Efficacy of Digital Cognitive Behavior Therapy for Insomnia for the Prevention of Perinatal Depression
Phase: NA
Conditions: Insomnia, Depression
Sponsor: University of California, San Francisco

  
 
Protocol 
Perinatal Research on Improving Sleep and Mental health 
(PRISM) Study 
  
 
 
 
National Clinical Trial (NCT) Identified Number:  TBD 
Principal Investigator: Jennifer Felder, PhD 
Sponsor: University of California, San Francisco 
Grant Title: Efficacy of digital cognitive behavior therapy for insomnia 
for the prevention of perinatal depression 
Grant Number: R01MH126040 
Funded by: National Institute of Mental Health 
Version Number:  1.0 
September 2, 2022 
  
 
 
 
 
 
 
 
 

CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be published 
or disclosed without prior approval of the Principal Investigator or other participating study 
leadership and as consistent with the NIH terms of award.  
 
 
 
 
 
 
 

TABLE OF CONTENTS 
TABLE OF CONTENTS...................................................................................................................... iv 
STATEMENT OF COMPLIANCE ........................................................................................................ 1 
INVESTIGATOR’S SIGNATURE .......................................................................................................... 2 
1. 
PROTOCOL SUMMARY.......................................................................................................... 3 
1.1 
Synopsis ....................................................................................................................... 3 
1.2 
Schema ...................................................................................................................... 4 
1.3 
Schedule of Activities .................................................................................................. 5 
2 
INTRODUCTION .................................................................................................................... 6 
2.1 
Study Rationale............................................................................................................ 6 
2.2 
Background .................................................................................................................. 6 
2.3 
Risk/Benefit Assessment ............................................................................................. 8 
2.3.1 
Known Potential Risks ................................................................................. 8 
2.3.2 
Known Potential Benefits ........................................................................... 8 
2.3.3 
Assessment of Potential Risks and Benefits ............................................... 9 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................. 11 
4 
STUDY DESIGN .................................................................................................................... 12 
4.1 
Overall Design ............................................................................................................ 12 
4.2 
Scientific Rationale for Study Design......................................................................... 13 
4.3 
Justification for Intervention ..................................................................................... 13 
4.4 
End-of-Study Definition ............................................................................................. 13 
5 
STUDY POPULATION ........................................................................................................... 13 
5.1 
Inclusion Criteria ........................................................................................................ 13 
5.2 
Exclusion Criteria ....................................................................................................... 14 
5.3 
Lifestyle Considerations ............................................................................................ 15 
5.4 
Screen Failures .......................................................................................................... 15 
5.5 
Strategies for Recruitment and Retention ................................................................ 15 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) .................................... 19 
6.1 
Study Intervention(s) or Experimental Manipulation(s) Administration .................. 19 
6.1.1 
Study Intervention or Experimental Manipulation Description ............... 19 
6.1.2 
Administration and/or Dosing .................................................................. 20 
6.2 
Fidelity ....................................................................................................................... 20 
6.2.1 
Interventionist Training and Tracking ....................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................ 21 
6.4 
Study Intervention/Experimental Manipulation Adherence .................................... 21 
6.5 
Concomitant Therapy ................................................................................................ 21 
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ........................................................................ 21 
7.1 
Discontinuation of Study Intervention/Experimental Manipulation ........................ 21 
7.2 
Participant Discontinuation/Withdrawal from the Study ......................................... 22 
7.3 
Lost to Follow-Up ...................................................................................................... 22 
8 
STUDY ASSESSMENTS AND PROCEDURE ............................................................................ 22 
8.1 
Endpoint and Other Non-Safety Assessments .......................................................... 23 

8.2 
Safety Assessments ................................................................................................... 26 
8.3 
Adverse Events and Serious Adverse Events ............................................................. 27 
8.3.1 
Definition of Adverse Events..................................................................... 27 
8.3.2 
Definition of Serious Adverse Events ........................................................ 27 
8.3.3 
Classification of an Adverse Event ............................................................ 27 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up .......... 29 
8.3.5 
Adverse Event Reporting .......................................................................... 29 
8.3.6 
Serious Adverse Event Reporting.............................................................. 29 
8.3.7 
Reporting of Pregnancy ............................................................................ 30 
9 
Unanticipated Problems ..................................................................................................... 30 
9.1.1 
Definition of Unanticipated Problems ...................................................... 30 
9.1.2 
Unanticipated Problems Reporting .......................................................... 30 
10 
STATISTICAL CONSIDERATIONS .......................................................................................... 30 
10.1 
Statistical Hypotheses ............................................................................................... 31 
10.2 
Sample Size Determination ....................................................................................... 31 
10.3 
Populations for Analyses ........................................................................................... 32 
10.4 
Statistical Analyses .................................................................................................... 32 
10.4.1 
General Approach ..................................................................................... 32 
10.4.2 
Analysis of the Primary Endpoint(s) .......................................................... 33 
10.4.3 
Analysis of the Secondary Endpoint(s) ..................................................... 33 
10.4.4 
Baseline Descriptive Statistics................................................................... 34 
10.4.5 
Planned Interim Analyses ......................................................................... 34 
10.4.6 
Sub-Group Analyses .................................................................................. 35 
10.4.7 
Tabulation of Individual Participant Data ................................................. 35 
10.4.8 
Exploratory Analyses ................................................................................. 35 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......................... 35 
11.1 
Regulatory, Ethical, and Study Oversight Considerations ......................................... 35 
11.1.1 
Informed Consent Process ........................................................................ 35 
11.1.2 
Study Discontinuation and Closure ........................................................... 36 
11.1.3 
Confidentiality and Privacy ....................................................................... 36 
11.1.4 
Future Use of Stored Specimens and Data ............................................... 37 
11.1.5 
Key Roles and Study Governance ............................................................. 38 
11.1.6 
Safety Oversight ........................................................................................ 38 
11.1.7 
Quality Assurance and Quality Control ..................................................... 38 
11.1.8 
Data Handling and Record Keeping .......................................................... 39 
11.1.9 
Protocol Deviations ................................................................................... 39 
11.1.10 
Publication and Data Sharing Policy ......................................................... 39 
11.1.11 
Conflict of Interest Policy .......................................................................... 40 
11.2 
Abbreviations and Special Terms .............................................................................. 40 
11.3 
Protocol Amendment History.................................................................................... 42 
12 
REFERENCES ....................................................................................................................... 43 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812).  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent forms, recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
forms must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent forms will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
 

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INVESTIGATOR’S SIGNATURE 
The signature below constitutes the approval of this protocol and provides the necessary 
assurances that this study will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines, as described in the 
Statement of Compliance above. 
 
Principal Investigator: 
 
Signed: 
 
Date: 
 
 
 
 
Jennifer Felder, PhD 
 
Assistant Professor 
Osher Center for Integrative Health 
University of California, San Francisco 
UCSF Box 1726                                                       
San Francisco CA 94143                       
Cell: (805) 708-9056 
Office: (415) 476-7014 
jennifer.felder@ucsf.edu 
 
 
 
 
 

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1. PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Grant Title: 
Efficacy of digital cognitive behavior therapy for insomnia for the 
prevention of perinatal depression 
Grant Number: 
R01MH126040 
Study Name: 
Perinatal Research on Improving Sleep and Mental health (PRISM) Study 
Study 
Description: 
The PRISM Study is a blinded randomized controlled trial to evaluate the 
efficacy of digital CBT-I for the prevention of depression during 
pregnancy and through 12 months postpartum among 498 non-
depressed people with insomnia disorder relative to a credible, 
clinically-relevant control condition.  
Objectives: 
 
• Primary Objective: To evaluate the efficacy of digital CBT-I for 
preventing perinatal depression; 
• Secondary Objectives:  To test whether the effect of digital CBT-I on 
perinatal depression is mediated through prenatal insomnia 
symptom improvement; To test whether the effect of digital CBT-I 
on perinatal depression is moderated by baseline depressive 
symptom severity. 
Endpoints: 
• Primary Endpoint: Depression incidence; Change in depression 
symptom severity 
• Secondary Endpoints: Suicidal ideation; Change in anxiety symptom 
severity; Change in prenatal insomnia as a mediator; Baseline 
depressive symptom severity as a moderator 
Study Population: 498 non-depressed pregnant people with insomnia disorder 
Phase: 
Confirmatory efficacy  
Description of 
Sites: 
Single site study at University of California, San Francisco 
Description of 
Study 
Interventions: 
• The study intervention is digital cognitive behavioral therapy for 
insomnia (CBT-I) from Big Hlth, Ltd, called Sleepio. This program 
involves 6 weekly sessions of 10-20 minutes each. The intervention 
also includes supplemental materials about prenatal, postpartum, 
and infant sleep.  
• The control condition is digital sleep hygiene education, a credible, 
clinically-relevant comparator that matches digital CBT-I in delivery 
format (digital), frequency (weekly), and number of sessions (six). 
Study Duration: 
4.25 years 
Participant 
Duration: 
Until 1 year postpartum; up to 18 months 
 
 
 

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1.2 
SCHEMA  
 
 
 

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1.3 SCHEDULE OF ACTIVITIES  
 
Screen. 
survey 
Screen. 
intvw. 
Base. 
5 w 
p-r 
10 
w p-
r 
36 w 
gest. 
3 m 
pp 
6 m 
pp 
9 m 
pp 
12 m 
pp 
Allowable 
window* 
Up to 1 
month 
before 
rand. 
Up to 1 
month 
before 
rand. 
Up to 2 
weeks 
before 
rand. 
+/- 7 
days 
+/- 7 
days 
+/- 7 
days 
+/- 1 
month 
+/- 1 
month 
+/- 1 
month 
+/- 1 
month 
Miscellaneous measures 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Documentation of 
pregnancy 
X 
 
 
 
 
 
 
 
 
 
TEQ* 
 
 
 
 
 
 
 
 
 
 
Birth date 
survey* 
 
 
 
 
 
 
 
 
 
 
Non-study 
treatment intvw. 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Adverse events 
intvw. 
 
