Clinical trial NCT03534284
Conditions: Insomnia End Stage Renal Disease
Keywords: Hemodialysis Kidney disease Trazodone Cognitive behavioral therapy
Sponsor: University of Washington
Start date: 2018-09-19; Completion date: 2022-11-17
Enrollment: 126 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Insomnia is a common and distressing symptom for patients on hemodialysis (HD), and there is evidence for a much larger impact on the health of patients. Chronic insomnia is disrupted sleep that occurs at least three nights per week and lasts at least three months.

The SLEEP-HD study is a randomized open-label clinical trial to compare two types of treatment for insomnia in participants who have end-stage renal disease on HD, and who have been diagnosed with chronic insomnia. The two types of treatment involved in the study are Cognitive Behavioral Therapy for Insomnia (CBT-I) or treatment with a drug (trazodone vs placebo).

126 participants will be enrolled who are undergoing HD in two study locations (Seattle, Washington and Albuquerque, New Mexico).

Detailed description:
Most HD patients have significant impairments in quality of life, largely from the high frequency of disabling symptoms. Insomnia is one of the most frequently reported symptoms and studies of HD patients and/or other populations suggest that it is a significant contributor to other common symptoms and poor health outcomes. There are unique contributors to chronic insomnia in HD patients and these include the biologic effects of residual uremia after partial correction as is achieved with current dialysis technology, maladaptation to treatment schedules, and patients' napping during treatments.

There is a compelling need to identify effective treatments for insomnia in HD patients and the interventions being studied in this clinical trial, telehealth cognitive behavioral therapy for insomnia (CBT-I) and trazodone, have a strong scientific premise. If telehealth (web-based) CBT-I is effective for insomnia in HD patients, it will make a treatment that is presently inaccessible available to patients. Trazodone is widely used but the data on efficacy for insomnia are limited; no such data exist for HD patients.

SLEEP-HD is a parallel group randomized controlled trial wherein 125 HD patients with chronic insomnia, treated in community-based dialysis facilities in Seattle and Albuquerque, will be randomized 1:1:1 over 31 months to 6-week treatment with telehealth CBT-I, trazodone, or medication placebo.

Arms: arm 1: Cognitive Behavioral Therapy for Insomnia sessions: a 30-minute treatment session once weekly for six weeks. arm 2: Trazodone (50-100 mg): arm 3: Placebo (for trazodone)
Interventions: intervention 1: Cognitive Behavioral Therapy for Insomnia intervention 2: Trazodone intervention 3: Placebo
Intervention descriptions: intervention 1: Once weekly treatment sessions for 6 weeks. The content of each of these sessions will be adapted to include changes in behavior during HD treatments (such as napping) and to help patients better adjust to treatment schedules. The CBT-I sessions will be delivered by a therapist face-to-face with the patient via a fully interactive video telehealth platform. intervention 2: trazodone tablet intervention 3: Inactive pill manufactured to mimic trazodone tablets.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
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SLEEP-HD:  
SHORT AND LONG-TERM EFFECTIVENESS OF 
EXISTING INSOMNIA THERAPIES FOR PATIENTS 
UNDERGOING HD 
Study Protocol 
 
Funding Agency:   
 
National Institutes of Health 
National Institute of Diabetes, Digestive and Kidney 
Diseases 
 
 
 
 
 
Investigators: 
 
 
 
University of Washington:  
Rajnish Mehrotra (PI)  
 
 
 
 
 
Susan McCurry 
Patrick Heagerty  
SUNY Downstate Medical Center: Daniel Cukor 
University of New Mexico:  
Mark Unruh 
 
 
 
 
 
Maria-Eleni Roumelioti 
 
 
 
 
 
 


 
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Table of Contents 
Study Summary ........................................................................................................................ 9 
1. 
Introduction ..................................................................................................................... 12 
1.1 
Background ................................................................................................................... 12 
1.2 
Rationale for Interventions Being Tested in this Clinical Trial ................................. 13 
1.2.1 
Comparative Efficacy of telehealth CBT-I and drug therapy........................... 13 
2. 
Study Objective and Aims ............................................................................................... 15 
2.1 
Comparative Efficacy of individual CBT-I, Trazodone, and Medication Placebo . 15 
2.1.1 
Primary Measure of Efficacy .............................................................................. 15 
2.1.2 
Secondary Measure of Efficacy .......................................................................... 16 
3. 
Study Design and Overview ............................................................................................ 17 
3.1  
Rationale for Key Components of the Study Design: .............................................. 18 
4. Participant Selection and Withdrawal ............................................................................ 19 
4.1 
Study Population ...................................................................................................... 19 
4.1.1 Inclusion and Exclusion Criteria: ............................................................................. 19 
4.1.2 Rationale for key decisions regarding inclusion and exclusion criteria ................20 
4.2 
Participant Pre-Screening and Recruitment ...........................................................20 
4.2.1 
Pre-Screening and Enrolling Patients in the Clinical Trial ..............................20 
4.2.2 
Diagnosis of Chronic Insomnia ......................................................................... 21 
4.3 
Early Termination of Study Treatment and Withdrawal of Patients ..................... 21 
5. 
Study Interventions ......................................................................................................... 22 
4.1 
Comparative Efficacy of Telehealth CBT-I vs Trazodone vs. Medication Placebo 22 
5.2 
Telehealth CBT-I ....................................................................................................... 22 
5.2.1 
 Overview of the Intervention ........................................................................... 22 
5.2.2  
Training and Certification Prior To Implementation in Trial ......................... 23 
5.2.3  
Monitoring the Fidelity of the Intervention ..................................................... 23 
5.2.4  
Monitoring Adherence to Intervention ............................................................24 
5.3 Drug Therapy .................................................................................................................24 
5.3.1 Overview of the Intervention ..................................................................................24 
5.3.2 
Drug Procurement and Dispensation ...............................................................24 


 
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5.3.3 
Monitoring Drug Adherence ............................................................................. 25 
6. Ascertainment of Outcomes ........................................................................................... 25 
6.1 
Patient-Reported Outcomes .................................................................................... 25 
6.2 
Cumulative Use of Sedatives and Hypnotics in Prior Week ................................. 26 
6.3 
Actigraphy ................................................................................................................ 26 
7. 
Study Procedures and Visits ........................................................................................... 26 
7.1 
Pre-Screening ............................................................................................................ 27 
7.2 
Screening ................................................................................................................... 27 
7.3 
Baseline CATI ............................................................................................................28 
7.4 
Baseline Visit .............................................................................................................28 
7.5 
Randomization ......................................................................................................... 29 
7.6 
Treatment Visits (Weeks One through 6, through 7 weeks from randomization)
 
29 
7.6.1 Telehealth CBT-I Visits ........................................................................................... 29 
7.6.2 CBT-I Treatment Assessment Visits ...................................................................... 29 
7.6.3 Medication Visits ..................................................................................................... 30 
7.6.4 CATI Visits in Treatment Phase ............................................................................. 33 
7.7 Long-Term Follow-Up Visits ......................................................................................... 33 
7.7.1 Long-Term Follow-Up Visit 0 ................................................................................. 33 
7.7.2 Long-Term Follow-Up Visit 1 .................................................................................. 34 
7.7.3 Long-Term Follow-Up Visit 2 ................................................................................. 34 
7.7.4 Long-Term Follow-Up Visit 3 ................................................................................. 34 
7.7.5 Long-Term CATI Visits ........................................................................................... 35 
7.8  
Early Closeout ........................................................................................................... 35 
8. Statistical Analyses ........................................................................................................... 35 
8.1 
Preliminary Analyses................................................................................................. 35 
8.2 Statistical Analysis for Aim One .................................................................................... 35 
8.2.1 Statistical Power for Aim One ................................................................................. 36 
8.3 
Statistical Analysis for Aim Two ............................................................................... 37 
8.3.2 Statistical Power for Aim Two ................................................................................ 37 


 
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8.4. Plan for Handling Missing Data .................................................................................. 37 
8.5 
Overall Approach for Avoidance of bias .................................................................. 37 
9. Adverse Events ................................................................................................................. 38 
9.1 Potential Adverse Events from Study Interventions .................................................... 38 
9.2 Anticipated Adverse Events in the Hemodialysis Population ..................................... 38 
9.3 Monitoring for Adverse Events ..................................................................................... 39 
9.4 Reporting of Adverse Events ......................................................................................... 39 
9.5 Management of Active Suicidal Intent ......................................................................... 39 
10. 
Data Management ....................................................................................................... 40 
10.1 Data Coordinating Center and Data Entry Overview ................................................ 40 
10.2 Computer and Data Security ...................................................................................... 40 
10.3 Training Procedures .................................................................................................... 40 
10.4 Responsibilities of the Clinical Sites ........................................................................... 41 
11. 
Study Oversight ............................................................................................................ 41 
References ...............................................................................................................................42 
Appendix One: Patient Reported Outcome Instruments ..................................................... 51 
Appendix Two: List of Drugs Used as Sedatives/Hypnotics ................................................. 52 
Appendix Three: Study Schedule ........................................................................................... 55 
Appendix Four: List of Concomitant Medications that are an Exclusion Criteria ..............56 
Appendix Five: Cognitive Behavioral Therapy for Insomnia Session Outlines ................... 58 
SESSION 1/6 .........................................................................................................................59 
SESSION 2/6 ....................................................................................................................... 60 
SESSION 3/6 ........................................................................................................................ 61 
SESSION 4/6 ....................................................................................................................... 62 
SESSION 5/6 ........................................................................................................................ 63 
SESSION 6/6 ....................................................................................................................... 64 
Appendix Six: Data Safety Monitoring Board Charter ..........................................................65 
Part 1: 
Introduction ......................................................................................................... 68 
1.1 
Charge to the DSMB ................................................................................................ 68 
1.2.1 
DSMB Chair ....................................................................................................... 69 


 
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1.2.2 
DSMB Biostatistician ........................................................................................ 69 
1.3 
Responsibilities of the Study Management Team and Data Coordinating Center
 
69 
1.3.1 
Principal Investigator ........................................................................................70 
1.3.2 
Data Coordinating Center Statistical Advisor ..................................................70 
1.3.3 
Unblinded Data Coordinating Center Statistician ...........................................70 
Part 2: Procedures of the DSMB ...................................................................................... 71 
2.1 
Blinding ..................................................................................................................... 71 
2.2 
DSMB Report ............................................................................................................ 71 
2.3 
Scheduled DSMB Meetings ...................................................................................... 72 
2.4 
DSMB Meeting Structure ......................................................................................... 72 
2.4.1 
Open Session ...................................................................................................... 72 
2.4.2 
Closed Session .................................................................................................... 72 
2.4.3 
Executive Session ............................................................................................... 73 
2.5 
DSMB Recommendations......................................................................................... 73 
2.6 
Meeting Minutes ....................................................................................................... 73 
2.6.1 
Open Minutes .................................................................................................... 73 
2.6.2 
Closed Minutes .................................................................................................. 74 
Appendix Seven: Data Safety and Monitoring Plan .............................................................. 75 
1. Overview ........................................................................................................................... 75 
2. Data and Safety Monitoring Board ................................................................................. 75 
3. Study Sample Size ............................................................................................................ 75 
4. Monitoring Guidelines .................................................................................................... 75 
4.1 Performance Monitoring ............................................................................................76 
4.2 Safety Monitoring ...................................................................................................... 77 
4.3 Treatment Efficacy Monitoring ................................................................................ 80 
4.4 Procedures for minimizing research-associated risk .............................................. 80 
5. Scheduled Reporting ...................................................................................................... 80 
Appendix Eight: COVID Risk Mitigation Plan for SLEEP-HD .............................................82 


 
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Study Summary 
Title 
Short and Long-Term Effectiveness of Existing Insomnia 
Therapies for Patients Undergoing HD (SLEEP-HD) 
Short Title 
SLEEP-HD Trial 
Protocol Number 
 RO1 DK 115468 
Clinicaltrials.gov 
Registration 
NCT03534284 
Phase 
Phase III 
Methodology 
Randomized, open-label trial 
Study Duration 
5 years 
Clinical Sites 
University of New Mexico, Albuquerque, NM 
University of Washington, Seattle, WA 
Data Coordinating 
Center 
Center for Biomedical Statistics, University of Washington, 
Seattle, WA 
Primary Objectives 
• Compare the efficacy of six-week treatment with telehealth 
CBT-I vs. trazodone vs. medication placebo for the 
treatment of chronic insomnia in patients undergoing HD 
• Compare the sustained efficacy of the 6-week treatment with 
telehealth CBT-I vs. trazodone vs. medication placebo for 
the treatment of chronic insomnia in patients undergoing 
HD by examining outcomes at 25 weeks from randomization 
Secondary 
Objectives 
In HD patients with chronic insomnia, compare the efficacy of 
CBT-I vs. trazodone vs. medication placebo, at 7 and 25 weeks 
from randomization, for  
• Other Patient-Reported Outcomes;  
• Cumulative weekly use of sedatives/hypnotics; and  
• Objective measurement of sleep by actigraphy 
Number of 
Participants 
126 
Diagnosis and Main 
Inclusion Criteria 
ESRD patients undergoing HD with chronic insomnia 
Interventions 
• Telehealth CBT-I 
• Trazodone drug therapy 
• Placebo 
Duration of study 
Up to 30 weeks 
Primary Outcome 
• Insomnia Severity Index    


 
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Statistical 
Methodology 
To maximize the use of information and to account for potential 
loss to follow-up and/or intermittent missing outcome 
measures, we will use linear mixed models to make inference 
regarding group differences across time, that includes the 
baseline, 4, 7, 13 and 25-week ISI measurements 
Study Oversight 
• Local Institutional Review Boards 
• Data Safety Monitory Board (Chair: Vernon Chinchilli) 
• NIDDK 


 
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Reviewed and approved by: 
 
Rajnish Mehrotra, Principal Investigator 
 
 
Chair, Data Safety Monitoring Board 
 
 


 
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1. Introduction 
 
1.1 
Background 
 
In the United States, 500,000 adults with end-stage renal disease (ESRD) are treated with 
maintenance dialysis; 88% with in-center hemodialysis (HD) in community-based 
facilities.[1] Dialysis patients have a short life expectancy, high healthcare utilization, with 
total annual societal expenses estimated at $50 billion. [1, 2] Yet, they have poor 
functional rehabilitation, in part from the high prevalence of many disabling symptoms 
(median, 9-11); [3] 40-85% has significant sleep disturbances.[4-9] In a nationally 
representative study of 1643 patients from 335 dialysis facilities in the United States 
selected using equal probability systematic random sampling, 50% had trouble falling 
asleep, 59% woke up at night, and 49% had early morning awakening; 53% reported one 
or more of these symptoms all or most of the time. [8] 
 
At least two factors contribute to the high prevalence of insomnia: First, day/night sleep 
reversal is a cardinal manifestation of uremia, the symptom complex associated with 
kidney failure. Animal and human studies indicate that kidney failure is characterized by 
significant alterations in circadian rhythm and sleep structure and attenuation of 
nocturnal melatonin surge. [10-17] Studies have also shown that the severity of sleep 
problems are associated with biochemical measures of kidney failure, suggesting 
insomnia to be a result of accumulation of various uremic toxins. [18-24] Second, while 
HD is partially effective in removing many uremic toxins, it introduces countervailing 
influences that worsen insomnia: several studies have shown that compared with kidney 
disease patients not treated with dialysis HD patients have a significantly shorter total 
sleep time and sleep efficiency and greater sleep fragmentation. [25-27] This is a direct 
result of unpredictable consequences from HD treatment schedules that makes 
maintaining regular sleep/wake routines challenging. One-third of HD patients are 
scheduled for the early morning shift, and many of them arrive at the facility at 5:00-6:00 
a.m.; these patients have significantly greater insomnia. [25] There is evidence that shows 
that half of all HD patients nap during dialysis treatments, but this occurs only thrice 
weekly, further disrupting their sleep routines. [28] Importantly, the higher frequency of 
sleep disturbances in HD patients is independent of sleep apnea and restless legs 
syndrome. [8, 12] Given the high frequency and severity of symptoms and the unique 
disease- and treatment-specific contributors, it is imperative to determine the efficacy of 
various approaches for treating insomnia in HD patients instead of extrapolating from 
results of studies in other populations.  
 
In addition to the direct distress, insomnia is an important contributor to other poor 
health outcomes in HD patients. Insomnia in dialysis patients is strongly associated with 
daytime sleepiness and worse quality of life. [6, 7, 28, 29] The link is likely causal as 
successful treatment of insomnia in other populations results in improvements in quality 


 
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of life. [30-34] However, this premise has never been tested for HD patients. Fatigue is the 
most troubling symptom experienced by > 50% of HD patients; studies have shown that 
poor self-reported sleep quality is associated with worse fatigue. [35-38]  There is also 
accumulating evidence linking insomnia with pain; [39-43] post-hoc analyses of two 
clinical trials has shown that improvement in insomnia is associated with lower long-term 
pain scores in patients with osteoarthritis. [44, 45] Insomnia is common in HD patients 
with comorbid depression. [8, 28, 46-48] There is strong evidence that this relationship is 
bidirectional: the summary data from longitudinal studies indicates that patients with 
insomnia have a 2-fold higher risk for incident depression 12-48 months later. [49-54] 
Over 50% of dialysis patients report daytime sleepiness, fatigue, pain, and impaired 
quality of life, and over 25% have depression.[3, 4, 55] Recent studies have also shown a 
higher adjusted risk for death in HD patients with poor sleep. [6, 56] In sum, it is evident 
that insomnia is a contributor to many highly prevalent symptoms and poor health 
outcomes in HD patients.  
 
