A Transdiagnostic Sleep and Circadian Treatment to Improve Community SMI Outcomes
Phase: NA
Conditions: Mental Disorders
Sponsor: University of California, Berkeley

1 
 
Title:  
A Transdiagnostic Sleep and Circadian Treatment 
to Improve Community SMI Outcomes 
CPHS Number: 
2014-07-6508 (Date of 1st approval: July 18, 2014  
ClinicalTrials.gov Number: 
NCT02469233 (Date of 1st release: June 9, 2015) 
 
ClinicalTrials.gov Amendment Release Dates 
Amendment 1 Date: 07/18/2016 
Amendment 2 Date: 10/25/2016 
 
Sponsor  
National Institute of Mental Health (Grant number: R01MH105513) 
 
Study Principal Investigator 
Allison G. Harvey, Ph.D. Psychology Department, 2121 Berkeley Way, 3rd floor. University of 
California, Berkeley, CA 94720-1650. USA. email: aharvey@berkeley.edu 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 2 
ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................... 3 
ABSTRACT ................................................................................................................................ 4 
Fig. 1 Flowchart of study design .............................................................................................. 5 
Table 1 SPIRIT checklist  .......................................................................................................... 6 
Table 2 Summary of the Transdiagnostic Intervention for Sleep and Circadian 
Dysfunction ............................................................................................................................... 7 
1 BACKGROUND ....................................................................................................................... 8 
1.1 Why is sleep and circadian dysfunction important in SMI? .............................................. 8 
1.2 Real-world setting: community mental health centers ...................................................... 9 
1.3 Sleep health .................................................................................................................... 9 
2 METHODS/DESIGN ................................................................................................................ 9 
2.1 Study design and setting ................................................................................................. 9 
2.2 Participants ................................................................................................................... 10 
2.2.1 Inclusion criteria .................................................................................................... 10 
2.2.2 Exclusion criteria .................................................................................................. 10 
2.3 Measures ...................................................................................................................... 11 
2.3.1 Primary outcomes ................................................................................................. 11 
2.3.2 Secondary outcomes ............................................................................................ 11 
2.3.3 Other measures .................................................................................................... 12 
2.4 Treatments .................................................................................................................... 12 
2.4.1 TranS-C ................................................................................................................ 12 
2.4.2 Usual care followed by delayed treatment with TranS-C ....................................... 12 
2.4.3 Treatment implementation and monitoring ............................................................ 13 
2.5 Data analysis ................................................................................................................. 13 
2.5.1 Preliminary data evaluation ................................................................................... 13 
2.5.2 Management of missing data ................................................................................ 13 
2.5.3 Main aim ............................................................................................................... 13 
2.5.4 Exploratory analyses ............................................................................................ 13 
2.5.5 Power analysis ..................................................................................................... 14 
3 ETHICS APPROVAL AND CONSENT TO PARTICIPATE .................................................... 14 
4 DISCUSSION ......................................................................................................................... 14 
4.1 Trial status ..................................................................................................................... 15 
5 CONSENT FOR PUBLICATION …………………………………………………………………...15 
REFERENCES ......................................................................................................................... 16 
 
 
 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACBHCS 
Alameda County Behavioral Health Care Services 
CBT-I 
Cognitive behavioral therapy for insomnia 
CPAP 
Continuous positive airway pressure 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DUKE 
Duke Structured Interview for Sleep Disorders 
HLM 
Hierarchical linear modeling 
MINI 
M.I.N.I. International Neuropsychiatric Interview 
PROMIS-SD 
Patient-Reported Outcomes Measurement Information System–Sleep Disturbance 
PROMIS-SRI 
Patient-Reported Outcomes Measurement Information System–Sleep-Related 
Impairment 
QIDS 
Quick Inventory of Depressive Symptomatology 
SMI 
Severe mental illness 
SPIRIT 
Standard Protocol Items: Recommendations for Interventional Trials 
TAU 
Treatment as usual 
TranS-C 
Transdiagnostic Intervention for Sleep and Circadian Dysfunction 
TST 
Total sleep time 
TWT 
Total wake time 
UC-DT 
Usual care followed by delayed treatment with Transdiagnostic Intervention for Sleep 
and Circadian Dysfunction 
 
