Study Results
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Basic Information
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ACTIVE_NOT_RECRUITING
PHASE3
673 participants
INTERVENTIONAL
2021-02-25
2026-02-28
Brief Summary
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Detailed Description
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Participants will be male and female Veterans with PTSD and moderate levels of insomnia as measured on the ISI. Veterans who meet inclusion and exclusion criteria will be randomized within each site to receive trazodone hydrochloride, eszopiclone or placebo. Permuted blocks randomization will be used within each participating site. A mid-point interim analysis will be conducted wherein active treatment arms meeting early futility stopping criteria may be dropped. If all active treatment arms are dropped at the interim analysis, the study will be stopped at that time. Otherwise, the study will continue, and the remaining sample size will be allocated to the remaining study arms with equal randomization probabilities. Study drug dose will ideally be increased using a flexible dose titration schedule over the initial 3-week period, and the maximally tolerated dose will be continued until the week 12 assessment.
The Insomnia Severity Index (ISI) is the primary outcome measure for this study. The Clinician Administered PTSD Scale for DSM-V (CAPS-5) will be the key secondary outcome measuring change in PTSD symptoms. Other secondary outcomes that measure PTSD and sleep include the PTSD Checklist (PCL-5) and Pittsburgh Sleep Quality Index Scale-Addendum for PTSD (PSQI-A). Other secondary outcomes include brief questionnaire secondary measures of comorbid depression (PHQ-9), anxiety (GAD-7), quality of life (WHOQOL-BREF), treatment satisfaction questionnaire for medication (TSQM-9), smoking and alcohol consumption (Timeline Follow-Back, or TLFB), clinical global change (CGI-S), resource utilization (Service Utilization and Resources Form, or SURF). Safety measures include: Suicide Screening Questionnaire, review of Adverse events, and measuring anger and aggression (Dimension of Anger Reaction-5, or DAR-5).
This study is designed to serve as a well-powered "screen" for efficacious medications for the treatment of PTSD-related insomnia from among the medications already widely prescribed for this purpose within VA. Thus, this study is powered to detect differences between trazodone and eszopiclone versus placebo. The 3-arm design will require a sample size of 774 in the three arms (trazodone, eszopiclone and placebo), based on a drop out rate of 10%, to provide 85% probability to establish efficacy of the two active medications (trazodone and eszopiclone) when both have an effect size of 0.35 as compared to placebo.
VA bears a unique responsibility for addressing the limited efficacy of current evidence-based pharmacotherapy practices for PTSD. Since 2001, there have been only two FDA-approved medications for PTSD, both serotonin reuptake inhibiting antidepressants (SRIs), and SRIs have limited efficacy for military-related PTSD. This "efficacy gap" results in widespread polypharmacy for PTSD in VA, such that Veterans with antidepressant-resistant symptoms are treated, on average, with more than three psychotropic medications that present risks without clear benefit. In particular, SRI-resistant insomnia in military-related PTSD is a significant problem for VA, with 88% of these patients reporting clinically significant sleep impairment. In PTSD, sleep disturbances contribute importantly to impairments in quality of life, reduced social and vocational function, suicide risk, and poorer health. Effective treatment of persisting insomnia in PTSD is a sufficiently serious unmet need that the 2017 VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder, called for "studies of non-benzodiazepine sedative/hypnotics." The purpose of the study is address this gap through testing the efficacy of three non-benzodiazepine hypnotics in comparison to placebo, representing the three medications or medication classes that are most commonly prescribed to Veterans with PTSD on an off-label basis and have yet to be tested in a definitive clinical trial. A novel aspect of this study is its implementation of an adaptive design in which arms would be dropped for evidence of futility based on pre-specified criteria at a designated interim analysis, intended to increase the efficiency of the trial and thereby improve the feasibility of its ambitious aim. The VA Cooperative Studies Program is uniquely suited to conduct this study.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Trazodone
Participants who are assigned to take trazodone, an active study medication.
Trazodone
Trazodone is approved by the Food and Drug Administration (FDA) for treating major depression in adults but not for PTSD. Although trazodone has not been approved by the FDA to treat insomnia or PTSD, some doctors have tried it for these purposes. The doses in this study will be lower than the doses used to treat depression.
Eszopiclone
Participants who are assigned to take eszopiclone, an active study medication.
Eszopiclone
Eszopiclone is approved by the FDA for treating insomnia, but it's unknown if eszopiclone can help treat insomnia when it's related to PTSD. Some doctors have tried it for this purpose. The doses in this study will be the same as the doses used to treat insomnia. A small study found it to be helpful for treating patients with PTSD.
Placebo
Participants who are assigned to take a placebo, a non-active study medication.
Placebo
The active study medications listed above will be compared with a placebo, which is a pill that looks like a study medication but has no medication in it.
