National Adaptive Trial for PTSD Related Insomnia

NCT03668041 | Completed Phase 3 DMC FDA Drug

• 1 other identifier: 2016
• Study Type: interventional
• Target: 673
• Locations: 1 country
• Sites: 35

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 or eszopiclone 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.

Conditions

Insomnia

Outcome Measures

Primary Outcomes (1)

• Insomnia Severity Index

  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)

  Baseline to 12 weeks

Secondary Outcomes (8)

• Clinician Administered PTSD Scale for DSM-5

  12 weeks

• Pittsburgh Sleep Quality Index Scale-Addendum for PTSD

  12 weeks

• Patient Health Questionnaire-9

  12 weeks

• The World Health Organization Quality of Life

  12 weeks

• Treatment Satisfaction Questionnaire for Medication-9

  12 weeks

Study Arms (3)

Trazodone

ACTIVE COMPARATOR

Participants who are assigned to take trazodone, an active study medication.

Drug: Trazodone

Eszopiclone

ACTIVE COMPARATOR

Participants who are assigned to take eszopiclone, an active study medication.

Drug: Eszopiclone

Placebo

PLACEBO COMPARATOR

Participants who are assigned to take a placebo, a non-active study medication.

Other: Placebo

Interventions

Trazodone DRUG

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.

Trazodone

Eszopiclone DRUG

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.

Eszopiclone

Placebo OTHER

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to comprehend and provision of signed and dated informed consent form
• 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)
• Individuals, between the ages of 18 and 75 years
• Allow digital recording of phone interviews
• PTSD related to military service
• Primary DSM-5 diagnosis of PTSD, assessed by structured interview using the CAPS-5
• Total CAPS-5 score 23
• ISI \>15
• 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
• 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.
• Females of childbearing potential:
• Must have a negative pregnancy test during screening
• Must agree not to become pregnant or breastfeed during the course of the study
• 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®)
• 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)

You may not qualify if:

• 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.)
• 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
• 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
• History of moderate or severe traumatic brain injury (TBI) or history of gross structural damage as shown on MRI.
• Positive urine test for an illicit substance, excluding cannabis, within the past 90 days prior to screening
• Inpatient psychiatric hospitalization within 30 days prior to screening
• Suicidal or homicidal ideation with intent or plan to harm themselves or others within 90 days prior to screening
• 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)
• Clinical and laboratory evidence of untreated hypothyroidism or hyperthyroidism
• A corrected QT (QTc) interval greater than 470 ms
• Unstable, serious medical condition or one requiring acute medical treatment, or planned hospitalization for extended care
• Dementia, epilepsy, stroke, or current treatment with warfarin for anticoagulation
• Under criminal investigation or pending legal charges with potential incarceration
• Individuals who lack stable contact information (including lack of a telephone number)
• Participants who anticipate working during the hours of midnight to 6am during the course of study trial

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (35)

Birmingham VA Medical Center, Birmingham, AL

Birmingham, Alabama, 35233, United States

Location

Tuscaloosa VA Medical Center, Tuscaloosa, AL

Tuscaloosa, Alabama, 35404, United States

Location

Phoenix VA Health Care System, Phoenix, AZ

Phoenix, Arizona, 85012, United States

Location

VA Loma Linda Healthcare System, Loma Linda, CA

Loma Linda, California, 92357-1000, United States

Location

VA Long Beach Healthcare System, Long Beach, CA

Long Beach, California, 90822, United States

Location

VA Palo Alto Health Care System, Palo Alto, CA

Palo Alto, California, 94304-1207, United States

Location

VA San Diego Healthcare System, San Diego, CA

San Diego, California, 92161, United States

Location

San Francisco VA Medical Center, San Francisco, CA

San Francisco, California, 94121-1563, United States

Location

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

West Haven, Connecticut, 06516-2770, United States

Location

CERC (VISN1, West Haven, CT)

West Haven, Connecticut, 06516, United States

Location

Bay Pines VA Healthcare System, Pay Pines, FL

Bay Pines, Florida, 33744-0000, United States

Location

Atlanta VA Medical and Rehab Center, Decatur, GA

Decatur, Georgia, 30033, United States

Location

Edward Hines Jr. VA Hospital, Hines, IL

Hines, Illinois, 60141-3030, United States

Location

Overton Brooks VA Medical Center, Shreveport, LA

Shreveport, Louisiana, 71101, United States

Location

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA

Boston, Massachusetts, 02130-4817, United States

Location

Minneapolis VA Health Care System, Minneapolis, MN

Minneapolis, Minnesota, 55417, United States

Location

New Mexico VA Health Care System, Albuquerque, NM

Albuquerque, New Mexico, 87108-5153, United States

Location

Asheville VA Medical Center, Asheville, NC

Asheville, North Carolina, 28805, United States

Location

Durham VA Medical Center, Durham, NC

Durham, North Carolina, 27705-3875, United States

Location

Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC

Salisbury, North Carolina, 28144, United States

Location

Cincinnati VA Medical Center, Cincinnati, OH

Cincinnati, Ohio, 45220-2213, United States

Location

Louis Stokes VA Medical Center, Cleveland, OH

Cleveland, Ohio, 44106, United States

Location

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Philadelphia, Pennsylvania, 19104, United States

Location

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Pittsburgh, Pennsylvania, 15240, United States

Location

Providence VA Medical Center, Providence, RI

Providence, Rhode Island, 02908, United States

Location

Ralph H. Johnson VA Medical Center, Charleston, SC

Charleston, South Carolina, 29401-5799, United States

Location

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX

Dallas, Texas, 75216-7167, United States

Location

Michael E. DeBakey VA Medical Center, Houston, TX

Houston, Texas, 77030-4211, United States

Location

South Texas Health Care System, San Antonio, TX

San Antonio, Texas, 78229, United States

Location

VA Salt Lake City Health Care System, Salt Lake City, UT

Salt Lake City, Utah, 84148, United States

Location

White River Junction VA Medical Center, White River Junction, VT

White River Junction, Vermont, 05009-0001, United States

Location

Salem VA Medical Center, Salem, VA

Salem, Virginia, 24153, United States

Location

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, 98108, United States

Location

William S. Middleton Memorial Veterans Hospital, Madison, WI

Madison, Wisconsin, 53705, United States

Location

Clement J. Zablocki VA Medical Center, Milwaukee, WI

Milwaukee, Wisconsin, 53295-0001, United States

Location

Related Publications (1)

• 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.

  PMID: 34416369 DERIVED

MeSH Terms

Conditions

Sleep Initiation and Maintenance Disorders

Interventions

Trazodone; Eszopiclone

Condition Hierarchy (Ancestors)

Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyridones; Pyridines; Pyrazines

Study Officials

• John H. Krystal, MD

  VA Connecticut Healthcare System West Haven Campus, West Haven, CT

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 10, 2018
• First Posted: September 12, 2018
• Study Start: February 25, 2021
• Primary Completion: March 30, 2026
• Study Completion: March 30, 2026
• Last Updated: April 2, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (35)