Predictors of Response to Insomnia Treatments for Gulf War Veterans

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and effectiveness of Sleep Restriction (SR) and Cognitive Therapy (CT) in Gulf War Veterans with insomnia. The primary hypothesis is that the efficacy of these treatments will depend upon an individual subject's baseline characteristics. For SR we expect that baseline measures of excessive time spent in bed may predict response and for CT we expect that baseline measures of cognitive arousal and pain may predict response. Exploratory analyses using signal detection techniques will systematically compare and contrast the potential usefulness of a number of additional potential moderator measures. Insomnia is a serious health problem in Gulf War Veterans that is often associated with extensive prescription of sleeping medications. Although safer, even the latest medications can lead to cognitive impairment and risk of abuse. Thus, non-pharmacological treatments for insomnia have been pursued as alternatives to medications. Cognitive Behavior Therapy for Insomnia (CBT-I) combines behavioral and cognitive components of therapy to address symptoms of insomnia. The combined CBT-I approach has well-documented efficacy. Between 2012 and 2014 over 650 VA mental health clinicians have received extensive training in CBT-I. Although CBT-I is efficacious, the optimal target populations for its major components has not yet been well-defined for Gulf War Veterans. We propose to address this gap and develop tools for clinicians to identify the best treatment for insomnia for individual Gulf War Veterans.

Detailed Description
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Our hypotheses will be tested in a randomized parallel groups design. Randomization will be based on type of treatment assignment: either to SR or CT. After screening and randomization in the 2-week baseline phase, subjects will receive SR or CT in the 6-week treatment phase. There will be no more treatment after this point. At the end of the 6-week treatment, subjects will return to repeat many of the psychological tests administered during baseline to determine the short-term benefit. This 4-year proposal will include 100 subjects (2 groups of 50 each) with outcome, mediator, and moderator measures collected at appropriate points. All subjects will receive education about basic sleep hygiene as well as information about the science of sleep including sleep stages and sleep regulation. Sleep Restriction Therapy (SR). The initial Time in Bed (TIB) prescription is calculated from the average total sleep time (TST) reported in the baseline sleep logs. After one week, depending on subject's daily sleep logs and adherence to treatment, the therapist suggests a new TIB prescription. Napping is neither prescribed nor proscribed. However, if subjects find themselves having difficulty staying awake during the day, they are advised to take a brief (15 to 30 minutes) nap to ensure their safety. Cognitive Therapy (CT). CT is designed to meet three general goals: 1) identify dysfunctional sleep cognitions, 2) challenge the validity of these thoughts, and 3) replace them with more adaptive substitutes. Several specific techniques designed to meet these goals are discussed in materials distributed to subjects. We will continue to monitor progress post-treatment during the follow-up period. The complete package of outcome measures will be repeated at the follow-up session. We will tell subjects that we expect the benefits of treatment to continue and/or improve with time and we will also encourage subjects to continue practicing the treatment instructions to maintain their progress after active treatment ends. Subjects will be screened for eligibility via a phone interview and an in-person evaluation. At the in-person evaluation, informed consent will be received and documented. The evaluation will consist of measures of cognitive impairment and depression, sleep disturbance, and medical and psychiatric history. Exclusion criteria will be evaluated by the following measures: Acute/Unstable Chronic Illness Checklist, Berlin Questionnaire, Columbia Suicide Severity Rating Scale (C-SSRS), the Duke Structured Interview for Sleep Disorders (Duke), Hamilton Depression Rating Scale (HDRS), Life Stressor Checklist, Mini International Neuropsychiatric Interview Version 5 (MINI), Montreal Cognitive Assessment (MOCA), Morningness-Eveningness Questionnaire (MEQ), Sleep Related Behavior Questionnaire, and the Thought Control Questionnaire Insomnia-Revised (TCQI). At Palo Alto, subjects will additionally be provided with and instructed in the use of at-home PSG equipment. A 24-channel EEG cap will be placed on the participant's head before they leave to ensure accurate recordings are obtained. The PSG will be completed in the subject's own home and be used to screen for Obstructive Sleep Apnea (OSA) and Periodic Limb Movement Disorder (PLMD). Subjects will return to the lab the next morning to have the equipment removed. At each visit during Weeks 1-8 and again at Week 32, participants will complete the Anxiety and Preoccupation about Sleep Questionnaire (APSQ), Depression Anxiety and Stress Scale (DASS-21), Epworth Sleepiness Scale, and the Insomnia Severity Index. Sleep diaries will be completed through the treatment phase (Weeks 1-8) and again at follow-up (Week 32). The following measures will be completed at weeks 1, 8, and 32: American Urological Association-8 (AUA-8) Nocturia Subscale; Brief Pain Inventory-Short Form (BPI-SF); Beck Anxiety Inventory (BAI); Beck Depression Inventory (BDI); Clinician Administered PTSD Scale (CAPS); Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS); Glasgow Content of Thoughts; Glasgow Sleep Effort Scale; Multidimensional Fatigue Inventory; Penn State Worry Questionnaire (PSWQ); Perceived Stress Scale (PSS); and the SF-36 (RAND). Subjects will be evaluated on Functional Outcomes of Sleep Questionnaire at weeks 1, 2, 8 and 32. Subjects will be evaluated on the Sleep Associated Monitoring Index (SAMI) at weeks 1 and 8. At Palo Alto, subjects will be evaluated on the Trail Making Test, MOCA, Color Word Interference Test, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) at weeks 1 and 32. Following the completion of treatment at Week 7, subjects will complete the Treatment Adherence Survey, Treatment Satisfaction Survey, and Working Alliance Inventory. The Working Alliance Inventory will also be given at the second treatment session (Week 3). Blood will be drawn at Baseline and Week 32 to measure levels of C-reactive protein (CRP). Urine samples will be collected during each of the 3 study phases to monitor abstinence from recreational drugs, with the exception of medical marijuana used less than four times per week. Samples will be collected by nurses at the VA Clinical Studies Unit and analyzed by the VA laboratory. Remaining blood will be banked for analysis of genetic factors. Due to the COVID-19 pandemic, participants may complete all study sessions including the evaluations through telehealth. The telehealth study will still be available even after in-person research has resumed. For participants completing the study through telehealth, we will not collect the following measures: urine screen, blood draw, overnight PSG, Trail Making Test, or Color Word Interference test. For telehealth participants, the MOCA-Blind may replace the MOCA. All other measures can feasibly be done through telehealth.