Given the wide-ranging effects of insomnia on the health and well-being of HD patients, 
it is not surprising to note that patients prioritize relieving insomnia highly. Using a 
nominal group technique to obtain consensus, HD patients and their caregivers ranked 
sleep, fatigue, and anxiety/stress among the top 10 most important outcomes for clinical 
trials; mortality ranked only 14th. [57] Yet, no clinical trial has ever been done to 
determine the efficacy of any treatments for insomnia in HD patients in the United 
States, and none is presently registered. Post-hoc analyses of HEMO and Frequent 
Hemodialysis Network trials has also shown that improved control of uremia with 
different dialyzers or by modifying HD frequency and/or treatment time is ineffective in 
improving insomnia. [58, 59] This indicates that within the constraints imposed by the 
range of clearances of uremic toxins possible with current dialysis technology, increasing 
the removal of the dialyzable uremic toxins does not result in meaningful improvement in 
insomnia. This further argues for testing alternative approaches for treating insomnia as 
with this clinical trial.  
1.2 
Rationale for Interventions Being Tested in this Clinical Trial 
1.2.1 Comparative Efficacy of telehealth CBT-I and drug therapy 
Cognitive Behavioral Therapy for Insomnia (CBT-I) is the first line therapy for insomnia 
but is largely inaccessible to dialysis patients. A large body of work in other populations 
has shown that in adults with insomnia, CBT-I improves sleep latency, wake after sleep 
onset, sleep efficiency, and sleep quality, and can induce insomnia remission. [60-79] 
Based on this evidence, the American College of Physicians strongly recommends CBT-I 
as the first-line treatment for insomnia. [80, 81] These studies have limited relevance for 
HD patients as they have unique challenges to maintaining regular sleep/wake routines; it 
is not known if CBT-I will be effective in favorably modifying these behaviors to improve 
sleep. Two clinical trials, one each from Taiwan and China, have demonstrated 
improvement in sleep quality, assessed with the Pittsburgh Sleep Quality Index, with 


 
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group CBT-I. [82, 83] However, these trials also are not useful to inform clinical practice 
in the United States where patients have to commit 5-6 hours thrice weekly to HD 
treatments in stand-alone dialysis facilities away from hospitals and medical facilities, 
making in-person CBT-I inaccessible. Thus, it is imperative to develop innovative 
solutions to make treatment for insomnia available to HD patients. Some treatment 
approaches have been tested in other groups such as self-help strategies, internet 
programs, or over the telephone. [84-87] They introduce newer limitations as they don’t 
involve a face-to-face interaction with a therapist; the effect size for internet-based CBT-I 
is smaller than when delivered in person. [88] Moreover, they are not useful for patients 
with limited health literacy or without an internet connection. Telehealth, a two-way 
video interaction between the patient and the therapist, overcomes the accessibility 
challenges and has been identified by the American Academy of Sleep Medicine in having 
the potential to narrow the gap between the availability of sleep providers and the 
number of patients needing insomnia treatment. [89, 90] To date, only one center has 
reported a case series of its experience with telehealth CBT-I showing improvement; 
however, there was no control group to reliably determine efficacy. [91]  In this clinical 
trial, we will use telehealth CBT-I as a comparator and this will serve the dual purpose of 
testing the efficacy of CBT-I itself for HD patients, and its delivery via telehealth.  
 
As for pharmacotherapy, there is limited evidence to support current practices for 
insomnia for dialysis patients.  Notwithstanding clinical practice guidelines, 
pharmacotherapy is widely used as a first-line therapy for insomnia including for HD 
patients; it is also an alternative for patients unwilling to engage with CBT-I or for whom 
behavioral therapy is unavailable or inaccessible. However, the drugs used widely have 
either concerns about safety or efficacy, or have been insufficiently studied for patients 
undergoing HD. Benzodiazepines and non-benzodiazepine benzodiazepine-receptor 
agonists such as zolpidem are prescribed for 8-26% of HD patients [92, 93] even though 
two cohort studies have shown that HD patients treated with these drug classes have a 
significantly higher risk for death. [6, 93] The clinical trials with melatonin in HD patients 
have been disappointing in demonstrating sustained efficacy. [17, 94, 95] Trazodone is an 
attractive option as population surveys show it to be the most common or second most 
common drug prescribed for insomnia in the United States including for HD patients, yet 
is remarkably understudied. [96-99] This oral triazolopyridine drug, approved by the 
Food and Drug Administration for treating depression in 1981, is sedating, has no 
significant anti-cholinergic or cardiotoxic effects, and as it has a short half-life it does not 
induce daytime sleepiness. [100] It has a low potential for abuse as it does not induce 
dependence in contrast to benzodiazepines. [101] The drug is metabolized in the liver into 
inactive metabolites and no dose adjustments are necessary with kidney disease. 
However, there are very limited data to guide clinical practice. Low-quality evidence 
suggests its efficacy for treating primary insomnia; in two placebo-controlled trials, 
treatment with trazodone lasted only 7-14 days, and the only trial testing its efficacy as 
add-on to CBT-I enrolled just 20 patients. [102-104] Studies have shown the efficacy of 
trazodone for insomnia in patients with depression, Alzheimer’s disease, and 
alcohol/opiate dependence. [49, 105-111] However, no studies have tested its efficacy and 


 
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safety in the setting of partial correction of uremia as with HD and none are underway. 
Furthermore, HD patients have unique behavioral and scheduling challenges and have 
greater risk with daytime sleepiness when overlaid upon hemodynamic fluctuations with 
HD and frailty. This study will generate much-needed evidence to support or refute its 
widespread use for treating insomnia in HD patients.  
 
To summarize, most HD patients have significant impairments in quality of life, largely 
from the high frequency of disabling symptoms. Insomnia is one of the most frequently 
reported symptoms and studies of HD patients and/or other populations suggest that it is 
a significant contributor to other common symptoms and poor health outcomes. There 
are unique contributors to chronic insomnia in HD patients and these include the 
biologic effects of residual uremia after partial correction as is achieved with current 
dialysis technology, maladaptation to treatment schedules, and patients’ napping during 
treatments. There is a compelling need to identify effective treatments for insomnia in 
HD patients and the interventions being studied in this clinical trial (telehealth CBT-I 
and trazodone) have a strong scientific premise. If telehealth CBT-I is effective for 
insomnia in HD patients, it will make a treatment that is presently inaccessible available 
to patients. Trazodone is widely used but the data on efficacy for insomnia are limited; no 
such data exist for HD patients.  
2. Study Objective and Aims 
 
SLEEP-HD has two specific aims designed to test two hypotheses: 
 
Specific Aim One – To compare the efficacy of six-week treatment with telehealth CBT-I 
vs. trazodone vs. placebo for the treatment of chronic insomnia in patients undergoing 
HD. 
Hypothesis One - We hypothesize that the efficacy of six-week treatment with 
both telehealth CBT-I and trazodone will be superior to medication placebo in 
improving self-reported sleep. 
 
Specific Aim Two – To compare the sustained efficacy of the 6-week treatment with 
telehealth CBT-I vs. trazodone vs. placebo for the treatment of chronic insomnia in 
patients undergoing HD by examining outcomes at 25 weeks from randomization. 
 
Hypothesis Two - We hypothesize that telehealth CBT-I will be superior to both 
trazodone and placebo in improving self-reported sleep at 25 weeks from 
randomization.  
2.1 
Comparative Efficacy of individual CBT-I, Trazodone, and Medication Placebo  
2.1.1 Primary Measure of Efficacy 
 


 
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The summary score from the Insomnia Severity Index (ISI) at weeks 7 and 25 from 
randomization will be the primary outcome measures for Aims One and Two, respectively 
(Appendix One).  
 
2.1.1.1 Rationale for the Primary Measure of Efficacy 
 
The ISI is an instrument that measures insomnia, the condition being treated, in contrast 
to the Pittsburgh Sleep Quality Index that measures the quality of sleep. This self-report 
instrument captures both patient perceived severity of insomnia and its effect on daytime 
function.[112, 113] The 7 items assess severity of sleep onset and maintenance difficulties 
(both nocturnal and early morning awakenings), satisfaction with current sleep pattern, 
interference with daily functioning, noticeability of impairment attributed to the sleep 
problem, and the degree of distress or concern caused by the sleep problem.[112] Each 
item is rated on a 0-4 scale with a total score range of 0-28. The instrument has been 
validated using both the classical test and the item response theory.[30, 112, 114-116] The 
instrument has an excellent internal consistency (Cronbach α, 0.90), and adequate 
discriminatory capacity with strong correlation with self-reports of sleep onset latency, 
waking after sleep onset, and early morning awakening.[114] It has strong convergent 
validity as supported by significant correlations between total ISI score and measures of 
fatigue, quality of life, anxiety, and depression.[114] ISI is also sensitive to detect changes 
with treatment and at least two studies have demonstrated that a 6-8 point change in ISI 
is the minimal clinically important difference that correlates with a significant 
improvement or worsening in health-related quality of life.[30, 114] These considerations 
provide a strong rationale for selecting ISI as the primary outcome measure. 
2.1.2 Secondary Measure of Efficacy 
 
There are three domains for secondary measure of efficacy 
• Patient-Reported Outcomes 
• Cumulative Weekly Use of Sedatives and Hypnotics 
• Objective Measures of Sleep with Actigraphy 
2.1.2.1 Patient-Reported Outcomes 
 
The following seven patient-reported outcomes will be assessed at weeks 7 and 25 from 
randomization (Appendix One): 
• Sleep: 
o Pittsburgh Sleep Quality Index 
• Sleepiness 
o Epworth Sleepiness Scale 
• Fatigue: 
o Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 


 
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• Pain: 
o Two-Item Graded Chronic Pain Scale 
• Depression: 
o Patient Health Questionnaire-9 
• Anxiety 
o Generalized Anxiety Disorder-7 Scale 
• Quality of Life 
o Short-Form 12 
 
2.1.2.2 Cumulative Weekly use of Sedatives/Hypnotics 
 
This will be defined as the number of days that the patient took a drug to help sleep, and 
the value of this variable will range from 0 to 7. The drug taken to help sleep will be 
further categorized as (1) prescription medication; (2) over-the-counter medication; (3) 
marijuana; or (4) other. A list of potential prescription, over-the-counter, or other 
sleeping aids is included in Appendix Two.  
 
Even though opiates are sedating, they are rarely primarily used as a sedative. Hence, for 
purposes of defining this outcome, use of opiates will not be considered when assessing 
cumulative weekly use of sedatives/hypnotics. Instead, any opiate use in the preceding 7 
days will be recorded for descriptive purposes. 
2.1.2.3 Objective Measures of Sleep with Actigraphy 
 
Actigraphy data will be collected at three time points – the one-week run-in period 
(baseline), the sixth week of treatment, and the 25th week from randomization.  
 
The key secondary outcome measure will be the average nighttime sleep efficiency 
(percent time asleep of time in bed). 
 
The actigraphy data will be used to compute the following variables for additional 
exploratory analyses:  
 
• Sleep onset latency; 
• Total sleep time; 
• Wake after sleep onset; 
• Daytime inactivity; and 
• Light exposure. 
3. Study Design and Overview 
 


 
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SLEEP-HD is a parallel group randomized controlled trial wherein 126 HD patients treated 
in community-based dialysis facilities in Seattle and Albuquerque will be randomized 1:1:1 
over 31 months to 6-week treatment with telehealth CBT-I, trazodone, or medication 
placebo (Figure 1). The primary and secondary outcomes for Aims One and Two will be 
ascertained at weeks 7 and 25 from randomization, respectively. A detailed schedule of 
study-related procedures is summarized in Appendix Three. 
 
3.1  
Rationale for Key Components of the Study Design:  
 
First, patients will be treated with CBT-I and trazodone for 6 weeks. This is the time 
taken to deliver effective CBT-I and is the period of treatment in previous studies of 
efficacy of CBT-I. [61, 65, 67, 71-73, 76, 78, 79, 87, 117]  Second, while 20% of the patients 
will be assigned to a medication placebo, none will be assigned to “attention/education 
control” in order to reduce study complexity. Numerous clinical trials have shown CBT-I 
to be superior to attention/education control including in patients with coexisting 
medical conditions making it unnecessary to repeat this comparison.[118] In contrast, 
despite its widespread use, there is a paucity of placebo-controlled clinical trials testing 
the efficacy of trazodone for treating insomnia in patients without comorbid depression. 
[102, 104, 111] Patients randomized to placebo will be able to receive other treatments 
during these 6 weeks for insomnia other than CBT-I or trazodone from their physicians. 
Third, the long-term effectiveness will be tested at 25 weeks after randomization, which is 
a meaningfully long follow-up period for a population with a median life-expectancy of 3 
years and will minimize attrition from death or kidney transplantation. Fourth, we 
considered various treatment options for patients randomized to trazodone or placebo 
during the 18-week period (weeks 7-24). In the absence of data on short-term efficacy of 
trazodone for HD patients, it was considered unreasonable to plan to treat patients with 
the drug for 6 months in a clinical trial. Moreover, the labels for sedatives approved by 
the Food and Drug Administration for insomnia recommend short-term treatment only: 
triazolam and temazepam, 7-10 days; and flurazepam, zolpidem, and zaleplon, 4-6 weeks; 
Pre-Screen with 
Insomnia Severity 
Screening  
Telehealth CBT-I 
Trazodone 
12 and 24-
wk follow-up 
≥ 10 
Randomize, 
1:1:1 
One-Week 
Run In 
Six-Week 
Treatment 
Figure 1: Study Overview 
Informed 
Consent 
Placebo 
7 weeks from 
randomization 
13 & 25 weeks from 
randomization 
Aim One 
Outcomes 
Aim Two 
Outcomes 


 
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studies with only eszopiclone lasted for longer period. We propose that during the 18-
week period following the 6-week treatment, all patients will be able to receive and be 
monitored for any treatments for insomnia prescribed by their physicians, including CBT-
I and trazodone. 
4. Participant Selection and Withdrawal 
4.1 
Study Population 
4.1.1 Inclusion and Exclusion Criteria:  
 
Inclusion Criteria: 
1. Age ≥ 18 years;  
2. Undergoing thrice-weekly maintenance HD for ≥ 3 months; 
3. Able to speak English;  
4. ISI score ≥ 10 at pre-screening with sleep disturbances for ≥ 3 nights per week for ≥ 3 
months. 
Exclusion Criteria: 
1. Severe depression assessed by Patient Health Questionnaire-2, PHQ-2 and if 
appropriate, Patient Health Questionnaire-9 [120]; 
2. Suicidal Ideation; 
3. Alcohol abuse on CAGE questionnaire (score ≥ 2) or substance abuse on DAST-10 
questionnaire (score > 5) [121, 122];  
4. Severe restless leg syndrome;  
5. Treatment with trazodone in the past one month; 
6. Known allergy to trazodone (self-report or by chart review);  
7. Current treatment with monoamine oxidase inhibitors or in the preceding 14 days 
(Appendix Four); 
8. Current treatment with linezolid (self-report or by char review);  
9. Current treatment with other drugs that are inhibitors of CYP3A4 (e.g., itraconazole, 
clarithromycin, voriconazole), or known to prolong QT interval including Class 1A 
antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., 
amiodarone, sotalol), antipsychotic medications (ziprasidone, chlorpromazine, 
thioridazine), and quinolone antibiotics (Appendix Four); 
10. Pregnancy, or lactation, or women of childbearing potential not willing to use 
adequate birth control; 
11. Life Expectancy < 3 months;   
12. Expected to receive a kidney transplant or transition to home dialysis (peritoneal 
dialysis or home HD) within 6 months;  
13. Any other condition including cognitive impairment that, in the opinion of the 
investigator, should preclude patient participation in the clinical trial. 


 
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4.1.2 Rationale for key decisions regarding inclusion and exclusion criteria 
 
This study will be limited to patients undergoing in-center HD and patients undergoing 
home dialysis (peritoneal dialysis, home HD) will not be eligible. The issues challenging 
patients’ ability to maintain regular sleep/wake routines differ by dialysis modality and 
our approach will limit patient heterogeneity and yield valid estimates. 
 
The other exclusion criteria are likely to make up to 20% of the prevalent population of 
HD patients ineligible, but this approach will maximize external validity for HD patients 
with chronic insomnia for whom the two interventions being tested are safe and 
appropriate. Our approach of allowing patients with sleep apnea to be randomized to a 
sedative is appropriate as there is evidence that trazodone increases the arousal threshold 
in patients with sleep apnea without worsening nocturnal hypoxemia.[123-125] To 
maximize external validity, patients using prescription or over-the-counter sleep 
medications will be eligible and the usage of such drugs for insomnia will be tracked and 
will be one of the key secondary outcomes. 
4.2 
Participant Pre-Screening and Recruitment  
4.2.1 Pre-Screening and Enrolling Patients in the Clinical Trial 
 
All patients with ESRD treated in participating dialysis facilities that meet the following 
three criteria will be eligible to participate in pre- screening: (1) age ≥ 18 years; (2) 
undergoing maintenance HD ≥ 3 months; and (3) speak English. These individuals will be 
invited to complete the 7-item Insomnia Severity Index (ISI) and two questions about the 
frequency and duration of sleep disturbances. Study personnel will provide all patients 
with an information sheet that will describe the purpose and nature of pre-screening and 
provide the patients with an option to opt-out of the pre-screening.  
 
The summary score on ISI will be computed and patients will be managed based on the 
summary score: 
• All patients with an ISI score ≥ 10 with symptoms three or more times per week for 
three months or more will be approached for their willingness to undergo screening 
activities for participation in the clinical trial within 10 days of pre-screening. Patients 
that agree to undergo screening will be invited to sign a consent form prior to any 
further research-related activities. Eligible individuals with a diagnosis of chronic 
insomnia will undergo a one-week run-in period, at the end of which they will be 
randomly assigned to (1) telehealth CBT-I, or (2) trazodone, or (3) medication placebo. 
• The information on patients with ISI score ≥ 10 with symptoms three or more times 
per week for three months or more who refuse to undergo additional screening 


 
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activities will be communicated to the patients’ treating nephrologist, with the 
patient’s permission.  
• Information on patients with ISI score < 10 or score ≥ 10 with less frequent symptoms 
and/or for < 3 months, will not be communicated to the patients’ treating 
nephrologist. 
 
4.2.1.1 Re-Administration of Pre-Screening 
 
Some patients may complete the 7-item Insomnia Severity Index (ISI) additional time(s). 
These include when a patient: 
• Scores ≥10 and meets the criteria for frequency and duration, but is not consented 
within 10-days or randomized to treatment within 25-days of pre-screening. Upon 
expiration of the 10-day or 25-day window, as appropriate, a second ISI will be 
administered for a valid score to continue screening procedures. 
• Score ≥10, meets the criteria for frequency and duration, but has taken trazodone 
in the preceding 30 days but meets other inclusion and exclusion criteria: If the 
patient is willing to participate in the clinical trial, s/he will be asked not to take 
trazodone any further, and an ISI will be re-administered ≥ 30-days from the last 
dose of the drug.  
• Scores < 10, 3 months have passed since previous administration. 
 