 
 
 
X 
X 
X 
X 
X 
X 
CSQ 
 
 
 
 
X 
 
 
 
 
X 
Exit survey 
 
 
 
 
X 
 
 
 
 
X 
Primary clinical outcome measures 
SCID (primary) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
EPDS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Secondary clinical outcome measures 
C-SSRS 
 
X 
 
 
X 
X 
X 
X 
X 
X 
GAD-7 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Birth outcomes 
 
 
 
 
 
 
X 
 
 
 
Primary mediator measures 
ISI (primary) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
SCISD 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Sleep diary 
X 
 
 
 
X 
 
 
 
 
 
PSQI 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Secondary mediator measures 
PTQ 
 
 
X 
 
X 
X 
X 
X 
X 
X 
DBAS-16 
 
 
X 
 
X 
X 
X 
X 
X 
X 
PSAS 
 
 
X 
 
X 
X 
X 
X 
X 
X 
DERS-SF 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Maternal-infant outcomes 
BISQ-R 
 
 
 
 
 
 
X 
X 
X 
X 
IBQ-R 
 
 
 
 
 
 
X 
X 
X 
X 
MPAS 
 
 
 
 
 
 
X 
X 
X 
X 
Abbreviations. Screen.=Screening survey; Intvw.=Interview; Orient.=orientation; Base.=Baseline; w=weeks; p-
r=post-randomization; rand.=randomization; m=months; gest.=gestation; pp=postpartum; TEQ=Treatment 
Credibility and Expectancy Questionnaire; CSQ=Client Satisfaction Questionnaire; SCID=Structured Clinical 
Interview for DSM-5 Disorders; EPDS=Edinburgh Postnatal Depression Scale; PHQ-9=Patient Health 
Questionnaire; C-SSRS=Columbia Suicide Severity Rating Scale; GAD-7=Generalized Anxiety Disorder Scale; 
ISI=Insomnia Severity Index; SCISD=Structured Clinical Interview for DSM-5 Sleep Disorders; PSQI=Pittsburgh 
Sleep Quality Index; PTQ=Perseverative Thinking Questionnaire; DBAS=Dysfunctional Beliefs About Sleep scale; 

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PSAS=Pre-sleep Arousal Scale; DERS-SF=Difficulties in Emotion Regulation Scale-Short Form; BISQ-R=Brief Infant 
Sleep Questionnaire – Revised; IBQ-R=Infant Behavior Questionnaire – Revised; MPAS=Maternal Postnatal 
Attachment Scale. 
*Notes. Allowable windows: For the 5 weeks post-randomization, 10 weeks post-randomization, and 36 weeks 
gestation timepoints, the preferred response window is +/- 7 days, but we will accept +/- 14 days in exceptional 
circumstances. The 36 weeks gestation timepoint will not be collected if < 7 days from the 10 weeks post-
randomization timepoint. If we are unable to obtain information about the date the participant delivered her 
baby, the postpartum timepoints will be tied to her estimated due date that is provided at screening; TEQ will 
be completed at randomization; Birth date survey will be completed 3 weeks after a participant’s expected due 
date. 
 
2 
 
INTRODUCTION 
2.1 STUDY RATIONALE  
Perinatal depression (i.e., during pregnancy or the postpartum period) is common and 
associated with long-lasting consequences, including increased risk of suicide, impairments in 
parenting, and immense societal costs.  
Prenatal insomnia is a robust risk factor for perinatal depression: nearly 1 in 4 women who 
experience prenatal insomnia develop postpartum depression. To date, no trials have 
investigated whether treating prenatal insomnia prevents perinatal depression. Digital 
cognitive behavior therapy (CBT-I) is safe and effective for treating prenatal insomnia and 
shows promise for preventing perinatal depression relative to standard care. Further, digital 
CBT-I may be of particular interest for pregnant women because it minimizes wait time, avoids 
burdensome traveling and scheduling requirements, and meets their preferences for flexible 
delivery options.  
The proposed project is a blinded randomized controlled trial to evaluate the efficacy of digital 
CBT-I for the prevention of depression during pregnancy and through 12 months postpartum 
among 498 non-depressed women with insomnia disorder relative to a credible, clinically-
relevant control condition. Consistent with other research, sleep hygiene education will be the 
control condition, and will match digital CBT-I in delivery format (digital), frequency (weekly), 
and number of sessions (six). The proposed confirmatory efficacy trial addresses three specific 
aims: 1) To evaluate the efficacy of digital CBT-I for preventing perinatal depression; 2) To test 
whether the effect of digital CBT-I on perinatal depression is mediated through prenatal 
insomnia symptom improvement; 3) To test whether the effect of digital CBT-I on perinatal 
depression is moderated by baseline depressive symptom severity.  
2.2 BACKGROUND  
Approximately 1 in 7 women experience depression during the perinatal period (i.e., during 
pregnancy or postpartum), making it the most common complication of childbirth.1 Perinatal 
depression is associated with long-lasting consequences, including increased risk of suicide,2 
impairments in parenting,3 and immense societal costs due to productivity loss, increased use 

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of welfare and Medicaid services, and higher health care expenditures.4 Preventing perinatal 
depression may avert the long reach of these negative consequences.  
Prenatal insomnia is a robust, yet modifiable, risk factor for perinatal depression.5-7 Nearly 25% 
of women with prenatal insomnia develop postpartum depression.7 Our recent randomized 
controlled trial (RCT) showed that digital cognitive behavior therapy for insomnia (CBT-I) is 
effective for treating prenatal insomnia.8 A post-hoc analysis revealed that 6% who were 
randomized to CBT-I experienced high perinatal depression symptoms compared to 22% 
randomized to standard care (Cohen’s H = 0.5). Based on these promising post-hoc findings, we 
will conduct a confirmatory efficacy trial sufficiently powered and designed to provide definitive 
evidence about whether treating prenatal insomnia prevents perinatal depression. This project 
will also provide valuable information about how and for whom CBT-I prevents perinatal 
depression. Based on our preliminary data, we will test the hypotheses that improvements in 
prenatal insomnia symptoms mediate the effect of digital CBT-I on perinatal depression, and 
that baseline depressive symptom severity moderates the effect. 
As in our previous trial,8 we will use digital, rather than therapist-led, CBT-I because demand for 
CBT-I exceeds the availability of trained clinicians,9 and digital CBT-I minimizes wait time, avoids 
burdensome traveling and scheduling requirements, and meets pregnant women’s preferences 
for flexible delivery options.10 The digital CBT-I intervention is an interactive, fully automated 
program that is delivered by an animated therapist over six weekly sessions via a website or 
app.11,12   
We will conduct a blinded RCT to evaluate the efficacy of digital CBT-I for the prevention of 
depression through 12 months postpartum compared with a credible, clinically-relevant 
comparator group. We will enroll 498 non-depressed pregnant women with insomnia disorder. 
We will use sleep hygiene education as the control condition, and it will match digital CBT-I on 
delivery format (digital), frequency (weekly), and total number of sessions (six). The content for 
our sleep hygiene education intervention has been used as a control condition in previous RCTs, 
and was rated as credible as CBT-I.13 We investigate the following aims: 
Aim 1: Evaluate the efficacy of digital CBT-I for preventing perinatal depression. Participants 
randomized to digital CBT-I will have significantly lower rates of incident major depression 
during the perinatal period (Hyp 1a) and lower depressive symptoms from baseline to 12 
months postpartum (Hyp 1b) relative to participants randomized to digital sleep hygiene 
education.  
Aim 2: Test mediators of the effect of digital CBT-I on perinatal depression. Change in prenatal 
insomnia symptom severity will mediate the effect of digital CBT-I on perinatal depression 
incidence (Hyp 2a) and perinatal depressive symptom severity (Hyp 2b). Secondary mediators 
include perseverative negative thinking, dysfunctional beliefs about sleep, nocturnal cognitive 
arousal, and emotion regulation. 
Aim 3: Test moderation of the effect of digital CBT-I on perinatal depression. Baseline 
depressive symptom severity will moderate the effect of digital CBT-I on perinatal depression 

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incidence (Hyp 3a) and depressive symptom severity from baseline to 12 months postpartum 
(Hyp 3b).  
2.3 RISK/BENEFIT ASSESSMENT  
2.3.1 KNOWN POTENTIAL RISKS  
Digital CBT-I. The sleep restriction component of CBT-I is designed to reduce the amount of 
time spent awake in bed, and to decrease sleep onset latency and wake after sleep onset by 
leveraging increased sleep drive. Participants may experience temporary increases in sleepiness 
during this component of treatment. Our previous trials of therapist-delivered and digital CBT-I 
among pregnant women found no unanticipated serious adverse events. We are aware of no 
other research to suggest that digital CBT-I would confer risk to fetal, obstetric, or infant 
outcomes. 
Digital SHE. SHE is a credible control condition and is a clinically relevant comparator, as it is 
frequently used in clinical care. As a stand-alone treatment, it has low efficacy for improving 
insomnia. Therefore, we expect that women randomized to SHE will not experience significant 
improvements in insomnia and will continue to experience associated impairments in 
functioning and distress. We know of no other potential risks. 
Self-report questionnaires. There are no known risks for completing the study questionnaires, 
though it is possible that participants may experience temporary discomfort from thinking 
about their insomnia and depression symptoms. 
Privacy of participants. Participants will complete study procedures and outcome measures 
remotely at a location that feels safe and private to them, which mitigates concerns about 
privacy. We address protections against privacy risk below in Section 2.3.3. 
Worsening depressive symptoms and/or suicidal ideation. As is true for non-perinatal 
individuals generally, participants with insomnia may experience increases in depressive 
symptoms and/or suicidal ideation. Although we do not expect these to be research-related 
risks, there is the risk that the study team may observe worsening depressive symptoms and/or 
suicidal ideation. 
Confidentiality of data. Although every reasonable effort will be taken, confidentiality on web-
based surveys cannot be guaranteed. It is possible that information may be captured and used 
by others who are not associated with this study. There are also limits to confidentiality, such as 
if the study team observes possible evidence of child abuse, elder abuse, or a threat to self or 
others that we are required to report.  
Inconvenience. There may be some burden associated with completing the questionnaires and 
completing intervention sessions. 
2.3.2 KNOWN POTENTIAL BENEFITS  

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Our previous data provide a strong empirical basis to predict reduction of insomnia symptoms 
and to suggest benefit for depression among women randomized to digital CBT-I. Participants 
may benefit from ongoing monitoring of and referral for depression incidence or suicidality. The 
minimal risks participants may experience in this study are reasonable in relation to anticipated 
benefits for those assigned to digital CBT-I. In the long-term, there are substantial benefits to be 
gained by evaluating digital CBT-I for the prevention of perinatal depression. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
We will ask all participants to notify us if they experience an increase in daytime sleepiness, and 
will advise them about the risks of driving or doing any activity where severe sleepiness puts 
them at danger, and will instruct them to take naps if they feel sleepy. 
Digital CBT-I. Participants will be provided with a thorough description of the intervention prior 
to randomization. They will be informed that they can withdraw participation at any time 
without penalty. 
Given our previous RCTs, we expect that digital CBT-I will be associated with improved insomnia 
and depression outcomes for some participants. However, important precautions will be taken 
to minimize risks associated with sleep deprivation. Specifically, participants will be instructed 
to keep their time in bed prescription ≥ 6 hours during the sleep restriction component of 
treatment. 
Digital SHE. As with digital CBT-I, participants will be provided with a thorough description of 
the intervention prior to randomization and informed that they can withdraw participation at 
any time without penalty. 
Self-report questionnaires. Participants will be allowed to skip any questions they do not feel 
comfortable answering. One exception is that participants will be informed during the initial 
screening and clinical interview that skipping questions that are necessary for determining 
eligibility may preclude their ability to participate in the study. 
Privacy of participants. We will display recruitment ads on social media platforms. People who 
are interested in participating will provide consent prior to completing the online screening 
survey. Participants will be reminded to complete all study activities, including completing 
study measures, clinical interviews, and digital intervention sessions, at a time and location that 
is private. We will report only de-identified data in study manuscripts. 
Worsening depressive symptoms and/or suicidal ideation. Participants will be instructed to 
make immediate contact with study personnel with any questions or concerns regarding 
worsening depression symptoms or suicidal ideation. At enrollment, we will provide contact 
information for Dr. Krystal, Dr. Felder, therapeutic resources, and crisis hotlines.  
Depression incidence will be monitored via clinical interviews at 6 timepoints after 
randomization. When a participant has an EPDS score > 9 or PHQ-9 score > 9, they will 
automatically view information for mental health resources. Additionally, email triggers will 