Official Title
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Predictors of Response to Insomnia Treatments for Gulf War Veterans

Conditions
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Insomnia

Intervention / Treatment
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* Behavioral: Sleep Restriction Therapy
* Behavioral: Cognitive Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Gulf War Veterans of any racial or ethnic group Independent Living (not in nursing home or VA Extended Care facility) Subjective complaint of insomnia on the Insomnia Severity Index (ISI) greater than or equal to 10 Subjects with PTSD will be included in this study as long as they do not meet criteria for depression described below Stable (3 weeks) CNS active medications that could significantly impact sleep or alertness Stable adult onset diabetes, controlled with insulin, oral medications or diet is acceptable Access to a device with video capabilities and ability to have the video on during study visits. Exclusion Criteria: Sleep-Related Excessive caffeine consumption (4 cups of coffee per day) and unable to reduce to 3 cups a day before lunch a day for 3 weeks prior to treatment Subjects will be initially screened by the Berlin Questionnaire (for sleep apnea) Those with responses suggestive of high risk for sleep apnea will be referred to Pulmonary Medicine for standard clinical screening including polysomnography Those in which apnea is primarily responsible for their sleep complaints should be excluded Subjects working a rotating shift or an unconventional daytime shift (ending after 1830 h) will be ineligible Neuropsychiatric Hamilton Depression Scale (HDRS 24) and classified as high risk on the Columbia Suicide Severity Rating Scale (C-SSRS) in the past month Individuals are considered high risk if they have endorsement of either of the following on the C-SSRS: A positive endorsement, relative to the past 30 days, in the Suicide Thoughts section of item #4 (Have you had these thoughts and had some intention of acting on them) or item #5 (Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? A positive endorsement, relative to the past 90 days, in the Suicide Behavior section of item #6 (Have you ever done anything, started to do anything, or prepared to do anything to end your life?) Current or lifetime history of a psychiatric disorder with primary psychotic features Current or lifetime bipolar disorder; prominent suicidal or homicidal ideation Current exposure to trauma, or exposure to trauma in the past 3 months Current or within the past 30 days: drug abuse or dependence (except nicotine) Current or expected cognitive behavior therapy for another condition (e.g.,: depression) Excessive alcohol consumption >14 drinks per week or > 4 drinks per occasion Presence of any acute or unstable psychiatric condition(s) that requires referral for treatment Montreal Cognitive Assessment (MOCA) < 20 or Montreal Cognitive Assessment Blind (MOCA-Blind) < 15 Medical Acute or unstable chronic illness, including but not limited to: Uncontrolled thyroid disease Kidney disease Prostate or bladder conditions causing excessively frequent urination (> 3 times per night) Medically unstable congestive heart failure Angina Other severe cardiac illness as defined by treatment regimen changes in the prior 3 months Stroke with serious sequelae Cancer if < 1 year since end of treatment Asthma Emphysema Or other severe respiratory diseases uncontrolled with medications Neurological disorders such as Alzheimer's disease, Parkinson's disease, and/or unstable epilepsy as defined by treatment regimen changes in the prior 3 months Unstable adult-onset diabetes will be excluded