4.2.2 Diagnosis of Chronic Insomnia  
 
Our approach to pre-screening will help us identify patients with chronic insomnia that 
meets the Diagnostic and Statistical Manual (DSM-5) criteria for the condition. [126-129]  
The key elements of the DSM-5 criteria include dissatisfaction with sleep quality or 
duration with (1) difficulty falling asleep, and/or night-time awakenings, and/or early 
morning awakening; (2) impact on day-time functioning; and (3) symptoms for ≥ 3 
nights/week for ≥ 3 months. [127] This approach will identify patients with persistent 
symptoms that are highly unlikely to remit spontaneously and hence in the greatest need 
for treatment. [130-134] 
4.3 
Early Termination of Study Treatment and Withdrawal of Patients  
 
Active treatment with the study interventions (telehealth CBT-I, or trazodone, or 
medication placebo) will be terminated if the patient: 
• Withdraws informed consent; or 
• Asks treatment to be discontinued; or 
• Sustains a serious adverse event directly attributable to the study interventions and 
the treatment cannot be safely reinstituted in the opinion of the site investigator;  


 
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• In the judgement of the investigator, continued participation of the patient in the 
clinical trial is a significant risk to the health of the patient;  
• Is unable to follow study procedures; or 
• Undergoes kidney transplantation; or 
• Transfers to home dialysis; or  
• Transfers care to a dialysis facility outside the participating metropolitan areas.  
If the patient withdraws informed consent, the patient will be withdrawn from the study 
(“drop-out”). Under all other circumstances all attempts will be made to continue to 
ascertain primary and secondary outcomes at 7 and 25 weeks from randomization.  
5. Study Interventions 
5.1 Comparative Efficacy of Telehealth CBT-I vs Trazodone vs. Medication Placebo 
 
The patients will be randomly assigned, 1:1:1 to CBT-I or trazodone or medication placebo 
using block randomization through the secure study web portal. 
5.2 
Telehealth CBT-I 
5.2.1  Overview of the Intervention 
 
Patients randomized to this arm will receive a treatment session once weekly for six 
weeks (Table 1 and Appendix Five); [87, 114, 135] each session is anticipated to last about 
30 minutes.  The content of each of these sessions will be adapted to include changes in 
behavior during HD treatments (such as napping) and to help patients better adjust to 
treatment schedules.  The CBT-I sessions will be delivered by a therapist face-to-face with 
the patient via a fully interactive HIPPA-compliant video telehealth platform, Zoom.  
  
Patients will receive CBT-I using a tablet or laptop provided by the study team, or at their 
home using a personal smart phone, tablet, laptop, or desktop. If the patients use a device 
provided by the study team, they will receive the telehealth CBT-I sessions in the dialysis 
facility, while undergoing HD or at another time. If the patients use their personal device, 
they can receive the telehealth CBT-I sessions at a place of their choosing.  The tablets 
from the study team will be placed in a fresh, transparent plastic bag for each session as 
recommended to prevent nosocomial transmission of infection in high-risk healthcare 
setting such as the HD facility. CBT-I therapists will be based in Seattle, WA and New 
York, NY. Patients will be asked to maintain a daily sleep diary throughout the 6-week 
treatment phase as for the run-in period, and weekly records will be made available to the 
therapists prior to each session to modify behavioral treatment recommendations, as 
appropriate.  
 
Table 1: Components of Telehealth CBT-I Intervention 


 
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Week 
Key Component 
Session-Specific 
1 
 
Sleep changes with ESRD; rationale for approach; 
stimulus control instructions 
2 
Review Diary and 
Behavioral Sleep Plan  
Sleep Scheduling/Bed Restriction 
3 
Sleep stages and cycles 
4 
Constructive Worry; Mindfulness/ Relaxation Exercise 
5 
Changing beliefs, attitudes about sleep/Sleep Hygiene 
6 
Maintenance/relapse prevention plan 
 
5.2.2  Training and Certification Prior To Implementation in Trial 
 
Each therapist will undergo in-person training by Drs. Cukor and McCurry. Following the 
completion of training, each therapist will be required to complete mock interventions 
prior to implementation of the intervention in the clinical trial. These mock sessions will 
be audio recorded and will be reviewed by Dr. Cukor using a structured fidelity adherence 
form. Once the therapists are deemed competent in the intervention, they will be ready 
to implement the intervention in a clinical trial.  
5.2.3  Monitoring the Fidelity of the Intervention 
 
During the conduct of the trial, weekly conference calls will be scheduled with the 
therapists during which clinical and implementation issues will be discussed, and cases 
reviewed. All individual CBT sessions will be audio-taped. All CBT-I sessions for the first five 
patients assigned to each therapist will be reviewed to provide rating for treatment fidelity 
using forms that outline the major skills and intervention pieces as follows: 
• For the first two cases for each therapist, both Drs. McCurry and Cukor will review 
and score the therapists’ fidelity and provide feedback; and  
• For the next two cases for each therapist, either Dr. McCurry or Cukor will review 
all audio recordings, rate fidelity, and provide feedback.  
Following the first four patients for each therapist, one sessions from each case will be 
selected at random and one not at random and be reviewed by either Dr. McCurry or Dr. 
Cukor.  Review of audio recording will be as timely as possible to provide meaningful 
feedback to therapists and feedback will be provided at the ongoing supervision calls or 
through email. 
This approach will allow therapists to receive support and real-time feedback to ensure 
the highest standards for delivering the behavioral intervention.  
 
 


 
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5.2.4  Monitoring Adherence to Intervention 
 
Adherence to CBT-I will be monitored by recording number of completed sessions, 
duration of each session, nights adhered with recommended sleep window, adherence to 
recommended sleep/nap routines, and relaxation exercise practice.  
 5.3 Drug Therapy 
5.3.1 Overview of the Intervention 
 
The site investigators will prescribe trazodone (50-100 mg) or corresponding medication 
placebo to the study participants randomized to the respective arms. The dose range 
selected for the trial (50-100 mg) is guided by prior studies with trazodone. In a double-
blind placebo controlled study in healthy adults, trazodone was effective in inducing deep 
sleep with this dose range and no further increase was evident at higher doses. [100] In a 
dose-finding study to improve sleep in patients with major depressive disorder, 31 of the 
33 patients treated with trazodone for six weeks with doses up to 100 mg reported 
improvement in insomnia. [136] Finally, this is the same dose range shown to be effective 
in improving sleep in several randomized trials in patients with primary insomnia, or 
sleep disturbances associated with major depression and Alzheimer’s. [49, 102-106, 108, 111, 
137]       
 
The starting dose for trazodone will be 50 mg, and if after the end of the first or second 
week of treatment the patients report inadequate improvement in sleep, they will have 
the option to increase the dose to 100 mg at weeks 2 or 3. The dose achieved by the end of 
week 3 will be maintained for the remaining three weeks.  
 
To the extent possible, the assessments will be done on the first dialysis day of the week 
(Monday or Tuesday, respectively, for patients on Monday-Wednesday-Friday or Tuesday-
Thursday-Saturday / Sunday-Tuesday-Thursday schedules).  
 
5.3.2 Drug Procurement and Dispensation 
 
Prior to launching the clinical trial, the Investigational Drug Services at Harborview 
Medical Center, where the PI is based, will procure 50-mg tablets of trazodone from the 
same manufacturing stock for both clinical sites and prepare matching placebo. A supply 
of the study medications will be shipped to the Investigational Drug Services at 
Albuquerque in New Mexico. The medications will be dispensed as per the protocol by 
the Investigational Drug Services at each site and the study coordinators will hand the 
study drug to the participants at the dialysis facility when they arrive for their routine HD 
treatments (during the COVID pandemic, this will be modified to allow coordinators to 
leave drug with dialysis unit or mail drug via US postal service or inter-office mail); this 
will occur once during week 1 where a 3-week supply of the drug will be provided (with 


 
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capacity to increase the dose to 100 mg starting week 2), and at week 4 where a -week 
supply of the drug for the dose being taken during week 3.  
 
5.3.3 Monitoring Drug Adherence 
The participants will be asked to bring in the medication bottles for study drug at week 4 
and week 7, and the coordinators will perform a pill count to assess adherence with the 
medication. All unused drug will be destroyed by IDS.  
6. Ascertainment of Outcomes 
6.1 
Patient-Reported Outcomes 
 
The primary (ISI) and secondary patient reported outcomes will be ascertained by 
Computer-Assisted Telephone Interviewing (CATI) at weeks 0, 4, 7, 13, and 25 from 
randomization by interviewers blinded to the study assignment. The baseline assessment 
will be performed during the run-in period and prior to randomization. The CATI will run 
out of Albuquerque, NM under the direction of Mark Unruh who will train the 
interviewers. CATI operators will conduct the assessments using scripts prepared for the 
call. The interview is expected to last about 30 minutes.   
 
The order of preference for the day of the week for completing CATI, from optimal to the 
least preferred, is as follows: 
• The day following the first dialysis treatment of the week (Tuesday for patients on a 
Monday-Wednesday-Friday schedule, and Wednesday for patients on a Tuesday-
Thursday- Saturday / Sunday-Tuesday-Thursday schedule); 
• The day following the second dialysis treatment of the week – Thursday, or Friday, 
respectively, for patients on a Monday-Wednesday-Friday or Tuesday-Thursday-
Saturday/Sunday schedule;  
• Within the first hour of the dialysis session according to the patient’s treatment 
schedule as noted above.   
 
To the extent possible, the calls for the 4, 7, 13, and 25 weeks will be done on the days as 
for the baseline call for the patient. If there are individuals that do not have access to a 
telephone, the study staff will make that available to them to complete the CATI. 
 
If all attempts to complete a follow up CATI call are unsuccessful, the Principal 
Investigator may authorize the site study coordinator to complete the PROs using paper 
forms at the bedside. We anticipate this approach to be used only under exceptional 
circumstances, if at all.  
 


 
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6.2 
Cumulative Use of Sedatives and Hypnotics in Prior Week 
 
This secondary outcome measure will be ascertained during the same week as the CATI 
call is completed, at baseline, and weeks 4, 7, 13, and 25 from randomization. The patients 
will be asked to report the number of nights during the previous 7 nights that they used a 
prescription, or over-the-counter, or other sleeping aid(s) (including marijuana, if taken 
for sleep).  This information will be supplemented by a review of the electronic medical 
records. The study coordinators will be provided with a reference document listing the 
generic and commercial name of the prescription, over-the-counter, or other sleeping 
aids as listed in Appendix Two. 
 
The cumulative use of prescription opiates in the previous 7 days will be recorded 
similarly.  
6.3 
Actigraphy 
 
Actigraphy will be performed at three time-points: (a) the one-week run-in period; (b) 
week 7 from randomization; and (c) week 25 from randomization. Each assessment will 
last 7 days, will be scheduled to start and end with a regularly scheduled dialysis 
treatment, and the coordinator will meet with the patient in the dialysis facility when the 
patient reports for treatment. The follow up assessments will be scheduled such that the 
seven-day period starts the week prior to the CATI and ends the week CATI is performed. 
It is anticipated that the study coordinators will assess the cumulative weekly use of 
sedatives and hypnotics (6.2 above) at the same visit as they go to retrieve the actiwatches 
from the patients.  
 
The actigraphy data will be downloaded and scored using Actiware 6.0.8 software 
(Phillips Respironics, Bend, OR) to determine wake and sleep based on one-minute 
epochs. The actigraphy scorers will blinded to the randomized treatment assignment of 
the patient. The validity of data from actigraphy will be increased by our approach of 
asking patients to maintain sleep diaries as this will control for artifacts in data collection, 
e.g., from removal of the device. [138] Additionally, light sensors, and actigraph event 
marker data will be used in conjunction to ensure that in-bed and out-of-bed (daytime) 
periods used for calculating sleep parameters are accurate. 
7. Study Procedures and Visits 
 
All study visits will occur in the participating dialysis facility or via a HIPPA-compliant 
telehealth platform. 


 
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7.1 
Pre-Screening  
• Information sheet will be handed to patients to invite them to complete ISI and two 
questions on (a) how many days in the week do the patients experience sleep 
disturbance, and (b) how many months they have been symptomatic; 
• Patients who agree will be provided with the questionnaire to complete; the study 
team will provide assistance for the patients to complete the questionnaire as 
appropriate.  
 
7.2 
Screening  
• This will occur in-person, within 10 days of completion of pre-screening; 
• Patients with ISI score ≥ 10 will be invited to sign an informed consent form to 
complete screening activities;  
• The demographic information of all patients who consent to participate in the study 
will be recorded and they will be registered on the online portal; 
• The following assessments will be completed (during the COVID pandemic, these 
may be administered over the telephone): 
o Medication Review to ascertain current use of trazodone or in the preceding 
one month;   
o Patient Health Questionnaire-2 (PHQ-2); if score on PHQ-2 is ≥ 3, PHQ-9 will 
be administered (score for exclusion, ≥ 20). Patients who answer “more than 
half the days” or “nearly every day” to question 9 of the PHQ-9 will be 
administered the Columbia Suicide Severity Rating Scale to determine the 
suicidal intent; those with suicidal ideation will be excluded; 
o CAGE questionnaire for alcohol abuse (score for exclusion ≥ 2) and DAST-10 for 
substance abuse (score > 5); 
o Cambridge-Hopkins Restless Legs syndrome questionnaire (criteria for 
exclusion – answer to question 11, moderately or extremely distressing, AND, 
answer to question 12, 4-5 days per week or every day);   
o Medical history for co-existing illnesses;  
o For women that have had menstrual periods in the last 12 months, will be asked 
if they are pregnant or currently lactating. Pregnancy will be further excluded 
by a blood pregnancy test for women randomized to trazodone or medication 
placebo;  and 
o Final review of inclusion and exclusion criteria; 
• Eligible participants will be provided with instructions to complete sleep diaries for 
the run-in period: 
o Patients that choose to complete the sleep diaries online will be provided with 
log-in details and instructions on how to enter the data in the web-portal; 
o Patients who choose to use the paper-form of sleep diaries will be provided 
with the sleep diary for the first week along with instructions on how to enter 
the data; 


 
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• The patients’ nephrologist will be informed about their enrollment in the clinical trial 
and if randomized to drug therapy, with a list of medications that could prolong QTc 
in patients treated with trazodone, as listed in the FDA package insert for the drug;  
• The coordinator will place the actiwatch on the patient and provide instructions on 
wearing the device. The actiwatch will be placed on the arm opposite to the upper 
extremity with the functional arteriovenous access being used for dialysis. In patients 
with a lower extremity arteriovenous access or with a central venous catheter, the 
actiwatch will be placed on the non-dominant arm;  
• The 7-day run-in period will start after completion of the screening procedures and 
placement of the actiwatch; and 
• The patients will be scheduled to receive a phone call for the baseline CATI.     
 
7.3 Baseline CATI 
• This will occur over the telephone, to the extent possible before the “Baseline Visit”; 
• A research assistant from Albuquerque, NM, will call the patient to initiate the CATI;  
• The following assessments will be completed: 
o Insomnia Severity Index (primary outcome measure); and  
o Seven pre-specified secondary patient-reported outcome measures; and 
• A system-configured email will be sent to the site study coordinator upon successful 
completion of CATI. 
7.4 Baseline Visit 
• This will occur in-person seven days after the start of the run-in period and to the 
extent possible, on the first dialysis day of the week (Monday or Tuesday) (during the 
COVID pandemic, this will be modified to occur over the telephone to the extent 
possible); and  
• The following procedures will be completed at this visit: 
o The patients will return the actiwatches;   
o The online or paper sleep diaries will be reviewed and/or collected;  
o The dialysis days and the start time for the scheduled shift for the preceding 
seven days; and 
o The case-report form on cumulative weekly use of sedatives/hypnotics and 
opiates will be completed, assessing the use of sleep aids for the preceding 7 
nights.  
• The patients will be scheduled to receive a phone call for the baseline CATI.  
 
 


 
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7.5 Randomization  
• This will occur electronically through the web-based portal after CATI is completed, 
and to the extent possible, the same week as the “Baseline” visit and the baseline 
CATI, and no more than 25 days after pre-screen with ISI; 
• Patients will be randomly assigned to telehealth CBT-I, trazodone, or medication 
placebo, stratified by site using blocks of varying size to ensure that the three groups 
are balanced at periodic intervals; and 
• The patients should begin treatment within 10 days from the date of randomization 
(first CBT-1 session or provided with the first supply of medication).  
 
7.6 Treatment Visits (Weeks One through 6, through 7 weeks from randomization) 
7.6.1 Telehealth CBT-I Visits  
• These visits will occur once a week for six weeks via telehealth using the Zoom 
platform delivered by a therapist based either in New York or Seattle; 
• For any given patient, the same therapist will administer each of the six treatments; 
• The sessions will be held with the patient either (a) at the dialysis facility (while 
undergoing HD or at another time), using a personal device or one provided by the 
research team; (b) or at home using a personal device; 
• Prior to each session data from the sleep diaries will be retrieved either from the 
online portal, or the coordinator collecting it from the patient in-person, or over the 
telephone by either the coordinator or the therapist; and 
• All therapy sessions will be audio-recorded with the permission of the patient. 
In the event that the scheduling of six weekly sessions over six weeks becomes 
impossible, the following priority list should be followed: 
1. An extra session (including all assigned homeworks) should be added, so that two 
sessions are done in the same week (but with maximal time in between them); 
priority will be given to scheduling sessions 5/6 in the same week. 
2. Two sessions can be scheduled back to back with priority given to doubling up 
sessions 5/6, ¾ (time of treatment should still be ½ hour per session, 1 hour for 
doubled up sessions). 
If a sessions is started, but could not be completed, providing the remainder of the 
content should follow the same priority list (extra session is preferred over adding extra 
time to the next session). 
7.6.2 CBT-I Treatment Assessment Visits 
 
7.6.2.1 CBT-I Treatment Assessment Visit One 
 


 
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• This will occur over the telephone about four weeks from the date of randomization; 
• The following procedures will be completed at this visit: 
o The online or paper sleep diaries will be reviewed and/or collected;  
o The dialysis days and the start time for the scheduled shift for the preceding 
seven days will be recorded; and 
o The case-report form on cumulative weekly use of sedatives/hypnotics and 
opiates will be completed, assessing the use of sleep aids for the preceding 7 
nights;  
•  The patients will be scheduled to receive a phone call for the 4-week CATI. 
 
7.6.2.2 CBT-I Treatment Assessment Visit Two  
 
• This will occur in person about six weeks from the date of randomization; 
• The following procedures will be completed at this visit: 
o The online or paper sleep diaries will be reviewed and/or collected; and 
o The coordinator will place the actiwatch on the patient and provide 
instructions on wearing the device. The actiwatch will be placed on the arm 
opposite to the upper extremity with the functional arteriovenous access being 
used for dialysis. In patients with a lower extremity arteriovenous access or 
with a central venous catheter, the actiwatch will be placed on the non-
dominant arm. 
 