 
 
 
 
 
 
 
 
 
 

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1 BACKGROUND 
Background:  
Severe mental illness (SMI) is common, chronic and difficult to treat. Sleep and circadian dysfunctions 
are prominent correlates of SMI, yet have been minimally studied in ways that reflect the complexity of 
the sleep problems experienced. Prior treatment studies have been disorder-focused—they have treated a 
specific sleep problem in a specific diagnostic group. However, real life sleep and circadian problems are 
not so neatly categorized, particularly in SMI where features of insomnia overlap with hypersomnia, 
delayed sleep phase and irregular sleep-wake schedules. Accordingly, the aim of this study protocol is to 
test the hypothesis that a Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) 
will improve functional impairment, disorder-focused symptoms and sleep and circadian functioning. 
Participants across DSM diagnoses and across common sleep and circadian problems are eligible. The 
elements of TranS-C are efficacious across SMI in research settings with research-based providers. The 
next step is to test TranS-C in a community setting. Accordingly, this study is being conducted within 
Alameda County Behavioral Health Care Services (ACBHCS), the Community Mental Health Centre 
(CMHC) for Alameda County.  
Methods/design:  
120 adults diagnosed with SMI and sleep and circadian dysfunction within ACBHCS will be randomly 
allocated to TranS-C (n = 60) or 6-months of Usual Care followed by Delayed Treatment with TranS-C 
(UC-DT; n = 60). TranS-C is modularized and delivered across eight to twelve 50-minute, weekly, 
individual sessions. All participants will be assessed before and immediately following treatment and 
again 6 months later. Primary analysis will examine whether TranS-C significantly improves functional 
impairment, disorder-specific symptoms and sleep and circadian functioning, relative to UC-DT. 
Exploratory analysis will examine whether improvements in sleep and circadian functioning predict 
reduction in functional impairment and disorder-specific symptoms, and whether the intervention effects 
are mediated by improved sleep and circadian functioning and moderated by previously reported risk 
factors (demographics, symptom severity, medications, psychiatric and medical comorbidity).  
Discussion:  
This trial tests an important and understudied mechanism—dysregulated sleep and circadian rhythms—in 
SMI, a novel transdiagnostic treatment approach, in a community setting so as to contribute to the goal of 
bridging the gap between research and practice. 
Keywords: Transdiagnostic, Sleep, circadian, Severe mental illness, Dissemination 
 
 
 
 
 

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Fig. 1 Flowchart of study design 
 
 
 
 
 
 
Assessed for Eligibility 
Randomized 
Allocated to TranS-C 
TranS-C 8-12 week post- 
intervention assessment 
Allocated to UC-DT 
TranS-C 6-month follow-
up assessment 
UC-DT 8-12 week post-
assessment 
UC-DT 6-month follow-up 
assessment 
Excluded: 
Not meeting inclusion criteria; 
refused to participate 

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Table 1 SPIRIT checklist  
Time point  
Study period 
Enrollment  
Pretreatment 
assessment  
Allocation  
Postallocation  
Intervention  
Post-Treatment 
Assessment  
6-Month 
follow-up 
Enrollment  
   Eligibility screen 
X 
   Informed consent 
X 
X 
   Allocation 
X 
Intervention 
   TranS-C 
X 
   UC-DT1 
Data collection 
   Demographics 
X 
X 
X 
   Primary outcomes 
X 
X 
X 
   Secondary outcomes 
X 
X 
X 
   Diagnostic measures 
X 
X 
X 
   Sleep/insomnia history 
X 
   Medication tracking 
X 
X 
X 
X 
   Credibility/expectancy 
X 
Abbreviations: TranS-C Transdiagnostic Intervention for Sleep and Circadian Dysfunction, UC-DT Usual care followed 
by delayed treatment with Transdiagnostic Intervention for Sleep and Circadian Dysfunction.1 Allocation to TranS-C after 
6-months of usual care 
 