Interventions
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Trazodone
Trazodone is approved by the Food and Drug Administration (FDA) for treating major depression in adults but not for PTSD. Although trazodone has not been approved by the FDA to treat insomnia or PTSD, some doctors have tried it for these purposes. The doses in this study will be lower than the doses used to treat depression.
Eszopiclone
Eszopiclone is approved by the FDA for treating insomnia, but it's unknown if eszopiclone can help treat insomnia when it's related to PTSD. Some doctors have tried it for this purpose. The doses in this study will be the same as the doses used to treat insomnia. A small study found it to be helpful for treating patients with PTSD.
Placebo
The active study medications listed above will be compared with a placebo, which is a pill that looks like a study medication but has no medication in it.
Eligibility Criteria
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Inclusion Criteria
2. Stated willingness to comply with all study procedures and availability for the duration of the study (approximately 17 weeks from the date of being randomized)
3. Individuals, between the ages of 18 and 75 years
4. Allow digital recording of phone interviews
5. PTSD related to military service
6. Primary DSM-5 diagnosis of PTSD, assessed by structured interview using the CAPS-5
7. Total CAPS-5 score 23
8. ISI \>15
9. Screening clinical laboratory tests without clinically significant abnormalities that would make study participation inappropriate, as determined by the site investigator with input, if needed, from the study chair
10. Electrocardiogram (ECG) at baseline without clinically significant abnormalities that would make study participation inappropriate, as determined by the site investigator with input, if needed, from the study chair and/or contingent upon approval by consulting medical physician.
11. Females of childbearing potential:
1. Must have a negative pregnancy test during screening
2. Must agree not to become pregnant or breastfeed during the course of the study
3. Must be willing to use a reliable form of contraception for 16 weeks (during study treatment and for 2 weeks after taking the last dose) which includes: barrier contraceptives (male or female condoms with or without a spermicide, diaphragm or cervical cap with spermicide, or intrauterine device) and hormone-based therapy (contraceptive pills, intrauterine devices, or Depo-Provera®)
4. Birth control for female participants is not necessary if surgically sterile or if with a partner with whom they are not capable of conceiving children (defined as a surgically sterile female by hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; surgically sterile male who has undergone a complete orchiectomy or successful vasectomy; or a same sex partner)
12. Agree to secure firearms while receiving study treatment
13. If individuals are undergoing evidence-based psychotherapy (EBT), which includes cognitive behavioral therapy (CBT), cognitive processing therapy (CPT), prolonged exposure therapy (PE), and/or stress inoculation therapy (SIT), they must have started these therapies at least 60 days prior to starting screening. If screening is started, and it is then discovered that EBT was started within 60 days prior to screening, participants must wait at least 60 days since staring the new EBT before they can complete the screening ISI, the screening PCL, and the Phone Assessment. (Supportive individual and group therapy is allowed)
14. Agreement to adhere to Lifestyle Considerations (see Section 5.3) throughout study participation
15. Clinical evidence of adequately treated sleep apnea or absence of sleep apnea having a severity that would make study participation problematic, established by meeting one of the criteria below:
1. Clinical evidence of adequately treated sleep apnea with a continuous positive airway pressure (CPAP) or alternative treatment device (as defined in Section 8.1) (Participants can be reevaluated at least 30 days after screen failure.)
2. If clinically tested, sleep study negative for sleep apnea or results indicating an Apnea-Hypopnea Index (AHI) \< 23 within the past 6 months
3. If tested for study eligibility, ApneaLink (or equivalent alternative device) result or other sleep study shows AHI \< 23.
Exclusion Criteria
2. Allergy and/or history of intolerance to trazodone hydrochloride and/or eszopiclone, or history of experiencing complex sleep behaviors (i.e., sleep walking, sleep driving, and/or engaging in other activities while not fully awake) while taking any sleep medication
3. A comorbid current or lifetime diagnosis of bipolar I disorder, bipolar II disorder, schizoaffective disorder, schizophrenia or delusional disorder, or current comorbid diagnosis of schizophreniform disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified (NOS) according to Structured Clinical Interview for DSM-5 (SCID)-I-RV/P
4. History of moderate or severe traumatic brain injury (TBI) or history of gross structural damage as shown on MRI.
5. Positive urine test for an illicit substance, excluding cannabis, within the past 90 days prior to screening
6. Substance use meeting DSM-5 criteria for moderate or severe dependence (excluding nicotine) within the past 12 months prior to screening. (Note: Current mild dependence for alcohol and cannabis use is acceptable, but current mild dependence of any other substances is exclusionary.)