7.6.2.3 CBT-I Treatment Assessment Visit Three 
 
• This will occur in person about seven weeks from the date of randomization (during 
the COVID pandemic, this will be modified to occur over the telephone to the extent 
possible);  
• The following procedures will be completed at this visit: 
o The patients will return the actiwatches;  
o The online or paper sleep diaries will be reviewed and/or collected;  
o The dialysis days and the start time for the scheduled shift for the preceding 
seven day will be recorded; and  
o The case-report form on cumulative weekly use of sedatives/hypnotics and 
opiates will be completed, assessing the use of sleep aids for the preceding 7 
nights.  
• The patients will be scheduled to receive a phone call for the 7-week CATI.  
 
7.6.3 Medication Visits 
For patients randomized to trazodone and medication placebo, the visits and related 
procedures will be identical. 


 
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7.6.3.1 Medication Assessment Visit One 
 
• This visit will occur in-person and, to the extent possible, on the day of the first 
dialysis treatment of the first week following randomization (during the COVID 
pandemic, this will be modified to occur over the telephone to the extent possible); 
and 
• The patients will be provided with three-week supply of 50-mg trazodone or matching 
placebo. The patients will be provided with a sufficient supply of drug to increase the 
dose of the medication to 100 mg starting week 2.  
 
 
7.6.3.2 Medication Assessment Visit Two 
 
• The visit will occur over the telephone and, to the extent possible, on the day of the 
first dialysis treatment of the second week following randomization and one week 
following the “Medication Assessment Visit One”; 
• The coordinator will ask the patient if they have been prescribed any new medications 
since the last visit to screen for contra-indicated drugs to prolong QTc;  
• The patients’ response to drug therapy will be assessed and they be advised to:  
o Continue on the 50 mg dose if they are satisfied with their sleep over the 
previous 7 days; or 
o Increase to 100 mg for patients with persistent problems with sleep in the 
previous 7 days.  
 
7.6.3.3 Medication Assessment Visit Three 
 
• The visit will occur over the telephone and, to the extent possible, on the day of the 
first dialysis treatment of the third week following randomization and one week 
following the “Medication Assessment Visit Two”; 
• The coordinator will ask the patient if they have been prescribed any new medications 
since the last visit to screen for contra-indicated drugs to prolong QTc;  
• The patients’ response to drug therapy will be assessed and they be advised to: 
o Patients who have been on 50 mg dose will be assessed and based upon 
patients’ satisfaction with their sleep will either continue with the 50 mg dose 
or the dose will be increased to 100 mg; 
o Patients who had been on 100 mg dose will be assessed and based upon 
patients’ tolerability of the higher dose will either continue with the 100 mg 
dose or the dose will be decreased to 50 mg.  
 


 
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7.6.3.4 Medication Assessment Visit Four 
 
• The visit will occur in-person and, to the extent possible, on the day of the first 
dialysis treatment of the fourth week following randomization and one week following 
the “Medication Assessment Visit Three” (during the COVID pandemic, this will be 
modified to occur over the telephone to the extent possible);  
• The coordinator will ask the patient if they have been prescribed any new medications 
since the last visit to screen for contra-indicated drugs to prolong QTc;  
• The medication bottle provided to the patient on the prior visit will be collected;  
• The coordinators will perform a pill count to assess adherence for the preceding 7 
days;  
• The dialysis days and the start time for the scheduled shift for the preceding seven 
days will be recorded;  
• The patients will be provided with a three-week supply of trazodone or medication 
placebo at the same dose that they were on the prior week;  
• The case-report form on cumulative weekly use of sedatives/hypnotics and opiates 
will be completed, assessing the use of sleep aids for the preceding 7 nights; and  
• The patients will be scheduled to receive a phone call for the 4-week CATI. 
 
7.6.3.5 Medication Assessment Visit Five 
 
• The visit will occur in-person and, to the extent possible, on the day of the first 
dialysis treatment of the sixth week following randomization and two weeks following 
the “Medication Assessment Visit Four”; 
• The coordinator will ask the patient if they have been prescribed any new medications 
since the last visit to screen for contra-indicated drugs to prolong QTc;  
• The patients will be reminded to start maintaining online or paper sleep diaries; and 
• The coordinator will place the actiwatch on the patient and provide instructions on 
wearing the device. The actiwatch will be placed on the arm opposite to the upper 
extremity with the functional arteriovenous access being used for dialysis. In patients 
with a lower extremity arteriovenous access or with a central venous catheter, the 
actiwatch will be placed on the non-dominant arm. 
 
7.6.3.6 Medication Assessment Visit Six 
 
• The visit will occur in-person and, to the extent possible, on the day of the first 
dialysis treatment of the seventh week following randomization and one week 
following the “Medication Assessment Visit Five” (during the COVID pandemic, this 
will be modified to occur over the telephone to the extent possible); 
• The medication bottle provided to the patient on the prior visit will be collected; 


 
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• The coordinators will perform a pill count to assess adherence for the preceding 14 
days;  
• The online or paper sleep diaries will be reviewed and/or collected;  
• The dialysis days and the start time for the scheduled shift for the preceding seven 
days will be recorded;  
• The patients will return the actiwatches;  
• The case-report form on cumulative weekly use of sedatives/hypnotics and opiates 
will be completed, assessing the use of sleep aids for the preceding 7 nights;   
• The patients will be scheduled to receive a phone-call for the 7-week CATI; and. 
• If the patient wants to continue trazodone past the six-week treatment period, the site 
investigator will facilitate the treatment plan in partnership with the primary 
nephrologist and/or the primary care physician.  
 
7.6.4 CATI Visits in Treatment Phase 
7.6.4.1 Four Week CATI 
• This will occur over the telephone at four weeks from the date of randomization; 
• A research assistant from Albuquerque, NM, will call the patient to initiate the CATI;  
• The following assessments will be completed: 
o Insomnia Severity Index (primary outcome measure); and 
o Seven pre-specified secondary patient-reported outcome measures; and 
• A system-configured email will be sent to the site study coordinator upon successful 
completion of CATI. 
7.6.4.2 Seven Week CATI 
• This will occur over the telephone at seven weeks from the date of randomization; 
• A research assistant from Albuquerque, NM will call the patient to initiate the CATI; 
• The following assessments will be completed: 
o Insomnia Severity Index (primary outcome measure); and 
o Seven pre-specified secondary patient-reported outcome measures; and 
• A system-configured email will be sent to the site study coordinator upon successful 
completion of CATI. 
7.7 Long-Term Follow-Up Visits 
7.7.1 Long-Term Follow-Up Visit 0 
 
• This will occur over the telephone, and to the extent possible on the day of the first 
dialysis treatment of the 12th week following randomization; and  
• The patients will be scheduled to receive the 13-week CATI. 
 


 
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7.7.2 Long-Term Follow-Up Visit 1 
 
• This visit will occur over the telephone, and to the extent possible on the day of the 
first dialysis treatment 13 weeks following randomization;  
• The dialysis days and the start time for the scheduled shift for the preceding seven 
days will be recorded;  
• The case-report form on cumulative weekly use of sedatives/hypnotics and opiates 
will be completed, assessing the use of sleep aids for the preceding 7 nights; and 
• Patients will be asked if they have received CBT-I or trazodone since the completion 
of the treatment phase of the clinical trial.  
 
7.7.3 Long-Term Follow-Up Visit 2 
 
• The visit will occur in-person and, to the extent possible, on the day of the first 
dialysis treatment 24 weeks following randomization; 
• The patients will either be provided with paper sleep diaries or be reminded to enter 
the sleep diaries online;    
• The coordinator will place the actiwatch on the patient and provide instructions on 
wearing the device. The actiwatch will be placed on the arm opposite to the upper 
extremity with the functional arteriovenous access being used for dialysis. In patients 
with a lower extremity arteriovenous access or with a central venous catheter, the 
actiwatch will be placed on the non-dominant arm; and 
• The patients will be scheduled to receive a phone call for the 25-week CATI 
 
7.7.4 Long-Term Follow-Up Visit 3 
• This visit will occur in-person and, to the extent possible, on the day of the first 
dialysis treatment 25 weeks following randomization (during the COVID 
pandemic,this will be modified to occur over the telephone to the extent possible); 
• The online or paper sleep diaries will be reviewed and/or collected;  
• The dialysis days and the start time for the scheduled shift for the preceding seven 
days will be recorded;  
• The patients will return the actiwatches;   
• The case-report form on cumulative weekly use of sedatives/hypnotics and opiates 
will be completed, assessing the use of sleep aids for the preceding 7 nights; and 
•  Patients will be asked if they have received CBT-I or trazodone since the completion 
of the treatment phase of the clinical trial. 
 


 
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7.7.5 Long-Term CATI Visits 
7.7.5.1 Thirteen Week CATI 
• This will occur over the telephone about 13 weeks from the date of randomization; 
• A research assistant from Albuquerque, NM, will call the patient to initiate the CATI;  
• The following assessments will be completed: 
o Insomnia Severity Index (primary outcome measure); and 
o Seven pre-specified secondary patient-reported outcome measures; and 
• A system-configured email will be sent to the site study coordinator upon successful 
completion of CATI. 
7.7.5.2 Twenty-Five Week CATI 
• This will occur over the telephone about 25 weeks from the date of randomization; 
• A research assistant from Albuquerque, NM will call the patient to initiate the CATI; 
• The following assessments will be completed: 
o Insomnia Severity Index (primary outcome measure); and 
o Seven pre-specified secondary patient-reported outcome measures; and 
• A system-configured email will be sent to the site study coordinator upon successful 
completion of CATI. 
 
 7.8  
Early Closeout 
 
For patients that choose to terminate participation in the study, all efforts will be made to 
collect the following information: 
• Cumulative use of sedatives and hypnotics and opiates in the previous 7 days; and 
• Schedule an early closeout CATI for collecting data on primary and secondary patient-
reported outcome measures.  
8. Statistical Analyses 
8.1 
Preliminary Analyses 
Descriptive statistics will be provided for continuous data and frequency distributions for 
categorical data. Pre-treatment characteristics of the three randomized groups will be 
compared to assess chance imbalances.  
8.2 Statistical Analysis for Aim One 
The primary outcome for Aim 1 is the ISI measured at 6 weeks after initiation of 
treatment.  Given that we have three arms, a simple analysis for this aim would be an 
ANOVA analysis of the outcome Y7 adjusted site (Seattle or Albuquerque) and the 
baseline measure Y0. However, to maximize the use of information and to account for 
potential loss to follow-up and/or intermittent missing outcome measures, we will use a 


 
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comprehensive longitudinal analysis to make inference regarding group differences across 
time.  Specifically, we will use linear mixed models for the analysis of all outcomes 
including the baseline, 4, 7, 13 and 25-week ISI measurements. [146] For longitudinal 
models we will use indicator variables to model the 4, 7, 13, and 25-week changes from 
baseline (control group temporal trend) and then use two sets of treatment-by-time 
interactions to characterize the difference in the change over time for the CBT-I group 
compared to placebo, and the trazodone group relative to placebo.  Our primary analysis 
will use linear mixed model estimation assuming an unstructured outcome covariance 
matrix in order to minimize model assumptions. Given randomization, we know the 
baseline group mean difference are zero and therefore, an appropriate longitudinal model 
imposes this known baseline constraint. The primary test for Aim 1 is a longitudinal 
variation on ANOVA that would simultaneously test that both the CBT-I treatment by 7-
week interaction, and the trazodone by 7-week interaction are zero.  This null hypothesis 
assumes that the change from baseline to 7-weeks is the same for each of the three 
treatment groups. Secondary analysis will estimate the confidence interval for the 
pairwise comparisons of each of the three groups from the longitudinal model. A similar 
analytic approach will be taken for analyses of data for each of the nine pre-specified 
secondary outcomes. Exploratory analyses will be undertaken to determine if there is 
preliminary evidence for effect modification by gender, race/ethnicity, restless legs 
syndrome, cumulative use of sedatives/hypnotics or opiates, dialysis shift, and treatment 
adherence to CBT-I or trazodone.    
8.2.1 Statistical Power for Aim One 
 
A power analysis using a simple pre-post analysis for 7-week outcomes controlling for 
baseline is a conservative estimate of the power for the longitudinal model since the 
simple analysis would only use 7-week complete cases.  In order to determine an 
appropriate sample size we focused on the literature that informs the variance in the 
primary outcome measure, and the literature that identifies individual-level clinically 
meaningful differences.  The standard deviation for ISI in large clinical trials in other 
patient populations has ranged from 3.8-5.6; [77, 139-144] based on these studies, we 
assume that the standard deviation of the 6-week ISI will be between 4.0 and 6.0 and we 
conservatively use 6.0 as the basis of sample size estimation.  Moreover, the minimal 
clinically important difference for this scale is between 6 and 8 for indication of an 
individual successful response to treatment, and in order to test for meaningful group 
differences we seek to have adequate power to detect a meaningful group difference. [30, 
114]  For patient-reported outcome measures “moderate” effect sizes have been 
characterized as those with a standardized difference (Cohen’s) of between 0.50 and 0.80. 
[145] Therefore, with a standard deviation of 6.0 we would seek to power our study to 
detect a group difference of 3.0-4.8 points on the ISI using this criterion.  Given that two 
studies have suggested that the minimal clinically important difference for ISI is between 
6 and 8 points we ultimately targeted a group difference of 4.0 as the alternative that we 
would power our study to detect. [30, 114]  This difference is smaller than the reported 
minimal clinically important difference and is in the moderate range of effect sizes based 


 
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on Cohen’s classification.  Using simulation methods and assuming a correlation of 0.50 
for baseline and follow-up measures we determined that 110 patients evaluated at 6 weeks 
is sufficient to obtain >90% power to detect the ANOVA alternative consistent with our 
hypothesis. Specifically, we assume that relative to placebo, CBT-I and trazodone groups 
differ by < 4.0 points (and hence are equally effective).  In order to have 110 evaluated 
patients we would need to inflate the enrolled sample size to account for an anticipated 
10% loss to follow-up and arrive at our final sample size of n=126 (note: the loss to follow-
up of 16/126 = 13%). 
 
8.3 
Statistical Analysis for Aim Two 
The primary outcome for Aim 2 is the ISI measured 25 weeks from randomization.  The 
analysis will leverage the same longitudinal model fit for aim 1, with a parallel primary 
hypothesis test and confidence interval estimation at 25-weeks as at 7-weeks. Secondary 
analysis will estimate the full trajectory over time for each treatment group and allow 
comparison of the group longitudinal profiles. A similar analytic approach will be taken 
for analyses of data for each of the 9 pre-specified secondary outcomes. Exploratory 
analyses will be undertaken to determine if there is evidence for effect modification by 
gender, race/ethnicity, restless legs syndrome, concomitant medications, and treatment 
adherence.    
 
8.3.2 Statistical Power for Aim Two 
 
We have based our sample size on Aim 1 yet we retain strong power to detect long-term 
treatment effects.  A power analysis using a simple pre-post analysis for 25-week 
outcomes controlling for baseline is a conservative estimate of the power for the 
longitudinal model since the simple analysis would only use 25-week complete cases.  If 
we assume 20% loss to follow-up through 24 weeks then we would have 100 evaluated 
patients.  For this Aim we would have 90% power to detect a CBT-I treatment effect of 4.0 
points relative to trazodone and placebo  and within the range of moderate treatment 
effects defined by standardized group differences of 3.0-4.8 points. 
 
8.4. Plan for Handling Missing Data  
 
The potential for bias due to loss-to-follow-up is a concern. The mixed effects modeling 
approach will mitigate the effects of loss-to-follow-up after the Week 4 visit by 
incorporating information from baseline and the Week 4 measurements for patients who 
subsequently drop out of the study when estimating treatment effects at Week 7.  
8.5 
Overall Approach for Avoidance of bias  
 


 
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Several features of study design will minimize bias. First, a randomized controlled study 
design will generate the highest level of evidence for treatment efficacy. Second, all HD 
patients in participating dialysis facilities will be systematically screened, which will assure 
the selection of a cohort highly representative of the HD patient population with chronic 
insomnia. Third, the primary and secondary outcomes will be measured at four time 
points after randomization, and hence data on intermediate time points will be available 
for participants who may drop out. Fourth, computer-assisted telephone interviewing will 
maximize patient participation and the assessor will be blinded to treatment assignment, 
both of which will minimize bias in an open-label clinical trial. Fifth, procedures to 
minimize missing data will be implemented, such as training and certification of study 
personnel, careful design of data collection forms, documentation of procedures, and 
implementation of a management system that minimizes data entry errors and patient 
tracking procedures.  
9. Adverse Events 
9.1 Potential Adverse Events from Study Interventions  
1. Adverse Effects from CBT: The risk classification for this arm is “not greater than 
minimal”. The greatest risk with CBT is discomfort/fatigue associated with 
restricting time in bed (including reducing daytime napping); these symptoms are 
usually temporary but will be monitored closely given their overlap with post-
dialysis symptoms.  Additional potential risks include breach of confidentiality if 
participants choose CBT to be done while undergoing HD. 
2. Adverse Effects from Trazodone:  
a. Side effects (>5%) reported more frequently than with placebo are (i) 
drowsiness; (ii) nervousness; (iii) dizziness; (iv) fatigue; (v) dry mouth; (vi) 
nausea; and (vii) vomiting.  
b. The most significant adverse event is priapism but is extremely rare.  
c. Anti-depressant drugs can increase suicidal thoughts in young adults  
3. Psychological discomfort from completing patient-reported scales 
4. Loss of patient confidentiality 
9.2 Anticipated Adverse Events in the Hemodialysis Population 
Patients undergoing HD experience a large number of adverse events from their 
underlying health, co-existing illnesses, and concomitant medications. These adverse 
events include (1) death; (2) fluid overload; (3) congestive heart failure; (4) vascular access 
events such as thrombosis or infection or dysfunction; (5) atherosclerotic cardiovascular 
events; (6) infections such as pneumonia; and (6) laboratory abnormalities such as 
anemia, hyperphosphatemia, and hyperparathyroidism. 


 
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9.3 Monitoring for Adverse Events 
The patients will be monitored for the occurrence of adverse events as:  
• 
The informed consent document will provide the name of a study staff with a 
phone number to be contacted in the case of an emergency or if an adverse event 
occurred outside the time frame of study visits; 
• 
The study staff will evaluate the patients 5-6 times during the six week treatment 
period either via tele-health or in-person, depending on the randomized arm;  and 
• 
Patients will be withdrawn from treatment if they experience a serious adverse 
event directly attributable to the study intervention and in the opinion of the site 
investigator, the treatment cannot be safely reinstituted. 
9.4 Reporting of Adverse Events 
All adverse events experienced by study patients from the time of registration into the 
study (randomization) will be recorded and summarized by random assignment group. 
The summary will be submitted to oversight groups at periodic intervals. 
 
