<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04468776</url>
  </required_header>
  <id_info>
    <org_study_id>CER-2018C2-13262</org_study_id>
    <secondary_id>CER-2018C2-13262</secondary_id>
    <nct_id>NCT04468776</nct_id>
  </id_info>
  <brief_title>CBT-I or Zolpidem/Trazodone for Insomnia</brief_title>
  <acronym>COZI</acronym>
  <official_title>Comparative Effectiveness of Zolpidem/Trazodone and Cognitive Behavioral Therapy for Insomnia in Rural Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>California Pacific Medical Center Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Patient-Centered Outcomes Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Arizona</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Virginia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Illinois at Chicago</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>California Pacific Medical Center Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is a randomized (1:1:1) comparative effectiveness trial of medication (zolpidem or&#xD;
      trazodone), cognitive-behavioral therapy for insomnia (CBT-I), and the combination&#xD;
      (medication + CBT-I) for the treatment of chronic insomnia in men and women aged 18-80 living&#xD;
      in rural areas with 1 year of follow-up. A total of 1200 participants will be enrolled and&#xD;
      randomized in the United States. This trial is funded by the Patient-Centered Outcomes&#xD;
      Research Institute.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Insomnia is a common health problem that causes distress, impaired function, and increased&#xD;
      risk for other health problems. Chronic insomnia is defined by problems with the quality or&#xD;
      amount of sleep, including difficulty falling asleep, frequent awakenings, and/or awakening&#xD;
      early and being unable to return to sleep. In developing this application, patients,&#xD;
      providers, payors, and the investigators identified both concerns and opportunities with&#xD;
      current treatments for chronic insomnia. Medications and Cognitive-Behavioral therapy for&#xD;
      insomnia (CBT-I; a treatment program to improve sleep through changes in behavior and&#xD;
      thinking) are both effective for treating insomnia. Zolpidem, the most frequently prescribed&#xD;
      insomnia medication, is widely available, but may cause side effects and dependency.&#xD;
      Trazodone is increasingly prescribed off-label for treatment of insomnia, but evidence of&#xD;
      efficacy and safety is more limited. CBT-I is the recommended first line treatment by many&#xD;
      professional organizations, but it is not widely available in physicians' practices.&#xD;
      Patients, providers, and payors face important unanswered questions: Which treatment should&#xD;
      be used for the treatment of chronic insomnia? Is combination therapy more effective, and&#xD;
      does it result in lower zolpidem use? Who responds best to which treatment? These dilemmas&#xD;
      are particularly relevant to patients and providers in rural areas, where access to&#xD;
      behavioral health specialists is limited, and concerns regarding use of controlled substances&#xD;
      is particularly acute.&#xD;
&#xD;
      To address these questions, we propose the study, Comparative Effectiveness of&#xD;
      Zolpidem/Trazodone and Cognitive Behavioral Therapy for Insomnia in Rural Adults (COZI). The&#xD;
      investigators will use a well-tested Internet version of CBT-I, which is just as effective as&#xD;
      in-person CBT-I, but more widely available. The aims of COZI are to: 1: Compare the&#xD;
      effectiveness of medication preference (zolpidem or trazodone), CBT-I, and combination&#xD;
      treatment for insomnia symptoms over 12 months. 2: Compare the effectiveness of medication&#xD;
      preference, CBT-I, and combination treatment for other symptoms and problems, including&#xD;
      health-related quality of life, mood, and health outcomes. 3: Compare the side effects of&#xD;
      medication preference, CBT-I, and combination treatment. 4: Conduct an exploratory analysis&#xD;
      of heterogeneity of treatment effects for common factors (age, gender, socio-economic status,&#xD;
      degree or rurality, and other factors). COZI will study 1200 patients (400 per treatment)&#xD;
      recruited from 8 health care systems across the country, each of which has established&#xD;
      practices in rural areas. Patients will be treated with medication prescribed by their own&#xD;
      physician (zolpidem or trazodone), Internet CBT-I, or a combination of the two. The&#xD;
      investigators will evaluate treatment effects at 9 weeks, and 6 and 12 months (with limited&#xD;
      additional assessments for adverse events and medication use at 1 and 9 months). Our study&#xD;
      questions and design reflect early and ongoing engagement of key stakeholders including&#xD;
      patients, providers, and payors, who are members of the Study Advisory Committee (SAC). SAC&#xD;
      members will work with study investigators to recommend the best strategies for recruiting&#xD;
      patients, measuring treatment effects, and disseminating study findings. The SAC will meet&#xD;
      quarterly. Patients and other stakeholders have already provided guidance on which treatments&#xD;
      are most worth studying, and which symptoms would best reflect the effects of treatment.&#xD;
      Patients and other stakeholders will also be part of the Steering Committee, which is the&#xD;
      main decision-making group for our study, and which will meet monthly. COZI will lead to&#xD;
      answers for patients and providers addressing insomnia; improved health and function for&#xD;
      millions of rural Americans; and sustainable changes in how insomnia is treated in rural&#xD;
      practices.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 25, 2022</start_date>
  <completion_date type="Anticipated">May 2024</completion_date>