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notify study staff. Study staff will conduct the SCID to determine if the participant meets criteria 
for a major depressive episode. Study staff will recommend that any participant who meets 
criteria for a major depressive episode or who scores above the EPDS or PHQ-9 cutoff notify her 
obstetrician or primary care provider.  
Suicidal ideation also will be monitored via self-report surveys and interviews at 6 timepoints 
after randomization. When a participant has an EPDS item 10 score > 0 or PHQ-9 item 9 > 0, 
they will complete the C-SSRS self-report, and automatically view information for suicide and 
mental health resources. Additionally, email triggers will notify study staff, who will follow our 
suicide risk assessment protocol. Please see the following documents for greater detail about 
the suicide risk assessment and response protocol: Suicide Ideation Response Flow and C-SSRS 
Response Scripts.  
Confidentiality of data. All data will be handled with the utmost attention to participants’ 
confidentiality. For more information, see Section 11.1.3. 
Inconvenience. Every effort will be taken to reduce participant burden, and we will 
accommodate participants’ work and childcare constraints when scheduling interviews. 
Participants will be compensated $50 per timepoint for the time to complete self-report 
measures and clinical interviews. 
Ensuring necessary intervention in the event of adverse events. Participants will be instructed 
to immediately inform their obstetrician or primary care physician if they experience any 
adverse events to determine whether intervention is needed. The study team will document, 
investigate, and follow-up all possible study-related AEs. 
Plans for handling incidental findings. It is possible we may detect a previously undiagnosed 
psychiatric or sleep disorder during the clinical interviews. We will advise that participants 
follow-up with a medical or mental health care provider for further assessment. 
The potential risks of participating in this study are minimal. Our previous research showed that 
digital CBT-I was associated with improved insomnia, depression, and anxiety during pregnancy 
and the postpartum period. All participants may benefit from ongoing monitoring of depression 
incidence or suicidality. In the long-term, there are substantial benefits to be gained by 
examining whether treating prenatal insomnia prevents perinatal depression. 
 
 

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3 
OBJECTIVES AND ENDPOINTS  
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Evaluate the efficacy 
of digital CBT-I for 
preventing perinatal 
depression relative to 
digital SHE.  
Depression incidence during the 
perinatal period (Hypothesis 1a) and 
depressive symptom severity from 
baseline to 12 months postpartum 
(Hypothesis 1b). 
This endpoint was selected 
based on our preliminary data. 
Secondary 
 
 
To evaluate the 
efficacy of digital 
CBT-I for improving 
secondary clinical 
outcomes relative to 
digital SHE. 
Suicidal ideation and anxiety 
symptom severity from baseline to 12 
months postpartum. 
We selected these endpoints 
in response to the FOA, which 
strongly encourages 
assessment of suicidal 
behavior, and because 
perinatal insomnia and 
depression are associated with 
suicidal ideation14 and 
anxiety15,16  
To test mediators of 
the effect of digital 
CBT-I on perinatal 
depression. 
 
Change in prenatal insomnia 
symptom severity as a mediator of 
the effect of digital CBT-I on perinatal 
depression incidence (Hypothesis 2a) 
and perinatal depressive symptom 
severity (Hypothesis 2b). 
This endpoint was selected 
based on our preliminary data. 
To test moderation of 
the effect of digital 
CBT-I on perinatal 
depression. 
Baseline depressive symptom severity 
as a moderator of the effect of digital 
CBT-I on perinatal depression 
incidence (Hypothesis 3a) and 
depressive symptom severity 
(Hypothesis 3B). 
This endpoint was selected 
based on our preliminary data. 
Exploratory  
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
To explore the effect 
of digital CBT-I on 
gestational length  
relative to digital 
SHE.  
Gestational length 
This endpoint was selected 
based on data showing that 
insomnia and poor sleep 
quality are associated with 
increased risk of preterm birth. 
To explore mediators 
of the effect of digital 
CBT-I on perinatal 
depression. 
 
Psychological mediators of the effect 
of digital CBT-I on depression 
incidence during the perinatal period 
and depressive symptom severity 
from baseline to 12 months 
postpartum. Endpoints include 
Perseverative negative thinking; 
Dysfunctional beliefs about sleep; 
Nocturnal arousal; Emotion regulation 
deficits. 
We selected measures that 
have been shown to mediate 
either the effect of CBT-I on 
depressive symptoms, or the 
relationship between insomnia 
and depression and that may 
be impacted by digital CBT-I. 
 
4 
STUDY DESIGN 
4.1 OVERALL DESIGN 
HYPOTHESIS 
The primary goal of this confirmatory efficacy trial is to provide definitive evidence about 
whether treating prenatal insomnia prevents perinatal depression. Secondarily, we will explore 
evidence of whether the effect of digital CBT-I on perinatal depression is mediated through 
prenatal insomnia symptom improvement.  Finally, we will test whether the effect of digital 
CBT-I on perinatal depression is moderated by baseline depressive symptom severity.  
TRIAL DESIGN 
This is a single-site, randomized controlled trial comparing CBT-I to SHE. 
RANDOMIZATION 
We will randomize participants to CBT-I or SHE after the baseline assessment using a 1:1 
allocation ratio with blocked randomization to balance the group sizes. See section 6.3 for more 
detail.  
DURATION AND ARMS 

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The study will have two arms: digital CBT-I and digital SHE. There will be six follow up time 
points after randomization, and participation will end at 12 months postpartum.  
INTERVENTIONS 
Section 6.1 describes the intervention and control conditions in greater detail. In brief, 
cognitive behavioral therapy for insomnia (CBT-I) is our intervention condition. We use digital 
CBT-I program called Sleepio (Big Health, Ltd), which is delivered through a webpage or app in 
six 10-20 minute weekly sessions.  
Sleep hygiene education (SHE) is our control condition. SHE matches digital CBT-I on delivery 
format (digital), frequency (weekly), and total number of sessions (six). The content for SHE has 
been used as a control condition previous RCTs. 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Our research question is whether digital CBT-I outperforms a clinically-relevant comparator. 
SHE has face validity, is frequently used in clinical practice,17,18 and is rated as credible as CBT-
I.13 We considered using the control from Dr. Manber’s previous trial and decided against it for 
two primary reasons: 1) it is not used in clinical practice and therefore does not address our 
research question, and 2) it contains several active components included in our study 
intervention, such as information about healthy sleep habits, information about sleep and sleep 
during pregnancy, and education about infant sleep development; use of this control condition 
would decrease our ability to accurately determine the effects of digital CBT-I.  
4.3 JUSTIFICATION FOR INTERVENTION 
The digital CBT-I program we will use is called Sleepio (Big Health, Ltd). We used Sleepio in our 
previous trial showing that digital CBT-I is effective tor treating prenatal insomnia.8,19 At the 
time, Sleepio was the only digital CBT-I option that was a stand-alone computer- and app-based 
intervention. We expected that some women would prefer to complete the intervention on 
their phone or tablet, and that a computer-only intervention would limit access. 
4.4 END-OF-STUDY DEFINITION 
A participant is considered to have completed the study upon completion of the 12-month 
follow-up assessment shown in the Schedule of Activities (SoA), Section 1.3. 
The trial is considered completed when participants are no longer being followed or the last 
participant’s last study visit has occurred. 
5 
STUDY POPULATION 
5.1 INCLUSION CRITERIA 

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Participants complete a consent form describing the screening procedures, and a study consent 
form describing study procedures. Participants are considered enrolled after they are 
randomized. Individuals must meet all of the following inclusion criteria in order to be eligible 
to participate: 
Inclusion criteria 
Rationale 
Ascertainment 
Pregnant 14-28 
weeks gestation 
Women who experience a miscarriage will become 
ineligible and will be withdrawn. We chose the 
lower limit of 14 weeks because the rate of first 
trimester miscarriage in women with a missed 
menstrual period and positive urine pregnancy test 
is 12-24%,20 and the upper limit of 28 weeks so 
women have time to complete the interventions 
prior to birth. 
Self-report; 
Documentation of 
pregnancy (e.g., 
dated ultrasound 
image, after visit 
summary) 
18 years or older 
Adolescents have unique sleep needs. 
Self-report 
Daily access to a 
web-enabled 
computer, smart 
phone, or tablet 
Interventions will be delivered digitally, and the 
sleep diary requires daily monitoring of sleep via 
online surveys. In 2019, over 90% of adults ages 18-
49 had a smart phone and 77% had broadband 
internet at home; 91% of women 18-49 years old 
with low income had a smartphone or high-speed 
broadband internet at home, thus mitigating 
concerns that requiring daily internet access will 
exclude individuals with low income.21 
Self-report 
Current elevated 
insomnia 
symptom 
severity and 
insomnia 
disorder 
We will include women who are likely to meet 
criteria for insomnia disorder using a cut-off of 11 on 
the ISI, which has been validated for identifying 
participants in clinical trials.22 Insomnia disorder is 
an inclusion criteria because CBT-I is indicated for 
insomnia disorder.23 
Insomnia Severity 
Index ≥ 11; 
Structured Clinical 
Interview for DSM-5 
Sleep Disorders 
(SCISD)24 
English speaking 
The digital CBT-I app is currently available in English 
only. 
Self-report 
5.2 EXCLUSION CRITERIA 
Individuals meeting any of the exclusion criteria below will be excluded from study 
participation: 
Exclusion criteria Rationale 
Ascertainment 

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Current major 
depression  
Our focus is on preventing, not treating, perinatal 
depression.  
Structured Clinical 
Interview for DSM-5, 
Research Version 
(SCID)25 
Taking or 
planning to take 
antidepressant 
medication 
(ADM) 
ADM use would make the effect of CBT-I on 
preventing depression difficult to interpret.  
Self-report 
Other diagnosed 
or suspected 
sleep disorder  
We will exclude sleep disorders not likely to benefit 
from digital CBT-I. 
SCISD; validated 
screeners for 
prenatal sleep 
apnea26  
Other psychiatric 
or medical issues 
(e.g., bipolar 
disorder, active 
suicidality, bed 
rest)  
We will exclude people who have any psychiatric or 
medical issues that necessitate priority treatment, 
could be exacerbated by the sleep restriction 
component of CBT-I, or would interfere with 
participation. 
SCID; Columbia-
Suicide Severity 
Rating Scale; Self-
report 
Night shift 
worker 
CBT-I would likely be ineffective, or the effect would 
be difficult to interpret. 
Self-report 
5.3 LIFESTYLE CONSIDERATIONS 
There are no restrictions related to lifestyle. 
5.4 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently randomized. Individuals who do not meet the criteria for participation in this trial 
(screen failure) because of meeting one or more exclusion criteria that are likely to change over 
time may be rescreened. An example includes the lifting of bed rest restrictions previously in 
place.  
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
ANTICIPATED NUMBER TO BE SCREENED 
Based on our previous trial, we anticipate we will need to screen approximately 5,500 people to 
randomize 498 participants. 
ANTICIPATED ENROLLMENT SAMPLE SIZE BY GENDER, RACE AND ETHNICITY, AND AGE 