All serious or unanticipated adverse events will be reported by each of the clinical sites to 
the Data Coordinating Center within 24 hours of becoming aware of these events using a 
structured reporting form. Each site will also be expected to follow local reporting policies 
such as to the Institutional Review Board. Serious adverse events are ones that result in 
death, or are life threatening, or lead to or prolong hospitalization, or result in disability 
or incapacity. Unanticipated adverse events are unexpected events, which in the opinion 
of the investigator, could reasonably be considered to be associated with participation in 
the research study.  The DCC will be responsible for communicating these to the DSMB 
consistent with the policies agreed upon and outlined in the DSMB charter. 
 
9.5 Management of Active Suicidal Intent 
 
It is possible that some patients who are administered the PHQ-9, may report an active 
suicidal intent. We anticipate this to be a rare but significant event. However, since 
individuals with ESRD are at a higher risk for committing suicide than the general 
population, care will be exercised to identify and provide appropriate help to individuals 
with suicidal intent. The suicidal intent could be ascertained by: 
• Study Coordinator (initial pre-screen with PHQ-9); or  
• CATI (while completing PHQ-9). 
The patients will be deemed to have active suicidal intent if they respond to question 9, 
“thoughts that you would be better off dead or of hurting yourself in some way” as “more 
than half the days” or “nearly every day”.  
 


 
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Each site will be asked to provide three emergency telephone numbers of study 
personnel; these telephone numbers will be made available to the CATI operator, and 
dialysis facility staff. Upon being informed of study patients with an active suicidal intent, 
the following process will be followed: 
• If the patient is at immediate risk for self-harm, call 911; 
• If the patient is not at immediate risk for self-harm, the clinical care team and the 
site investigator will be immediately contacted by telephone to collectively 
develop a plan for further care. In addition, an electronic communication will be 
sent to the site study team and DCC. 
10. Data Management 
10.1 Data Coordinating Center and Data Entry Overview 
 
The DCC will be based at the Center for Biomedical Statistics (CBS) at the University of 
Washington. Data collection and management of the clinical trial will be web-based and 
the DCC will support https-secured study-specific ‘.NET’ web page that will provide a 
centralized location for public information about the project for participants, 
investigators, and institutional agencies. The web page will contain a link to a study-
specific portal. Study personnel will log on to the private portal with individual 
Shibboleth-based user names and passwords to securely perform data management 
activities. Shibboleth is a standards-based, open source software package for web single 
sign-on across organizational boundaries. The web portal will serve as the wrapper for all 
data management tools and software utilized in the project, including study ID 
assignment, screening, randomization, prospective data collection, and study operations 
reporting.  
10.2 Computer and Data Security  
 
Access to research data will be restricted to study team members at each site and DCC 
personnel. The clinical recruitment sites will maintain a secure electronic database that 
links the study participant ID generated by the portal to participant contact information. 
Efforts made by clinical sites to contact patients for follow-up visits will be documented in 
this database. The database will be stored on a secure electronic server with user name and 
passwords log in for individual users and will be backed up nightly.  
10.3 Training Procedures 
 
After the planning phase and before the recruitment begins, a training session will be held 
to train study staff on data collection procedures, including orientation to the Manual of 
Operations, data entry and management principles, review of study interventions, and 
quality control procedures.  


 
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10.4 Responsibilities of the Clinical Sites 
 
Each of the clinical sites will be responsible for maintaining a regulatory binder and 
maintaining source documents for all data entry. The web portal will generate queries 
and the sites will be responsible for completing these queries in a timely manner.  
11.  
Study Oversight 
 
The research will operate under the oversight provided by the: 
• Data Safety and Monitoring Board (DSMB); 
• Institutional Review Boards of each participating site; and  
• NIDDK. 
The DSMB Charter and the Data Safety Monitoring Plan is available as Appendices Five 
and Six, respectively and will be convened via a teleconference at least once every six 
months, or more frequently if deemed necessary.  
 
 
 


 
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References 
 
1. 
United States Renal Data System, Annual Data Report. US Department of Public 
Health and Human Services, Public Health Service, National Institutes of Health, 
Bethesda. 2017. 
2. 
Mehrotra, R., et al., Similar outcomes with hemodialysis and peritoneal dialysis in 
patients with end-stage renal disease. Arch Intern Med, 2011. 171(2): p. 110-8. 
3. 
Murtagh, F.E., J. Addington-Hall, and I.J. Higginson, The prevalence of symptoms in 
end-stage renal disease: a systematic review. Adv Chronic Kidney Dis, 2007. 14(1): p. 
82-99. 
4. 
Weisbord, S.D., et al., Prevalence, severity, and importance of physical and 
emotional symptoms in chronic hemodialysis patients. J Am Soc Nephrol, 2005. 
16(8): p. 2487-94. 
5. 
Abdel-Kader, K., M.L. Unruh, and S.D. Weisbord, Symptom burden, depression, 
and quality of life in chronic and end-stage kidney disease. Clin J Am Soc Nephrol, 
2009. 4(6): p. 1057-64. 
6. 
Elder, S.J., et al., Sleep quality predicts quality of life and mortality risk in 
haemodialysis patients: results from the Dialysis Outcomes and Practice Patterns 
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Cohen, J., Statistical Power Analysis for Behavioral Sciences. 1988, New York: 
Academic Press. 
146. 
Diggle, P., et al., Analysis of Longitudinal Data. 2002, Oxford: Oxford University 
Press. 
 
 


 
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Appendix One: Patient Reported Outcome Instruments  
 
1. Insomnia Severity Index (ISI) 
2. Pittsburgh Sleep Quality Index (PSQI) 
3. Epworth Sleepiness Scale 
4. FACIT Fatigue Scale 
5. Graded Chronic Pain Scale (GCPS) 
6. Patient Health Questionnaire-2 (PHQ 2) 
7. Patient Health Questionnaire-9 (PHQ-9) 
8. Generalized Anxiety (GAD-7); 
9. Short Form 12 (SF-12) 
10. CAGE Questionnaire 
11. Drug Abuse Screening Test (DAST-10) 
12. Cambridge-Hopkins Restless Legs Syndrome (RLS-SFDQ13) 
 
 
 


 
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Appendix Two: List of Drugs Used as Sedatives/Hypnotics 
 
Brand Name 
Generic Name 
PRESCRIPTION MEDICATIONS 
Ambien 
Zolpidem 
Amytal Sodium 
Amorbarbital sodium 
Ativan 
Lorazepam 
Belsomra 
Suvorexant 
Butisol 
Butabarbital sodium 
Dalmane 
Flurazepam 
Desyrel 
Trazodone 
Doral 
Quazepam 
Edluar 
Zolpidem 
Elavil 
Amitriptyline 
Gabitril 
Tiagabine 
Halcion 
Triazolam 
Hetiloz 
Tasimelteon 
Intermezzo 
Zolpidem 
Klonopin 
Clonazepam 
Librium 
Chlordiazepoxide 
Lunesta 
Eszopiclone 
Lyrica 
Pregabalin 
Mebaral 
Mephobarbital 
Minipress 
Prazosin 
Nembutal 
Pentobarbital 
Neurontin 
Gabapentin 
Notec 
Chloral hydrate 
Oleptro  
Trazodone 
Phenobarbital 
Phenobarbital 
Precedex 
Dexmedetomidine hydrochloride 
Prosom 
Estazolam 
Pulvules 
Secobarbital 
Quetiapine 
Quetiapine 
Remeron 
Mirtazapine 
Restoril 
Temazepam 
Risperdal 
Risperidone 
Rozerem 
Ramelteon 
Seconal 
Secobarbital 


 
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Brand Name 
Generic Name 
Serax 
Oxazepam 
Serzone 
Nefazodone 
Seroquel 
Quetiapine 
Silenor 
Doxepin 
Sinequan 
Doxepin 
Sonata 
Zaleplon 
Tasimelteon 
Tasimelteon 
Valium  
Diazepam 
Xanax 
Alprazolam 
Zolpimist 
Zolpidem 
Zyprexa 
Olanzapine 
OVER THE COUNTER MEDICATIONS 
Aceta-Gesic 
Acetaminophen / diphenhydramine 
Advil PM 
Diphenhydramine / ibuprofen 
Aleve PM 
Diphenhydramine / naproxen 
Alluna 
Valerian-Hops 
Bayer PM 
Aspirin / diphenhydramine 
Care One Sleep Aid 
Doxylamine 
Compoz Nighttime Sleep Aid 
Diphenhydramine 
dimenhydrinate 
Dimenhydrinate 
Doans PM 
Diphenhydramine / magnesium salicylate 
Dormin 
Diphenhydramine 
Doxytex 
Doxylamine 
Equaline Sleep Aid 
Doxylamine 
Equate Sleep Aid 
Doxylamine 
Excedrin PM 
Acetaminophen / diphenhydramine 
Headache Relief PM 
Acetaminophen / diphenhydramine 
Ibuprofen PM 
Diphenhydramine / ibuprofen 
Legatrin PM 
Acetaminophen / diphenhydramine 
Mapap PM 
Acetaminophen / diphenhydramine 
Midol PM 
Acetaminophen / diphenhydramine 
Motrin PM 
diphenhydramine / ibuprofen 
Night Time Pain 
Acetaminophen / diphenhydramine 
Nighttime Sleepaid 
Doxylamine 
Nytol 
Diphenhydramine 
Nytol QuickCaps 
Diphenhydramine 
Pain Relief PM Extra Strength 
Acetaminophen / diphenhydramine 
Percogesic Extra Strength 
Acetaminophen / diphenhydramine 


 
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Brand Name 
Generic Name 
Simply Sleep 
Diphenhydramine 
Sleep Aid 
Doxylamine 
Sleepinal 
Diphenhydramine 
Sominex 
Diphenhydramine 
Tranquil Nighttime Sleep Aid 
Diphenhydramine 
Tylenol PM 
Acetaminophen / diphenhydramine 
Tylenol Sore Throat Nighttime 
Acetaminophen / diphenhydramine 
Twilite 
Diphenydramine 
Unisom Sleeptabs 
Doxylamine 
Unisom SleepTabs 
Doxylamine 
Unisom PM Pain 
Acetaminophen / diphenhydramine 
Unisom SleepGels 
Diphenhydramine 
Unisom SleepMelts 
Diphenhydramine 
ZzzQuil 
Diphenhydramine 
Z-Sleep 
Diphenhydramine 
OTHERS 
5-hydroxytryptophane 
5-HTP 
Chamomile 
Kava 
 
Lemom Balm 
Melissa Officinalis 
L-tryptophan 
 
Marijuana 
 
Melatonin 
Passion flower 
Passiflora Incarnate 
St. john Wort 
 
Valerian 
 
 
 


 
 
 
 
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Appendix Three: Study Schedule 
 
*Patient randomized to CBT-I will maintain sleep diaries for each of the six-week treatment period 
 
 
 
 
 
Pre-
Screen 
Screen 
Run-In 
Treatment 
Follow-up from 
Randomization 
WEEK 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
13 
25 
Insomnia Severity Index 
x 
 
x 
x 
x 
x 
x 
Structured Interview, 
Inclusion/Exclusion Criteria 
x 
 
 
Randomization 
 
x 
 
CBT-I Telehealth Visits* 
 
x 
x 
x 
x 
x 
x 
 
CBT-I Visits (coordinator) 
 
x 
x 
 
Trazodone/Placebo In-
Person Visits 
 
 
 
 
x 
 
 
x 
 
x 
 
 
 
Trazodone/Placebo 
Telephone Visits 
 
x 
x 
 
Treatment Adherence 
Assessment 
 
x 
x 
x 
CATI 
 
x 
x 
x 
x 
x 
Actigraphy with sleep diary 
x 
x 
 
x 
Concomitant 
Sedatives/Hypnotics 
 
x 
x 
x 
x 
x 


 
 
 
 
Version: V1.3.4  June 10, 2020 
 
Appendix Four: List of Concomitant Medications that are an Exclusion Criteria 
Brand Name 
Generic Name 
Anti-Microbials 
Avelon 
Moxifloxacin 
Avelox 
Moxifloxacin 
Biaxin 
Clarithromycin 
Cipro 
Ciprofloxacin 
Diflucan 
Fluconazole 
Levaquin 
Levofloxacin 
Neofloxin 
Ciprofloxacin 
Onmel 
Itraconazole 
Prevpac 
Clarithromycin 
Sporanox 
Itraconazole 
Trican 
Fluconazole 
Vfend 
Voriconazole 
Zithromax 
Azithromycin 
Zyvox 
Linezolid 
Other Medications 
Almarytm 
Flecainide 
Apocard 
Flecainide 
Azilect 
Rasagiline 
Betapace 
Sotalol 
Cin-Quin 
Quinidine 
Cordarone 
Amiodorane 
Corvert 
Ibutilide 
Dridol 
Droperidol 
Droleptan 
Droperidol 
Duraquin 
Quinidine 
Ecrinal 
Flecainide 
Eldepryl 
Selegiline 
Emsam 
Selegiline 
Flecaine 
Flecainide 
Geodon 
Ziprasidone 
Haldol 
Haloperidol 
Inapsine 
Droperidol 


 
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Brand Name 
Generic Name 
Marplan 
Isocarboxazid 
Mellaril 
Thioridazine 
Nardil 
Phenelzine 
Nexterone 
Amiodorane 
Novoridazine 
Thioridazine 
Orap 
Pimozide 
Ormazine 
Chlorpromazine 
Pacerone 
Amiodorane 
Parnate 
Tranylcypromine 
Procan 
Procainamide 
Pronestyl 
Procainamide 
Quinact 
Quinidine 
Quinaglute 
Quinidine 
Quinidex 
Quinidine 
Quinora 
Quinidine 
Sotacor 
Sotalol 
Sotalex 
Sotalol 
Tambocor 
Flecainide 
Thioril 
Thioridazine 
Thorazine 
Chlorpromazine 
Xomolix 
Droperidol 
Zelapar 
Selegiline 
 
 
 


 
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Appendix Five: Cognitive Behavioral Therapy for Insomnia Session Outlines 
 
Session 1  
 Treatment overview 
 Information on insomnia in ESRD patients and sleep 1 
 Behavioral/sleep scheduling strategies 1 
Session 2  
 Follow-up on goal setting, 3Ps, behavioral/scheduling 
strategies 1 
 Behavioral/scheduling strategies 2 
Session 3  
 Follow-up on behavioral/scheduling strategies 1 and 2 
 Information on insomnia, sleep, and ESRD 
Session 4  
 Follow-up on behavioral/scheduling strategies 
 Constructive worry  
 Relaxation/mindfulness 
Session 5  
 Follow-up on behavioral/scheduling, constructive worry 
techniques, and relaxation practice 
 Sleep hygiene recommendations 
 Adopting beliefs and attitudes that contribute to good 
sleep 
Session 6  
 Review of all behavioral and cognitive strategies  
 Evaluate progress and review goal attainment 
 Maintenance of treatment gains and relapse prevention 
 
These outlines prepared by  
Susan M. McCurry, Ph.D., Research Professor          &             Daniel Cukor, Ph.D., Associate 
Professor 
University of Washington, Seattle, Washington           Rogosin Institute, New York, NY 
 
With acknowledgement to original content prepared by: 
Charles M. Morin, Ph.D., Professor of Psychology & Simon Beaulieu-Bonneau, Ph.D., Research 
Associate 
Université Laval, Québec, QC, Canada 
Susan M. McCurry, Ph.D., Research Professor 
University of Washington, Seattle, Washington 
 
 


 
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SESSION 1/6 
1. Introduction (1 min) 
 
2. Treatment overview and agenda (3 min) 
 
3. Insomnia and living your life on hemodialysis (7 min) 
3.1. What is important in your life and how is insomnia impacting that? 
3.2. Futility of trying to “control” sleep 
3.3. Treatment will teach you skills that will prepare you to sleep (“surfing the sleep 
wave”) and to keep moving towards your valued goals even when you have a bad 
night 
 
4. Information on sleep and insomnia 1/2 (5 min) 
4.1. General information on the definition, prevalence, impact, and risk factors of 
insomnia 
4.2. Spielman’s “3P” model with predisposing, precipitating, and perpetuating factors 
4.3. Information on how kidney disease and dialysis treatment precipitate and 
perpetuate insomnia symptoms 
 
5. Behavioral/scheduling strategies 1/2: Reinforcing the associations between 
bed/bedroom, bedtime, and sleep (10 min) 
5.1. Present rationale 
5.2. Discuss each recommendation: 
- 
Do not use the bed/bedroom for non-sleeping activities  
- 
Allow at least one hour to unwind before bedtime  
- 
Go to bed only when sleepy  
- 
Get out of bed at the same time every morning  
- 
Avoid prolonged daytime naps or napping after 3:00 pm  
- 
Get out of bed when unable to sleep within 15-20 min 
- 
How to account for an early morning or late night dialysis shift 
 
6. Self-monitoring: The sleep diary (3 min) 
6.1. Rationale for good record keeping 
6.2. Review baseline sleep diaries for adherence, missing or unclear data 
 
7. Homework assignment (1 min) 
7.1. Apply first behavioral/scheduling strategy (stimulus control) 
7.2. Set treatment goals 
7.3. Identify predisposing, precipitating, and perpetuating factors 
7.4. Review handouts 
 
 


 
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SESSION 2/6 
 
1. Set agenda (1 min) 
 
2. Review sleep diary of the past week (2 min) 
 
3. Review treatment goals and identification of predisposing, precipitating, and 
perpetuating factors (1 min) 
 
4. Review application of stimulus control strategies (10 min) 
4.1. Review rationale 
4.2. Evaluate adherence  
4.3. Identify methods to enhance adherence 
 
5. Behavioral/sleep scheduling strategies 2/2: Limiting time spent in bed to actual 
sleep time (15) min) 
5.1. Introduce rationale 
5.2. Set initial sleep window based on non-dialysis days 
5.3. Explain the procedure to readjust the sleep window on a weekly basis 
5.4. Explain accommodations if dialysis treatment begins or ends during the sleep 
window 
 
6. Homework assignment (1 min) 
6.1. Apply behavioral/scheduling strategies  
6.2. Review handouts 
 
 
 