7. Inpatient psychiatric hospitalization within 30 days prior to screening
8. Suicidal or homicidal ideation with intent or plan to harm themselves or others within 90 days prior to screening
9. Chronic liver disease with two or more of the following occurring within the past six months: international normalized ratio (INR) greater than or equal to 1.7 (not on warfarin therapy), bilirubin greater than or equal to 2 mg/dL, serum albumin less than or equal to 3.5 g/dL, ascites, or encephalopathy (Participants can be reevaluated in 30 days)
10. Clinical and laboratory evidence of untreated hypothyroidism or hyperthyroidism
11. A corrected QT (QTc) interval greater than 470 ms
12. Unstable, serious medical condition or one requiring acute medical treatment, or planned hospitalization for extended care
13. Dementia, epilepsy, stroke, or current treatment with warfarin for anticoagulation
14. Taking any of the exclusionary medications listed in Appendix A. Note- an individual taking one of these medications for the sole purpose of improving sleep that elects to undergo an adequate wash-out period of at least 5 half-lives of the parent compound or active metabolite (e.g., for medications like diazepam), under the care of the individual's clinical provider, would not be excluded by this criterion.
15. Under criminal investigation or pending legal charges with potential incarceration
16. Individuals who lack stable contact information (including lack of a telephone number)
17. Participants who anticipate working during the hours of midnight to 6am during the course of study trial
18. Participants with narcolepsy
18 Years
75 Years
ALL
No
Sponsors
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VA Office of Research and Development
FED
Responsible Party
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Principal Investigators
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John H. Krystal, MD
Role: STUDY_CHAIR
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
Locations
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Birmingham VA Medical Center, Birmingham, AL
Birmingham, Alabama, United States
Tuscaloosa VA Medical Center, Tuscaloosa, AL
Tuscaloosa, Alabama, United States
Phoenix VA Health Care System, Phoenix, AZ
Phoenix, Arizona, United States
VA Loma Linda Healthcare System, Loma Linda, CA
Loma Linda, California, United States
VA Long Beach Healthcare System, Long Beach, CA
Long Beach, California, United States
VA Palo Alto Health Care System, Palo Alto, CA
Palo Alto, California, United States
VA San Diego Healthcare System, San Diego, CA
San Diego, California, United States
San Francisco VA Medical Center, San Francisco, CA
San Francisco, California, United States
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
West Haven, Connecticut, United States
CERC (VISN1, West Haven, CT)
West Haven, Connecticut, United States
Bay Pines VA Healthcare System, Pay Pines, FL
Bay Pines, Florida, United States
Atlanta VA Medical and Rehab Center, Decatur, GA
Decatur, Georgia, United States
Edward Hines Jr. VA Hospital, Hines, IL
Hines, Illinois, United States
Overton Brooks VA Medical Center, Shreveport, LA
Shreveport, Louisiana, United States
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
Boston, Massachusetts, United States
Minneapolis VA Health Care System, Minneapolis, MN
Minneapolis, Minnesota, United States
New Mexico VA Health Care System, Albuquerque, NM
Albuquerque, New Mexico, United States
Asheville VA Medical Center, Asheville, NC
Asheville, North Carolina, United States
Durham VA Medical Center, Durham, NC
Durham, North Carolina, United States
Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
Salisbury, North Carolina, United States
Cincinnati VA Medical Center, Cincinnati, OH
Cincinnati, Ohio, United States
Louis Stokes VA Medical Center, Cleveland, OH
Cleveland, Ohio, United States
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
Philadelphia, Pennsylvania, United States
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Pittsburgh, Pennsylvania, United States
Providence VA Medical Center, Providence, RI
Providence, Rhode Island, United States
Ralph H. Johnson VA Medical Center, Charleston, SC
Charleston, South Carolina, United States
VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
Dallas, Texas, United States
Michael E. DeBakey VA Medical Center, Houston, TX
Houston, Texas, United States
South Texas Health Care System, San Antonio, TX
San Antonio, Texas, United States
VA Salt Lake City Health Care System, Salt Lake City, UT
Salt Lake City, Utah, United States
White River Junction VA Medical Center, White River Junction, VT
White River Junction, Vermont, United States
Salem VA Medical Center, Salem, VA
Salem, Virginia, United States
VA Puget Sound Health Care System Seattle Division, Seattle, WA
Seattle, Washington, United States
William S. Middleton Memorial Veterans Hospital, Madison, WI
Madison, Wisconsin, United States
Clement J. Zablocki VA Medical Center, Milwaukee, WI
Milwaukee, Wisconsin, United States
Countries
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References
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Krystal JH, Chow B, Vessicchio J, Henrie AM, Neylan TC, Krystal AD, Marx BP, Xu K, Jindal RD, Davis LL, Schnurr PP, Stein MB, Thase ME, Ventura B, Huang GD, Shih MC; CSP 2016 Study Team. Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016. Contemp Clin Trials. 2021 Oct;109:106540. doi: 10.1016/j.cct.2021.106540. Epub 2021 Aug 18.
Provided Documents
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Document Type: Informed Consent Form
Other Identifiers
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2016
Identifier Type: -
Identifier Source: org_study_id
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