C. Z. (2021). Internet-based interventions for postpartum
depression: A systematic review and meta-analysis. Nursing open, 8(3), 1125–1134.
https://doi.org/10.1002/nop2.724
43. National Institute for Health and Care Excellence. (2020, February 11). Antenatal and postnatal mental health: Clinical
management and service guidance. NICE.
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Page 69 of 82

CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
https://www.nice.org.uk/guidance/cg192/chapter/1-Recommendations#principles-of-care-in-pregnancy-and-the-po
stnatal-period-2
44. Norhayati, M. N., Hazlina, N. H. N., Asrenee, A. R., & Emilin, W. M. A. W. (2015). Magnitude and risk factors for
postpartum symptoms: A literature review. Journal of Affective Disorders, 175, 34–52.
https://doi.org/10.1016/j.jad.2014.12.041
45. O’Connor, E., Rossom, R. C., Henninger, M., Groom, H. C., & Burda, B. U. (2016). Primary Care Screening for and
Treatment of Depression in Pregnant and Postpartum  Women: Evidence Report and Systematic Review for the US
Preventive Services Task  Force. JAMA, 315(4), 388–406. https://doi.org/10.1001/jama.2015.18948
46. O'Sullivan, R. L., Fava, M., Agustin, C., Baer, L., & Rosenbaum, J. F. (1997). Sensitivity of the six‐item hamilton
depression rating scale. Acta Psychiatrica Scandinavica, 95(5), 379-384.
47. Palladino, C. L., Singh, V., Campbell, J., Flynn, H., & Gold, K. J. (2011). Homicide and suicide during the perinatal
period: Findings from the National Violent Death Reporting System. Obstetrics and Gynecology, 118(5),
1056–1063. https://doi.org/10.1097/AOG.0b013e31823294da
48. Pearlstein, T., Howard, M., Salisbury, A., & Zlotnick, C. (2009). Postpartum depression. American Journal of
Obstetrics and Gynecology, 200(4), 357–364. https://doi.org/10.1016/j.ajog.2008.11.033
49. Pilling, S., Anderson, I., Goldberg, D., Meader, N., Taylor, C., & Two Guideline Development Groups. (2009).
Depression in adults, including those with a chronic physical health problem: Summary of NICE guidance. BMJ
(Clinical Research Ed.), 339, b4108. https://doi.org/10.1136/bmj.b4108
50. Ramachandran. S., Suharwardy, S., Leonard, S., Gunaseelan, A., Robinson, A, Darcy, A., Lyell, D., Judy A. (2020)
Acceptability of postnatal mood management through a smartphone-based automated conversational agent,
74. https://doi.org/10.1016/j.ajog.2019.11.090
51. Rasmussen, A., Lunde, M., Poulsen, D. L., Sørensen, K., Qvitzau, S., & Bech, P. (2003). A double-blind,
placebo-controlled study of sertraline in the prevention of depression in stroke patients. Psychosomatics, 44(3),
216-221.
Version 1.6
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Page 70 of 82

CONFIDENTIAL
Sponsor Name: Woebot Health
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52. Reynolds, W. M., & Kobak, K. A. (1995). Reliability and validity of the Hamilton Depression Inventory: A
paper-and-pencil version of the Hamilton Depression Rating Scale Clinical Interview. Psychological Assessment,
7(4), 472.
53. Ruhé, H. G., Dekker, J. J., Peen, J., Holman, R., & de Jonghe, F. (2005). Clinical use of the Hamilton Depression Rating
Scale: is increased efficiency possible? A post hoc comparison of Hamilton Depression Rating Scale, Maier and
Bech subscales, Clinical Global Impression, and Symptom Checklist-90 scores. Comprehensive psychiatry, 46(6),
417–427. https://doi.org/10.1016/j.comppsych.2005.03.001
54. Rush, A. J., South, C., Jain, S., Agha, R., Zhang, M., Shrestha, S., Khan, Z., Hassan, M., & Trivedi, M. H. (2021).
Clinically Significant Changes in the 17- and 6-Item Hamilton Rating Scales for Depression: A STAR*D Report.
