CBT-I or Zolpidem/Trazodone for Insomnia (COZI)

Comparative Effectiveness of Zolpidem/Trazodone and Cognitive Behavioral Therapy for Insomnia in Rural Adults

Patient-Centered Outcomes Research Institute, University of Pittsburgh, University of Arizona, University of Virginia, University of Illinois at Chicago

This study is a randomized (1:1:1) comparative effectiveness trial of medication (zolpidem or trazodone), cognitive-behavioral therapy for insomnia (CBT-I), and the combination (medication + CBT-I) for the treatment of chronic insomnia in men and women aged 18-80 living in rural areas with 1 year of follow-up. A total of 1200 participants will be enrolled and randomized in the United States. This trial is funded by the Patient-Centered Outcomes Research Institute.

Insomnia is a common health problem that causes distress, impaired function, and increased risk for other health problems. Chronic insomnia is defined by problems with the quality or amount of sleep, including difficulty falling asleep, frequent awakenings, and/or awakening early and being unable to return to sleep. In developing this application, patients, providers, payors, and the investigators identified both concerns and opportunities with current treatments for chronic insomnia. Medications and Cognitive-Behavioral therapy for insomnia (CBT-I; a treatment program to improve sleep through changes in behavior and thinking) are both effective for treating insomnia. Zolpidem, the most frequently prescribed insomnia medication, is widely available, but may cause side effects and dependency. Trazodone is increasingly prescribed off-label for treatment of insomnia, but evidence of efficacy and safety is more limited. CBT-I is the recommended first line treatment by many professional organizations, but it is not widely available in physicians' practices. Patients, providers, and payors face important unanswered questions: Which treatment should be used for the treatment of chronic insomnia? Is combination therapy more effective, and does it result in lower zolpidem use? Who responds best to which treatment? These dilemmas are particularly relevant to patients and providers in rural areas, where access to behavioral health specialists is limited, and concerns regarding use of controlled substances is particularly acute. To address these questions, we propose the study, Comparative Effectiveness of Zolpidem/Trazodone and Cognitive Behavioral Therapy for Insomnia in Rural Adults (COZI). The investigators will use a well-tested Internet version of CBT-I, which is just as effective as in-person CBT-I, but more widely available. The aims of COZI are to: 1: Compare the effectiveness of medication preference (zolpidem or trazodone), CBT-I, and combination treatment for insomnia symptoms over 12 months. 2: Compare the effectiveness of medication preference, CBT-I, and combination treatment for other symptoms and problems, including health-related quality of life, mood, and health outcomes. 3: Compare the side effects of medication preference, CBT-I, and combination treatment. 4: Conduct an exploratory analysis of heterogeneity of treatment effects for common factors (age, gender, socio-economic status, degree or rurality, and other factors). COZI will study 1200 patients (400 per treatment) recruited from 8 health care systems across the country, each of which has established practices in rural areas. Patients will be treated with medication prescribed by their own physician (zolpidem or trazodone), Internet CBT-I, or a combination of the two. The investigators will evaluate treatment effects at 9 weeks, and 6 and 12 months (with limited additional assessments for adverse events and medication use at 1 and 9 months). Our study questions and design reflect early and ongoing engagement of key stakeholders including patients, providers, and payors, who are members of the Study Advisory Committee (SAC). SAC members will work with study investigators to recommend the best strategies for recruiting patients, measuring treatment effects, and disseminating study findings. The SAC will meet quarterly. Patients and other stakeholders have already provided guidance on which treatments are most worth studying, and which symptoms would best reflect the effects of treatment. Patients and other stakeholders will also be part of the Steering Committee, which is the main decision-making group for our study, and which will meet monthly. COZI will lead to answers for patients and providers addressing insomnia; improved health and function for millions of rural Americans; and sustainable changes in how insomnia is treated in rural practices.

Insomnia, Chronic Insomnia, Zolpidem, Ambien, Cognitive-behavioral therapy for insomnia, CBT-I, Rural, Primary Care, Pragmatic Clinical Trial, Comparative Effectiveness, Trazodone

This study is a randomized (1:1:1) comparative effectiveness trial of medication preference (zolpidem or trazodone), CBT-I, and the combination for the treatment of insomnia in 1200 men and women aged 18-80 years living in rural areas.

Masking of participants and providers is not possible given two very different treatment types. The Prime Principal Investigator and a statistician at the Data Coordinating Center will be masked to individual treatment assignment.

6-week internet CBT-I multi-component intervention (SHUTi) including sleep restriction, stimulus control, cognitive restructuring, sleep behaviors, and relapse prevention

Change in Insomnia Severity Index score from baseline to follow-up. The Insomnia Severity Index is a 7-item self-report questionnaire that measures severity of insomnia symptoms during the last two weeks. Each item is scored 0 (no problem) to 4 (very severe problem) and total between 0-28, with higher scores indicating more severe insomnia symptoms.

