Clinical trial NCT03668041: National Adaptive Trial for PTSD Related Insomnia
Official title: CSP #2016 - National Adaptive Trial for PTSD Related Insomnia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Insomnia
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2018-09-12
Enrollment: 774
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: VA Cooperative Studies Program #2016 is a double-blind three-arm adaptive clinical trial to compare the efficacy of trazodone hydrochloride and eszopiclone to placebo, as adjunctive therapies in the treatment of insomnia symptoms among Veterans with military related PTSD, as measured by statistically significant difference in change from baseline in Insomnia Severity Index (ISI) total score at Week 12.

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 Pittsburg 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.

Eligibility criteria: 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 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:

1. 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 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

Primary outcomes:
measure: Insomnia Severity Index
timeFrame: Baseline to 12 weeks
Secondary outcomes:
measure: Clinician Administered PTSD Scale for DSM-5
timeFrame: 12 weeks
measure: Pittsburgh Sleep Quality Index Scale-Addendum for PTSD
timeFrame: 12 weeks
measure: Patient Health Questionnaire-9
timeFrame: 12 weeks
measure: The World Health Organization Quality of Life
timeFrame: 12 weeks
measure: Treatment Satisfaction Questionnaire for Medication-9
timeFrame: 12 weeks
measure: Service Utilization and Resources Form
timeFrame: 12 weeks
measure: PTSD Checklist
timeFrame: 12 weeks
measure: Generalized Anxiety Disorder-7 Scale
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham VA Medical Center, Birmingham, AL
state: Alabama
city: Tuscaloosa
country: United States
facility: Tuscaloosa VA Medical Center, Tuscaloosa, AL
state: Alabama
city: Phoenix
country: United States
facility: Phoenix VA Health Care System, Phoenix, AZ
state: Arizona
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System, San Diego, CA
state: California
city: San Francisco
country: United States
facility: San Francisco VA Medical Center, San Francisco, CA
state: California
city: West Haven
country: United States
facility: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
state: Connecticut
city: West Haven
country: United States
facility: CERC (VISN1, West Haven, CT)
state: Connecticut
city: Bay Pines
country: United States
facility: Bay Pines VA Healthcare System, Pay Pines, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Shreveport
country: United States
facility: Overton Brooks VA Medical Center, Shreveport, LA
state: Louisiana
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Albuquerque
country: United States
facility: New Mexico VA Health Care System, Albuquerque, NM
state: New Mexico
city: Asheville
country: United States
facility: Asheville VA Medical Center, Asheville, NC
state: North Carolina
city: Durham
country: United States
facility: Durham VA Medical Center, Durham, NC
state: North Carolina
city: Salisbury
country: United States
facility: Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center, Cincinnati, OH
state: Ohio
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Philadelphia
country: United States
facility: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
city: Providence
country: United States
facility: Providence VA Medical Center, Providence, RI
state: Rhode Island
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center, Charleston, SC
state: South Carolina
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: San Antonio
country: United States
facility: South Texas Health Care System, San Antonio, TX
state: Texas
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
city: White River Junction
country: United States
facility: White River Junction VA Medical Center, White River Junction, VT
state: Vermont
city: Salem
country: United States
facility: Salem VA Medical Center, Salem, VA
state: Virginia
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
city: Madison
country: United States
facility: William S. Middleton Memorial Veterans Hospital, Madison, WI
state: Wisconsin
city: Milwaukee
country: United States
facility: Clement J. Zablocki VA Medical Center, Milwaukee, WI
state: Wisconsin
Study officials:
affiliation: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
name: John H. Krystal, MD
role: STUDY_CHAIR
References:
citation: 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.