Neuropsychiatric disease and treatment, 17, 2333–2345. https://doi.org/10.2147/NDT.S305331
55. Segre, L. S., Davis, W. (2013) Postpartum Depression and Perinatal Mood Disorders in the DSM.
https://www.postpartum.net/wp-content/uploads/2014/11/DSM-5-Summary-PSI.pdf
56. Shaw, D. S., Connell, A., Dishion, T. J., Wilson, M. N., & Gardner, F. (2009). Improvements in maternal depression as a
mediator of intervention effects on early childhood problem behavior. Development and Psychopathology, 21(2),
417–439. https://doi.org/10.1017/S0954579409000236
57. Snyder ES, Tao P, Svetnik V, Lines C, Herring WJ. Use of the single-item Patient Global Impression-Severity scale as a
self-reported assessment of insomnia severity. J Sleep Res. 2021 Feb;30(1):e13141. doi: 10.1111/jsr.13141. Epub
2020 Jul 30. PMID: 33210445.
58. Spitzer, R. L., Kroenke, K., Williams, J. B. W., & Löwe, B. (2006). A brief measure for assessing generalized anxiety
disorder: The GAD-7. Archives of Internal Medicine, 166(10), 1092–1097.
https://doi.org/10.1001/archinte.166.10.1092
59. Sriraman, N. K., Melvin, K., Meltzer-Brody, S., & the Academy of Breastfeeding Medicine. (2015). ABM Clinical
Protocol #18: Use of Antidepressants in Breastfeeding Mothers. Breastfeeding Medicine, 10(6), 290–299.
https://doi.org/10.1089/bfm.2015.29002
Version 1.6
Confidential
Page 71 of 82

CONFIDENTIAL
Sponsor Name: Woebot Health
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60. Stein, A., Gath, D. H., Bucher, J., Bond, A., Day, A., & Cooper, P. J. (1991). The relationship between post-natal
depression and mother-child interaction. The British Journal of Psychiatry: The Journal of Mental Science, 158,
46–52. https://doi.org/10.1192/bjp.158.1.46
61. Stamou, G., García-Palacios, A., & Botella, C. (2018). Cognitive-Behavioural therapy and interpersonal psychotherapy
for the treatment of post-natal depression: a narrative review. BMC psychology, 6(1), 28.
https://doi.org/10.1186/s40359-018-0240-5
62. Stuart, S. (2012). Interpersonal psychotherapy for postpartum depression. Clinical Psychology & Psychotherapy, 19(2),
134–140. https://doi.org/10.1002/cpp.1778
63. Taylor, A., Atkins, R., Kumar, R., Adams, D., & Glover, V. (2005). A new Mother-to-Infant Bonding Scale: Links with
early maternal mood. Archives of Women’s Mental Health, 8(1), 45–51. https://doi.org/10.1007/s00737-005-074-z
64. The American College of Obstetricians and Gynecologists. (2018). ACOG Committee Opinion No. 757: Screening for
Perinatal Depression. Obstetrics and Gynecology, 132(5), e208–e212. https://doi.org/us p
65. The Columbia Lighthouse Project/Center for Suicide Risk Assessment. (2019). The Columbia Suicide Severity Rating
Scale (C-SSRS): Supporting Evidence.
https://cssrs.columbia.edu/wp-content/uploads/CSSRS_Supporting-Evidence_Book_2019-12-12.pdf
66. United States Preventative Services Taskforce. (2016, January 26). Depression in Adults: Screening.
https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/depression-in-adults-screening
67. Weissman, M. M., Markowitz, J. C., & Klerman, G. (2008). Comprehensive Guide To Interpersonal Psychotherapy.
Basic Books.
68. Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988
Aug;45(8):742-7. doi: 10.1001/archpsyc.1988.01800320058007. PMID: 3395203.
69. Whitton, A., Warner, R., & Appleby, L. (1996). The pathway to care in post-natal depression: Women’s attitudes to
post-natal depression and its treatment. The British Journal of General Practice: The Journal of the Royal College
of General Practitioners, 46(408), 427–428.