 
 
 
 
 
 
 

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Table 2 Summary of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction 
Cross-cutting modules introduced in 
sessions 1-3 (and featured in all 
sessions thereafter) 
Module Topics in TranS-C 
Treatment module 
Case formulation 
Establishing regular sleep-wake times 
Core module 1, part a 
Education 
Learning a wind-down routine  
Core module 1, part b 
Behavior change and motivation  
Learning a wake-up routine  
Core module 1, part c 
Goal-setting 
Improving daytime functioning 
Core module 2 
Correcting unhelpful sleep-related beliefs 
 
Core module 3 
Improving sleep efficiency 
Optional module 1 
Reducing time in bed 
Optional module 2 
Dealing with delayed or advanced phase 
Optional module 3 
Reducing sleep-related worry/vigilance 
Optional module 4 
Promoting compliance with CPAP/exposure 
therapy for claustrophobic reactions to CPAP 
Optional module 5 
Negotiating sleep in a complicated environment Optional module 6 
Reducing nightmares 
Optional module 7 
Maintenance of behavior change 
Core module 4 
Abbreviations: CPAP Continuous positive airway pressure, SMI Severe mental illness, TranS-C Transdiagnostic 
Intervention for Sleep and Circadian Dysfunction 
 
 
 
 
 
 
 
 
 
 
 
 

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1 BACKGROUND 
The number of people receiving a treatment for severe mental illness (SMI) has risen [1–3], and health 
care expenditures have skyrocketed [2]. Yet, less than half of the treatments delivered have an evidence 
base [4–6], and there is no evidence that available treatments decrease disability [7]. Instead, the 
prevalence of mental illness is increasing [8–10]. Accordingly, providing the large number of people with 
an SMI access to evidence-based treatments requires fundamentally new approaches [11, 12].  
One relatively new approach is to target research and treatment at a transdiagnostic process. A 
transdiagnostic process is defined, in mental health, as a clinical feature in common across more than one 
mental illness [13–16]. The advantage of targeting research and treatment at a transdiagnostic process is 
threefold. First, if a transdiagnostic process contributes to the maintenance of symptoms across multiple 
disorders, then one approach is to develop treatments based on the process rather than on the large 
number of discrete disorders currently listed in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5) [14]. Second, comorbidity is the norm [17, 18]. Hence, a significant clinical 
dilemma is which disorders to prioritize for treatment [14]. Treating transdiagnostic processes provides 
one path forward [13, 14]. Third, a transdiagnostic approach may reduce the heavy burden on clinicians, 
who must learn multiple disorder-focused protocols, by focusing on common theoretical underpinnings 
and interventions [13].  
Sleep and circadian dysfunction has been highlighted as a biologically [19] and theoretically [20] 
plausible transdiagnostic contributor to SMI [13], and a transdiagnostic treatment for sleep and circadian 
disturbance has been proposed [21]. The present study protocol tests the hypothesis that the 
Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for participants with SMI 
will improve functional impairment, disorder focused symptoms, and sleep and circadian dysfunction. 
1.1 Why is sleep and circadian dysfunction important in SMI?  
First, sleep and circadian dysfunction coexists with, predates, and predicts SMI. Insomnia, hypersomnia, 
delayed sleep phase, and irregular sleep-wake schedules are commonly comorbid with SMI [22–26]. The 
rate of insomnia across DSM disorders is approximately 50% [25]. The rate of hypersomnia is as high as 
75% across the mood disorders [26]. These problems often persist even with best practice treatment for 
SMI [27–31]. Across multiple longitudinal studies, sleep and circadian dysfunction predicts and predates 
the onset and worsening of SMI symptoms [32–41]. Second, sleep and circadian dysfunction contributes 
to vicious cycles of mutually reinforcing symptoms in SMI, including emotional dysfunction [42, 43], 
poor health [44, 45], cognitive dysfunction [46, 47], and behavior problems [48, 49]. Third, sleep and 
circadian dysfunction is modifiable in SMI. Cognitive behavioral therapy for insomnia (CBT-I) 
effectively treats insomnia that is comorbid with a wide range of SMIs, including major depressive 
disorder [50], posttraumatic stress disorder [51–54], schizophrenia [55], bipolar disorder [56, 57], alcohol 
dependence [58], and mixed SMI [59–61]. There is evidence that these gains are well maintained 
following the cessation of treatment [62]. There is also evidence that treating insomnia improves the 
symptoms of the comorbid disorder [50, 51, 55, 63]. In our study, we will test a treatment that addresses 
an important and understudied transdiagnostic mechanism— dysregulated sleep and circadian rhythms—
in SMI. It also addresses an understudied conceptual framework, namely that sleep and circadian 
dysfunction contributes to vicious cycles of escalating vulnerability and increased risk in SMI. 
The majority of prior studies have been disorder focused—they have been designed to treat a specific 
sleep problem (e.g., insomnia) in a specific diagnostic group (e.g., depression, posttraumatic stress 
disorder). Real-life sleep and circadian problems are not so neatly categorized, particularly in SMI. 
Indeed, insomnia can overlap with hypersomnia [26, 33, 64–67], delayed sleep phase [68], and irregular 
sleep-wake schedules [28]. In a prior study, CBT-I was modified to address the broader range of sleep 
dysfunctions in SMI [56, 57], adding elements from interpersonal and social rhythm therapy [69, 70], 

