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Obstructive sleep apnea (OSA) is commonly reported in Veterans with post-traumatic stress disorder, which can potentiate symptoms of anxiety and depression, daytime symptoms and worsen nightmares. Continuous positive airway pressure (CPAP) is the most effective therapy but adherence to treatment is suboptimal. Insomnia is considered a barrier to long-term adherence. The overarching theme of the proposal is to compare the effectiveness of cognitive behavioral therapy for insomnia (CBT) plus eszopiclone, a nonbenzodiazepine hypnotic, versus CBT alone in Veterans with PTSD who are diagnosed with both OSA and insomnia, using a randomized, clinical trial, on sleep quality of life, PTSD severity, and CPAP adherence.
As many as 90% of Veterans with posttraumatic stress disorder (PTSD) report nightmares and insomnia and even when nightmares are excluded, sleep disturbances are the most prevalent symptoms of PTSD with roughly 50%-70% of patients suffering from co-occurring sleep disorders. The typical sleep complaints include nightmares, distressed awakenings, nocturnal panic attacks, sleep terrors and insomnia.
While it has long been established that PTSD engenders sleep disturbances and averse clinical outcomes, current investigations indicate that disordered sleep is also a risk factor for the development of PTSD. In military personnel with combat exposure, comorbid insomnia and OSA, a condition originally labeled as "complex insomnia" has emerged as one of the most challenging sleep disorder to manage. In the presence of PTSD, the co-occurrence of OSA and insomnia is also associated with significant morbidity. Veterans with both PTSD and complex insomnia report more psychiatric symptoms, chronic pain, and higher rates of suicide. Further, these Veterans may have more difficulty adhering to CPAP because of increased awareness of the mask due to frequent awakenings and an inability to initiate or return to sleep with the mask in place. Fortunately, there are effective treatments for each of these sleep disorders. Traditional treatment models consist of treating OSA first, followed by adjunctive or concurrent treatment for insomnia only if the response to CPAP is deemed unsatisfactory. However, the suboptimal response observed in Veterans with PTSD from such an approach in terms of quality of life, PTSD symptoms, and CPAP adherence highlights the need to examine alternative modalities of treatment. At present, there are no general guidelines on the best strategy to treat complex insomnia in Veterans with PTSD. Prior studies have shown that cognitive behavioral therapy (CBT) is effective for treating insomnia when compared with hypnotic agents.Whether combination therapy offers a therapeutic advantage over CBT alone for complex insomnia in Veterans with PTSD is yet to be determined. The objective of this proposal is to conduct a pragmatic, randomized, parallel clinical trial comparing the effectiveness of Brief Behavioral Therapy for Insomnia in Military Veterans (BBTI-MV) plus eszopiclone, a non-benzodiazepine hypnotic, versus BBTI-MV alone in 52 combat-exposed Veterans with PTSD and OSA with coexisting insomnia on global sleep quality of life, PTSD symptoms, and CPAP adherence. The topic addresses several key areas of unmet needs for Veterans with PTSD and sleep disordered breathing. Among these are: 1) the association between complex insomnia and PTSD on global sleep quality of life; and 2) the effectiveness of combined treatment of CBT and eszopiclone versus CBT alone in improving sleep quality and PTSD symptoms; and 3) the impact of each treatment regimen on CPAP adherence. By establishing the most effective therapy in alleviating insomnia that complicates the presence of OSA in Veterans with PTSD, higher CPAP adherence will ultimately translate into improved cognitive function, enhanced quality of life, and suppression of PTSD symptoms. The long term benefit of this trial will also lead to opportunities for more personalized treatment including delivery method via mobile health technologies which will allow greater assimilation of results across several domains.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| BBTI plus eszopiclone | Experimental | participants randomized to the combination therapy will receive eszopiclone 2 mg orally at bedtime or placebo starting with the BBTI sessions for a period of 2 weeks in combination with 4 sessions of BBTI over 4 weeks. |
|
