Complex Insomnia
Conditions
Keywords
post traumatic stress disorder, complex insomnia, cognitive behavioral therapy, eszopiclone
Brief summary
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.
Detailed description
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.
Interventions
DRUGeszopiclone
Eszopiclone is a nonbenzodiazepine benzodiazepine receptor agonists, effective for both sleep onset insomnia and sleep maintenance insomnia
BEHAVIORALBrief 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.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age \>18 years and \<65 years old * Diagnosis of PTSD as determined by the intake conducted through the PTSD Clinic or the Mental Health Clinic * Documented obstructive sleep apnea by polysomnography (AHI 5 or more/hour) who are non-adherent to CPAP as defined by device usage of less than 4 hours per night * Chronic ( 3 months' duration) insomnia disorder * Psychotherapeutic treatment stable for at least 4 weeks prior to randomization * Capable of giving informed consent
Exclusion criteria
* Insomnia secondary to pain * History of narcolepsy and/or cataplexy * Treatment for seizure disorders * Pregnant or lactating * History of clinically significant hepatic impairment * History of hypersensitivity, intolerance, or contraindication to eszopiclone * Use of potent cytochrome p450 3A4 inhibitor medications (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, troleandomycin, ketoconazole, itraconazole) and is unwilling or it is clinically contraindicated to stop the medication * Unwilling to try or use CPAP * Diagnosis of current schizophrenia or schizoaffective disorder * Diagnosis of a substance dependence/abuse disorder in the past year * History of complex nocturnal behaviors while using eszopiclone * Severe psychiatric instability or severe situational life crises, including evidence of being actively suicidal or homicidal, or any behavior which poses an immediate danger to patient or others * Diagnosis of bipolar disorder * Consumption of more than two alcoholic beverages per night * Documented or self-reported resolution of insomnia from current behavioral or pharmacological treatment of insomnia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pittsburgh Sleep Quality Index (PSQI) (32) at 6 Months Post-randomization | repeated measures between baseline and 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in PTSD Checklist-5 (PCL-5) | repeated measures between baseline and 6 months post randomization | 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. |
| Change in Insomnia Severity Index (ISI) | repeated measures between baseline and 6 months post randomization | 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. |
| Change in Beck Depression Inventory-II (BDI-II) | repeated measures between baseline and 6 months post randomization | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| CPAP Adherence | repeated measures between baseline and 6 months post randomization | 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. |
Countries
United States
Participant flow
Recruitment details
During the period extending from January 4th, 2020, and December 28th, 2023, we assessed 425 veterans with PTSD for eligibility.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 26 |
| 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. | 27 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 6 |
Baseline characteristics
| Characteristic | BBTI Plus Eszopiclone | BBTI | Total |
|---|---|---|---|
| Age, Continuous | 48.0 years STANDARD_DEVIATION 7.3 | 48.4 years STANDARD_DEVIATION 9.3 | 48.2 years STANDARD_DEVIATION 8.1 |
| Apnea-Hypopnea Index (AHI) | 29.2 events per hour STANDARD_DEVIATION 22.9 | 32.7 events per hour STANDARD_DEVIATION 25.3 | 31.0 events per hour STANDARD_DEVIATION 24.1 |
| Beck Depression Inventory (BDI) | 15.7 units on a scale STANDARD_DEVIATION 8.5 | 16.1 units on a scale STANDARD_DEVIATION 13.1 | 15.9 units on a scale STANDARD_DEVIATION 11.1 |
| BMI | 32.8 kg.m(-2) STANDARD_DEVIATION 6.8 | 33.0 kg.m(-2) STANDARD_DEVIATION 6.6 | 32.9 kg.m(-2) STANDARD_DEVIATION 6.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 27 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Insomnia Severity Index (ISI) | 18.2 units on a scale STANDARD_DEVIATION 4.3 | 18.7 units on a scale STANDARD_DEVIATION 4.1 | 18.3 units on a scale STANDARD_DEVIATION 4.2 |
| Pittsburgh Sleep Quality Index (PSQI) | 13.0 units on a scale STANDARD_DEVIATION 3.4 | 13.7 units on a scale STANDARD_DEVIATION 2.7 | 13.4 units on a scale STANDARD_DEVIATION 3.1 |
| PTSD checklist-5 (PCL-5) | 34.5 units on a scale STANDARD_DEVIATION 11.5 | 30.1 units on a scale STANDARD_DEVIATION 12.8 | 32.2 units on a scale STANDARD_DEVIATION 12.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 8 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 21 Participants | 18 Participants | 39 Participants |
| Region of Enrollment United States | 26 participants | 27 participants | 53 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 22 Participants | 24 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 27 |
| other Total, other adverse events | 4 / 26 | 1 / 27 |
| serious Total, serious adverse events | 0 / 26 | 0 / 27 |
Outcome results
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.
Time frame: repeated measures between baseline and 6 months post randomization
Population: All analyses were based on the intention-to-treat principle
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BBTI Plus Eszopiclone | Change in Pittsburgh Sleep Quality Index (PSQI) (32) at 6 Months Post-randomization | -5.25 units on a scale |
| BBTI | Change in Pittsburgh Sleep Quality Index (PSQI) (32) at 6 Months Post-randomization | -5.45 units on a scale |
Comparison: The sample size selected for this preliminary trial was based on the analysis of the PSQI as the primary outcome. Assuming a correlation coefficient of 0.7 between pre-and post-treatment, 21 patients per arm were needed to achieve 80% power at a significance level of 5% in order to detect a clinically significant difference of 3 units in PSQI. To compensate for an anticipated attrition rate of 25%, the recruitment target was set at 52 participants.p-value: 0.05Mixed Models Analysis
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.
Time frame: repeated measures between baseline and 6 months post randomization
Population: All analyses were based on the intention-to-treat principle
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BBTI Plus Eszopiclone | Change in Beck Depression Inventory-II (BDI-II) | -4.34 units on a scale |
| BBTI | Change in Beck Depression Inventory-II (BDI-II) | -3.07 units on a scale |
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.
Time frame: repeated measures between baseline and 6 months post randomization
Population: All analyses were based on the intention-to-treat principle
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BBTI Plus Eszopiclone | Change in Insomnia Severity Index (ISI) | -8.32 units on a scale |
| BBTI | Change in Insomnia Severity Index (ISI) | -8.64 units on a scale |
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.
Time frame: repeated measures between baseline and 6 months post randomization
Population: All analyses were based on the intention-to-treat principle
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BBTI Plus Eszopiclone | Change in PTSD Checklist-5 (PCL-5) | -10.63 units on a scale |
| BBTI | Change in PTSD Checklist-5 (PCL-5) | -4.46 units on a scale |
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.
Time frame: repeated measures between baseline and 6 months post randomization
Population: All analyses were based on the intention-to-treat principle
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BBTI Plus Eszopiclone | CPAP Adherence | 37.15 percentage of participants |
| BBTI | CPAP Adherence | 16.85 percentage of participants |