Treatment response defined as a ≥6 point reduction in Insomnia Severity Index score from baseline to follow-up. The Insomnia Severity Index is a 7-item self-report questionnaire that measures severity of insomnia symptoms during the last two weeks. Each item is scored 0 (no problem) to 4 (very severe problem) and total between 0-28, with higher scores indicating more severe insomnia symptoms.

Remission of Insomnia defined as Insomnia Severity Index <8 at follow-up. The Insomnia Severity Index is a 7-item self-report questionnaire that measures severity of insomnia symptoms during the last two weeks. Each item is scored 0 (no problem) to 4 (very severe problem) and total between 0-28, with higher scores indicating more severe insomnia symptoms.

The Patient Health Questionnaire (PHQ-8) is an 8-item self-report measure for assessing depression severity. The items are summed to yield a score between 0 and 24, with higher scores indicating more frequent depression symptoms. The Generalized Anxiety Disorder (GAD) Scale is a 7-item self-report measure used for screening and assessing severity of GAD. The items are summed to yield a score between 0 and 21, with higher scores indicating more severe GAD symptoms.

The Pittsburgh Sleep Quality Index (PSQI) is an 18-item self-report measure that assesses sleep quality in the past month. These items are combined into seven component scores (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleep medication, and daytime dysfunction). The seven component scores are added to produce a global sleep quality score ranging from 0 to 21. Higher global scores reflect lower sleep quality.

The Epworth Sleepiness Scale (ESS) is an 8-item self-report measure that assesses daytime sleepiness by asking about the likelihood of dozing in certain situations. Individual items are summed to yield the ESS score between 0 (never doze) to 24 (doze a lot).

The PROMIS Cognitive Function Short Form (8a) is an 8-item self-report measure related to executive functioning. Individual item responses range from 1 (very often) to 5 (never) with higher scores signifying higher cognitive function.

The PROMIS Global Health is a 10-item self-report measure that assess general domains of health and functioning. Individual item responses range from 1 (excellent/none) to 5 (poor/always) and a single pain item ranges from 0 (no pain) to 10 (worst pain). Lower scores indicate greater health-related quality of life. The Medical Outcome Survey (SF-12) is a 12-item self-report measure of physical and mental health. Scores can be expressed with two component scores: Physical Component Score (PCS) and Mental Component Score (MCS). The component scores can range from 0 to 100, with higher scores indicating better health.

Side effects (frequency, severity, impairment) are recorded via self-report adapted from the FIBSER. Scores range from 0 (no side effects; better) to 21 (worse). Those reporting severity of greater than moderate and/or frequency greater than 50% of the time in their self-report, or who spontaneously report a side effect, are contacted by the study coordinator. Information is gathered regarding the nature and duration of the event and action taken. Determination of causality and outcomes attributed to the event are then made.

Falls are reported via self-report, including context, location, and consequences of falls. Those reporting two or more falls, or a fall resulting in medical care, are contacted by the study coordinator. Information is gathered regarding the nature and duration of the event and action taken. Determination of causality and outcomes attributed to the event are then made.

Medication use is assessed using self-reported prescription, over-the-counter, and supplement name and frequency.

The PROMIS Fatigue instrument is a 7-item self-report measure that assesses recent fatigue and how fatigue interfered with daily activities. Scores range from 7 to 35, with higher scores indicating greater fatigue.

The PROMIS Pain Intensity scale is a 3-item instrument used to assess how much pain a person has. Scores range from 3-15, with higher scores indicating greater pain intensity. The PROMIS Pain Interference scale is a 6-item instrument used to assess the consequences of pain in different domains of daily life. Scores range from 6-30, with higher scores indicating greater interference.

The Munich Chronotype Questionnaire (MCTQ) is a self-report scale to assess sleep structure, patterns, duration, and quality. Scores range from 16 to 86, with the lower scores representing later chronotypes.

Dysfunctional Beliefs and Attitudes about Sleep (DBAS) Scale is a 16-item instrument used to evaluate dysfunctional thoughts related to insomnia. Each item is scored 0-10 and the total is the average of the 16 item scores (range 0-10), with higher scores indicating greater dysfunctional beliefs about sleep.

Sleep diary, Covid-19, nocturia symptoms, treatment expectancy, treatment satisfaction, tobacco use, alcohol use, caffeine use, demographics, and medical history.

Inclusion Criteria: Age 18-80 Insomnia Severity Index score > 10 Regular internet and computer access Receives primary care in a Non-metropolitan/Rural residence Exclusion Criteria: Use of hypnotic medication >2 times in the past week Current cognitive or cognitive behavioral treatment for insomnia Psychotic disorder Bipolar disorder Current substance use disorder Severe Chronic obstructive pulmonary disease (COPD) or other severe pulmonary disease (such as asthma or lung fibrosis) Cognitive impairment or dementia History of spontaneous or hypnotic-induced complex sleep behavior Delayed sleep phase disorder (DSPD) Shift work that includes working the night shift (between the hours of 12:00 a.m. - 6:00 a.m.) History of fracture or injurious fall in the past 12 months Currently pregnant, planning to become pregnant, or breastfeeding Other severe or uncontrolled mental or physical disorders that would make participation difficult or unsafe