| Brief Behavioral Therapy for Insomnia | Active Comparator | participants randomized to BBTI will receive 4 sessions of BBTI over 4 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| eszopiclone | Drug | Eszopiclone is a nonbenzodiazepine benzodiazepine receptor agonists, effective for both sleep onset insomnia and sleep maintenance insomnia |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Pittsburgh Sleep Quality Index (PSQI) (32) at 6 Months Post-randomization | The Pittsburgh Sleep Quality Index is a 19-item, self-rated questionnaire, assessed various aspects of sleep, sleep quality, and sleep disturbances. The PSQI is composed of 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these 7 components yields 1 global score. An overall score ranges from 0 to 21, where lower scores denote a healthier sleep quality. | repeated measures between baseline and 6 months post randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Change in PTSD Checklist-5 (PCL-5) | PCL-5 is a 20-item self-report measures that have been widely used in military and civilian population to assess the severity of PTSD symptoms. A total symptom severity score (range 0-80) can be obtained by summing the scores from each of the 20 items that have response options from 0 "not at all" to 4 "extremely". Higher score indicates worse symptoms. | repeated measures between baseline and 6 months post randomization |
| Measure | Description | Time Frame |
|---|---|---|
| CPAP Adherence | CPAP adherence will be obtained by downloading the data stored on the SmartCard. CPAP adherence is defined as the use of CPAP for 4 hours or more per night during a 28 consecutive day period. The outcome measure is the percentage of patients who met the definition of CPAP adherence based on the last 28 days prior to the 6 month time point. | repeated measures between baseline and 6 months post randomization |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ali A El-Solh, MD MPH | VA Western New York Healthcare System, Buffalo, NY | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA Western New York Healthcare System, Buffalo, NY | Buffalo | New York | 14215-1129 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40202618 | Derived | El-Solh AA, Lawson Y, Martinson A, Wilding G. Cognitive Behavioral Therapy Alone or in Combination with Eszopiclone in Comorbid Insomnia and Obstructive Sleep Apnea in Veterans with Posttraumatic Stress Disorder: A Randomized Trial. Psychiatr Q. 2025 Dec;96(4):787-802. doi: 10.1007/s11126-025-10143-9. Epub 2025 Apr 9. |
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Final de-identified data sets will be made available upon specific request and under and authorized DUA. This, in addition to the publications being made available via PubMed Central will enable validation of results by recipients.
The de-identified data will be available after the primary manuscript is published
The de-identified data will be available after the primary manuscript is published for a period of 6 years
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Three hundred sixty-three Veterans were excluded because of prior treatment with CBT-I and/or active use of hypnotics (81%), presence of concurrent active medical or unstable psychiatric conditions (5%), active substance abuse (1%), documented sleep disorders other than COMISA (4%), or unable to commit for the duration of the trial (9%). Of the 62 veterans who met eligibility, nine did not meet the criteria for clinical insomnia by ISI.
During the period extending from January 4th, 2020, and December 28th, 2023, we assessed 425 veterans with PTSD for eligibility.
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| ID | Title | Description |
|---|---|---|
| FG000 | BBTI Plus Eszopiclone | participants randomized to the combination therapy will receive eszopiclone 2 mg orally at bedtime or placebo starting with the BBTI sessions for a period of 2 weeks in combination with 4 sessions of BBTI over 4 weeks. eszopiclone: Eszopiclone is a nonbenzodiazepine benzodiazepine receptor agonists, effective for both sleep onset insomnia and sleep maintenance insomnia Brief behavioral therapy for insomnia: BBTI is based on the core principles that are fundamental to other empirically-supported behavioral treatments of insomnia delivered over four consecutive weeks. |
| FG001 | BBTI | participants randomized to BBTI will receive 4 sessions of BBTI over 4 weeks. Brief behavioral therapy for insomnia: BBTI is based on the core principles that are fundamental to other empirically-supported behavioral treatments of insomnia delivered over four consecutive weeks. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | BBTI Plus Eszopiclone | participants randomized to the combination therapy will receive eszopiclone 2 mg orally at bedtime or placebo starting with the BBTI sessions for a period of 2 weeks in combination with 4 sessions of BBTI over 4 weeks. eszopiclone: Eszopiclone is a nonbenzodiazepine benzodiazepine receptor agonists, effective for both sleep onset insomnia and sleep maintenance insomnia Brief behavioral therapy for insomnia: BBTI is based on the core principles that are fundamental to other empirically-supported behavioral treatments of insomnia delivered over four consecutive weeks. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Pittsburgh Sleep Quality Index (PSQI) (32) at 6 Months Post-randomization | The Pittsburgh Sleep Quality Index is a 19-item, self-rated questionnaire, assessed various aspects of sleep, sleep quality, and sleep disturbances. The PSQI is composed of 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these 7 components yields 1 global score. An overall score ranges from 0 to 21, where lower scores denote a healthier sleep quality. | All analyses were based on the intention-to-treat principle | Posted | Mean | 95% Confidence Interval | units on a scale | repeated measures between baseline and 6 months post randomization |
|
6 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | BBTI Plus Eszopiclone | participants randomized to the combination therapy will receive eszopiclone 2 mg orally at bedtime or placebo starting with the BBTI sessions for a period of 2 weeks in combination with 4 sessions of BBTI over 4 weeks. eszopiclone: Eszopiclone is a nonbenzodiazepine benzodiazepine receptor agonists, effective for both sleep onset insomnia and sleep maintenance insomnia Brief behavioral therapy for insomnia: BBTI is based on the core principles that are fundamental to other empirically-supported behavioral treatments of insomnia delivered over four consecutive weeks. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Associate Chief of Staff for Research | VA ORD | 716-862-6528 | ali.el-solh@va.gov |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 5, 2020 | Jul 7, 2025 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 23, 2020 | Apr 24, 2023 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D013313 | Stress Disorders, Post-Traumatic |
| ID | Term |
|---|---|
| D040921 | Stress Disorders, Traumatic |
| D000068099 | Trauma and Stressor Related Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D000069582 | Eszopiclone |
| ID | Term |
|---|---|
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011719 | Pyrazines |
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A randomized comparator 1:1 to explore the comparative effectiveness of combination treatment of behavioral and pharmacological interventions with behavioral therapy alone in improving sleep quality of life, Veterans with PTSD and complex insomnia.
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| Brief behavioral therapy for insomnia | Behavioral | BBTI is based on the core principles that are fundamental to other empirically-supported behavioral treatments of insomnia delivered over four consecutive weeks. |
|
|
| Change in Insomnia Severity Index (ISI) | The ISI is a 7-item patient-reported outcome assessing the severity of initial, middle, and late insomnia; sleep satisfaction; interference of insomnia with daytime functioning; noticeability of sleep problems by others; and distress about sleep difficulties. The 5 point scale provides a score ranging from 0 to 28 with higher scores indicating more severe insomnia. | repeated measures between baseline and 6 months post randomization |
| Change in Beck Depression Inventory-II (BDI-II) | The BDI-II is a 21-item questionnaire in which respondents indicate on a four-point Likert-type scale (0=minimal to 3=severe) the presence and severity of depressive symptoms during the past 2 weeks. Items are scored on a 4-point scale ranging from 0 to 3, with higher scores indicating the presence of more depressive symptoms. The BDI-score ranges from 0 to 63. Higher scores indicate worse outcomes. | repeated measures between baseline and 6 months post randomization |
| BG001 | BBTI | participants randomized to BBTI will receive 4 sessions of BBTI over 4 weeks. Brief behavioral therapy for insomnia: BBTI is based on the core principles that are fundamental to other empirically-supported behavioral treatments of insomnia delivered over four consecutive weeks. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| BMI | Body Mass Index | Mean | Standard Deviation | kg.m(-2) |
|
| Pittsburgh Sleep Quality Index (PSQI) | Pittsburgh Sleep Quality Index. An overall score ranges from 0 to 21, where lower scores denote a healthier sleep quality. | Mean | Standard Deviation | units on a scale |
|
| PTSD checklist-5 (PCL-5) | PTSD Checklist. A total symptom severity score (range 0-80) can be obtained by summing the scores from each of the 20 items that have response options from 0 "not at all" to 4 "extremely". Higher score indicates worse symptoms. | Mean | Standard Deviation | units on a scale |
|