 
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SESSION 3/6 
 
 
1. Set agenda (1 min) 
 
2. Review sleep diary of the past week (3 min) 
2.1. Set new sleep window based on non-dialysis days 
 
3. Review application of behavioral/scheduling strategies (15 min) 
3.1. Review rationale 
3.2. Evaluate adherence  
3.3. Identify methods to enhance adherence 
 
4. Information on sleep and insomnia 2/2 (10 min) 
4.1. Present sleep stages and cycles 
4.2. Review changes in sleep patterns over the lifespan 
4.3. Sleep and ESRD 
 
5. Homework assignment (1 min) 
5.1. Apply behavioral/scheduling strategies  
5.2. Review handouts 
 
 
 
 


 
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SESSION 4/6 
 
1. Set agenda (1 min) 
 
2. Review sleep diary of the past week (2 min) 
2.1. Set new sleep window based on non-dialysis days 
 
3. Review application of behavioral/scheduling strategies (5 min) 
3.1. Evaluate adherence  
3.2. Identify methods to enhance adherence 
3.3. Set new sleep window 
 
4. Constructive worry (10 min) 
4.1. Present rationale  
4.2. Discuss types of thoughts for which constructive worry can be helpful/unhelpful  
4.3. Plan application of constructive worry strategy 
 
5. Relaxation/mindfulness (10 min)  
5.1. Present rationale 
5.2. Practice 
 
6. Homework assignment (2 min) 
6.1. Apply behavioral/scheduling strategies  
6.2. Complete constructive worry sheet as needed 
6.3. Practice relaxation during day and night 
6.4. Review handouts 
 


 
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SESSION 5/6 
 
1. Set agenda (1 min) 
 
2. Review sleep diary of the past two weeks (2 min) 
2.1. Set new sleep window 
 
3. Review homework and use of constructive worry and relaxation techniques (1 min) 
 
4. Review application of behavioral/scheduling strategies (5 min) 
4.1. Review rationale 
4.2. Evaluate adherence  
4.3. Identify methods to enhance adherence 
4.4. Set new sleep window 
 
5. Sleep hygiene recommendations (5 min) 
 
6. Changing beliefs and attitudes about sleep and insomnia (15 min) 
6.1. Keep realistic expectations 
6.2. Avoid blaming insomnia for all daytime misfortunes 
6.3. Revise misconceptions about the causes of insomnia 
6.4. Do not catastrophize after a poor night’s sleep 
6.5. Avoid placing too much emphasis on sleep 
6.6. Develop tolerance to the effects of sleep loss 
 
7. Homework assignment (1 min) 
7.1. Apply behavioral/scheduling strategies  
7.2. Complete treatment summary and relapse prevention booklet 
7.3. Review handouts 
 
 


 
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SESSION 6/6 
 
1. Set agenda (1 min) 
 
2. Review sleep diary of the past two weeks (2 min) 
 
3. Review treatment components (5 min) 
3.1. Behavioral/scheduling strategies 
3.2. Sleep hygiene and information on sleep and insomnia 
3.3. Beliefs and attitudes about sleep and insomnia 
3.4. Values review 
3.5. Constructive worry 
3.6. Relaxation 
 
4. Evaluate progress and goal attainment (10 min) 
4.1. Chart progress 
4.2. Review valued areas of life and any changes that have occurred in how much 
insomnia interferes 
4.3. Check goal attainment and provide feedback on progress and adherence 
4.4. Emphasize areas needing more attention 
 
5. Relapse prevention (10 min) 
5.1. Make distinction between lapse and relapse 
5.2. Discuss the inevitability of occasional poor nights 
5.3. Identify high risk situations/circumstances 
5.4. Devise action plan for insomnia lapses 
 
6. Closure (2 min) 
 
 


 
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Appendix Six: Data Safety Monitoring Board Charter 
 
 
 
Reviewed and Accepted by DSMB Members: 
Vernon Chinchilli, PhD (Chair and Biostatistician) 
Deidra Crews , MD 
Jennifer Flythe, MD  
 
Prepared and Accepted by: 
Rajnish Mehrotra, MD MS, Principal Investigator   
Patrick Heagerty, PhD, Data Coordinating Center Statistical Advisor 
Tessa Rue, MD, Unblinded Data Coordinating Center Biostatistician 


 
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Terms used in this document related to the Data Safety Monitoring Board 
activities 
Term 
Definition 
Blinding Status 
Blinded 
Access to aggregate (i.e., total) results only. 
Semi-Blinded 
Access to results split by randomized treatment arm, but without 
knowledge of the actual treatment assignment (i.e., Treatment A 
versus Treatment B versus Treatment C) 
Unblinded 
Access to the decode information for A, B, and C as described in 
the Semi-Blinded definition 
Individuals and Groups 
Data Safety 
Monitoring Board 
(DSMB) 
Unblinded 
An independent group charged with monitoring the safety of 
patients in the SLEEP-HD trial, and the scientific integrity of the 
trial 
Funder 
Initially Blinded 
The Funder is the organization that provides funding and other 
support and oversees trial implementation. 
Principal 
Investigator 
Initially Blinded 
The Principal Investigator is the physician who serves as the 
scientific leader of the trial 
Clinical 
Coordinating 
Center / Study 
Management Team 
Initially Blinded 
The Coordinating Center and Study Management Teams are 
responsible for trial logistics, including interaction with sites, data 
collection and cleaning, supply of study materials and updates to 
the Funder. 
 Unblinded Data 
Coordinating 
Center Statistician* 
Initially Unblinded 
The unblinded statistician who prepared the Closed Report 


 
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Data Coordinating 
Center Statistical 
Advisor** 
Initially Semi-Blinded 
The semi-blinded statistician who will assist with the 
interpretation of the Closed Report. 
Open and Closed Report, Session, Minutes 
Open 
The Open Session may be attended by all groups described above. 
The Open Report will be discussed, and Open Minutes will be 
recorded. 
Closed 
The Closed session may be attended by semi-blinded and 
unblinded persons only. The (Semi-Blinded) Closed Report will 
be discussed, and Closed Minutes will be recorded. 
* The Unblinded Data Coordinating Center Statistician is unblinded, but has no contact 
with patients or the day-to-day study activities.  
** The Data Coordinating Center Statistical Advisor is semi-blinded, but has no contact 
with patients or the day-to-day study activities. 
 
 
 


 
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Part 1: 
Introduction 
The Data and Safety Monitoring Board (DSMB) will be responsible for assessing safety 
and efficacy during conduct of the SLEEP-HD trial, as well as ensuring the validity and 
scientific merit of the trial.  This charter describes the roles and responsibilities of the 
DSMB for this trial.  The DSMB will meet on a regular basis and will provide 
recommendations to the Principal Investigator for the SLEEP-HD study on whether to 
continue, modify, or terminate the study.  
1.1 
Charge to the DSMB 
The DSMB will monitor the conduct of the study and review interim results for the 
purpose of recommending whether or not to continue the trial as designed. The 
fundamental responsibilities of the DSMB are to assure: 
• The ongoing safety of study participants, and  
• The scientific integrity of the trial. 
In addition, the DSMB will use established guidelines to monitor the study for important 
safety variables suggesting harm.  
The DSMB is also charged to recommend whether to continue the study, terminate the 
study, continue the study with major or minor modifications (such as modifications to 
inclusion/exclusion criteria or criteria to determine eligibility for cross-over), or 
temporarily suspend enrollment and/or treatment in the study until uncertainty is 
resolved. 
1.2 
 DSMB Membership and Responsibilities 
The DSMB is an independent multidisciplinary group consisting of two nephrologists and 
one biostatistician who collectively have experience in the treatment of patients 
undergoing maintenance hemodialysis, and/or in the conduct and monitoring of 
randomized clinical trials in nephrology.  The duration of membership will span until six 
months after the end of patient recruitment.   
All DSMB Members have agreed that proceedings from DSMB meetings and related 
activities are confidential.  DSMB Members will not act as investigators or sub-
investigators for these trials and will have no trial involvement outside their role on the 
DSMB.   
No Member of the DSMB will be an employee of NIH/NIDDK.  DSMB Members must 
disclose all active agreements (direct or indirect) with pharmaceutical companies, 
biotechnology companies, or contract research organizations.  Members of the DSMB will 
be responsible for advising the Board of any changes in their financial interests in the 
aforementioned companies. 


 
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The DSMB membership has been restricted to individuals free of apparent significant 
conflict of interest.  The source of conflict may be financial, scientific and/or regulatory in 
nature.  Thus, neither study investigators nor individuals employed by the funder or 
regulatory agencies are to be Members of the DSMB. 
The DSMB will be responsible for deciding whether consultant agreements or financial 
interests of the members have the potential for conflict of interest.  Members of the 
DSMB who develop significant potential or perceived conflicts of interest will be asked to 
resign from the committee. 
As part of this study, the DSMB is established to provide an independent review and 
assessment of the accumulating safety and efficacy data, and to further safeguard the 
interests and safety of the participating patients. The primary role of the DSMB is to make 
a recommendation to the Principal Investigator based on analysis of available data. 
The objective of the DSMB is to independently monitor and assess the study.  At each 
interim meeting, the DSMB will undertake a comprehensive review and assessment of the 
cumulative study safety data.  The DSMB will determine if safety of trazodone is sufficient 
to allow the trial to continue.  The DSMB will use a priori defined, and, where 
appropriate, ad hoc analyses to assess safety. The DSMB will utilize all available trial data 
when forming any recommendation to discontinue the study or unblind the results.  The 
Study Management Team will consult with the DSMB as needed on substantive changes 
to the protocol or study conduct once the trial begins. 
The DSMB will be responsible for ensuring the timely review of the accumulated safety 
data.  Based on the reviews and assessments of the data, the DSMB will inform the 
Principal Investigator of any safety concerns and will provide recommendations for 
appropriate actions. 
1.2.1 DSMB Chair 
The DSMB Chair will have the following additional responsibilities: chair the meeting, 
confirm quorum, summarize recommendations, set an agenda for the Closed Session of 
the meeting, and record Open and Closed Minutes of the DSMB meetings. If a DSMB 
member can no longer continue, the Chair is responsible for selecting his or her 
replacement. 
1.2.2 DSMB Biostatistician  
The DSMB biostatistician will provide guidance to the voting Members of the DSMB on 
issues of a statistical nature. 
1.3 
Responsibilities of the Study Management Team and Data Coordinating Center 
The Study Management Team and Data Coordinating Center work in tandem but are 
distinct entities.  Representatives from the Study Management Team are charged with the 
day-to-day management of the trial; the Unblinded Data Coordinating Center Statistician 


 
Version: V1.3.4  June 10, 2020 
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and Semi-blinded Data Coordinating Center Statistical Advisor are not involved in these 
activities and have no contact with sites or patients.   
The Study Management Team is responsible for providing timely and accurate data to the 
Unblinded Coordinating Center Statistician for inclusion in reports to the DSMB.  In 
addition, the Study Management Team will review the Open Report and present 
information about the status of the trial and any issues related to study execution during 
the Open Session. The Study Management Team must maintain an up-to-date, accurate 
study database by such processes as retrieving CRFs promptly, entering and validating the 
data, querying suspicious data, and coding adverse events. 
1.3.1 Principal Investigator 
The Principal Investigator for the SLEEP-HD study will be the physician leading the 
conduct of the clinical trial, and will oversee activities of the Study Management Team.  
The Principal Investigator must set an agenda for the Open portion of the meeting and 
will receive the recommendations of the DSMB. The Principal Investigator will distribute 
the recommendations to the Study Management Team, Institutional Review Boards, and 
others as appropriate. 
1.3.2 Data Coordinating Center Statistical Advisor 
The Data Coordinating Center Statistical Advisor must review and present the Closed 
Report during the Closed Session and answer questions from the DSMB that are of a 
statistical nature, or other questions as deemed appropriate by the DSMB.  
Due to potential for bias, the Data Coordinating Center Statistical Advisor should not 
make study design decisions after viewing the semi-blinded results; after the first data 
review, such decisions should be made by a blinded person as appointed by the Principal 
Investigator.  
1.3.3 Unblinded Data Coordinating Center Statistician 
The Unblinded Data Coordinating Center Statistician must produce and validate the 
DSMB report, keeping any potentially unblinding information confidential and out of 
reach of other members of the data coordinating center (with the exception of unblinded 
programmers). This individual will also be responsible for delivering the Open and Closed 
Reports to the DSMB. 
The Unblinded Data Coordinating Center Statistician will be responsible for getting 
approval from the DSMB in the event that personnel directly associated with the study 
must be given information that could potentially unblind them. 


 
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Part 2: Procedures of the DSMB 
2.1 
Blinding 
The DSMB will be unblinded in its assessment of safety data.  The DSMB will have full 
access to all data as needed for safety assessment and will have access to comparative 
results of safety data, aggregated by treatment arm.  
To maintain the integrity of the trial, the Funder, Principal Investigator and the study 
investigators will not have access to any unblinded or semi-blinded summaries of interim 
data prior to the conclusion of the trial and the final database lock.  Access to semi-
blinded information will be restricted to the DSMB, Data Coordinating Center 
Statistician, and the Unblinded Data Coordinating Center Statistician.  The Unblinded 
Data Coordinating Center Statistician will generate an Open Report that includes 
aggregate information and a Closed Report that includes unblinded information by 
randomized treatment assignment.  
The DSMB may direct questions and request further data from the Unblinded Data 
Coordinating Center Statistician, Data Coordinating Center Statistical Advisor or Study 
Management Team directly. The DSMB will determine what is communicated to blinded 
persons regarding additional requests. 
2.2 
DSMB Report 
The DSMB Report should provide information that is accurate to the extent possible, 
although all data will not be clean.  Follow-up should be complete, if possible, to within 
three weeks of the date of the DSMB meeting, and the data snapshot should occur 
approximately 10 days in advance of the meeting.  Some "last-minute" data (e.g., Serious 
Adverse Events, Enrollment, and Follow-up Rates) will be even more current.  The reports 
should be sent to the DSMB Members at least ten days prior to the date of the meeting.  
Based upon the enrollment rate, the Study Management team will determine target dates 
for the DSMB meetings.  The report will be based mainly on monitored data but will 
include all safety data available at the time the report is prepared.   If major changes occur 
due to data corrections, those changes will be highlighted in future DSMB Reports.   
Each DSMB Report will have two main sections:  Open Section (blinded information) that 
contains information on recruitment, eligibility violations, baseline characteristics, data 
on completeness of follow-up and adherence, and other study management issues; and a 
Closed Section (unblinded information) which contains safety information displayed by 
treatment arm, analyses of Adverse Events, and efficacy data based on intent-to-treat 
analyses of primary endpoints.  The details of these reports can be found in the Data 
Safety Management Plan (DSMP).  DSMB Members will receive both the Open and 
Closed Sections of the Report.  The Principal Investigator may communicate information 
from the Open Section of the DSMB Report to the Study Management Team. 


 
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This DSMB Report will be assembled by Unblinded Data Coordinating Center Statistician 
in consultation with the Data Coordinating Center Statistical Advisor. 
Open and Closed Minutes will be recorded by the Chair of the DSMB.  Copies of the 
Open Minutes will be distributed to the Principal Investigator and DSMB.  Copies of the 
Closed Minutes will be distributed only to the DSMB and will be archived by the Chair 
until after the study database has been locked and treatment results unblinded. 
The DSMB may wish to request clarification on existing reports or additional information.  
The Unblinded Data Coordinating Center Statistician will create ad hoc reports to address 
these questions. The Study Management Team and other persons may be informed about 
these ad hoc requests at the discretion of the DSMB. 
2.3 
Scheduled DSMB Meetings 
The DSMB will plan on meeting via teleconference every six months; the first meeting 
will be scheduled about six months from the start of recruitment but no later than 
December 2018. The DSMB may request interim meetings in between the six-month 
periods. 
Unscheduled DSMB meetings can be called as necessary by the DSMB.  To call an 
unscheduled meeting, the DSMB Chair will contact the Data Coordinating Center 
Statistical Advisor.  Typically, the Principal Investigator will not be told the reason for the 
meeting.  Information to be communicated to the Principal Investigator regarding the 
meeting is determined by the DSMB. 
2.4 
DSMB Meeting Structure 
The meetings will typically begin with an Open Session, followed by a Closed Session. All 
Closed Sessions will also include an Executive Session. There may also be a final open 
session where the DSMB may verbally give recommendations and answer questions from 
the Principal Investigator and Study Management Team.  
2.4.1 Open Session 
In order to allow the DSMB to have adequate access to insights from the Study 
Management Team, an Open Session of the DSMB meeting will be held during each 
DSMB meeting.  The Principal Investigator will present the results of the Open Report 
and will be available to answer any questions from the members of the DSMB.  
2.4.2 Closed Session 
Closed DSMB Sessions involving only DSMB Members and the Data Coordinating Center 
Statistical Advisor will be held after the Open Session to allow discussion of unblinded 
data from the Closed Report.  The information covered in the Closed Session will be 
contained in the Closed Report.  
 


 
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2.4.3 Executive Session 
Executive DSMB Sessions involving only DSMB Members will be held to allow discussion 
of study data without the members of the study team present. 
A representative of the Funder may be present at DSMB open sessions unless the DSMB 
Chair decides that the presence will inhibit free and open discussion or appear to 
compromise the DSMB’s independence.  The Funder may be permitted to attend Closed 
and Executive Sessions at the discretion of the DSMB Chair. 
2.5 
DSMB Recommendations 
During the DSMB meetings, issues relating to patient safety and scientific integrity of the 
trial will be reviewed and discussed.  Afterward, the DSMB may hold a brief meeting with 
the Principal Investigator to review the status of the study and make its 
recommendations.  These recommendations will primarily use the guidelines defined in 
this Charter or the DSMP.  The DSMB will also make recommendations, as appropriate, 
regarding the conduct and management of the trial.  
A quorum, defined as 2 DSMB Members including the Chair, must be present or available 
by teleconference in order for the DSMB to make any formal recommendations. Further, 
a recommendation to stop the trial must be made by a majority vote of the DSMB (i.e., 
either unanimously or two to one in favor of the recommendation). Other 
recommendations may be made by simple majority. 
Any recommendations which could compromise the blind will be communicated in 
writing to the Principal Investigator within 5 business days of the meeting.  
In the event that the study is recommended to be terminated, the Data Coordinating 
Center Statistical Advisor and the Principal Investigator will meet with the DSMB to 
review the semi-blinded report and discuss the reasons for this recommendation. At this 
time the Principal Investigator may become semi-blinded before deciding whether to 
accept the recommendation to terminate the study.  
2.6 
Meeting Minutes 
2.6.1 Open Minutes 
The Open Session Minutes will be recorded by the DSMB Chair and will summarize the 
DSMB's findings during the Open Session in addition to the overall recommendation 
from the Closed Session discussions as to whether the trial should continue, continue 
with modifications or be terminated.  A copy of the Open Minutes will be sent to the 
Principal Investigator, who will disseminate the recommendations to the Study 
Management Team as appropriate.  