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All participants will be pregnant adults 18 years or older. Per our inclusion enrollment report, 
we plan to enroll 115 Hispanic or Latina people and 383 non-Hispanic or Latina people. We plan 
to enroll 6 American Indian/Alaska Native people, 32 Asian people, 5 Native Hawaiian or Other 
Pacific Islander people, 79 Black or African American people, 364 white people, and 12 multi-
racial people. 
ANTICIPATED ACCRUAL RATE OVER THE COURSE OF THE STUDY 
 
RECRUITMENT AND REFERRAL SOURCES  
As in our previous research, we will use online sources, such as Facebook and Ovia Pregnancy, 
to recruit 498 non-depressed pregnant women with insomnia disorder. Facebook is a global 
social network site. The Facebook audience selection tool suggests that there are currently 
210,000 women in the United States whose behaviors on Facebook suggest they are pregnant 
and experiencing insomnia. In our previous trial of digital CBT-I, at least 1,600 of the people 
who completed our screening survey learned about the study from Facebook, and 74 ultimately 
enrolled in the study. In our previous trial of therapist-led CBT-I, we also had great success 
using targeted Facebook advertisements to recruit pregnant people with insomnia. Ovia 
Pregnancy is an app that provides clinical guidance, a personalized pregnancy timeline, and 
anonymous community to over 950,000 monthly active users. Users access the app an average 
of 21 times per month. Other investigators have used Ovia Pregnancy to successfully recruit 
research participants, including for an RCT of a digital depression prevention program.27  
Other possible recruitment sources include: 
Study website: Potential participants can view our study website (prismstudy.ucsf.edu) to learn 
more about the study or take the eligibility survey.  
Clinicaltrials.gov: Potential participants can view our study information and click a button to 
request more information from study staff.  
0
100
200
300
400
500
600
1-Dec
1-Apr
1-Aug
1-Dec
1-Apr
1-Aug
1-Dec
1-Apr
1-Aug
1-Dec
2022
2023
2024
2025
Cumulative Recruitment Target

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Word of mouth: People who view our ads may, with or without our awareness, share our study 
information. Thus, potential participants may learn about the study by word of mouth.  
Our team has extensive experience recruiting pregnant women with insomnia using these 
sources and we are confident we can meet recruitment goals on time.8,28 However, if we face 
enrollment shortfalls, we will utilize alternate online referral sources, such as::  
Google Advertisements: Google AdWords is a pay-per-click online advertising platform that 
allows advertisers to display their ads on Google's search engine results page. Google ads have 
been used in previous research studies to recruit participants.  
Other online sources: We will identify blogs, Reddit pages, listservs, websites, Facebook pages, 
Twitter accounts, Instagram accounts, and Pinterest accounts that serve the population we are 
targeting for recruitment (e.g., pregnant people) to host IRB-approved ads. Advertisements will 
include IRB-approved recruitment text with a brief description of the study, study contact 
information, and a link to the online eligibility survey.  
Conventional, Passive Recruitment: Study ads will be posted in community, medical, and retail 
settings serving a high volume of people (e.g., coffee shops, grocery stores, etc.), women who 
are pregnant (e.g., WIC, Black Infant Health, maternity clothing stores, etc.), and families (e.g., 
toy stores).  
Recruitment of under-represented minority groups is critical to obtain accurate and useful 
outcome data. To ensure that under-represented minorities are enrolled, we will work with the 
NIH-funded Clinical and Translational Awards’ (CTSA) Participant Recruitment Program (PRP) at 
UCSF. PRP provides tools, resources, and services to support enrollment of under-represented 
populations. We will partner with the PRP to: 
• Develop culturally concordant recruitment materials for under-represented populations 
by partnering with community members through the PRP’s Virtual Feedback Advisory 
Board. Community members will provide feedback on images, text, and overall user 
experience of the recruitment materials.  
• Engage the PRP Plain Language Consultation Service to ensure that recruitment 
advertisements, study website, and screening materials are accessible to a wide range 
of literacy levels. 
• Engage a PRP social media recruitment specialist with expertise in recruiting under-
represented minorities. 
If we begin to fall short of planned inclusion targets, we will convene a work group, comprised 
of three members from the UCSF Preterm Birth Initiative Community Advisory Board (PTBi CAB) 
who are women of color dedicated to improving reproductive health equity. The work group 
will meet quarterly to assist with our efforts to enroll under-represented populations by 
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materials. If needed, they will help us expand our recruitment efforts to community-based 
organizations that primarily serve women of color in San Francisco, Oakland, and Fresno.  
Finally, we will: 
• Use advertisement images featuring racially and ethnically diverse pregnant women. 
• Use targeted recruitment text (e.g., “Recruiting pregnant Latina women”).  
• Utilize Facebook’s audience selection tool to display our ads in zip codes that have a 
higher proportion of racially and ethnically diverse populations.  
• Offer flexible appointment times for interviews to accommodate a range of schedules. 
• Employ study staff who are under-represented minorities. 
PARTICIPANT IDENTIFICATION 
People who view our IRB-approved ads will be directed to complete the online eligibility survey 
or to contact study staff directly to learn more about the study.  
PARTICIPANT TRACKING  
As in our previous research, we will use a REDCap database to monitor enrollment by 
recruitment strategy to optimize our recruitment approach, and to track and retain participants 
for follow-up assessments. The tracking file will contain each participant’s current status in the 
study (e.g., enrolled, completed); dates when consent documents are completed, when 
measures are due, and when measures are completed; and an open text field for comments. 
REDCap is a HIPAA-compliant and secure web application designed for data capture for clinical 
research and trials.  
PARTICIPANT RETENTION 
We will employ several strategies that we believe contributed to high retention in our previous 
RCT of digital CBT-I: 
• Use of daily sleep diaries as behavioral run-in 
• Orientation session prior to enrollment to discuss the rationale and importance of the 
trial, the required commitment, what to expect if randomized to digital CBT-I or sleep 
hygiene, the rationale for random assignment, and the detrimental effects of attrition 
bias on the success of the study.29  
• Recognizable project identity by use of a study logo, and similar colors and fonts on trial 
materials 
• Protocols to address common participant questions 
• Employ “gracious but tenacious” research assistants who can offer flexible schedules for 
conducting clinical interviews, and who will send reminders about interview 
appointments, and make multiple attempts to contact participants to complete follow-
up measures.  
• Request contact information for a back-up contact person who can help us locate the 
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• Send birthday cards and study branded baby onesies 
• Participants will be compensated $50 for completing study surveys at each main 
timepoint (i.e., up to $350).  
In our previous trial, retention rates were > 80% at each timepoint. 
INCENTIVES 
We will compensate research participants $50 upon completing the study surveys and clinical 
interview at each timepoint.  
JUSTIFICATION FOR INCLUSION OF VULNERABLE PARTICIPANTS 
We focus on the vulnerable population of pregnant people because we want to decrease the 
risk of depression during this critical lifecycle phase, and there are limited prevention 
interventions for non-depressed pregnant women with insomnia disorder. Our proposed study 
meets each of the Department of Health and Human Services conditions for involving pregnant 
women in research (section §46.204): 
• Our previous trials found very few adverse events, and the unanticipated events that 
were detected were not likely to be related to participation in the study; 
• Study interventions that may have potential, unforeseen risks to the fetus have the 
prospect of direct benefit for the woman; 
• We believe that the risks are the least possible for achieving the research objectives; 
• We will obtain informed consent; 
• No inducements will be offered to terminate the pregnancy; 
• Study staff will not be involved in decisions about pregnancy termination;  
• Study staff will have no part in determining the viability of a neonate 
6 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
6.1 
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) 
ADMINISTRATION 
6.1.1 STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION 
INTERVENTIONS 
The digital cognitive behavioral therapy for insomnia (CBT-I) program we will use is called 
Sleepio (Big Health, Ltd). Digital CBT-I will be delivered by an animated therapist in six weekly 
sessions that are approximately 10-20 minutes each. Sessions can be accessed via website, iOS 
app, or Android app at a time that is convenient for the participant. Session content is based on 
standard, in-person CBT-I protocols, and includes sleep consolidation, stimulus control, 
cognitive therapy, relaxation techniques, and sleep hygiene education. The program is 
interactive, automated, and tailored to participant progress. Participants receive reminders to 
complete each session, and have access to a moderated community of other users and to a 

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library of sleep information, including recommendations tailored for pregnant and postpartum 
women. Additionally, participants will receive supplemental content about prenatal, 
postpartum, and infant sleep, previously evaluated in Dr. Manber’s trial of therapist-delivered 
CBT-I for prenatal insomnia. Content includes sleep hygiene recommendations specific for 
pregnancy, suggestions for improving postpartum sleep, instructions on how to adjust the time 
in bed prescription during the postpartum period, psychoeducation about infant sleep, and tips 
for promoting healthy sleep development among babies 0-3 months and 3-6 months of age.  
The control condition is sleep hygiene education (SHE) that matches the CBT-I intervention in 
delivery format (digital), frequency (weekly), and number of sessions (six). It includes 
information about sleep hygiene, the impact of sleep on performance, healthy sleep habits, 
lifestyle influences on sleep, and creating a sleep-friendly bedroom. 
INTENDED MECHANISTIC TARGET OF THE INTERVENTION 
We examine insomnia symptom severity reduction as a mediator and explore secondary 
mediators including perseverative negative thinking; dysfunctional beliefs about sleep; 
nocturnal arousal; emotion regulation deficits. 
6.1.2 ADMINISTRATION AND/OR DOSING 
The full-dose digital CBT-I program consists of: 
Sleepio (Big Health, Ltd): 
• Content delivered in 6 weekly 10-20 minute sessions  
• Accessed via website or app 
• Accessed independently at a time and location that is convenient for the participant 
Supplemental CBT-I content: 
• Available as downloadable PDF files 
• Prenatal content delivered upon starting Sleepio 
• Postpartum and infant content delivered at 36 weeks gestation and 3 months 
postpartum 
The full-dose digital SHE program will consist of: 
• Content delivered in 6 weekly 10-20 minute sessions 
• Accessed online 
• Accessed independently at a time and location that is convenient for the participant 
6.2 FIDELITY 
6.2.1 INTERVENTIONIST TRAINING AND TRACKING 

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The digital CBT-I program, Sleepio (Big Health, Ltd), is a standardized, automated program 
where the same content will be delivered to each participant in 6 weekly sessions.  
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Based on our previous research using this intervention with this population we do not expect to 
break the randomization code. At their discretion, the DSMB can break the randomization blind 
to protect participant safety if needed.  
We will use a 1:1 allocation ratio with blocked randomization to balance the group sizes. The 
randomization sequence will be generated by the study biostatistician and a masked 
randomization table will be uploaded to the REDCap database. The randomization sequence 
and block sizes will be concealed from all other study team members and participants. Study 
team members will not be able to influence randomization. Once an eligible participant 
completes baseline measures, unmasked study staff will reveal the allocation assignment, and 
notify participants of their assigned condition. 
The principal investigator and any staff member involved in conducting outcome assessments 
will be blinded from condition assignment. Although we cannot blind participants from 
condition assignment, allocation will occur after the participant has enrolled to avoid selection 
bias, and we will mitigate the effect of participant expectations by comparing two credible 
conditions. Interviewers will instruct participants to not reveal their study assignment during 
clinical interviews. 
6.4 STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE 
Participant adherence to the intervention is defined as completion of the weekly sessions. 
Completion of digital CBT-I sessions is captured by Sleepio and shared with the study team. 
Completion of digital SHE sessions is captured by REDCap by the study team. 
6.5 CONCOMITANT THERAPY 
At each follow-up timepoint, we will assess use of non-study treatments (type, dose, 
frequency). We will conduct sensitivity analyses to examine whether study findings change 
substantively when omitting participants with non-study treatments.  
7 
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION 
AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
The study intervention may be discontinued when the principal investigator believes that 
continuing the study intervention is not in subject’s best interest, for safety or other reasons. 
This decision will be made in consultation with the study medical monitors. 

