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National Adaptive Trial for PTSD Related Insomnia (NAP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03668041
Recruitment Status : Recruiting
First Posted : September 12, 2018
Last Update Posted : June 13, 2022
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
Many Veterans with posttraumatic stress disorder (PTSD) have trouble sleeping or have frequent nightmares. So far, no medication has been approved for treatment of insomnia in PTSD. The purpose of this research study is to find out if taking medications called trazodone, eszopiclone, or gabapentin can help decrease symptoms of insomnia in patients with PTSD. PTSD is a form of intense anxiety which sometimes results from severe trauma. Symptoms may include nightmares, flashbacks, troublesome memories, difficulty sleeping, poor concentration, irritability, anger, and emotional withdrawal. Insomnia is a disorder that can make it hard to fall sleep, stay asleep or cause a person to wake up too early and not be able to fall back to sleep.

Condition or disease Intervention/treatment Phase
Insomnia Drug: Trazodone Drug: Eszopiclone Drug: Gabapentin Other: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1224 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: CSP #2016 - National Adaptive Trial for PTSD Related Insomnia
Actual Study Start Date : February 25, 2021
Estimated Primary Completion Date : October 25, 2025
Estimated Study Completion Date : October 25, 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Trazodone

Arm Intervention/treatment
Active Comparator: Trazodone
Participants who are assigned to take trazodone, an active study medication.
Drug: 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.

Active Comparator: Eszopiclone
Participants who are assigned to take eszopiclone, an active study medication.
Drug: 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.

Active Comparator: Gabapentin
Participants who are assigned to take gabapentin, an active study medication.
Drug: Gabapentin
Gabapentin is an FDA approved medication for the treatment of seizures, a type of nerve pain and some forms of chronic pain. Some doctors have prescribed it for insomnia. While the total daily doses in this study are less than the usual total daily dose, the highest dose of gabapentin used in this study will be higher than the typical dose taken at a single time. Doses even higher than this have been taken and observed to be acceptable for treating patients with PTSD.

Placebo Comparator: Placebo
Participants who are assigned to take a placebo, a non-active study medication.
Other: 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.

Primary Outcome Measures :
  1. Insomnia Severity Index [ Time Frame: Baseline to 12 weeks ]

    Change in the Insomnia Severity Index score from baseline to the 12-week follow-up will serve as the primary outcome. Possible range for ISI 0-28. Higher score indicates more severe insomnia problem(s).

    0-7 = No clinically significant insomnia 8-14 = Subthreshold insomnia 15-21 = Clinical insomnia (moderate severity) 22-28 = Clinical insomnia (severe)

Secondary Outcome Measures :
  1. Clinician Administered PTSD Scale for DSM-5 [ Time Frame: 12 weeks ]
    The scale consists of 20 DSM-5 symptoms rated on a 0-4 scale of how much that symptom bothered the individual in the prior month. Possible range for CAPS-5 total score 0-80, CAPS symptom cluster subscores of: Re-experiencing (B) 0-20, Avoidance (C) 0-8, Alteration in Cognition and Mood (D) 0-28, Hyperarousal (E) 0-24, Significant Distress (G) 0-12, and Dissociation (I) 0-8. Higher score indicates more severe PTSD.

  2. Pittsburgh Sleep Quality Index Scale-Addendum for PTSD [ Time Frame: 12 weeks ]
    It is a self-administered questionnaire that assesses sleep quality and disturbances over a 1-month period of time. The 7 items in the addendum generate a summary score, with three additional questions if memories or nightmares of a traumatic experience are present. Possible range for PSQI-A score 0-21, and possible range for each item 0-3. Higher PSQI-A score indicates worse quality of sleep.

  3. Patient Health Questionnaire-9 [ Time Frame: 12 weeks ]
    It is a tool to measure comorbid depression. This scale is frequently used in VA settings, has been well validated, and is a quick self-administered questionnaire. Possible range for PHQ-9 0-27. Higher score indicates more severe depression. 0-4: None/Minimal depression, 5-9: Mild depression, 10-14: Moderate depression, 15-19: Moderately severe depression, 20-27: Severe depression.

  4. The World Health Organization Quality of Life [ Time Frame: 12 weeks ]
    It is a 26-item self-administered questionnaire scaled to assess functioning and quality of life. Possible range for WHOQOL-BREF Overall 4-20, WHOQOL-BREF domain subscores of: Physical Health 4-20, Psychological 4-20, Social Relationships 4-20, and Environment 4-20. Higher score indicates better satisfaction with life.

  5. Treatment Satisfaction Questionnaire for Medication-9 [ Time Frame: 12 weeks ]
    It is a 9-item questionnaire to measure treatment satisfaction. TSQM-9 are scored on 3 domains: Effectiveness, Convenience, Global Satisfaction. Possible range for TSQM-9 domain scores 0-100. Higher score indicates higher satisfaction with medication.

  6. Service Utilization and Resources Form [ Time Frame: 12 weeks ]
    An abbreviated subset of the Service Utilization and Resources Form (SURF) assessment will be used to evaluate alcohol and other substance use (cannabis, smoking, and caffeine) using Timeline Follow-Back and resource utilization (e.g., outpatient medical and/or psychiatric visits and use of inpatient treatment and housing services). Questionnaire; no summary score.

  7. PTSD Checklist [ Time Frame: 12 weeks ]
    It is a brief questionnaire measure of PTSD symptom severity that is widely used within and outside VA. Possible range for PCL-5 0-80. Higher score indicates greater propensity for chronic and delayed PTSD.

  8. Generalized Anxiety Disorder-7 Scale [ Time Frame: 12 weeks ]
    It is a self-administered tool to assess anxiety. Possible range for GAD-7 0-21. Higher score indicates more severe anxiety disorder. 0-4: None/Minimal anxiety, 5-9: Mild Anxiety, 15-21: Severe anxiety.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Ability to comprehend and provision of signed and dated informed consent form
  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 26
  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:

Currently enrolled in any other interventional study unless prior approval is provided by the study team (It is a CSP policy that exemptions will be assessed for individual patients on a case-by-case basis. Exemptions require the agreement in writing of the following individuals or groups: (1) the SIs of both studies; (2) the Study Chairs of the involved studies; (3) the appropriate CSP Center Director(s); and (4) the VA Central IRB.) 2. Allergy and/or history of intolerance to trazodone hydrochloride, gabapentin, 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. Creatinine clearance (CrCl) less than 60 mL/min (estimated using the Cockcroft-Gault equation, using ideal or adjusted body weight for overweight or obesity), or 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03668041

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Contact: Beverly A Ventura (650) 493-5000 ext 22303

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Sponsors and Collaborators
VA Office of Research and Development
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Study Chair: John H. Krystal, MD VA Connecticut Healthcare System West Haven Campus, West Haven, CT
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: VA Office of Research and Development Identifier: NCT03668041    
Other Study ID Numbers: 2016
First Posted: September 12, 2018    Key Record Dates
Last Update Posted: June 13, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sleep Initiation and Maintenance Disorders
Sleep Disorders, Intrinsic
Sleep Wake Disorders
Nervous System Diseases
Mental Disorders
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antimanic Agents
Hypnotics and Sedatives
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Serotonin Agents
Antidepressive Agents, Second-Generation
Antidepressive Agents