 
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These Open Session Minutes must be devoid of any statements having the potential to 
compromise the blinding of the study, since these minutes will be distributed to the 
Principal Investigator.   
At a minimum, the following question should be addressed by the DSMB: 
• Does the DSMB feel that it is ethical to continue the trial as presently designed? 
The results of deliberations should be communicated to the Principal Investigator in 
writing following the meeting.  
2.6.2 Closed Minutes 
The Closed Session Minutes will be recorded by the DSMB Chair and will summarize the 
discussion of the semi-blinded data and other issues the DSMB wishes to document but 
keep in confidence.  
 
 
 
 


 
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Appendix Seven: Data Safety and Monitoring Plan 
 
1. Overview 
This Data Safety and Monitoring Plan (DSMP) defines the oversight and monitoring 
activities that will ensure and maintain both the safety of participants and the scientific 
integrity and validity of the trial data. The plan also describes the procedures for adverse 
event reporting and details guidelines for recommendations related to trial continuance.  
2. Data and Safety Monitoring Board 
Review of the SLEEP-HD trial’s study performance and safety outcomes will be conducted 
by the Data Safety and Monitoring Board (DSMB). The DSMB consists of 3 members, 
(Chair: Dr. Vernon Chinchilli, PhD, Dr. Deidra Crews MD, and Dr. Jennifer Flythe, 
MD). The DSMB is expected to meet twice annually (every 6 months) to review study 
performance and safety outcomes in Open and Closed Reports, and to review study 
enrollment reports quarterly. Ad hoc sessions may be scheduled as required should a 
serious adverse event need to be reviewed as a group.  
Aggregate study performance and safety data will be presented during the open sessions 
of DSMB meetings. Safety and efficacy data will be presented by treatment arm during 
the closed sessions. Review by the DSMB provides assurances that the trial can continue, 
without jeopardizing patient safety. The DSMB is also responsible for protecting the 
confidentiality of the trial data and for monitoring the quality of both the data and study 
implementation procedures.   
3. Study Sample Size  
A total of 126 patients will be recruited into this clinical trial, with 75 patients anticipated 
to be enrolled in Seattle and 50 in Albuquerque. The randomization will be block 
randomized on site, with random size block assignment within site to maintain balance 
between treatment groups.  
4. Monitoring Guidelines  
Based on findings following review of study data by the DSMB, the Board may 
recommend: continuation of the trial, termination of the trial, or modifications to the 
protocol (e.g. adding new measurements for safety monitoring, discontinuing high risk 
patients, extending the trial in time, increasing the trial sample). Decision guidelines in 
the SLEEP-HD trial are based on group differences in adverse event rates as explained 
below.  
 


 
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4.1 Performance Monitoring  
Performance monitoring will be an ongoing activity performed by the study Principal 
Investigator and statistician, and status reports will be reviewed by the DSMB during 
their regular meetings. Procedural reviews to address protocol adherence with respect to 
patient recruitment and eligibility, retention and follow-up, randomization and blinding, 
and quality of data will be conducted and monthly reports generated. 
Performance data will be reviewed in aggregate and by site. It is expected that: 
(1) the overall enrollment rate will not drop below the expected rate by more than 
50%; and  
(2) the response rate for the ISI by CATI will be no less than 85% at the 7-week 
time-point among those randomized to CBT-I, trazodone, or placebo;  
Data will be entered on-line into a REDCap database hosted at the Data Coordinating 
Center (DCC).  Data will be entered into fields with automated validation and logical 
checks built in.  Outcome measures will be collected by Computer Assisted Telephone 
Interview (CATI).  Adherence will be assessed based on the weekly conference calls and 
data submitted to the DCC on a weekly basis.  If it is determined by the study PI that 
either study protocol is not being followed or that reporting is inadequate at any site, 
further action will be taken to address these issues.  These actions may include additional 
in-person site visits if appropriate or additional educational/problem-solving sessions by 
phone regarding the study protocol.  Compliance rates and any concerns regarding 
deviation from study protocol will be reported to the DSMB on a quarterly basis for 
review and determination if additional measures need to be employed such as protocol 
changes or discontinuing enrollment at that site.  
The SLEEP-HD study aims to enroll up to 126 patients with the following distribution 
among the sites: 76 patients at Seattle and 50 patients at Albuquerque. Tables 1 and 2 and 
Figure 1 are performance monitoring examples that will be included in future Open 
DSMB Reports. 
Table 1. Cumulative and Current Report Period Study Recruitment  
 
 
Current Report Period 
Cumulative 
Site 
Seattle 
Albuquerque 
Total 
 
Seattle 
Albuquerque 
Total 
Screened 
 
 
 
 
 
 
Eligible 
 
 
 
 
 
 
Enrolled 
 
 
 
 
 
 
Randomized to 
CBT-I, 
trazodone, or 
placebo  
 
 
 
 
 
 


 
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Table 2. Follow-up rates by site, n / N (%).  
 
Seattle 
Albuquerque 
Total 
Randomized to CBT-I, trazodone, or placebo   
 
 
CATI assessment completed at 7 weeks 
 
 
 
CATI assessment completed at 25 weeks 
 
 
 
Figure 1. Cumulative Enrollment. 
 
 
4.2 Safety Monitoring:  
Safety reports will summarize adverse and serious adverse event data and will be reviewed 
at regular and ad hoc DSMB meetings. A serious adverse event is defined as any 
experience that is fatal or life-threatening, is permanently disabling, or requires or 
prolongs hospitalization.  
Patients undergoing hemodialysis experience a large number of adverse events from their 
underlying health, co-existing illnesses, and concomitant medications. These adverse 
events include death, fluid overload, congestive heart failure, vascular access events such 
as thrombosis or infection or dysfunction, atherosclerotic cardiovascular events, 
infections such as pneumonia, and laboratory abnormalities such as anemia, 


 
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hyperphosphatemia, and hyperparathyroidism. Adverse events possibly associated with 
use of trazodone include drowsiness, nervousness, dizziness, fatigue, dry mouth, nausea, 
vomiting, or priapism. CBT is considered minimal risk to a patient, although there is a 
potential for a loss of patient confidentiality since CBT-I may be done while patient is 
undergoing HD. Among patients randomized to CBT-I or trazodone or medication 
placebo, all adverse events possibly associated with trazodone or medication placebo will 
be reported in Table 4. All serious adverse events regardless of possible association to 
intervention will be reported in Table 4. Detailed reporting of serious adverse events will 
be given in Table 5, by treatment group sorted chronologically. If adverse or serious 
adverse events occur in different proportion in the study groups and there are concerns 
regarding the negative effects of either intervention, then the research team in 
consultation with both the study statistician and the DSMB may make protocol changes 
or discontinue the study.  
Table 4. Adverse event incidence rate (number of events / number at risk) and 
threshold for action (Closed Report) 
Event 
Group A’ Group B’ Group C’ 
Expected* 
(over 6-month 
period) 
Threshold 
For Action 
p-
value** 
Adverse Event 
Priapism 
 
 
 
1% 
5% 
 
Serious Adverse Event 
Death 
 
 
 
8% 
12% 
 
Any 
Hospitalization  
 
 
25% 
40% 
 
* Expected rates calculated based on expected number of events in a population 
** P-value calculated for the rate ratio comparing treatment Group A to Group B to Group 
C 
Rates of death and hospitalization were estimated from annual rates reported in the 
USRDS Annual Data Report and projected for the 6-month study period  
 


 
 
 
 
 
 
Table 5. Detailed tabulation of (Closed Report) Serious Adverse Events that have occurred during the SLEEP-HD study. 
 
 
 
1System Organ Class:  
1. Blood and Lymphatic System Disorders 
 
 
2. Cardiac Disorders 
 
 
… 
 
 
26. Vascular Disorders  
 
2Relationship:  1. Unrelated 
 
 
2. Unlikely related 
 
 
3. Possibly related 
 
 
4. Related 
 
3Action Taken:  1. None 
 
 
2. Study Rx dosage reduced 
 
 
3. Study Rx interrupted 
 
 
4. Study Rx discontinued permanently 
 
 
 
4Outcome:  
1. Resolved, no follow-up needed 
 
 
2. Ongoing/treatment continued 
 
 
3. ER visit/Prolongation of hospitalization 
 
 
4. Patient died 
Patient ID 
SAE Description 
System 
Organ 
Class1 
Treatment 
Group 
Age 
Sex 
Enrollment 
Date 
SAE Date 
Date of PI 
review 
Relationship 
to Study2 
Action 
Taken3 
Outcome4 
Ex1 
Death 
2 
A 
70 
F 
22Jul2018 
23Jul2018 
25Jul2018 
1 
1 
5 
Ex2 
Hospitalization-CHF 
2 
B 
70 
M 
30Oct2018 
30Nov2018 
4Dec2018 
2 
4 
2 


 
 
4.3 Treatment Efficacy Monitoring 
We will report aggregate 7-week and 25-week ISI scores by blinded treatment group for 
monitoring by the DSMB. We will also provide a z-score assessment of the evidence for 
the difference between treatment arms at 7- and 25-weeks. However, the DSMB is charged 
not to make a recommendation to terminate the study based on interim efficacy 
estimates. CBT-I and trazodone are accepted standard of care treatments for insomnia. 
The study aims to provide valid estimates of treatment efficacy and early stopping for 
efficacy would jeopardize the primary analysis. Efficacy data is provided only to inform 
any safety or performance concerns that may arise.  
4.4 Procedures for minimizing research-associated risk 
A number of strategies for minimizing research-associated risk to patients are built into 
the study protocol.  CBT-I and trazodone are standard treatments frequently used in 
clinical practice.  This protocol only randomizes the choice of treatment.  The doses being 
used are also standard doses without any additional risks posed to patients.  Patients will 
also be monitored more frequently than in usual clinical practice and at all follow up time 
points, patients will be asked about adverse events and unanticipated health events that 
may or may not be related to the study procedures.  
The study protocol is designed to allow close monitoring of patients randomized to either 
of the three arms with a total of five visits during the six-week treatment period for 
patients randomized to trazodone or medication placebo.  
5. Scheduled Reporting 
Three weeks prior to each DSMB review, the Data Coordinating Center (DCC) will 
summarize administrative reports that describe study progress including patient accrual 
by site, demographics, and the sites’ adherence to inclusion/exclusion criteria and other 
protocol requirements, including retention rates at each follow up point. These reports 
are prepared monthly and reviewed internally by the study research team for ongoing 
quality control. The DCC will also produce safety reports that list adverse events, serious 
adverse events, deaths, and in aggregate to the DSMB. 
With each review the DSMB will decide to approve the study and protocol as is, 
recommend protocol changes in the interest of patient safety, or stop the study based on 
overwhelming evidence of safety concerns.  The DSMB will provide the recommendation 
in a written letter to the principal investigator.  In addition the DSMB will inform the 
investigator of any changes in the proposed timing of future DSMB reviews. The review 
may result in an amendment to the protocol, which must be approved by the IRB.  


 
 
The DSMB report will begin with a brief narrative section that describes the status of the 
study, progress or findings to-date, issues, and the procedures that produced the report 
(e.g., data obtained by a specific date). The report will provide a study description along 
with a current organization chart, current timetable and study schedule as well as a list of 
study clinical and administrative centers. Data will be presented that describe the 
administrative status of the study including recruitment and forms handling. Study data 
reports describe demographic and baseline clinical characteristics and provide a safety 
assessment. Tables will be provided by site as well as for the whole study population. 
AE/SAE rates for each group will be presented in the closed report. Finally, the report will 
include a brief evaluation by the DSMB, with recommendations as to whether or not the 
trial will continue.  
The DSMB will transmit a copy of their recommendations to the Principal Investigator 
who will disseminate to the clinical investigators at each recruitment site. The clinical 
investigators are responsible for forwarding the information to their local IRB.  
5.1 Serious Adverse Event Reporting 
Since reporting rules vary by institution, the following statements are a conservative guide 
to reporting adverse events for this trial and may be further amplified with DSMB 
guidance. 
Unexpected adverse events which are serious, but not life threatening, and have a causal 
relation to the research, (unexpected in this context means not mentioned in the 
informed consent) must be reported to the DSMB within 7 days and to the local IRB 
within two weeks of the event. Serious adverse events related or possibly related to the 
study will be reported to the DSMB chair, as they occur. The DSMB may call an 
emergency meeting, if necessary.  
 


 
 
Appendix Eight: COVID Risk Mitigation Plan for SLEEP-HD 
 
Pre-screening (ISI) 
 
In person (need <5 minutes which are very important to build 
up the rapport with the patient) 
Consent & Screening 
In person- 
Consent process  
Screening questionnaire packet (as much as possible in person) 
 
On phone/online 
Any screening questions not completed in person 
Review of EMR for inclusion/exclusion determination 
 
  
Run-In visits 
In person 
1) Actiwatch placement & instruction, sleep diary delivery & 
instruction, CBT Manual delivery 
On phone/online 
2)  randomization, CATI, sedative/hypnotics  
 
*Participants can return Actiwatches and completed diaries to 
unit where RC’s will pick up, OR mail back to RC’s. Watches 
and diaries will be placed in sealed ziplock bag and kept 
untouched for 3-4 days. 
Treatment visits 
 
 – Study medication 
(Trazodone/Placebo) 
-Actigraphy, data 
collection 
In person 
 
3) Actiwatch placement & instruction, sleep diary delivery & 
instruction 
Mail 
4) Drug delivery/collection (can be done the inter-office 
mail or US Postal Service with return label directly to the 
patient; follow-up with a phone call) 
On Phone/online 
5) Study Medication Follow-Up Visits (all via phone). 
6) Visit Assessments and sedative/hypnotics can be done 
via phone/online. 
7) CATI calls over the phone/online. 
 
*Participants can return Actiwatches and completed diaries to 
unit where RC’s will pick up, OR mail back to RC’s. Watches 
and diaries will be placed in sealed ziplock bag and be kept 
untouched for 3-4 days. 
Drug collection 
Collection process 


 
 
1) Patient brings bottle to dialysis unit, to hold at unit for 
coordinator or to be sent to research team through inter-
office mail 
2) Keep it untouched in zip lock bags for 3-4 days 
3) Use mask and gloves during accountability and sanitize 
the bag 
4) Drop off at pharmacy in zip lock bag (UNM) or store in 
research office (UW). 
CBT-I Telehealth Visits 
Process 
1) Participants can use their own device or a device 
provided by the study 
2) If participants using their own device, coordinator may 
need to help participant set up zoom and use a laminated 
card with step-by-step instructions 
3) If participants use study device, one device and one 
earbud/headphone set will be left at the study unit for 
the six-week duration of treatment 
4) Either dialysis unit staff or coordinator will bring tablet 
and headphones to patients at each CBT-I visit   
5) Coordinator visits at weeks 4 and 6 can be done 
online/over the phone or in person 
Follow-up visits 
In person 
6) Actiwatch placement & instruction, sleep diary delivery & 
instruction 
On phone/online 
7) Treatment Adherence Assessment, ISI and 
sedative/hypnotics can be done via phone/online. 
Mail 
8) Gift cards can be sent by inter-office mail or US postal 
service, or can be delivered at the time of Actiwatch & 
diary collection; 
9) Signed gift card receipt can be left at the unit, scanned 
and sent or inter office back to research staff.  
 
Key Touchpoints 
1) Initial survey/ISI 
2) Consent form & Screening 
3) Drug delivery/collection 
4) Watch/sleep diary set-up 
5) Tablet for CBT-I set-up 
Actiwatch 
cleaning/sanitizing 
1) Follow current manual of procedure with updated 
cleaning protocol provided by vendor 
2) Keep watch sealed in zip lock bags for 3-4 days after each 
use 


 
 
3) Watches and wristbands will be removed from zip locks 
and cleaned per vendor instructions between wearings. 
4) Use mask, gloves during this process 
5) Each participant will be provided with a new, disposable 
wristband and will use it for all 3 Actigraphy collection 
time points. It will be disposed of once Actigraphy 
collection is complete. 
 