9 
chronotherapy [71], and motivational enhancement [72–74]. Strong results reported by other groups [75] 
and advice from dissemination experts [76, 77] led us to develop a modularized transdiagnostic treatment 
[21].  
1.2 Real-world setting: community mental health centers  
There has been ample testing of sleep and circadian interventions in specific disorders in research settings 
with research-based providers. Hence, the next step is to conduct an “efficacy in the real world” study in 
community settings with community-based providers while maintaining the high level of control 
necessary to establish internal validity. This next step is important because there is currently a 15- to 20-
year lag between treatment discovery and incorporating new treatments into routine practice [12, 78]. 
Initial results indicate that providing CBT-I in various real-world settings is effective [79–81].  
1.3 Sleep health  
The sleep health framework [82] underpins and guides TranS-C. The sleep health framework prompts a 
shift from a singular focus on the identification and treatment of sleep disorders to a health promotion 
perspective, which emphasizes universal attributes of sleep that can be optimized to promote well-being. 
The sleep health framework encourages sleep improvement along six dimensions that have been linked to 
mental and physical health outcomes [82]. The dimensions are (a) regularity of sleep and waking up; (b) 
satisfaction with sleep or sleep quality; (c) alertness during waking hours or daytime sleepiness; (d) 
appropriate timing of the patient’s sleep within a 24-h day; (e) sleep efficiency (i.e., the ability to sleep for 
a large percentage of the time in bed), as indicated by ease of falling asleep at the beginning of the night 
and the ease of returning to sleep after awakenings across the night; and (f ) sleep duration, which is the 
total amount of sleep obtained by the patient per 24 h. 
The main aim of this study protocol is to evaluate the effects of TranS-C vs. usual care followed by 
delayed treatment with TranS-C (UC-DT) on functional impairment, disorder-focused symptoms, and 
sleep and circadian function in participants receiving treatment for SMI in a community mental health 
center. The hypothesis tested is that TranS-C will be superior to UC-DT at posttreatment and 6-month 
follow-up for functional impairment, disorder-focused symptoms, and sleep and circadian function. 
In exploratory analyses, we will address (a) whether improved sleep and circadian functioning predicts 
reduced functional impairment and disorder-focused symptoms, regardless of treatment condition; (b) 
whether improved sleep and circadian functioning mediates the intervention effects (TranS-C vs. UC-DT) 
on functional impairment and disorder-focused symptoms; and (c) whether intervention effects are 
moderated by previously reported risk factors. 
2 METHODS/DESIGN  
2.1 Study design and setting  
We are conducting a prospective randomized controlled study. Adults (n = 120) who meet criteria for 
SMI and sleep and circadian dysfunction will be randomly assigned, in a 1:1 parallel-group design, to 
undergo TranS-C (n = 60) or UC-DT (n = 60) (see Fig. 1 for study design flowchart). Randomization is 
stratified by psychosis (yes or no) and age (older or younger than 49 years). Participants will receive a 
battery of outcome measures pretreatment and again at posttreatment (i.e., 9–14 weeks later) and at 6-
month follow-up. Those in the UC-DT group will receive two additional assessments: 9–14 weeks and 6 
months into UC-DT. An additional assessment of sleep and circadian function will take place in session 4 
for the mediation analysis. 
The assessment and therapy teams are blinded to treatment allocation. Randomization will be conducted 
using a computerized random number generator where the planned stratification randomization is part of 