| Apnea-Hypopnea Index (AHI) | The Apnea-Hypopnea Index (AHI) is a metric used to assess the severity of sleep apnea. It represents the number of apneas (complete cessation of airflow) and hypopneas (partial reduction of airflow) that occur per hour of sleep. The AHI is calculated by dividing the total number of apneas and hypopneas by the total hours of sleep. the formula for calculating AHI: AHI = Number of Apneas + Number of Hypopneas Total Sleep Time in Hours AHI= Total Sleep Time in Hours Number of Apneas + Number of Hypopneas | Mean | Standard Deviation | events per hour |
|
| Beck Depression Inventory (BDI) | The Beck Depression Inventory (BDI) is a self-report questionnaire used to assess the severity of depression. The BDI consists of 21 items, each reflecting a specific symptom or attitude related to depression. Each item is scored on a scale from 0 to 3, with 0 indicating the absence of the symptom and 3 indicating a severe presence of the symptom. The total score is the sum of the scores for all 21 items, and it can range from 0 to 63. Higher scores indicate a worse outcome, reflecting more severe depressive symptoms. | Mean | Standard Deviation | units on a scale |
|
| Insomnia Severity Index (ISI) | The Insomnia Severity Index (ISI) is a self-report questionnaire used to assess the severity of insomnia in adults. The ISI consists of seven items, with each item scored on a scale from 0 to 4. The total score is the sum of the scores for all seven items, and it can range from 0 to 28.Higher scores indicate a worse outcome, reflecting more severe insomnia symptoms. | Mean | Standard Deviation | units on a scale |
|
| OG001 | BBTI | participants randomized to BBTI will receive 4 sessions of BBTI over 4 weeks. Brief behavioral therapy for insomnia: BBTI is based on the core principles that are fundamental to other empirically-supported behavioral treatments of insomnia delivered over four consecutive weeks. |
|
|
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| Secondary | Change in PTSD Checklist-5 (PCL-5) | PCL-5 is a 20-item self-report measures that have been widely used in military and civilian population to assess the severity of PTSD symptoms. A total symptom severity score (range 0-80) can be obtained by summing the scores from each of the 20 items that have response options from 0 "not at all" to 4 "extremely". Higher score indicates worse symptoms. | All analyses were based on the intention-to-treat principle | Posted | Mean | 95% Confidence Interval | units on a scale | repeated measures between baseline and 6 months post randomization |
|
|
|
| Secondary | Change in Insomnia Severity Index (ISI) | The ISI is a 7-item patient-reported outcome assessing the severity of initial, middle, and late insomnia; sleep satisfaction; interference of insomnia with daytime functioning; noticeability of sleep problems by others; and distress about sleep difficulties. The 5 point scale provides a score ranging from 0 to 28 with higher scores indicating more severe insomnia. | All analyses were based on the intention-to-treat principle | Posted | Mean | 95% Confidence Interval | units on a scale | repeated measures between baseline and 6 months post randomization |
|
|
|
| Secondary | Change in Beck Depression Inventory-II (BDI-II) | The BDI-II is a 21-item questionnaire in which respondents indicate on a four-point Likert-type scale (0=minimal to 3=severe) the presence and severity of depressive symptoms during the past 2 weeks. Items are scored on a 4-point scale ranging from 0 to 3, with higher scores indicating the presence of more depressive symptoms. The BDI-score ranges from 0 to 63. Higher scores indicate worse outcomes. | All analyses were based on the intention-to-treat principle | Posted | Mean | 95% Confidence Interval | units on a scale | repeated measures between baseline and 6 months post randomization |
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| Other Pre-specified | CPAP Adherence | CPAP adherence will be obtained by downloading the data stored on the SmartCard. CPAP adherence is defined as the use of CPAP for 4 hours or more per night during a 28 consecutive day period. The outcome measure is the percentage of patients who met the definition of CPAP adherence based on the last 28 days prior to the 6 month time point. | All analyses were based on the intention-to-treat principle | Posted | Number | percentage of participants | repeated measures between baseline and 6 months post randomization |
|
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|
| 0 |
| 26 |
| 0 |
| 26 |
| 4 |
| 26 |
| EG001 | BBTI | participants randomized to BBTI will receive 4 sessions of BBTI over 4 weeks. Brief behavioral therapy for insomnia: BBTI is based on the core principles that are fundamental to other empirically-supported behavioral treatments of insomnia delivered over four consecutive weeks. | 0 | 27 | 0 | 27 | 1 | 27 |
| Diziness | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
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| D011725 |
| Pyridines |