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UNIVERSITY OF WASHINGTON
CONSENT FORM
Short and Long-Term Effectiveness of Existing Insomnia Therapies for Patients 
Undergoing Hemodialysis (Sleep-HD)
Researchers: 
UW Medicine/Nephrology and the Kidney Research Institute
Business hours 8 am- 4:30 pm, or leave message - (206) 616-8574
Rajnish Mehrotra, MD
Principal Investigator
Professor, Section Head HMC
(206) 744-4933
Lori Linke                                     
Study Contact
Research Coordinator
(206) 720-3835
24-hour emergency telephone number:
UW Medical Center Operator:  (206) 598-6190; ask for nephrologist on call.
Researchers’ statement
We are asking you to be in a research study.  The purpose of this consent form is to give you the 
information you will need to help you decide whether to be in the study or not.  Please read the 
form carefully.  You may ask questions about the purpose of the research, what we would ask 
you to do, the possible risks and benefits, your rights as a volunteer, and anything else about the 
research or this form that is not clear.  When we have answered all your questions, you can 
decide if you want to be in the study or not.  This process is called “informed consent.”  We will 
give you a copy of this form for your records.
PURPOSE OF THE STUDY
Insomnia is difficulty falling asleep or staying asleep, even when a person has the chance to do 
so. Insomnia is a common and distressing symptom for patients on hemodialysis, and there is 
evidence for a much larger impact on the health of patients. Chronic insomnia is disrupted sleep 
that occurs at least three nights per week and lasts at least three months. 
The purpose of the SLEEP-HD study is to compare two types of treatment for insomnia in 
participants who have end-stage renal disease and who have been diagnosed with chronic 
insomnia. The two types of treatment involved in the study are Cognitive Behavioral Therapy 
(CBT) or treatment with a drug for sleep or with a placebo. The researchers hope to enroll 126 
participants who are undergoing hemodialysis in two study locations (Seattle, Washington and 
Albuquerque, New Mexico). Participation in the study will last about 25 weeks. The entire study 
will take about 5 years to complete.
STUDY PROCEDURES
We are inviting you to take part in this study based on responses to the Insomnia Severity Index 
that you recently completed. If you choose to take part we will ask you additional questions to 
 
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find out if you are suffering from insomnia and if you are eligible for the study. You may discuss 
taking part in this study with your family, friends, or doctor.
If you agree to participate we will obtain demographic information such as your name, age, 
gender and contact information. We will review your medical record and current medication list. 
If you are already on a medicine called trazodone, we will ask you to taper off in order to qualify 
to be in the study (you will need to be off of it for 30 days). If you take it:
as needed, you’ll just stop taking it. 
100 mg a day, then you’ll reduce the dose to 50 mg daily for 5 days, then 50 mg every 
other day for 5 days, then stop. 
50 mg a day, then you’ll take it just every other day for 5 days , then stop.
.We will ask you to complete the following surveys:
A Patient Health Questionnaire-2 or -9 to screen for depression, 3-5 minutes.
The CAGE survey to screen for alcohol use/abuse, 2-3 minutes.
The Drug Abuse Screening Tool (DAST) to screen for drug use/abuse, 2-3 minutes.
The Cambridge-Hopkins Restless Legs syndrome questionnaire to assess Restless Leg 
Syndrome, 3-5 minutes.
It is possible that you will be excluded from the study based on the scores from these surveys. If 
you are, then we’ll refer you, as needed, for treatment.
If you are eligible for the study, you will be provided with instructions to complete a sleep diary 
for one week prior to treatment. This diary documents information about your sleep habits and 
the duration and quality of your sleep. If you choose to complete the sleep diary online you will 
be provided with log-in details and instructions on how to enter the information in the web-
portal. If you choose to use the paper-form of sleep diary, you will be provided with the sleep 
diary for the first week along with instructions on how to complete it. If you need help with 
reading, you will need to have a caregiver available to assist you with completing the sleep diary.
We will ask you to wear an Actiwatch Spectrum Plus for one week that study staff will provide 
for you. This is a wrist activity monitor that you will wear on the wrist opposite to the side of 
your HD access. The Actiwatch records sleep/wake activity.
After one week of wearing the Actiwatch and completing the sleep diary, you will be assigned to 
one of two treatment methods-
A form of counseling called Cognitive Behavioral Therapy (CBT)
Treatment with a medication
You will be randomly assigned to one of these two treatment methods. The random assignment 
is like the toss of a coin and you will have a chance of being in the CBT group, or the medication 
group. The ratio will be 1:2, which means that for every 3 people, 1 will get CBT and 2 will get 
medication.
For the medication group, some will get trazodone and some will get placebo.  This is also a 
random assignment with a chance of getting either. The ratio will be 1:1, which means that for 
every 2 people getting medication, 1 will get trazodone and 1 will get placebo.
 
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A placebo is an inactive substance that looks just like the investigational drug but does not have 
any medical effects. Neither you nor the research team, nor your doctors will know whether you 
are receiving the trazodone or the placebo. 
Description of Treatment Arm:
Cognitive Behavioral Therapy (CBT) using Telehealth
What is individual CBT?
It is one-on-one psychotherapy or “talk therapy” that involves changing the way you behave and 
the way you think about a problem. In this study CBT is focused on improving sleep. You will 
talk with a therapist about your sleep-related habits and behaviors, about your thoughts about 
your sleep, and about the things you can be doing to make sure that problems with sleep are not 
interfering with your living a meaningful life. An example of a question the therapist might ask 
are “what are 3 things that are important for your quality of life”?
You will be provided with a booklet of educational material about sleep and the therapist will ask 
you to try some things to improve your sleep over the course of the treatment.
What is Telehealth?
Telehealth is the remote provision of healthcare, health education or support, using 
telecommunication technologies. In this study participants will meet one-on-one with a therapist 
once a week for 6 weeks, using a confidential video telehealth platform called Zoom. The 
telehealth sessions will each last about 20-30 minutes. You can use a personal smart phone, 
tablet, laptop or desktop computer, and can schedule sessions at a time that is convenient for 
them. If you choose to have your session while at the dialysis unit and need a telehealth device, 
the study team can provide a tablet for use. The sessions will be audio-recorded with your 
permission, for quality purposes.
Sleep Diary
If you are in the CBT arm, you will also keep the sleep diary throughout the 6 week treatment 
phase. You will do it just like you did previously.
Drug Therapy using Trazodone or Placebo
What is Trazodone drug therapy?
This treatment involves taking pills of a medicine called Trazodone, or an identical looking pill 
that is a placebo, by mouth once a day. A member of the study team make sure that you get the 
supply of the drug each week. At the end of each treatment period you will be asked to return 
any unused drug and/or the empty bottle before you are given a fresh supply of the drug. This 
will occur in your dialysis facility while you are receiving hemodialysis. 
The medicine will be started at a dose of 50 mg for the first week. You will continue on this dose 
if you are satisfied with your sleep over the previous 7 days. You have the option to increase the 
dose to 100 mg at week 2 or week 3 of treatment, if you have persistent problems with sleep in 
the previous 7 days. Based on your satisfaction with sleep and tolerability of the medication, you 
will continue on either the 50 mg or 100 mg dose after week 3, and will be provided with a two-
week supply of the medication. 
 
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For women who are of child bearing potential, we will collect about 3.5 ml (about ½ teaspoon) 
blood from your dialysis line before you take any Trazodone. We will test it to make sure you 
are not pregnant. If the test is positive, you will not receive any Trazodone, but you will continue 
with the other procedures in the study (unless you decide to withdraw from it).  
If necessary, we may repeat the pregnancy test for confirmation as agreed on by you and the 
study doctor. The same amount of blood will be taken for additional tests.
For all Study Participants: 
You will be asked to wear the Actiwatch again for one week at week 6 and for one week at week 
24. Study staff will deliver the Actiwatch to you and you will return it after each one week time 
period, while you are at the dialysis unit. The Actiwatch gives the study team information about 
whether your sleep has improved over the treatment phase. You will also keep a sleep diary for 
the week you are wearing the Actiwatch. You will do it just like you did previously.
Phone Calls to Check Your Response to Treatment:
Whether you are getting CBT or taking a pill for the treatment of insomnia, a member of the 
research team at the University of New Mexico or at the UW will call you at five different times 
– once before the start of any treatment, at 4 weeks from the start of treatment, at 7 weeks from 
the start of treatment, at 13 weeks, and at 25 weeks. The call will happen either Tuesday if you 
are on a Mon-Wed-Fri dialysis schedule, or Wednesday if you are on the Tues-Thurs-Sat 
schedule. If for some reason the call cannot be completed on Tuesday or Wednesday, we will try 
to complete it on the next day that you do not go for dialysis. If you are unavailable to take the 
call on a non-dialysis day, then you can do the call during the first hour of your dialysis session.  
We will ask that you do the other two calls the same way (either a dialysis or non-dialysis day).  
The person from the research team will not know what form of treatment you are getting. He/she 
will ask you to answer questions about your sleep, fatigue, pain, depression, anxiety and quality 
of life.  These phone calls will take about 30 minutes each time.
Follow-up Phase
You will participate in the study treatment (either CBT or medication) for six weeks. After that, there is 
an 18 week (4 ½ month) follow up phase. You will no longer receive any treatment through the study, 
though you will continue with study follow-up procedures as described in this form. 
If you were in the medication group, and you have improved by 6 weeks, you and your doctor 
may choose to continue the pills for insomnia. You will then pay for the drug yourself or through 
your insurance, since it will now be a part of your regular health care, rather than a study procedure.  If 
you decide that you do not want to continue treatment with the drug or if you are not feeling 
better with the drug, we will slowly reduce the dose of the medicine over a few weeks until it is 
stopped completely.
If you were in the CBT group, you are free to address insomnia as you wish with your care provider, 
including taking trazodone. Whatever means you choose, you or your insurance will pay for it, since it 
will now be a part of your regular health care, rather than a study procedure.
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We will check your clinical medical records periodically throughout the study. We will check them to 
confirm that you are eligible for the study, including current medications and health problems, any 
updates to your contact information, dialysis schedule or unit, to help monitor for any side effects if 
you’re on the medication.
RISKS, STRESS, OR DISCOMFORT
During CBT and the study phone calls, we will ask questions about your health and habits. You 
may find some of these questions uncomfortable or inconvenient. You do not have to answer any 
question you do not want to or stop the surveys at any time. 
There is a risk of discomfort from lack of privacy when we talk to you at the dialysis unit during 
research visits. You may request that our discussions take place in a private setting, though this 
will be outside of the time of your dialysis session.
There is a risk of discomfort from lack of privacy if you choose to complete CBT sessions at the 
dialysis unit. You may request that the sessions take place in a private setting, though this will be 
outside of the time of your dialysis session. Using Zoom CBT is University of Washington 
HIPAA compliant. 
People that receive trazodone pills for the treatment of insomnia may suffer some side effects of 
the drug:
Common side effects (>5%) are drowsiness, nervousness, dizziness, fatigue, dry mouth, 
nausea, and vomiting.
Extremely rare side effect is priapism, an erection that lasts more than 4 hours. If you 
experience this, you should call 911 and go to the nearest emergency room for treatment. 
If you taper off trazodone that you were already on in order to be in the study, you may 
experience worsening of your insomnia.
Young adults may experience suicidal ideas. We will monitor you closely so that we can 
refer you to someone who can help you, if you experience this. If you have thoughts of 
harming yourself, call 911 or let us know right away so that we can find help for you.
Do not use alcohol or take other medications that make you sleepy or dizzy while taking 
study medication.
There is minimal risk with the use of the Actiwatch. The Actiwatch band may cause mild 
irritation to the skin.
Pregnancy
We do not know for sure how safe trazodone is during pregnancy and breast feeding.  For all 
women in this study whom we randomize to take study medication: if have not had a 
hysterectomy or tubal ligation, or have not gone through menopause at least one year ago, you 
must use a method of preventing pregnancy during the study. This can be birth control pills or 
implant, an intrauterine device (IUD), or a barrier method (male or female condom, diaphragm 
with intravaginal spermicide, cervical cap).
If you are in the study medication arm of the study and suspect that you have become pregnant, 
you must stop taking study medication. You should immediately notify the study investigator or 
study staff and they will instruct you how to taper off of the study medication. If you become 
pregnant, you will not be able to continue taking study medication. You may work with your 
 
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doctors to find another way to treat insomnia. However, you will continue to participate in the 
study, unless you decide to withdraw from it. We will follow you throughout your pregnancy and 
child-birth (including medical record access), even after you are done with the study, in order to 
check for any problems that may be related to the study medication.
If you need a pregnancy test for this study, we will use a blood sample drawn from your dialysis 
line, as described above. This will introduce a small risk of infection when we access the line. 
The dialysis staff is trained in how to draw blood from the line in a way that minimizes this risk.
ALTERNATIVES TO TAKING PART IN THIS STUDY
If you choose not to take part in the study, the same options for treatment of insomnia will be 
available to you.  These include therapy and a variety of medications, including trazodone and 
others.  Your care will not be affected by your decision to take part in this study. 
BENEFITS OF THE STUDY
If you choose to participate in this study, you may not receive any benefit.  Your symptoms of 
insomnia may get better or worse or stay the same. Society may benefit if the study shows that 
the treatment is effective and safe.  This study is the first large-scale comparison of benefits and 
safety of CBT and pills for the treatment of insomnia among hemodialysis patients. You may help 
contribute to knowledge about insomnia in hemodialysis patients that my help patients in the 
future. You may benefit from learning about different options for treatment of insomnia. 
SOURCE OF FUNDING
The study team and/or the University of Washington are receiving financial support from the 
National Institute of Diabetes, Digestive, and Kidney Disease (NIDDK) of the National 
Institutes of Health (NIH).
CONFIDENTIALITY OF RESEARCH INFORMATION
All the information you provide will be considered confidential.  Your name and other 
identifying information will be linked to a unique study ID.  Your study ID will not display any 
information that can identify you.  All of the data we collect from you will be coded with your 
study ID and kept in a locked cabinet, and/or password protected computer files.  The master list 
linking your identifying information to your study data will be kept in a separate, secure location. 
The study team will have access to the master list.  We will keep the link between your 
identifying information and study data until the end of the research study. 
The Center for Biomedical Statistics at the University of Washington will be the Data Collection 
Center (DCC) for this study.  For those enrolled in the treatment phase of this study, we will send 
all study information to the DCC, including your identifying information and contact 
information.  The master list linking your identifying information to your study data will be 
available to the DCC and the local study team at the Kidney Research Institute.  
An interview team at the either the University of New Mexico or the UW will make the 5 phone 
calls to you for the follow up evaluations.  The DCC will give the interview team your name and 
contact information so that they can call you.  Your name and contact information will only be 
 
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available to the interview team on the day of your call.  They will not use it for any other 
purpose.
Your responses on the surveys will be kept strictly confidential and staff members at your 
dialysis unit will not have any knowledge of your answers to the questions. During the course of 
the study, if we learn that you intend to harm yourself or others, we will try to get immediate 
help for you. 
The certified therapists will also follow a strict code of confidentiality. The CBT sessions and 
will only be audiotaped with your permission. The audiotapes will be encrypted and coded with 
your study ID so as to not reveal your identity or any personal information.  These recordings 
will be stored at the DCC along with your other study information.
A Data Safety and Monitoring Board (DSMB) will monitor the conduct of the study at least twice 
yearly to check for safety.
Government or university staff sometimes review studies such as this one to make sure they are 
being done safely and legally.  If a review of this study takes place, your records may be 
examined.  The reviewers will protect your privacy.  The study records will not be used to put 
you at legal risk or harm.
The study information will be available to the study doctors here at the University of Washington 
and the University of New Mexico. Only study staff here at the UW will have your identifying 
information. After this study is over, the study doctors may share study information with other 
researchers. If they do, they will not share your identifying information. Only coded information 
will be shared (the information will be anonymous). Also, we will never release any information 
that anyone could combine to identify an individual participant or study site. Any researcher to 
whom we may release anonymous study data is bound to strict confidentiality and data-use 
guidelines.
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
We will not use your name or other information that could identify you in any published reports.
A copy of this consent form will be placed in your medical record.
A copy of this consent form and the HIPAA authorization form will go into your medical 
records.
We have a Certificate of Confidentiality from the federal National Institutes of Health.  This 
helps us protect your privacy.  The Certificate means that we do not have to give out identifying 
information about you even if we are asked to by a court of law.  We will use the Certificate to 
resist any demands for identifying information.  
We can’t use the Certificate to withhold your research information if you give your written 
consent to give it to an insurer, employer, or other person.  Also, you or a member of your family 
can share information about yourself or your part in this research if you wish.    
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
a member of the federal government who needs it in order to audit or evaluate the 
research;

individuals at the University of Washington, the funding agency, and other groups 
involved in the research, if they need the information to make sure the research is being 
done correctly;

the federal Food and Drug Administration (FDA), if required by the FDA;

local authorities, if we learn of child abuse, elder abuse, or the intent to harm yourself or 
others. 
OTHER INFORMATION
You may refuse to participate and you are free to withdraw from this study at any time without 
penalty or loss of benefits to which you are otherwise entitled. 
If you do join and want to drop out later, please inform us. Please contact Dr. Mehrotra or a 
member of the study staff using the contact information listed at the front page. 
You may also ask to have your information no longer used for research. If studies have already 
been done on your information, the results of the study will be kept, but your identity will be 
removed and no further studies will be done on them.
You will not have to pay for the CBT or drug therapy while in the treatment phase of the study. 
If you decide to continue therapy after the 6 week treatment phase is over, then you (or your 
insurance company) will have to pay for it.
We will give you $100 for completing the whole study. You will receive the payment in the form 
of a Visa cash card at the end of your participation. If you only do part of the study, we will give 
you $50 if you did at least 3 study phone calls before you stopped, $75 if you did 4, and the full 
$100 if you did all 5 phone calls.
You may also elect to receive the payment in installments: $50 after you complete 3 study phone 
calls, another $25 after you complete the 4th, and another $25 after the 5th phone call.”
RESEARCH-RELATED INJURY
What to do. For a life-threatening problem, call 911 right away or seek help immediately. 
Contact Dr. Mehrotra at (206) 744 – 4933, when the medical emergency is over or as soon as 
you can. 
For all other problems: contact Dr. Mehrotra (206) 744 – 4933, or Lori Linke (206) 720 – 3835 
right away. They will treat you or refer you for treatment. 
Who will pay. The costs of the treatment may be billed to you or your health insurance just like 
other medical costs, or it may be covered by the UW’s discretionary Human Subjects Assistance 
Program (HSAP), depending on a number of factors.  The researcher may request HSAP 
coverage by following established procedures. If you wish to request HSAP coverage yourself, 
contact the researcher or the UW Human Subjects Division at hsdinfo@uw.edu or 206-543-
0098. You may also call collect to the UW Human Subjects Division at 206-221-5940 if you do 
not otherwise have access to a telephone. Ask the researcher if you would like information about 
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compensation for injury. However, the law may allow you to seek payment for injury-related 
expenses if they are caused by malpractice or the fault of the researchers. You do not waive any 
right to seek payment by signing this consent form. We will bill your health insurance for 
treating problems that result from your kidney disease, insomnia, or from standard clinical care. 
If you have no health insurance or your insurance refuses to pay, we will bill you.
Printed name of study staff obtaining consent
Signature
Date
Subject’s statement
This study has been explained to me.  I volunteer to take part in this research.  I have had a 
chance to ask questions.  If I have questions later about the research, or if I have been harmed by 
participating in this study, I can contact one of the researchers listed on the first page of this 
consent form.  If I have questions about my rights as a research subject, I can call the Human 
Subjects Division at (206) 543-0098 or call collect at (206) 221-5940. I give permission to 
researchers to use my medical records as described in this consent form. I will receive a copy of 
this consent form.
- If selected for Cognitive Behavioral Therapy, I give permission for my sessions to be 
audiotaped: 
Yes □   No □
Printed name of subject
Signature of subject
Date
When the consent form is read to a subject, an impartial witness must be present and sign here:
:
Printed name of witness
Signature of witness
Date
Copies to:
Researcher
Subject
Subject’s Medical Record
 
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Pre-
Screen
Screen
Baseline
Treatment
Follow-up from Randomization
WEEK
-1
0
1
2
3
4
5
6
7
13
25
Insomnia Severity Index (ISI)
x
x
x
x
x
x
Inclusion/Exclusion Criteria
x
Randomization
x
Sleep Diary for CBT arm 
x
x
x
x
x
x
CBT-I Arm Visits 
x
x
x
x
x
x
Trazodone/Placebo Visits
x
x
x
x
x
Treatment Adherence Assessment
x
x
x
x
x
Phone call to check treatment response
x
x
x
x
x
Actigraphy with sleep diary
x
x
x
Concomitant Sedatives/Hypnotics
x
x
x
x
x