10 
the allocation sequence. Only the statistician (LD), the project coordinator, and the assigned therapist 
know the treatment allocation of each participant. Participants are financially compensated for their time. 
A Data and Safety Monitoring Board will review the study every 6 months during the active treatment 
phase. A Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT 2013) checklist 
(see Additional file 1) and figure (see Table 1) are provided [83]. 
For participants who discontinue, the assessment team will endeavor to collect all assessment data, 
prioritizing the primary outcomes.  
2.2 Participants  
A total of 120 adults who meet criteria for SMI and sleep and circadian dysfunction are recruited from 
multiple sites within Alameda County Behavioral Health Care Services (ACBHCS; Alameda County, 
CA, USA). To date, these sites are Oakland Community Support Center (Oakland), Eden Mental Health 
Services (San Leandro), Tri City Community Support Center (Fremont), Alameda Support Center 
(Alameda), Axis Community Health (Pleasanton), La Familia Counseling (Hayward), and multiple board 
and care homes. Participants are referred via ACBHCS case managers and doctors. The inclusion and 
exclusion criteria are presented below. To enhance representativeness and generalizability, the inclusion 
and exclusion criteria are kept to a minimum. 
2.2.1 Inclusion criteria  
The inclusion criteria are as follows:  
● Aged 18+ years 
● English language fluency 
● Presence of at least one DSM-5 mental disorder for 12 months 
● One or more of the following sleep or circadian problems for 3 months assessed with the Sleep 
and Circadian Problems Interview: 
○ ≥30 minutes to get to sleep on three or more nights per week  
○ Waking in the middle of the night for ≥30 minutes on three or more nights per week 
○ Obtaining <6 h of sleep per night on three or more nights per week. Obtaining more than 
9 hours of sleep per 24 hour period (i.e., nighttime sleep plus daytime napping), 3 or 
more nights per week  
○ More than 2.78 h of variability in sleep-wake schedule across 1 week 
○ Bedtime later than 2:00 a.m. on three or more nights per week   
● Having a guaranteed bed to sleep in for 3 months 
● Receiving care for SMI at ACBHCS and consent to regular communications between research 
team and psychiatrist and/or case manager 
2.2.2 Exclusion criteria 
The exclusion criteria are as follows: 