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When a subject discontinues from digital CBT-I or digital SHE but not from the study, the 
remaining study procedures will be completed as indicated by the study protocol.   
The data to be collected at the time of study intervention discontinuation will include the 
following: 
• The reason(s) for discontinuing the participant from the intervention. 
• If the participant is due to complete assessments within 2 weeks of being discontinued 
from the study intervention, those assessments will be administered at the time of 
discontinuation; if the next scheduled assessments are more than 2 weeks from the 
discontinuation date, the discontinued participant will wait for the next scheduled 
assessment. Thereafter, the participant will be included in all future scheduled 
assessments, even though not participating in the intervention. 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
Participants with pregnancy loss or fetal demise or whose baby dies during the postpartum 
period will be withdrawn from the study. Otherwise, no randomized participants will be 
withdrawn to permit intention-to-treat analyses.  
The reason for participant discontinuation or withdrawal from the study will be recorded. 
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up at a particular timepoint if she fails to respond 
within the allowable response window (See table in Section 1.3). The following actions will be 
taken to minimize loss to follow-up: 
• Study staff will contact participants via a range of methods (email, phone, text) at least 3 
times to remind them to complete study measures within the allowable response 
window. These contact attempts will be documented in the participant tracking 
database.  
• If the above attempts are unsuccessful, study staff will contact the participant’s 
secondary contact person to find out the best method of reaching the participant 
and/or to have the secondary contact person ask the study participant to contact study 
staff. 
• Should the participant continue to be unreachable at a particular timepoint, study staff 
will continue to contact at each subsequent timepoint. Participants will not be 
withdrawn due to lost to follow-up at any timepoint. 
8 
STUDY ASSESSMENTS AND PROCEDURE 

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8.1 ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS 
PROCEDURES 
All study procedures are remote (e.g., surveys completed via REDCap, orientation and 
interviews completed via video-conferencing).  
Screening survey. People interested in participating will complete an electronic consent form 
describing the screening survey, baseline sleep diaries, and orientation session. Those who 
consent to the screening process will then complete the online screening survey to determine 
potential eligibility. Those determined to be potentially eligible with next complete baseline 
sleep diaries. 
Baseline sleep diaries. Each morning for 7 consecutive days, potential participants will receive a 
link to a brief online sleep diary. Sleep diaries will establish baseline sleep behaviors, such as 
sleep onset latency, wake after sleep onset, sleep duration, and sleep efficiency, prior to 
randomization. Additionally, they will serve as a behavioral run-in to identify women who are 
likely to complete study measures after randomization. Those who complete at least 4 of 7 
sleep diaries will be invited to complete the orientation session.  
Orientation session. In a video conference appointment, study staff will discuss the importance 
of the study question, the required commitments, what to expect if randomized to digital CBT-I 
or digital SHE, the rationale for random assignment, and the consequences of attrition bias. 
These appointments may be one-on-one or in a group. Women who decide to participate after 
the orientation session will be invited to complete the clinical interview.  
Consenting and clinical interviews. Study staff will review the study consent form with 
participants. Those who consent to participate will complete clinical interviews to determine 
eligibility and fully characterize the sample.  
Baseline measures. Participants will complete baseline measures via online survey prior to 
randomization. See the “Measures” section below. 
Randomization and intervention. Participants will be randomized to digital CBT-I or digital SHE 
after completing baseline measures, and complete a brief measures of treatment expectations 
and credibility. See 6.1 for a description of the interventions. 
Follow-up measures. At 5-weeks post-randomization, participants will complete brief online 
measures of insomnia and depressive symptom severity. Participants will complete follow-up 
measures via online surveys and clinical interviews via video-conferencing at 10-weeks post-
randomization, 36 weeks gestation, and every three months after delivery (i.e., 3, 6, 9, and 12 
months postpartum). These are described below in the “Measures” section. 
MEASURES 
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Screening measures. We will collect information about recruitment source, pregnancy status, 
and demographics, and assess several eligibility criteria (e.g., access to the Internet, ability to 
speak and read English, no history of bipolar disorder, etc.). Potential participants will be asked 
to submit documentation of their pregnancy (e.g., dated ultrasound image). 
We will assess insomnia symptom severity using the Insomnia Severity Index (ISI), a 7-item 
measure that assesses difficulty initiating or maintaining sleep, satisfaction with sleep, 
impairment, distress, and the extent to which others have noticed symptoms over the last two 
weeks.30 The ISI had high internal consistency in a clinical sample seeking treatment for 
insomnia (Cronbach’s alpha = 0.91). At screening, we will exclude women who are unlikely to 
meet criteria for insomnia disorder using a cut-off validated for identifying participants in 
clinical trials (ISI < 11).22 This cut-off yielded 97% sensitivity and 100% specificity when 
compared to a semi-structured diagnostic interview.  
We will use the consensus sleep diary to establish baseline sleep behaviors and to serve as a 
behavioral run-in.31 The consensus sleep diary is the gold standard measure of subjective sleep, 
and was developed in part by co-Investigator Dr. Krystal. The psychometrics suggest that the 
consensus sleep diary is associated with subjective and objective measures of sleep, 
differentiates good sleepers from those with insomnia disorder, and is sensitive to 
improvements over the course of CBT-I treatment.32 From the sleep diaries, we will compute 
average sleep onset latency, wake after sleep onset, sleep efficiency, and sleep duration. 
To screen out women with probable sleep apnea, we will use a validated pregnancy-specific 
screening tool for sleep apnea,26 which has sensitivity of 86% and specificity of 74% for the 
diagnosis of sleep apnea.  
Eligibility interviews. We will use the Structured Clinical Interview for DSM-5, Research Version 
(SCID) to exclude women with current major depression and other psychiatric disorders that 
necessitate priority treatment, could be exacerbated by the sleep restriction component of 
CBT-I, or would interfere with participation, and to fully characterize the sample.25  
We will use the Columbia-Suicide Severity Rating Scale (C-SSRS), Lifetime Recent33 version to 
exclude women with active suicidality in the past month or who have attempted suicide in the 
past 6 months.13 It was developed with support by NIMH and is recommended by the Centers 
for Disease Control and Food and Drug Administration. Psychometric data indicate that the C-
SSRS has convergent, divergent, and predictive validity, is sensitive to change, and has high 
internal consistency.33  
We will use the Structured Clinical Interview for DSM-5 Sleep Disorders (SCISD) to include 
women with current insomnia disorder and to exclude women with other sleep disorders, such 
as restless legs syndrome, hypersomnia, circadian rhythm disorder, nightmare disorder, or 
suspected sleep apnea.24 Inter-rater reliability was good to excellent for each of these 
disorders. In order to include women whose insomnia symptoms began during pregnancy, we 
will enroll women with either episodic (symptoms present 1-3 months) or persistent (symptoms 
present ≥3 months) insomnia, consistent with our previous trials of CBT-I for prenatal 
insomnia.8,28  

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Primary clinical outcome measures. We will use the depression module of the SCID-5, described 
in the “Eligibility interviews” section, to assess our primary clinical outcome, incidence of 
perinatal depression. This is a binary outcome that measures whether a participant experienced 
a depressive episode at any point since randomization. To reduce recall bias, we will conduct 
interviews at each follow-up timepoint (i.e., 10 weeks post-randomization, 36 weeks gestation, 
3, 6, 9, and 12 months postpartum). The stem question will be revised from “in the last month, 
have you experienced…” to “since the last interview on [date], have you experienced…” This 
interview will also provide estimates of time to depression onset, and duration and severity of 
symptoms among participants who experience a depressive episode.  
We will use the Edinburgh Postnatal Depression Scale (EPDS)34 to quantify depressive symptom 
severity.34 Participants will complete the EPDS at each follow-up timepoint, allowing us to 
measure changes in depressive symptoms from baseline to 12 months postpartum. The EPDS is 
a 10-item self-report measure that omits depressive symptoms that can be conflated with 
normal perinatal symptoms. It is frequently used and validated to assess depressive symptom 
severity during pregnancy,35,36 with estimates of sensitivity and specificity for detecting major 
depression ranging from 70-100% and 74-97%, respectively, depending on cut-off and sample.37 
Among postpartum women, estimates of sensitivity and specificity are 86% and 78%, 
respectively.34 We will also use the Patient Health Questionnaire (PHQ-9) to quantify depressive 
symptom severity.38 This is a 9-item measure frequently used in research and clinical practice. 
Secondary clinical outcome measures. We will assess suicidal ideation and anxiety because 
perinatal insomnia and depression are associated with suicidal ideation and 14 anxiety.15,16 We 
will use the C-SSRS, Since Last Contact version to assess suicidal ideation, intensity of ideation, 
and suicidal behavior since the last interview, and provide appropriate referrals as needed (see 
“Protection of Human Subjects” section for more detail).  
We will use the Generalized Anxiety Disorder Scale (GAD-7) to assess anxiety symptom 
severity.39 Among pregnant and postpartum women, a cut-off of 13 on the GAD-7 has 
sensitivity of 61% and specificity of 73% for detecting diagnoses of generalized anxiety 
disorder.40  
Exploratory clinical outcome measure. We will assess gestational length because perinatal 
insomnia and depression are associated with poorer birth outcomes.41,42 We will use a self-
report measure to assess birth outcomes. Research shows that women reliably self-report their 
birth outcomes when compared with medical record data.43,44 At four months postpartum, 
maternal recall of birth outcomes had high agreement with medical record data: sensitivity and 
specificity were > 82% for caesarean delivery, epidural usage, infant gender, low birth weight, 
labor induction, multiple gestation pregnancy, post-term birth, and preterm birth.43 
 
Primary mediator measure. We will use the ISI, described above in the “Screening measures” 
section, to assess our primary mediator, change in insomnia symptom severity. We selected the 
ISI as our primary mediator measure because we have preliminary data indicating target 
engagement and validation using this measure. We will also use the consensus sleep diary to 
assess sleep behaviors.  