Version 1.6
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Page 72 of 82

CONFIDENTIAL
Sponsor Name: Woebot Health
Protocol Number: WB001-001
70. Wisner, K. L., Peindl, K., & Hanusa, B. H. (1994). Symptomatology of affective and psychotic illnesses related to
childbearing. Journal of Affective Disorders, 30(2), 77–87. https://doi.org/10.1016/0165-0327(94)90034-5
71. Wouk, K., Stuebe, A. M., & Meltzer-Brody, S. (2017). Postpartum Mental Health and Breastfeeding Practices: An
Analysis Using the 2010-2011 Pregnancy Risk Assessment Monitoring System. Maternal and Child Health
Journal, 21(3), 636–647. https://doi.org/10.1007/s10995-016-2150-6
72. Yawn, B. P., Pace, W., Wollan, P. C., Bertram, S., Kurland, M., Graham, D., & Dietrich, A. (2009). Concordance of
Edinburgh Postnatal Depression Scale (EPDS) and Patient Health Questionnaire (PHQ-9) to assess increased risk
of depression among postpartum women. Journal of the American Board of Family Medicine: JABFM, 22(5),
483–491. https://doi.org/10.3122/jabfm.2009.05.080155
73. Yonkers. (2009). The management of depression during pregnancy: A report from the American Psychiatric Association
and the American College of Obstetricians and Gynecologists. Obstetrics and Gynecology, 114(3), 703–713.
https://doi.org/10.1097/AOG.0b013e3181ba0632
74. Zhong, Q., Gelaye, B., Rondon, M., Sánchez, S. E., García, P. J., Sánchez, E., Barrios, Y. V., Simon, G. E., Henderson,
D. C., Cripe, S. M., & Williams, M. A. (2014). Comparative performance of Patient Health Questionnaire-9 and
Edinburgh Postnatal Depression Scale for screening antepartum depression. Journal of Affective Disorders, 162,
1–7. https://doi.org/10.1016/j.jad.2014.03.028
75. Zimmerman, M., Martinez, J. H., Young, D., Chelminski, I., & Dalrymple, K. (2013). Severity classification on the
Hamilton depression rating scale. Journal of affective disorders, 150(2), 384-388.
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APPENDIX 1: LIST OF ABBREVIATIONS
ACOG
American College of Obstetricians and Gynecologists
ADL
Activity of Daily Living
AE
Adverse Event
APA
American Psychiatric Association
CBT
Cognitive Behavioral Therapy
cCBT
computerized Cognitive Behavioral Therapy
CDC
Centers for Disease Control
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impression – Improvement
CGI-S
Clinical Global Impression – Severity
CID
Clinically Important Difference
CRF
Case Report Form
CRO
Contract Research Organization
CSQ
Customer Satisfaction Questionnaire
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
DMP
Data Management Plan
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DSM
Diagnostic and Statistical Manual of Mental Disorders
DVP
Data Validation Plan
eCRF
electronic Case Report Form
EOT
End of Treatment
EPDS
Edinburgh Postnatal Depression Scale
FDA
Food and Drug Administration
GAD
Generalized Anxiety Disorder
GCP
Good Clinical Practice
HAM-D
Hamilton Rating Scale for Depression
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IPT
Interpersonal Psychotherapy
IRB
Institutional Review Board
ITT
Intention-To-Treat
IXRS
Interactive Voice/Web Response System
MID
Minimally Important Difference
MCT
Meaningful Change Threshold
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MDE
Major Depressive Episode
MedDRA
Medical Dictionary for Regulatory Activities
MIBS
Mother-to-Infant Bonding Scale
MMRM
Multilevel Modeling for Repeated Measures (Mixed Model with Repeated
Measures)
NSR
Non-Significant Risk
PGI-C
Patient Global Impression - Change in Clinical Status
PGI-S
Patient Global Impression – Disease Severity
PHQ-9
9-item Patient Health Questionnaire
PI
Principal Investigator
PPD
Postpartum Depression
PRAMS
Pregnancy Risk Assessment Monitoring System
PRN
pro re nata
QTL
Quality Tolerance Limit
RCT
Randomized Controlled Trial
SAE
Serious Adverse Event
SaMD
Software as a Medical Device
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SAP
Statistical Analysis Plan
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SCID-5-CT
Structured Clinical Interview for DSM-5 Clinical Trials Version
SD
Standard Deviation
TAU
Treatment As Usual
TRD
Treatment Resistant Depression
USADE
Unanticipated Serious Adverse Device Effect
USPSTF
United States Preventive Services Task Force
WDQ
Woebot Depression Question
WHO
World Health Organizations
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APPENDIX 3: SCHEDULE OF EVENTS
Mechanism
to
Execute