11 
● Presence of an active and progressive physical illness or neurological degenerative disease and/or 
substance abuse/dependence making participation in the study infeasible 
● Current serious suicide risk (assessed by our staff, a case manager, or a psychiatrist) or homicide 
risk (assessed by our staff, a case manager, or a psychiatrist) 
● Night shift work >2 nights per week in the past 3 months 
● Pregnancy or breastfeeding 
● Not able/willing to participate in and/or complete the pretreatment assessments 
For the present study protocol, SMI is operationalized according to U.S. Public Law 102-321 and 
previous research [84–86] as the presence, for 12 months, of at least one DSM-5-defined mental disorder 
that leads to substantial interference with one or more major life activities [87]. 
Sleep apnea and periodic limb movement disorder are often comorbid with insomnia [88, 89], and 
individuals with these sleep disorders typically have poor sleep habits. Hence, we elected to include these 
individuals. Indeed, there is already some evidence that these participants benefit from CBT-I [63, 90]. 
Pharmacotherapy for SMI is a complex undertaking guided both by empirical evidence and by the 
specific experiences and responses of individual participants. Excluding participants whose medications 
need to be changed is neither feasible nor representative of clinical practice [91]. Medication use and 
changes will be recorded. All medication decisions will ultimately rest with the treating physician and 
participant. 
2.3 Measures 
In addition to demographics (age, contact information, sex, race/ethnicity, family, education, 
employment, living arrangements, government assistance, housing), the measures described in the 
subsections below will be administered. 
2.3.1 Primary outcomes 
Functional impairment is assessed with the Sheehan Disability Scale [92], which is a widely used brief 
measure. The DSM-5 Cross-Cutting Measure is used as a measure of disorder-focused symptoms. Sleep 
and circadian function is assessed with the Patient-Reported Outcomes Measurement Information 
System–Sleep Disturbance (PROMIS-SD) [93, 94] and the Patient-Reported Outcomes Measurement 
Information System– Sleep-Related Impairment (PROMIS-SRI) [93, 94], which are brief, comprehensive, 
and well-validated. The PROMIS scales are also administered at session 4 for the mediation analysis.  
2.3.2 Secondary outcomes 
Impairment is assessed with the self-administered version of the World Health Organization Disability 
Assessment Schedule 2.0 and the 4-question healthy days core module developed by the Centers for 
Disease Control and Prevention [95]. Disorder-focused symptoms are assessed using the Quick Inventory 
of Depressive Symptoms [96]; the Alcohol, Smoking and Substance Involvement Screening Test [97]; 
and the Psychotic Symptoms Rating Scales [98]. Sleep and circadian function is assessed with the daily 
sleep diary and actigraphy, collected for 7 days at each assessment point. The outcomes to be analyzed 
using the sleep diary are the mean and variability in sleep efficiency (total sleep time/time in bed × 100), 
total sleep time (TST), total wake time (TWT), bedtime, wake time, and rise time. In addition, nap 
duration will be calculated. The actigraphy outcomes to be analyzed are the means and variability for TST 
and TWT, as well as the daytime activity count. In addition, we will calculate a composite sleep health 