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Exploratory mediator measures. We will assess perseverative negative thinking using the 
Perseverative Thinking Questionnaire (PTQ),45 which was shown to mediate the depression 
prevention effect of digital CBT-I in a non-perinatal population.46 The PTQ has 15 items and 
total scores range from 0-60, with higher scores indicating greater tendency to engage in 
transdiagnostic repetitive negative thinking.45,47 Among pregnant and postpartum samples, the 
PTQ demonstrates high internal consistency (α >=.95).48,49  
We will assess dysfunctional beliefs about sleep using the brief Dysfunctional Beliefs and 
Attitudes about Sleep Scale (DBAS-16),50 which were shown to mediate reductions in depressive 
symptom severity via CBT-I in a non-perinatal population (18% variance explained).51 The DBAS 
has 16 items and total scores range from 0-10, with higher scores indicating more dysfunctional 
beliefs and attitudes about sleep.50 Among non-perinatal samples, the DBAS-16 demonstrates 
adequate internal consistency (α >=.77) and temporal stability (r=.83).50  
We will assess cognitive and somatic manifestations of nocturnal arousal using the Pre-sleep 
Arousal Scale (PSAS).52 In a perinatal sample, nocturnal cognitive arousal was shown to mediate 
23-43% of the effect of insomnia on depression.53 The PSAS has 16 items and total scores for 
the two subscales range from 8-40, with higher scores indicating greater nocturnal arousal.52 
We will use the Difficulties in Emotion Regulation Scale-Short Form (DERS-SF) to assess emotion 
regulation deficits.54 In a non-perinatal sample, DERS scores mediated the effect of probable 
insomnia disorder on depressive symptoms (37% total effect mediated).55 The DERS-SF has 18 
items and 6 subscales, and the psychometric properties are at least comparable to the original 
full-length scale.54,56 The Cronbach’s alpha for the total score was 0.89 in an adult sample, with 
adequate concurrent validity.54  
Moderator measure. We will use the EPDS, described above in the “Screening Measures” 
section, to assess our primary moderator, baseline depressive symptom severity. We selected 
baseline depressive symptom severity as our primary moderator based on our strong 
preliminary data, as well as similar findings in a non-perinatal population.57  
Other measures. We will use the Treatment Credibility/Expectancy Questionnaire to measure 
expectations about the sleep program at randomization.58 We will use the Client Satisfaction 
Questionnaire to measure satisfaction with the sleep program.59 We will use a birth date 
questionnaire to assess the date a participant had her baby in order to determine when to send 
the postpartum follow-up questionnaires. We will use an exit questionnaire to collect 
information on participants' experiences with the program in order to inform future research. 
We will collect information about use of non-study treatments in an interview. We will collect 
information about any adverse events in an interview. 
8.2 SAFETY ASSESSMENTS 
Adverse events may be identified via the adverse events interview administered at each follow-
up timepoint, via self-report questionnaires or interviews, or by other participant report. Upon 
identification of a possible adverse event, trained study staff will conduct an adverse event 

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interview to characterize the type and severity of the event and the relationship to the study 
intervention and study procedures. Dr. Krystal will review psychiatric events and Dr. Yeaton-
Massey will review medical events. These medical monitors will advise on additional event 
assessment and follow-up. 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS 
Per the UCSF Human Research Protection Program, an adverse event is defined as any 
untoward or unfavorable medical occurrence in a human subject, including any abnormal sign 
(for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in the research, whether or not considered related to 
the subject’s participation in the research. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS 
Per the UCSF Human Research Protection Program, a serious adverse event is defined as any 
adverse event that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening adverse experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect, or cancer 
• 
Any other experience that suggests a significant hazard, contraindication, side effect or 
precaution that may require medical or surgical intervention to prevent one of the 
outcomes listed above 
• 
Event that changes the risk/benefit ratio of the study 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
The following guidelines will be used to describe severity.  
• Mild: Participant is aware of symptoms, but is able to tolerate them, and no to minimal 
intervention is required.  
• Moderate: Participant experiences enough symptoms to require intervention. 
• Severe: Participant experiences symptoms or findings that require significant 
intervention or is life threatening. Severity is not synonymous with seriousness. 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION 
All adverse events (AEs) will have their relationship to study procedures, including the 
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his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below, per the UCSF Human Research Protection Program: 
• Definitely related: An AE is definitely related to study participation if it is clear that the 
event was caused by study participation. A definitely related event has a strong 
temporal relationship, and an alternative cause is unlikely. 
• Probably related: An AE is probably related when there is a reasonable possibility that 
the event is likely to have been caused by study participation. The AE has a timely 
relationship to the study procedure(s) and follows a known pattern of response, but a 
potential alternative cause may be present. 
• Possibly related: An AE is possibly related when there is a reasonable possibility that the 
event might have been caused by study participation. A possibly related event may 
follow no known pattern of response and an alternative cause seems more likely. In 
other circumstances there may be significant uncertainty about the cause of the event, 
or a possible relationship to study participation cannot reasonably be ruled out. 
• Unrelated: The cause of the AE is known and the event is in no way related to any 
aspect of study participation. If there is any uncertainty regarding AE causality, then the 
event must be assessed as possibly related to research participation and reported to the 
IRB as indicated. Often, the cause of an unrelated AE is disease progression. 
8.3.3.3 EXPECTEDNESS  
Per the UCSF Human Research Protection Program, expected adverse events are defined as 
those that may be reasonably anticipated to occur as a result of the study procedures or study 
participation or is part of the normal disease process or progression.  
An AE or suspected adverse reaction is considered "unexpected" if it is unlikely to occur in the 
study population, or it is unlikely to occur at the severity that has been observed. An 
unexpected AE also includes any AE that meets any of the following criteria: 
• Results in subject withdrawal from study participation, 
• Due to a deviation from the IRB approved study protocol 
The events below are considered expected and will not be reported to the IRB: 
• COVID diagnosis 
• Increased sleepiness, which is a common short-term side effect of the sleep 
consolidation component of CBT-I 
• Events that are expected among individuals with insomnia, including worsening 
depressive or anxiety symptoms, and/or suicidal ideation 
• Events that are expected during pregnancy, including but not limited to: depression, 
anxiety, worsening sleep quality, fatigue, gestational diabetes, hypertensive disorders, 
pregnancy loss including miscarriage and stillbirth, hyperemesis gravidarum, nausea or 
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bleeding, preterm labor, premature rupture of amniotic sac, preterm delivery, cesarean 
delivery, operative vaginal delivery, induction of labor. 
• Events that are expected during the postpartum period, including but not limited to: 
lacerations and stitches, pain, postpartum hemorrhage, hypertension and hypertensive 
disorders, sleep disturbances, depression, anxiety. 
Individual reports of AEs determined to be unrelated to research participation will not be 
reported to the IRB. Instead, these events will be documented, retained in the study files, and 
reported to the DSMB on an annual basis. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel via participant report on the adverse event interview, other study 
questionnaires, or via other participant report. 
All AEs will be captured on the adverse event report form. Information to be collected includes 
event description, time of onset, severity, relationship to study procedures, and time of 
resolution/stabilization of the event. All AEs will be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
Any medical or psychiatric condition that is present at the time that the participant signs the 
study consent form will be considered as baseline and not reported as an AE. However, if the 
study participant’s condition deteriorates at any time during the study, it will be recorded as an 
AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. Documentation of onset and duration of 
each episode will be maintained for AEs characterized as intermittent. 
The study team will record events with start dates occurring any time after the study consent is 
signed until the last day of study participation. Events will be followed for outcome information 
until resolution or stabilization. 
8.3.5 ADVERSE EVENT REPORTING  
Adverse events will be reported to the UCSF IRB per the reporting requirements 
(https://irb.ucsf.edu/adverse-event#Reporting-requirements-chart). Internal (on-site) adverse 
events that the PI determines to be: 
1. Definitely, probably or possibly related AND  
2. Serious or unexpected  
Will be reported to the IRB, DSMB, NIMH within 5 working days of UCSF PI awareness.  
8.3.6 SERIOUS ADVERSE EVENT REPORTING  

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SAEs that are unexpected, serious, and definitely, probably, or possibly related to the study 
intervention will be reported to UCSF IRB and DSMB in accordance with the reporting 
requirements detailed above.   
Internal, related deaths and life-threatening events will be reported to the UCSF IRB and DSMB 
immediately. 
8.3.7 REPORTING OF PREGNANCY  
N/A because pregnancy is an inclusion criteria for the study.  
9 
UNANTICIPATED PROBLEMS 
9.1.1 DEFINITION OF UNANTICIPATED PROBLEMS 
Per the UCSF Human Research Protection Program, we define unanticipated problems (also 
known as unexpected problems) as an unexpected, research-related event where the risk 
exceeds the nature, severity, or frequency described in the protocol, study consent form, or 
other study information previously reviewed and approved by the IRB.  
9.1.2  UNANTICIPATED PROBLEMS REPORTING  
The investigator will report unanticipated problems (UPs) to the UCSF Institutional Review 
Board (IRB) and Data Safety Monitoring Board. The UP report will include the following 
information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number 
• A detailed description of the event, incident, experience, or outcome  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP 
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
• UPs that are serious adverse events (SAEs) will be reported to the IRB, DSMB, and to the 
funding agency within 5 working days of the investigator becoming aware of the event  
• Any other UP will be reported to the IRB, DSMB, and to the funding agency within 10 
days of the investigator becoming aware of the problem  
The UP report will be completed by qualified study staff, reviewed by the relevant medical 
monitor, and reviewed and signed off by the Principal Investigator. 
10 STATISTICAL CONSIDERATIONS  

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10.1 STATISTICAL HYPOTHESES 
Aim 1: Evaluate the efficacy of digital CBT-I for preventing perinatal depression. We 
hypothesize that participants randomized to digital CBT-I will have significantly lower rates of 
incident major depression during the perinatal period (Hyp 1a) and lower depressive symptoms 
from baseline to 12 months postpartum (Hyp 1b) relative to participants randomized to digital 
sleep hygiene education.  
Aim 2: Test mediators of the effect of digital CBT-I on perinatal depression. We hypothesize 
that change in prenatal insomnia symptom severity will mediate the effect of digital CBT-I on 
perinatal depression incidence (Hyp 2a) and perinatal depressive symptom severity (Hyp 2b). 
Secondary mediators include perseverative negative thinking, dysfunctional beliefs about sleep, 
nocturnal cognitive arousal, and emotion regulation. 
Aim 3: Test moderation of the effect of digital CBT-I on perinatal depression. We hypothesize 
that baseline depressive symptom severity will moderate the effect of digital CBT-I on perinatal 
depression incidence (Hyp 3a) and depressive symptom severity from baseline to 12 months 
postpartum (Hyp 3b).  
10.2 SAMPLE SIZE DETERMINATION 
Aim 1: Based on our preliminary data, we expect a 16% lower rate of depression among women 
in the digital CBT-I condition relative to women in the digital SHE condition. We conservatively 
power the study to detect a between-group difference of 10% in case the effect is smaller than 
expected. Standard power calculations for the comparison of two proportions show that with 
alpha set at 0.05, chi-square tests with 199 women per group would have power greater than 
0.8 to detect this difference (Hypothesis 1A).60  
The proposed sample size and number of repeated measures per woman are large enough to 
allow us to detect important differences in the magnitude of within-woman change in 
depressive symptom severity, measured by the EPDS, between the two conditions with high 
power (Hypothesis 1B). We will measure depression outcomes at 7 time points throughout the 
study period. The statistical analyses will compare within-subject changes in the EPDS over time 
between the two intervention conditions using linear mixed effects models. Sample size 
calculations for repeated measures studies require estimates of the magnitude of the within-
subject correlation of the outcome; data from our previous trial of digital CBT-I provide us with 
an estimate of 0.5 for this correlation for the EPDS outcome.8 Our previous trial also provides 
an estimate of 9.2 units for the within-subject variance of the EPDS measure. Standard power 
calculations for linear mixed effects models show that with an alpha set at the 0.05 level and 
with two conditions of 199 subjects each, we will have power greater than 80% to detect a 
difference in within-subject slopes of 0.04 (units of EPDS) per month between the two 
intervention groups.61 In our previous trial, the estimated difference in slopes between digital 
CBT-I and standard care was 0.12. 

