CSP #2016 - National Adaptive Trial for PTSD Related Insomnia
概览
- 阶段
- 3 期
- 干预措施
- Trazodone
- 疾病 / 适应症
- Insomnia
- 发起方
- VA Office of Research and Development
- 入组人数
- 673
- 试验地点
- 35
- 主要终点
- Insomnia Severity Index
- 状态
- 进行中（未招募）
- 最后更新
- 上个月
概览
简要总结
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.
详细描述
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 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.
研究者
入排标准
入选标准
- •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
- •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:
排除标准
- •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
- •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.)
- •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
研究组 & 干预措施
Trazodone
Participants who are assigned to take trazodone, an active study medication.
干预措施: Trazodone
Eszopiclone
Participants who are assigned to take eszopiclone, an active study medication.
干预措施: Eszopiclone
Placebo
Participants who are assigned to take a placebo, a non-active study medication.
干预措施: Placebo
结局指标
主要结局
Insomnia Severity Index
时间窗: 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)
次要结局
- Patient Health Questionnaire-9(12 weeks)
- Pittsburgh Sleep Quality Index Scale-Addendum for PTSD(12 weeks)
- Clinician Administered PTSD Scale for DSM-5(12 weeks)
- The World Health Organization Quality of Life(12 weeks)
- Treatment Satisfaction Questionnaire for Medication-9(12 weeks)
- Service Utilization and Resources Form(12 weeks)
- PTSD Checklist(12 weeks)
- Generalized Anxiety Disorder-7 Scale(12 weeks)