  <primary_completion_date type="Anticipated">May 2024</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Investigator, Outcomes Assessor)</masking>
    <masking_description>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.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Insomnia Symptoms</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment Response of Insomnia Symptoms</measure>
    <time_frame>9 weeks, 6 months, 12 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Remission of Insomnia Symptoms</measure>
    <time_frame>9 weeks, 6 months, 12 months</time_frame>
    <description>Remission of Insomnia defined as Insomnia Severity Index &lt;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.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Anxiety and Depression</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.&#xD;
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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pittsburgh Sleep Quality Index</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Daytime Sleepiness</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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).</description>
  </other_outcome>
  <other_outcome>
    <measure>Cognitive Function</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Patient-Reported Health</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.&#xD;
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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Insomnia Treatment Side Effects</measure>
    <time_frame>1 month, 9 weeks, 6 months, 9 months, 12 months</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Falls</measure>
    <time_frame>Baseline, 1 month, 9 weeks, 6 months, 9 months, 12 months</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Medications</measure>
    <time_frame>Baseline, 1 month, 9 weeks, 6 months, 9 months, 12 months</time_frame>
    <description>Medication use is assessed using self-reported prescription, over-the-counter, and supplement name and frequency.</description>
  </other_outcome>
  <other_outcome>
    <measure>Fatigue</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pain Intensity and Interference</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.&#xD;
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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Munich Chronotype Questionnaire</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Dysfunctional Beliefs and Attitudes about Sleep</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Other factors that may affect treatment response (exploratory)</measure>
    <time_frame>Baseline, 9 weeks, 6 months, 12 months</time_frame>
    <description>Sleep diary, Covid-19, nocturia symptoms, treatment expectancy, treatment satisfaction, tobacco use, alcohol use, caffeine use, demographics, and medical history.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">1200</enrollment>
  <condition>Chronic Insomnia</condition>
  <arm_group>
    <arm_group_label>Medication (zolpidem or trazodone)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Zolpidem or trazodone, as prescribed by physician</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Internet Cognitive Behavioral Therapy for Insomnia (CBT-I)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Internet-based CBT-I program</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Combination</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Medication (zolpidem or trazodone) as prescribed by physician and Internet-based CBT-I program</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Zolpidem</intervention_name>
    <description>Zolpidem, as prescribed by physician</description>
    <arm_group_label>Combination</arm_group_label>
    <arm_group_label>Medication (zolpidem or trazodone)</arm_group_label>
    <other_name>Ambien</other_name>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Internet Cognitive Behavioral Therapy for Insomnia (CBT-I)</intervention_name>
    <description>6-week internet CBT-I multi-component intervention (SHUTi) including sleep restriction, stimulus control, cognitive restructuring, sleep behaviors, and relapse prevention</description>
    <arm_group_label>Combination</arm_group_label>
    <arm_group_label>Internet Cognitive Behavioral Therapy for Insomnia (CBT-I)</arm_group_label>
    <other_name>SHUTi</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trazodone</intervention_name>
    <description>Trazodone, as prescribed by physician</description>
    <arm_group_label>Combination</arm_group_label>
    <arm_group_label>Medication (zolpidem or trazodone)</arm_group_label>
    <other_name>Desyrel</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-80&#xD;
&#xD;
          -  Insomnia Severity Index score &gt; 10&#xD;
&#xD;
          -  Regular internet and computer access&#xD;
&#xD;
          -  Receives primary care in a Non-metropolitan/Rural residence&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of hypnotic medication &gt;2 times in the past week&#xD;
&#xD;
          -  Current cognitive or cognitive behavioral treatment for insomnia&#xD;
&#xD;
          -  Psychotic disorder&#xD;
&#xD;
          -  Bipolar disorder&#xD;
&#xD;
          -  Current substance use disorder&#xD;
&#xD;
          -  Severe Chronic obstructive pulmonary disease (COPD) or other severe pulmonary disease&#xD;
             (such as asthma or lung fibrosis)&#xD;
&#xD;
          -  Cognitive impairment or dementia&#xD;
&#xD;
          -  History of spontaneous or hypnotic-induced complex sleep behavior&#xD;
&#xD;
          -  Delayed sleep phase disorder (DSPD)&#xD;
&#xD;
          -  Shift work that includes working the night shift (between the hours of 12:00 a.m. -&#xD;
             6:00 a.m.)&#xD;
&#xD;
          -  History of fracture or injurious fall in the past 12 months&#xD;
&#xD;
          -  Currently pregnant, planning to become pregnant, or breastfeeding&#xD;
&#xD;
          -  Other severe or uncontrolled mental or physical disorders that would make&#xD;