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Aim 2: We base sample size calculations on a statistical test to detect statistically significant 
mediation of the treatment effect on within-subject change in EPDS through within-subject 
change in ISI using linear regression. Standard sample size calculations for mediation using 
linear regression analysis require the specification of the variances of the depression outcome 
(EPDS), the treatment predictor, and the sleep mediator (ISI), the magnitude of the treatment 
effects without adjustment for the mediator, and the correlation of the mediator and 
treatment variables.62 Data from our previous trial of digital CBT-I provide estimates for all of 
these quantities. Calculations62 show that a standard test for mediation using our proposed 
sample will have power greater than 80% to detect a proportion of treatment effect explained 
(PTE) of 0.02. Using data from our previous trial of digital CBT-I for women and changes from 
baseline to 10 weeks, a linear regression with change in EPDS from baseline to 6 months 
postpartum as the outcome and treatment as the single predictor yielded an estimated 
regression coefficient of -0.14 (units of EPDS). Adding change in ISI to the model reduced the 
estimated treatment effect to -0.12 (units of EPDS), with an estimated PTE of 0.10, far 
exceeding 0.02.  
Aim 3: We base sample size calculations on tests of the interaction of treatment condition with 
depressive symptoms at baseline (using established cutoff of EPDS < 10) in logistic regressions 
with incidence of probable major depression as the outcome. These sample size methods 
require the specification of several inputs that describe the anticipated prevalence of the 
outcome, predictors, and their relationships.63 Calculations based on inputs from our previous 
digital CBT-I trial show that the proposed sample of 398 participants provide 80% power to 
detect an interaction odds ratio (ratio of odds ratio for baseline EPDS < 10 compared to 
baseline EPDS ≥ 10) of 4.1 with binary indicators for condition and depressive symptoms at 
baseline. Our previous trial yielded an estimated odds ratio of 10, indicating that the detectable 
interaction odds ratio of 4 is a realistic objective. 
These calculations show that the proposed sample size will allow us to detect clinically 
important differences in depression incidence and changes in depressive symptom severity 
between women in the two intervention conditions, as well as clinically meaningful mediation 
and moderation effects, with 80% power. Based on our previous trial, we set our attrition rate 
at 20%, yielding a total enrolled sample size of 498.  
10.3 POPULATIONS FOR ANALYSES 
All analyses will be conducted on the intention-to-treat sample defined as all randomized 
participants. We will examine whether the depression prevention effect is dose dependent by 
including number of sessions completed as a covariate. 
10.4 STATISTICAL ANALYSES 
10.4.1 GENERAL APPROACH 
For descriptive statistics, categorical data will be presented with frequency and percentage. 
Continuous data will be presented with mean, standard deviation, median, and range.  

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10.4.2 ANALYSIS OF THE PRIMARY ENDPOINT(S) 
Aim 1: To test Hypothesis 1a, we will compare the rate of major depression among women 
randomized to digital CBT-I to women randomized to digital SHE using a standard chi-square 
test for two proportions. The outcome is binary and indicates whether a participant 
experienced a depressive episode at any point since randomization (SCID-5). We will calculate a 
95% confidence interval for the difference in the two proportions to quantify the magnitude of 
the CBT-I effect.  
To test Hypothesis 1b, we will compare within-woman changes in depressive symptoms (EPDS; 
including data from baseline; 10-weeks post-randomization; 36 weeks gestation; 3, 6, 9, and 12 
months postpartum) between women in the digital CBT-I and digital SHE groups using linear 
mixed effects models.64 These models will include repeated measures of depressive symptoms 
as the outcome, along with time, treatment group, and time by group interactions as 
predictors. Models also will include random intercepts to accommodate the correlation among 
the repeated responses within subjects, and possibly random slopes to accommodate between 
subject differences in rates of change. The regression coefficient of the time by group 
interaction measures the differences in the rate of within-subject change in the outcomes 
between the treatment groups. We will calculate 95% confidence intervals for the time by 
group interaction to provide a range of differences in change that are consistent with the data. 
We will assess the statistical significance of the time by group interaction using likelihood ratio 
tests. We note that mixed effects models do not require the same number of repeated 
measures for each subject so that our approach will include all women who provide any data 
and will be an intention-to-treat approach. We will fit the mixed models using routines in Stata. 
Although we expect that randomization will balance baseline characteristics (e.g., gestational 
age, parity, insomnia symptom severity) between the two conditions, we will calculate 
standardized mean differences to identify any imbalances. If we identify imbalances, we will 
conduct secondary analyses including imbalanced covariates as predictors. Additionally, we will 
conduct sensitivity analyses to examine whether findings change substantively when omitting 
participants with new onset of sleep, medical, or psychiatric disorders, or initiation of mental 
health treatment. Finally, we will examine whether the depression prevention effect of digital 
CBT-I is dose-dependent by including number of sessions completed as a covariate. 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Aim 2: To test Hypothesis 2a, we will fit two logistic regression models to assess whether 
change in prenatal insomnia symptoms (ISI) mediates the effect of digital CBT-I on incidence of 
major depression from baseline to 12 months postpartum.65 The first model will include the 
binary indicator of depression as the outcome and treatment group as the single predictor. The 
second model will additionally include subject-specific change in insomnia severity from 
baseline to 10-weeks post-randomization. We will estimate subject-specific changes in 
insomnia severity as the predicted random slopes from a linear mixed effects model with the 
repeated measures of insomnia severity as the outcome and time as the single predictor, along 
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between the two models indicate mediation by insomnia severity. We will assess whether the 
conditions for mediation are met by fitting two additional models: first, a linear regression 
model for subject-specific change in insomnia severity on treatment group; second, a logistic 
regression model for major depression on subject-specific change in insomnia severity. 
Statistically significant predictor effects in each of these models are consistent with mediation.  
To test Hypothesis 2b, we will follow a similar approach to assess the potential mediation of the 
treatment effect on the changes in depressive symptoms (EPDS; including data from baseline; 
10-weeks post-randomization; 36 weeks gestation; 3, 6, 9, and 12 months postpartum) by 
changes in prenatal insomnia severity (ISI) by fitting two linear mixed effects regression models. 
The first model is the linear mixed effects model for repeated measures of depressive 
symptoms we fit to test the hypothesis of Aim 1b, namely a model that includes treatment 
group, time, and the time by group interactions as the predictors, along with random intercepts 
and time effects. The second model will additionally include repeated measures of insomnia 
severity (ISI). We will decompose insomnia severity variable into between- and within-woman 
components in order to isolate pure within-woman change.66 Differences in the estimated time 
by treatment interaction effects between the two models indicate mediation by changes in 
prenatal insomnia severity. 
Aim 3: To test Hypothesis 3a, we will fit a logistic regression model with perinatal depression 
incidence as the outcome, along with treatment group, baseline depressive symptom severity, 
and their interaction as the predictors. The regression coefficient of the interaction term 
measures the difference in the effect of the digital CBT-I intervention as a function of level of 
baseline depressive symptom severity. We will test the statistical significance of the interaction 
using a likelihood ratio test and quantify the magnitude of the interaction effects using 95% 
confidence intervals for the interaction regression coefficient.  
To test Hypothesis 3b, models will include repeated measures of depressive symptoms as the 
outcome, along with time, treatment group, and two-way interactions of depressive symptom 
severity with time and depressive symptom severity with treatment, as well as a three-way 
interaction of time, treatment, and depressive symptom severity. The three-way interaction 
term assesses whether the magnitude of the time by treatment group interaction (a primary 
treatment effect of Aim 1) differs as a function of baseline depression.  We will assess the 
statistical significance of the three-way interaction using a likelihood ratio test and quantify the 
magnitude of the interaction effects using 95% confidence intervals for the interaction 
regression coefficient. 
10.4.4 BASELINE DESCRIPTIVE STATISTICS 
We will collect the following baseline characteristics: age, race, ethnicity, highest level of 
education attained, income, marital status, number of children and their ages, zip code, 
insurance type, employment status, gestational age at enrollment.  
10.4.5 PLANNED INTERIM ANALYSES  