Epochs
Screening/Baseline**
Day 1
must be completed on same day
Week 4
Day 28 ±3
Week 8 (EOT/ET)
Day 56 ±3
Clinical Outcome Assessments
Intervention Period
In-person by
site staff
Randomization
*After the following assessments are
completed and patient meets all I/E
Criteria
X
In-person by
blinded site
staff via tablet
or paper copy
Informed Consent
X
In-person by
blinded site
staff for input
in EDC
Inclusion/Exclusion Criteria
X
In-person by
blinded site
staff for input
in EDC
Demographics
X
In-person by
blinded site
staff for input
in EDC
Previous Medications
X
In-person by
blinded site
staff for input
in EDC
Psychiatric History
X
In-person by
blinded site
staff/PI via
tablet
SCID-5-CT a, e
X
Hybrid by
blinded site
staff/PI for
input in EDC
Concomitant Medications
and Therapy
*Post randomization, will rely on
self-report from participant on
continued TAU
X
X
X
Hybrid by
blinded site
staff/PI for
input in EDC
Pregnancy History and
Status
*Post randomization, will rely on
self-report from participant on
pregnancy status
X
X
X
Virtual by
blinded CIR
HAM-D17c
*Primary endpoint is HAM-D 6 derived
from HAM-D17
X
X
X
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Sponsor Name: Woebot Health
Protocol Number: WB001-001
Hybrid by
blinded site
staff/PI
C-SSRSa
*Safety endpoint and will be
administered virtually by PI if safety
event is flagged and confirmed
X
X
X
Self-report via
link
EPDSb
*If safety flag is raised due to score of >2
on item #10, EPDS, PI/site staff are
notified immediately for review, and
action, if needed
X
X
X
Self-report via
link
PHQ-9b
*If safety flag is raised due to score of ≥2
on item #9, PHQ-9PI/site staff are
notified immediately for review and
action
X
X
X
Self-report via
link
GAD-7b
X
X
X
Hybrid by
blinded site
staff/PI into
EDC
CGI-Sa
X
X
X
Virtual by
blinded site
staff/PI into
EDC
CGI-Ia
X
X
Self-report via
link
PGI- Sb
X
X
X
Self-report via
link
PGI- Cb
X
X
Self-report via
link
MIBSb
X
X
X
Self-report via
link
Healthcare Utilization
X
X
X
Self-report via
link
Program Assignment
Assessment (Blinding)
X
Hybrid by
blinded site
staff/PI into
EDC
AEs/SAEs Assessment a
*Includes confirming no recent
hospitalizations for mental
health-related incidence
X
X
X
Self-report via
link
CSQ-8b
X
Virtual by
blinded PI
Escalation Trigger Follow-Up
X d
Version 1.6
Confidential
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CONFID
L
Sponsor Name: Woebot Health
Protocol Number: WB001-001
AE = adverse event; BL = baseline; CGI-I = Clinical Global Impression of Improvement;  CGI-S = Clinical Global Impression of Severity; C-SSRS =
Columbia-Suicide Severity Rating Scale; CSQ = Customer Satisfaction Questionnaire;  EOT = end of treatment; EPDS = Edinburgh Postnatal Depression Scale;
ET= Early Termination visit; GAD = Generalized Anxiety Disorder Questionnaire; HAM-D = Hamilton Depression rating scale; MIBS = Mother-to-Infant
Bonding Scale; PHQ = Patient Health Questionnaire; PGI-C = Patient Global Impression of Improvement of Change;  PGI-S = Patient Global Impression of
Disease Severity; SCID-5-CT = Structured Clinical Interview for DSM-5 - Clinical Trials Version; Hybrid = indicates conducted in-person at BL and virtual by
participant post-randomization through link; CIR = Central Independent Rater;
a These assessments will be administered by blinded investigator or qualified designee (e.g., sub-investigator, or dually qualified site staff).
b These assessments will be self-administered and completed independently by participant s as a link (±3 days of visit date)
c Will be administered by a CIR
dAny confirmed Escalation trigger through the following three scenarios will result in PI-administered C-SSRS:
●
e Only includes modules for major depressive disorder (MDD), current and lifetime diagnosis of a psychotic disorder including postpartum
psychosis and Schizophrenia, bipolar disorder, homicidal or infanticidal ideation, and history of drug and/or alcohol
AE/SAE collection will begin at the time ICF is signed. AEs/SAEs should be recorded until the EOT visit.
*Note: the HAM-D will be administered as the Structured Interview Guide for the Hamilton Depression Rating Scale – 17 item version (SIGH-D
17-item HAM-D) to derive the HAM-D6 as the primary endpoint
**Final Screening and Baseline visit assessments must be completed on the same day.
Version 1.6
Confidential
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