             participation difficult or unsafe&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Katie L. Stone, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>California Pacific Medical Center/Sutter Bay Hospitals</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Daniel J. Buysse, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Arizona</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85721</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California, San Francisco-Fresno</name>
      <address>
        <city>Fresno</city>
        <state>California</state>
        <zip>93701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sutter Health</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Jewish Health</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80206</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Missouri</name>
      <address>
        <city>Columbia</city>
        <state>Missouri</state>
        <zip>65212</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Penn State Hershey Medical Center</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 26, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 13, 2020</study_first_posted>
  <last_update_submitted>June 2, 2023</last_update_submitted>
  <last_update_submitted_qc>June 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Insomnia</keyword>
  <keyword>Chronic Insomnia</keyword>
  <keyword>Zolpidem</keyword>
  <keyword>Ambien</keyword>
  <keyword>Cognitive-behavioral therapy for insomnia</keyword>
  <keyword>CBT-I</keyword>
  <keyword>Rural</keyword>
  <keyword>Primary Care</keyword>
  <keyword>Pragmatic Clinical Trial</keyword>
  <keyword>Comparative Effectiveness</keyword>
  <keyword>Trazodone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sleep Initiation and Maintenance Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Zolpidem</mesh_term>
    <mesh_term>Trazodone</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04468776
org study id: CER-2018C2-13262
secondary id: CER-2018C2-13262
nct id: NCT04468776
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: 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.
primary purpose: Treatment
masking: Double (Investigator, Outcomes Assessor)
masking description: 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.
measure: Insomnia Symptoms
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Treatment Response of Insomnia Symptoms
time frame: 9 weeks, 6 months, 12 months
description: 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.
measure: Remission of Insomnia Symptoms
time frame: 9 weeks, 6 months, 12 months
description: 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.
measure: Anxiety and Depression
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Pittsburgh Sleep Quality Index
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Daytime Sleepiness
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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).
measure: Cognitive Function
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Patient-Reported Health
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Insomnia Treatment Side Effects
time frame: 1 month, 9 weeks, 6 months, 9 months, 12 months
description: 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.
measure: Falls
time frame: Baseline, 1 month, 9 weeks, 6 months, 9 months, 12 months
description: 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.
measure: Medications
time frame: Baseline, 1 month, 9 weeks, 6 months, 9 months, 12 months
description: Medication use is assessed using self-reported prescription, over-the-counter, and supplement name and frequency.
measure: Fatigue
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Pain Intensity and Interference
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Munich Chronotype Questionnaire
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Dysfunctional Beliefs and Attitudes about Sleep
time frame: Baseline, 9 weeks, 6 months, 12 months
description: 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.
measure: Other factors that may affect treatment response (exploratory)
time frame: Baseline, 9 weeks, 6 months, 12 months
description: Sleep diary, Covid-19, nocturia symptoms, treatment expectancy, treatment satisfaction, tobacco use, alcohol use, caffeine use, demographics, and medical history.
arm group label: Medication (zolpidem or trazodone)
arm group type: Active Comparator
description: Zolpidem or trazodone, as prescribed by physician
arm group label: Internet Cognitive Behavioral Therapy for Insomnia (CBT-I)
arm group type: Active Comparator
description: Internet-based CBT-I program
arm group label: Combination
arm group type: Experimental
description: Medication (zolpidem or trazodone) as prescribed by physician and Internet-based CBT-I program
intervention type: Drug
intervention name: Zolpidem
description: Zolpidem, as prescribed by physician
arm group label: Combination
arm group label: Medication (zolpidem or trazodone)
other name: Ambien
intervention type: Behavioral
intervention name: Internet Cognitive Behavioral Therapy for Insomnia (CBT-I)
description: 6-week internet CBT-I multi-component intervention (SHUTi) including sleep restriction, stimulus control, cognitive restructuring, sleep behaviors, and relapse prevention
arm group label: Combination
arm group label: Internet Cognitive Behavioral Therapy for Insomnia (CBT-I)
other name: SHUTi
intervention type: Drug
intervention name: Trazodone
description: Trazodone, as prescribed by physician
arm group label: Combination
arm group label: Medication (zolpidem or trazodone)
other name: Desyrel
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Katie L. Stone, PhD
role: Principal Investigator
affiliation: California Pacific Medical Center/Sutter Bay Hospitals
last name: Daniel J. Buysse, MD
role: Principal Investigator
affiliation: University of Pittsburgh
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country: United States
responsible party type: Sponsor
mesh term: Sleep Initiation and Maintenance Disorders
mesh term: Zolpidem
mesh term: Trazodone