12 
score [82], which is defined as the sum of scores on six sleep health dimensions: regularity (midpoint 
fluctuation across the 7-day sleep diary), satisfaction (sleep quality question on PROMIS-SD), alertness 
(daytime sleepiness question on PROMIS-SRI), timing (mean midpoint across the 7-day sleep diary), 
efficiency (sleep efficiency based on the 7-day sleep diary), and duration (TST based on 7-day sleep 
diary). This measure is proposed to capture the complexity of the sleep problems covered by TranS-C. 
2.3.3 Other measures 
The diagnostic measure used for mental disorders is the M.I.N.I. International Neuropsychiatric Interview 
(MINI) (version 7.0.0, including schizophrenia and psychotic disorders). The MINI is included as an 
evaluation of the presence of current and past SMI. The MINI was developed to meet the need for a 
simple, short, but accurate structured psychiatric interview. Its validity has been well supported [99–101]. 
At each assessment, we will report the number of DSM-5 diagnoses derived from the MINI. The 
diagnostic measure we will use for sleep disorders is the Duke Structured Interview for Sleep Disorders 
(DUKE) [102]. 
Sleep/insomnia history is obtained with the Sleep and Circadian Problems Interview, which is an adapted 
version of the Insomnia Interview Schedule [103]. To improve our ability to identify obstructive sleep 
apnea, we will supplement the proposed DUKE assessment with the STOP-BANG Questionnaire [104], 
which is an 8-item screen for obstructive sleep apnea. Both measures are well-validated and widely used. 
Those suspected to have another sleep disorder will receive nonstudy evaluation/treatment and will not be 
excluded. At each assessment, we will report the number of sleep diagnoses derived from the DUKE. The 
medication tracking log will be used to record the treatments patients are receiving. Treatment 
credibility/expectancy is administered at session 2 via the Credibility/Expectancy Questionnaire [105, 
106]. 
2.4 Treatments 
2.4.1 TranS-C  
TranS-C is administered by master’s-level therapists hired within the University of California, Berkeley, 
for this study, who travel between the ACBHCS clinic sites. As participants move through the treatment 
at different rates, TranS-C is provided in eight weekly 50-minute sessions. If patients need additional 
sessions to cover the treatment, up to four additional sessions may be offered (i.e., maximum of 12 
sessions). TranS-C includes four cross-cutting interventions featured in every session; four core modules 
that apply to the vast majority of participants; and seven optional modules used less commonly, 
depending on the presentation. Table 2 summarizes the approach. 
2.4.2 Usual care followed by delayed treatment with TranS-C 
The aim of the choice to compare TranS-C with UC-DT is to strike a balance between (a) including a 
comparison group to test the effectiveness of TranS-C in community settings, information critical to 
determining the potential of TranS-C for broader dissemination; and (b) ensuring that all participants 
receive what is hypothesized to be a more active treatment (TranS-C). Usual care in ACBHCS starts with 
a case manager who coordinates care and refers each client for a medication review and to various 
rehabilitation programs (e.g., health care, housing, nutrition, physical activity, finding a job, meditation 
group, tobacco cessation group, peer monitoring). The content of usual care will be monitored using the 
medication and other treatment tracking logs. As depicted in Fig. 1, at the end of 8 months in UC-DT, the 
participants will receive 8 to 12 sessions of TranS-C. 

13 
2.4.3 Treatment implementation and monitoring 
Clinicians attend a one-day workshop, use a treatment manual and receive weekly supervision to 
standardize treatment administration. Treatment sessions are audiotaped, and a random selection are rated 
using the Cognitive Therapy Scale [107], which is a measure of general intervention skills and CBT-
specific skills. 
2.5 Data analysis 
2.5.1 Preliminary data evaluation 
Missing or aberrant data will be verified. Data will be audited for quality and completeness. We will 
detect outliers by evaluation of distributions and ensure that assumptions of planned analyses are met. 
Prior to hypothesis testing, appropriate statistical tests will be used to examine baseline differences 
between groups (e.g., race/ethnicity, age, sex, education, employment, psychiatric and medical 
comorbidities). These tests will not be used to select covariates in the primary intention-to-treat analysis 
[108–110]. Instead, the potential influences of baseline differences will be evaluated as moderators 
(described below).  
2.5.2 Management of missing data 
Recruiting 120 participants allows for attrition as per the power calculation below. In longitudinal 
analyses, we will use all available data and produce valid inferences if attrition depends on treatment 
group or on previous outcomes for the same participant [111]. If dropout is related to other variables, 
these data will be included as predictors to reduce any bias due to nonrandom missing data. 
2.5.3 Main aim 
TranS-C will be superior to UC-DT for reducing functional impairment and disorder-focused symptoms, 
and for improving sleep and circadian functioning, at posttreatment and 6-month follow-up on primary 
outcomes. To address these aims, we will test whether there are differences in the mean trajectories across 
time points between TranS-C and UC-DT using hierarchical linear modeling (HLM) [112–114]. The first-
level equation will represent within-person variation and will include time indicators (or dummy 
variables) as predictors (posttreatment, 6-month follow-up assessment, with baseline as a reference). The 
second-level equation represents between-person variation in the intercept and coefficients of the time 
indicators, and will include a dummy variable for arm (TranS-C vs. UC-DT) as the predictor variable. 
Interactions between arm and time indicators will be retained only if found to be significant at the 5% 
level. A significant interaction between arm and a time indicator suggests that there are different 
trajectories of change in outcome across time for each arm, and will be displayed as a graph to interpret 
the interaction. 
2.5.4 Exploratory analyses 
For the exploratory analyses, we will use only the primary outcome measures for impairment, disorder-
focused symptoms, and sleep and circadian function: 
1. Do improved sleep and circadian functioning predict reduced functional impairment and 
disorder-focused symptoms from baseline to posttreatment? We will use HLM to test whether 
changes in sleep and circadian functioning predict changes in functional impairment and disorder-
focused symptoms from baseline to posttreatment. 
2. Do improved sleep and circadian functioning mediate intervention effects on primary outcomes? 
We will conduct mediation analysis using product of coefficients, a powerful method for 