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No planned interim analyses. The Data Safety Monitoring Board (DSMB) will review any serious 
adverse events to determine whether the trial should be stopped.  
10.4.6 SUB-GROUP ANALYSES 
We do not plan sub-group analyses.  
10.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will not be listed by measure and time point in any publications. 
10.4.8 EXPLORATORY ANALYSES 
We will explore condition differences in gestational length, and explore potential mediators 
including perseverative negative thinking, dysfunctional beliefs about sleep, nocturnal arousal, 
and emotion regulation. 
11 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
11.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
11.1.1 INFORMED CONSENT PROCESS 
11.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 
Consent forms describing the study intervention, study procedures, and risks will be given to 
the participant and documentation of electronic consent will be completed prior to starting the 
study intervention.  Prior to the beginning of the trial, we will receive the IRB’s written approval 
for the protocol and the informed consent procedures and documents. 
11.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
Because this study involves no in-person visits, all consenting will occur electronically. There will 
be three consent forms: the screening consent, the future contact consent, and the study 
consent.  
For all consents, potential participants will have the option to decline participation, consider 
their decision further, or consent to participate. Consent forms will be written at an eighth-
grade education level, use lay language, and provide information about the background and 
purpose of the study, scope and length of participation, study procedures, legal and ethical 
limits to confidentiality, clinical interview audio and videotaping procedures, risks, benefits, 
alternatives, ability to discontinue participation, privacy and confidentiality, compensation, and 
whom to contact with questions. Potential participants will be assured that their decision to 
participate or decline participation in the study will have no effect on their current or future 
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instructed to contact study staff with any questions, and will be able to download a copy of the 
consent forms for their records.  
Screening consent: First, potential participants will view an introduction page that briefly 
describes the study. Next, the screening consent form will be displayed and participants can 
choose to decline to agree to participate. Participants who decline will be automatically 
directed to the end of the survey and thanked for their time. Participants who agree will begin 
the screening survey.  
Future contact consent: After completing the screening survey, regardless of eligibility, 
participants will be given the opportunity to input their contact information if they are 
interested in being contacted for future research studies at UCSF.  
Study consent: The orientation session provides another opportunity to engage participants in 
the informed consent process. In this session, study staff will discuss the importance of the 
study question, the required commitments, what to expect if randomized to CBT-I or SHE, the 
rationale for random assignment, the consequences of attrition bias, and answer any questions 
that participants have.29  Individuals who are interested in participating after the orientation 
session will be scheduled for a 1:1 appointment to complete the consenting process and the 
clinical interview to determine eligibility. Consenting participants will provide an electronic 
signature via REDCap.  
Staff obtaining consent will receive training from Dr. Felder.  
11.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause as determined by the DSMB. The study may resume once concerns about 
safety, protocol compliance, and data quality are addressed, and satisfy relevant regulatory or 
oversight bodies (e.g., DSMB, IRB, or NIMH). 
If the study is prematurely terminated or temporarily suspended, the PI will promptly inform 
ongoing study participants, the IRB, and sponsor/funding agency and provide the reason(s) for 
the termination or temporary suspension.  
11.1.3 CONFIDENTIALITY AND PRIVACY  
Participants will be instructed to complete all research activities in a private setting. 
Clinical interviews will be recorded for the purpose of assessing reliability. As is standard UCSF 
Zoom procedure, participants must agree before joining a recorded meeting. Any transcriptions 
of these recordings will not include information that links participant identity to the recording. 
All recordings will be destroyed 5 years after the project is complete, but researchers will retain 
de-identified transcripts of the recordings indefinitely.  

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All data will be handled with the utmost attention to participants’ confidentiality. Participants 
will be assigned unique, coded, confidential identifiers that will be used to label all data forms, 
data entries, and questionnaires. The key linking participant identity to their unique coded 
identifier will be stored on REDCap. Access to all data will be limited to the PI and trained, 
authorized study staff. Below we provide a brief overview of how the programs and platforms 
used to collect data handle data confidentiality and security:  
• 
REDCap (Participant tracking database; Online survey platform): Secure web application; 
HIPAA-compliant  
• 
BigHealth (Sleepio; Digital CBT-I program): Dated stored in encrypted form on secure 
servers owned and operated by Amazon Web Services; HIPAA-compliant. We will sign a 
data use agreement form with BigHealth prior to data collection.  
• 
Zoom: Provides encryption and meeting access controls (e.g., password) so data in 
transit cannot be intercepted; all audio, video, and screen sharing data is encrypted; 
Enables HIPAA-compliance.  
• 
Qualtrics (Online survey platform): Certified by Health Information Trust Alliance, the 
industry standard for HIPAA security requirements; data encrypted in transit to protect 
from attacks, eavesdropping, and session hijacking; all data treated as highly 
confidential; physical security controls monitored 24/7  
One limit to confidentiality is if a participant indicates during a clinical interview or on the EPDS 
or PHQ-9 that she is at imminent risk of harming herself. The procedures for responding to 
suicide risk are detailed in the Suicide Ideation Response Flow and C-SSRS Response Scripts.  
 
Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary, Health and Human Services 
(HHS), has issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, 
behavioral, clinical or other human subjects research funded wholly or in part by the federal 
government.  Recipients of NIH funding for human subjects research are required to protect 
identifiable research information from forced disclosure per the terms of the NIH Policy (see 
https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 75.303(a) and NIHGPS 
Chapter 8.3, recipients conducting NIH-supported research covered by this Policy are required 
to establish and maintain effective internal controls (e.g., policies and procedures) that provide 
reasonable assurance that the award is managed in compliance with Federal statutes, 
regulations, and the terms and conditions of award. It is the NIH policy that investigators and 
others who have access to research records will not disclose identifying information except 
when the participant consents or in certain instances when federal, state, or local law or 
regulation requires disclosure. NIH expects investigators to inform research participants of the 
protections and the limits to protections provided by a Certificate issued by this Policy. 
11.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  

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Data collected for this study will be analyzed and stored at the University of California, San 
Francisco. After the study is completed, the de-identified, archived data will be stored at the 
National Database for Clinical Trials related to Mental Illness (NDCT), for use by other 
researchers including those outside of the study. Permission to transmit data to the NDCT will 
be included in the informed consent.  
11.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Medical Monitor 
(Psychiatric) 
Medical Monitor (Medical) 
Jennifer Felder, PhD, Assistant 
Professor and Principal 
Investigator 
Andrew Krystal, MD, 
Professor and Co-Investigator 
Amanda Yeaton-Massey, 
MD, Assistant Professor 
and Co-Investigator 
University of California, San 
Francisco 
University of California, San 
Francisco 
University of California, San 
Francisco 
Jennifer.felder@ucsf.edu 
Andrew.krystal@ucsf.edu 
Amanda.yeaton-
massey@ucsf.edu 
+1 (415) 476-7014 
+1 (415) 476-7702 
+1 (415) 353-2566 
1545 Divisadero Street 
3rd Floor 
San Francisco, CA 94143 
401 Parnassus Avenue, 372 
Box 0984 
San Francisco, CA 94143 
490 Illinois St 
San Francisco, CA 94143 
 
11.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of individuals with appropriate expertise, including in perinatal mood and sleep, 
obstetrics and gynecology, and biostatistics. Members of the DSMB will be independent from 
the study conduct and free of conflict of interest. The DSMB will meet at least annually to 
assess safety and efficacy data from each arm of the study. The DSMB will operate under the 
rules of an approved charter that will be reviewed at the organizational meeting of the DSMB.  
11.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
Study staff will undergo rigorous training prior to collecting or monitoring data. Self-report 
questionnaires will be designed to only accept valid responses. In real time and as close to data 
collection as possible, study staff will check each submitted self-report measure to identify and 
correct any potential issues (e.g., participant indicated on sleep diary that she went to sleep at 
10:00 AM instead of 10:00 PM). Errors and their corrections will be logged in a data anomaly 
log. Clinical research coordinators will send reminders about interview appointments, and make 
multiple attempts to contact participants to complete follow-up measures.  
Training and reliability of clinical interviewers. Training will be led by Dr. Manber, who has 
extensive experience training study staff to competently administer clinical interviews. Staff will 
complete an intensive 8- hour didactic and experiential training. For the didactic training, Dr. 

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Manber will review diagnostic criteria, orient staff to the interview questions, and discuss 
challenges for assessing sleep and psychopathology during the perinatal period. For the 
experiential training, staff will conduct role play interviews with self-critique and trainer 
feedback. After the intensive training, staff will rate training videos, and conduct and observe 
practice interviews with a confederate. Interviewers will need to establish interrater reliability > 
0.8 with Dr. Manber before interviewing study participants. All interviews will be recorded. To 
prevent rater drift, Dr. Manber will lead quarterly reliability meetings during which staff will 
rate a randomly-selected interview. Dr. Manber will provide corrective feedback as needed and 
the team will discuss any variability in ratings. At study midpoint and endpoint, a random 
subset of 25% interviews will be selected to assess inter-rater reliability.  
11.1.8 DATA HANDLING AND RECORD KEEPING  
11.1.8.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data will be collected directly from participants via electronic self-report questionnaires on 
REDCap and/or Qualtrics. Interview data will be entered directly into REDCap. Additionally, for 
participants randomized to digital CBT-I, BigHealth will provide information about number of 
sessions completed and sleep diary data.  
11.1.8.2 
STUDY RECORDS RETENTION  
Per University of California policy regarding IRB and academic research records pertaining to 
pregnant women, study documents will be retained for a minimum of 10 years after the end of 
the calendar year in which the research is completed. 
11.1.9 PROTOCOL DEVIATIONS   
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol, 
which may be on the part of the participant, the investigator, or the study site staff. We will 
follow the reporting requirements described by the UCSF IRB (https://irb.ucsf.edu/protocol-
violation-or-incident#Reporting-requirements-chart). 
11.1.10 
PUBLICATION AND DATA SHARING POLICY  
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
• National Institutes of Health (NIH) Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. It requires scientists to 
submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital 
archive PubMed Central upon acceptance for publication. 
• This trial will be registered at ClinicalTrials.gov, and results information from this trial 
will be submitted to ClinicalTrials.gov.  
• Every attempt will be made to publish results in peer-reviewed journals.   

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• We will share de-identified data with the research community via the National Database 
for Clinical Trials related to Mental Illness (NDCT).  
11.1.11 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence is critical. Therefore, any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons 
who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  
11.2 ABBREVIATIONS AND SPECIAL TERMS 
ADM 
Antidepressant Medication 
AE 
adverse events 
BISQ-R 
Brief Infant Sleep Questionnaire – Revised 
C-SSRS  
Columbia Suicide Severity Rating Scale 
CBT-I  
Cognitive Behavioral Therapy for Insomnia  
CFR 
Code of Federal Regulations 
CoC  
Certificate of Confidentiality 
CRF 
Case Report Form 
CTSA  
Clinical and Translational Awards 
DBAS  
Dysfunctional Beliefs About Sleep scale  
DERS-SF  
Difficulties in Emotion Regulation Scale-Short 
Form 
DSMB 
Data Safety and Monitoring Board 
EPDS 
Edinburgh Postnatal Depression Scale 
GAD-7 
Generalized Anxiety Disorder Scale 
HHS 
Health and Human Services 
HIPAA 
Health Insurance Portability and Accountability 
Act 
Hyp 
hypothesis 
IBQ-R  
Infant Behavior Questionnaire – Revised 
ICH GCP 
International Council on Harmonisation Good 
Clinical Practice 
iOS 
iPhone Operating System 
IRB 
International Review Board 
ISI 
Insomnia Severity Index 
MPAS 
Maternal Postnatal Attachment Scale 

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NCT 
National Clinical Trial 
NDCT 
National Database for Clinical Trials 
NIH 
National Institutes of Health 
NIHGPS 
National Institutes of Health Grants Policy 
Statement 
PDF 
Portable Document Format 
PHQ-9  
Patient Health Questionnaire  
PI 
Primary Investigator  
PRP 
Participant Recruitment Program  
PSAS 
Pre-sleep Arousal Scale 
PSQI 
Pittsburgh Sleep Quality Index 
PTBi CAB 
Preterm Birth Initiative Community Advisory 
Board 
PTE 
proportion of treatment effect 
PTQ  
Perseverative Thinking Questionnaire 
RCT 
Randomized Control Trial  
SOA 
Schedule of Activities 
RLS 
Restless Leg Syndrome 
SAE 
Serious Adverse Event 
SCID 
Structured Clinical Interview for DSM-5 Disorders 
SCISD  
Structured Clinical Interview for DSM-5 Sleep 
Disorders 
SHE 
sleep hygiene education 
UCSF  
University of California San Francisco 
UPs 
unanticipated problems 
US 
United States 
 
 
 

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11.3 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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