National Adaptive Trial for PTSD Related Insomnia

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.

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. Male or female, between the ages of 18 and 75 years

4. Allow digital recording of phone interviews

5. Military service connected PTSD

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 as
determined by the site investigator with input, if needed, from the study chair

10. Electrocardiogram (ECG) at baseline without clinically significant abnormalities
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)

11. Agree to secure firearms while receiving study treatment 12. If individuals are
undergoing evidence-based psychotherapy 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 30 days prior to
starting screening. (Supportive individual and group therapy is allowed) 13. Agreement to
adhere to Lifestyle Considerations throughout study participation

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 SI 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

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. Clinical evidence of inadequately treated sleep apnea as detected by using ApneaLink
to assess the presence of sleep apnea or not

5. History of moderate or severe traumatic brain injury (TBI) or history of gross
structural damage as shown on MRI (occurring during period of military service).

6. Positive urine test for an illicit substance, excluding cannabis, within the past 90
days prior to screening

7. 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).

8. Inpatient psychiatric hospitalization within 30 days prior to randomization

9. Suicidal or homicidal ideation with intent or plan to harm themselves or others within
90 days prior to randomization

10. Creatinine clearance (CrCl) less than 60 mL/min, 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)

11. Clinical and laboratory evidence of untreated hypothyroidism or hyperthyroidism

12. A corrected QT (QTc) interval greater than 470 ms

13. Unstable, serious medical condition or one requiring acute medical treatment, or
planned hospitalization for extended care

14. Dementia, epilepsy, stroke, or current treatment with warfarin for anticoagulation

15. 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, wouldn't be excluded by this criterion.

16. Under criminal investigation or pending legal charges with potential incarceration

17. Individuals who lack stable contact information (including lack of a telephone number)

18. Participants who anticipate working during the hours of midnight to 6am during the
course of study trial