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

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

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 155 participants will be enrolled and randomized in the United States. This trial is funded by the Patient-Centered Outcomes Research Institute.

Study Overview

• Status: Completed
• Conditions: Chronic Insomnia
• Intervention / Treatment: Drug: Zolpidem; Drug: Trazodone; Behavioral: Internet Cognitive Behavioral Therapy for Insomnia (CBT-I)

Detailed Description

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 6 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. COZI will study 155 patients recruited from 7 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.

• Study Type: Interventional
• Enrollment (Actual): 155
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85721
      • University of Arizona
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Medication (zolpidem or trazodone); Zolpidem or trazodone, as prescribed by physician	Drug: Zolpidem; Zolpidem, as prescribed by physician; Other Names: Ambien; Drug: Trazodone; Trazodone, as prescribed by physician; Other Names: Desyrel
Active Comparator: Internet Cognitive Behavioral Therapy for Insomnia (CBT-I); Internet-based CBT-I program	Behavioral: Internet Cognitive Behavioral Therapy for Insomnia (CBT-I); 6-week internet CBT-I multi-component intervention (SHUTi) including sleep restriction, stimulus control, cognitive restructuring, sleep behaviors, and relapse prevention; Other Names: SHUTi
Experimental: Combination; Medication (zolpidem or trazodone) as prescribed by physician and Internet-based CBT-I program	Drug: Zolpidem; Zolpidem, as prescribed by physician; Other Names: Ambien; Drug: Trazodone; Trazodone, as prescribed by physician; Other Names: Desyrel; Behavioral: Internet Cognitive Behavioral Therapy for Insomnia (CBT-I); 6-week internet CBT-I multi-component intervention (SHUTi) including sleep restriction, stimulus control, cognitive restructuring, sleep behaviors, and relapse prevention; Other Names: SHUTi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Insomnia Symptom Severity	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. Change is estimated mean change from mixed-effects linear regression model. Fixed effects: Baseline ISI, Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site.	Baseline, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Response of 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. Data presented as count of participants meeting treatment response criteria at 6 months.	Baseline, 6 months
Number of Participants With Remission of Insomnia Symptoms	Remission of Insomnia symptoms 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. Data presented as count of participants meeting insomnia remission criteria at 6 months.	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Anxiety and Depression	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-7) 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. Change is estimated mean change in mixed-effects linear regression model. Fixed effects: Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site.	Baseline, 6 months
Change in Cognitive Function	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) and the total raw score is converted to standardized T-scores using established United States general adult population with a mean of 50 and a standard deviation of 10. Higher T-scores signify better cognitive function. Estimated mean change in T-score from baseline to follow-up is reported from mixed-effects linear regression model. Fixed effects: Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site. Positive change indicates improved cognitive function.	Baseline, 6 months
Change in Patient-Reported Health	The PROMIS Global Health is a 10-item self-report measure that assess general health and functioning. 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). Physical and mental health sub-scores are calculated from 4 items each, and the total raw sub-scores (range: 4-20) are converted to T-scores using distributions standardized to mean 50 (SD 10) for the US general population. Higher score indicates greater health-related quality of life. The Medical Outcome Survey (SF-12) is a 12-item self-report measure of physical and mental health. The Physical Component Score (PCS) and Mental Component Score (MCS) sub-scores range 0-100; higher score indicates better health. Change is estimated mean change from baseline to follow-up in mixed-effects linear regression model. Fixed effects: Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site.	Baseline, 6 months
Change in Fatigue	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. Change is estimated mean change from mixed-effects linear regression model. Fixed effects: Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site.	Baseline, 6 months
Change in Pain Intensity and Interference	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. Change is estimated mean change from mixed-effects linear regression model. Fixed effects: Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site.	Baseline, 6 months
Change in Pittsburgh Sleep Quality Index	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 total score indicates worse sleep quality. Change is estimated mean change from mixed-effects linear regression model. Fixed effects: Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site.	Baseline, 6 months
Change in Daytime Sleepiness	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) with higher scores indicating more sleepiness. Change is estimated mean change from mixed-effects linear regression model. Fixed effects: Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site.	Baseline, 6 months
Change in Munich Chronotype	The Munich Chronotype Questionnaire (MCTQ) is a self-report scale to assess sleep structure, patterns, duration, and quality. The chronotype sub-score represents the mid-point time of sleep which is converted to a numeric value by adding the hour plus minutes divided by 60. Greater values indicate later chronotype. Positive change values indicate a shift to later chronotype. Change is estimated mean change from mixed-effects linear regression model. Fixed effects: Treatment Arm, Visit and Treatment Arm*Visit interaction. Random effects: intercept for Subject, nested within Site.	Baseline, 6 months
Dysfunctional Beliefs and Attitudes About Sleep	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.	Baseline, 6 months
Number of Participants With Insomnia Treatment Side Effects	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). Side effects were analyzed if participant reported severity of greater than moderate and/or frequency greater than 50% of the time. Count of participants meeting the threshold for analysis up through the 6 month follow-up.	1 month, 9 weeks, 6 months
Medication Adherence	Medication use is assessed using self-reported prescription, over-the-counter, and supplement name and frequency. Count of participants reporting zolpidem or trazodone use for sleep is recorded for adherence to the Medication and Combination treatment arms.	1 month, 9 weeks, 6 months, 9 months, 12 months
Self-reported Falls	Participants self-reported number of falls including context, location, and consequences of falls. Count of participants with one or more falls up through the 6 month follow-up.	1 month, 9 weeks, 6 months

Collaborators and Investigators

• Sponsor: California Pacific Medical Center Research Institute
• Collaborators: Patient-Centered Outcomes Research Institute; University of Pittsburgh; University of Illinois at Chicago; University of Virginia; University of Arizona
• Investigators: Principal Investigator: Daniel J. Buysse, MD, University of Pittsburgh; Principal Investigator: Katie L. Stone, PhD, California Pacific Medical Center/Sutter Bay Hospitals

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2022
• Primary Completion (Actual): June 30, 2024
• Study Completion (Actual): June 30, 2024

Study Registration Dates

• First Submitted: June 26, 2020
• First Submitted That Met QC Criteria: July 8, 2020
• First Posted (Actual): July 13, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 3, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Primary Care; Insomnia; Zolpidem; Rural; Trazodone; Chronic Insomnia; CBT-I; Comparative Effectiveness; Ambien; Pragmatic Clinical Trial; Cognitive-behavioral therapy for insomnia
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Initiation and Maintenance Disorders; Sleep Aids, Pharmaceutical; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Neurotransmitter Agents; Membrane Transport Modulators; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Neurotransmitter Uptake Inhibitors; Antidepressive Agents; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Antidepressive Agents, Second-Generation; GABA-A Receptor Agonists; GABA Agonists; Zolpidem; Trazodone
• Other Study ID Numbers: CER-2018C2-13262 (Other Grant/Funding Number: Patient-Centered Outcomes Research Institute)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No