National Adaptive Trial for PTSD Related Insomnia (NAP)

Description

VA Cooperative Studies Program #2016 is a double-blind four-arm adaptive clinical trial to compare the efficacy of trazodone hydrochloride, eszopiclone, and gabapentin 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 approximately 1224 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, gabapentin 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 futility early stopping criteria will be dropped. If all active treatment arms are dropped at the interim analysis, the study is 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 be increased using a flexible dose titration schedule over a period of up to 3 weeks and continued for up to 12 weeks.

The Insomnia Severity Index (ISI) is the primary outcome for this study. The Clinician Administered PTSD Scale for DSM-V (CAPS-5) will be the primary 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), anger and aggression (DAR-5), smoking and alcohol consumption (Timeline Follow-Back, or TLFB), clinical global change (CGI-S), resource utilization (an abbreviated subset of the Service Utilization and Resources Form, or SURF), Columbia Suicide Severity Rating Scale (C-SSRS), optional wearable device (Actiwatch Spectrum Plus by Philips) to measure actigraphy.

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 significant differences between trazodone, eszopiclone, and gabapentin versus placebo. The investigators have powered the study to detect a small effect size, recognizing that the effect size of s-zopiclone is larger ( 0.5) in a small short-term pilot study in PTSD but that the effect size of s-zopiclone declines over time in a well-powered study of primary insomnia, stabilizing at 12 weeks of treatment at a level that is sustained over subsequent months of treatment. Presuming that the widespread prescription rates of these three medications for PTSD patients suggests that they have some efficacy for PTSD-related insomnia, the investigators would expect that the effect size for the comparisons among the active medications would be very small. Therefore, the study is not powered to detect differences among the active medications. The investigators have chosen the ISI as the primary outcome for several reasons: (a) it has excellent psychometric properties, (b) it is feasible (in terms of subject burden and cost) to administer the ISI at multiple timepoints during the 12-week trial, (c) according to the insomnia experts who provided input into the study design it has displaced sleep diary-related measures as the primary outcome in clinical trials for sleep, and d) it has been accepted by the FDA as the primary outcome measure in registration trials.

Based on the literature, an effect size of 0.35 in the primary endpoint (ISI) is plausible and clinically meaningful. The investigators estimated the overall participant dropout rate is between 10% to 15%. With a conservative estimate drop-out rate of 15%, the total sample size will be 1224. From the previous CSP PTSD trials, the investigators anticipate each participating site can randomize on average 1.25 participants per month, or 15 patients per site per year. With 3 years of recruitment, the investigators would need 28 sites to reach sample 1224. The investigators plan to start the study with 32 sites to allow dropping of non-performing sites.

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.

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