14 
estimating indirect effects [115]. The mediator will be sleep and circadian functioning measured 
at session 4, and outcomes will be functional impairment and disorder-focused symptoms 
measured at posttreatment. 
3. Are intervention effects moderated by risk factors, including demographics, symptom severity, 
medications, and psychiatric and medical comorbidities? We will conduct moderation analysis 
by testing a three-way interaction of treatment arm, time, and the moderator variable in the 
second-level equation using the HLM model described above [116, 117]. A significant coefficient 
for the arm × time × moderator interaction would indicate a moderating effect and will be 
followed with graphs to interpret the modification [116].  
A statistical significance level of 0.05 will be used throughout. 
2.5.5 Power analysis 
Average effect size across outcomes akin to those proposed were drawn from prior research [56, 79, 80] 
(0.60). Using G*Power 3.1.7 software, 80% power, and a two-tailed alpha of 5%, we will need 92 
participants to detect group differences. An additional 30% to account for potential attrition yields 120 
participants. 
3 ETHICS APPROVAL AND CONSENT TO PARTICIPATE 
The University of California, Berkeley, Committee for the Protection of Human Subjects (CPHS) 
approved the study (protocol 2014-07-6508). As depicted in Table 1, verbal informed consent is obtained 
during the initial eligibility assessment, which is typically conducted over the telephone. This is followed 
by written informed consent obtained at the beginning of the preassessment, which confirms eligibility, 
by a member of the assessment team. Adverse events and other unintended effects will be report to the 
CPHS and the NIH, following the rules stipulated by these two oversight bodies. If important protocol 
modifications are made, these will be reviewed by the CPHS and reported on the trial’s ClinicalTrials.gov 
registration web page. 
4 DISCUSSION 
The study protocol addresses several research priorities. First, this study provides a test of a treatment that 
addresses an important and understudied mechanism— dysregulated sleep and circadian rhythms—in 
SMI. It also addresses an understudied conceptual framework, namely that sleep and circadian 
dysfunction contributes to vicious cycles of escalating symptoms, vulnerability, and risk in SMI. Second, 
this study provides a test of a transdiagnostic treatment designed to treat a wide range of sleep and 
circadian problems experienced by adults with a wide range of SMIs. As such, the study contributes to the 
goal of developing interventions that use broad, dimensional approaches to assessment and intervention 
[118, 119]. Third, the sleep health framework [82] that underpins the approach is relatively new. This 
approach emphasizes the identification and treatment of sleep disorders as well as the universal attributes 
of sleep that can be optimized to promote well-being. Fourth, the modular design of TranS-C, as well as 
the personalized behavioral “prescriptions,” are responsive to the calls to “develop a personalized 
approach to the diverse needs and circumstances of people with mental illness” [120, page 128]. Finally, 
this study will be conducted in a community setting. Conducting the study in a community setting 
contributes to the goal of bridging the gap between research and practice and testing treatments in the 
community. If the study is successful, this research will establish the potential for widespread 
dissemination of TranS-C to improve SMI outcomes in the community. 

15 
4.1 Trial status 
The trial is funded for 4 years. A ‘skeleton’ research staff team started setting up the study in February 
2015. Patients began to be randomized in July 2015. The treatment phase will be completed in July 2018. 
Final outcome assessments will be complete by January 2019. As of November 2016, 70 participants of 
the required 120 had been enrolled.  
5 CONSENT FOR PUBLICATION 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

16 
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