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Our hypotheses will be tested in a randomized parallel groups design. Randomization will be based on type of treatment assignment: either to Sleep Restriction (SR) or to Cognitive Therapy (CT). After screening and randomization in the 2-week baseline phase, subjects will receive SR or CT in the 6-week treatment phase. There will be no more treatment after this point. At the end of the 6-week treatment, subjects will return to repeat many of the psychological tests.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sleep Restriction Therapy<br>Sleep Restriction Therapy (SR). The initial Time in Bed (TIB) prescription is calculated on the average total sleep time (TST) reported in the baseline sleep logs. After one week, depending on subject's daily sleep logs and adherence to treatment, the therapist suggests a new TIB prescription. Napping is neither prescribed nor proscribed. However, if subjects find themselves having difficulty staying awake during the day, they are advised to take a brief (15 to 30 minutes) nap to ensure their safety. | Behavioral: Sleep Restriction Therapy<br>* Sleep Restriction Therapy will regulate time spent in bed based on information collected from sleep diaries during evaluation and treatment. Sleep Restriction therapy is designed to improve sleep quality by matching opportunity for sleep to the amount of average total sleep calculated from sleep diaries. Once the quality of sleep has improved, sleep quantity is gradually increased by slowly increasing sleep opportunity. Stimulus control will strengthen the bed/sleep association by eliminating non-sleep activities from the bedroom.<br>|
| Experimental: Cognitive Therapy<br>Cognitive Therapy (CT). The CT treatment module is designed to meet three general goals: 1) identify dysfunctional sleep cognitions, 2) challenge their validity, and 3) replace them with more adaptive substitutes. Several specific techniques designed to meet these goals are discussed in materials distributed to subjects. Similar to SR, subjects in CT are provided with information about relevant elements of the science of sleep and healthy sleep practices. | Behavioral: Cognitive Therapy<br>* Cognitive Therapy is designed to identify maladaptive beliefs about sleep, challenge their validity, and replace them with more adaptive thinking patterns. This therapy aims to reduce sleep-related worry, anxiety, and fear. The treatment phase of the study lasts six weeks. During treatment, you will meet with a study therapist for a total of six sessions: once per week for six consecutive weeks. Each session lasts approximately 60 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insomnia Severity Index | The Veteran's subjective experience of severity of insomnia using the Insomnia Severity Index (ISI). The ISI has been shown to be a reliable subjective measure of insomnia severity as well as a sensitive measure of symptom change including in Veteran insomnia treatment studies. Recently it has also been related to objective polysomnography measures. The scale ranges from 0 to 28, with a score of 0-7 indicating no clinically significant insomnia, scores 8-14 indicating sub-threshold insomnia, 15-21 indicating moderate insomnia and 22-28 indicating severe insomnia. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Wake After Sleep Onset | Wake After Sleep Onset (WASO) will be measured by daily sleep logs. This is included as a secondary measure because difficulty in maintaining sleep is the most commonly reported insomnia complaint; i.e., they either experience unwanted wake time during the night and/or they wake earlier than they want in the morning. | 6 weeks | 
| SF 36-Item Health Survey 1.0 (SF-36) | The SF-36 measures Quality of Life (QOL), including both emotional and physical disabilities, is easy to understand, brief, widely used, and has been found to be useful as a measure of health status. It covers 8 domains of QOL: physical functioning, role functioning/physical, role functioning/emotional, energy/fatigue, emotional well-being, social functioning, pain, general health, and a single-item ninth component: reported health transition (health compared to 1 year ago). Each of the dimensions of the SF-36 yields a score (1-100). Large sample means and standard deviations of the 8 dimensional scales have been published for various subject populations and disease groups. We will use the general health domain as our overall indicator of health-related QOL and perform additional analyses on the 8 individual scales. | 6 weeks | 
| Functional Outcomes of Sleep Questionnaire (FOSQ) | The FOSQ is designed to be administered to individuals who have a sleep disorder and is recommended for use in intervention studies as an outcome measure. The questionnaire is designed to measure functional status in situations that produce sleepiness. There are five subscales: vigilance, intimacy and sexual relationships, general productivity, activity level, and social outcome. Test-retest reliability for the scale has been found to be .91 when administered a week apart. The internal consistency of the components and the total score was above .85 (Cronbach's alpha). | 6 weeks | 
| Multidimensional Fatigue Inventory (MFI) | The MFI is designed to measure domains of fatigue including General Fatigue, Physical Fatigue, Mental Fatigue Reduced Motivation and Reduced Activity. CBT for insomnia has previously been associated with improvements in overall fatigue levels. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insomnia, CBT, Gulf War Veterans, Sleep