Suvorexant: A Dual Orexin Receptor Antagonist for Treating Sleep Disturbance in Posttraumatic Stress

The investigators propose a two-site parallel group, randomized, double-blind,
placebo-controlled Phase IV clinical trial to test the efficacy and safety of suvorexant on
trauma-related sleep disturbance and PTSD symptoms in Veterans. The investigators will use a
flexible dose design of suvorexant with a 2-week titration followed by a 10-week steady-dose
phase. The investigators predict that suvorexant, as compared to placebo, will result in a
greater decrease in insomnia on the Insomnia Severity Index (ISI) over the 12-week trial. The
investigators also predict that suvorexant, as compared to placebo, will result in a greater
reduction in non-sleep PTSD symptoms in the Clinician Administered PTSD Scale for Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition (DSMV) (CAPS-5) over the 12-week
trial. Secondarily, the investigators will examine potential objectively measured wrist
actigraphy as a biological mechanism of clinical improvement with as well as concomitant
effects on PTSD-related nightmares using the Pittsburgh Sleep Quality Index-PTSD addendum
(PSQI-A). Pending a significant effect of suvorexant on PTSD, the investigators will perform
exploratory analyses to evaluate whether sleep improvement mediates the effect of suvorexant
on PTSD symptoms. The investigators will also examine safety and tolerability of suvorexant
compared to placebo (including depression, mood, vigor, suicidality, and daytime somnolence,
psychomotor vigilance, and functional disability). Results from this study will provide
substantive rationale for the use of Suvorexant in the treatment of Veterans with these
concerns. This study will be the first to examine a selective orexin-receptor antagonist in a
Veteran sample with PTSD. Suvorexant is an accessible, non-stigmatized medication whose use
and safety has been well-established in non-mental-health settings. It has outstanding
promise for treating common and distressing symptoms in Veterans as well as civilians with
trauma-related sleep disturbance and PTSD.

Inclusion Criteria:

- Men and Women, age range of 18 to 75, with a history of US military service, capable
of reading and understanding English, and able to provide written informed consent

- Criterion A event meets DSM-5 criteria and occurred during military service, including
combat and military sexual trauma

- Chronic full syndromal PTSD diagnosis >3 months duration as indexed by CAPS-5 at
screening, and CAPS-5 score > 30 CAPS-5 total score for the past week at baseline

- Insomnia indicated by an ISI score > 14

- Subjects on non-exclusionary medications must be on a stable dose for at least 4 weeks
prior to randomization, which includes the Selective Serotonin Reuptake Inhibitors
(SSRIs) e.g.:

- Sertraline

- Paroxetine

- Fluoxetine

- Fluvoxamine

- Citalopram

- Escitalopram

- Serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g.:

- Desvenlafaxine

- Duloxetine

- Levomilnacipran

- Venlafaxine

- For subjects who are in psychotherapy, treatment must be stable for 6 weeks

- Women of child-bearing potential must not be pregnant or have plans for pregnancy or
breastfeeding during the study and must use a medically acceptable method of birth
control, e.g.:

- oral

- implantable

- injectable

- transdermal contraceptive

- intrauterine device

- double-barrier method

Exclusion Criteria:

- DSM-5 alcohol, marijuana, and/or other drug use disorder in the last 3 months

- Mild alcohol and marijuana use not being criteria for use disorder will be
allowed

- Lifetime bipolar disorder I or II, schizophrenia, schizoaffective disorder,
obsessive-compulsive disorder, or major depressive disorder with psychotic features

- Exposure to trauma in the last 3 months

- Use of exclusionary antidepressant (trazodone, mirtazapine, doxepin, tricyclics), mood
stabilizers (e.g., lithium), antipsychotic medication

- Prominent suicidal or homicidal ideation or any suicidal behavior in the past 3 months
on the Columbia Suicide Severity Rating Scale (C-SSRS) or increased risk of suicide
that necessitates additional therapy or inpatient treatment

- Pre-existing sleep apnea in the absence of adherence to effective treatment (such as
CPAP or oral device) or positive screen for sleep apnea by type III device

- Night shift work or extreme morning or evening tendencies in order to avoid the impact
of circadian factors on subjective and objective sleep measures

- Neurologic disorder or systemic illness affecting CNS function

- Chronic or unstable medical illness including:

- unstable angina

- myocardial infarction within the past 6 months

- congestive heart failure

- preexisting hypotension or orthostatic hypotension

- heart block or arrhythmia

- chronic renal or hepatic failure

- pancreatitis

- severe chronic obstructive pulmonary disease

- History of moderate or severe traumatic brain injury

- Mild cognitive impairment assessed by the Montreal Cognitive Assessment

- Pregnancy, breastfeeding and/or refusal to use effective birth control (for women)

- Previous adverse reaction to a hypnotic

- Current use of sedative-hypnotics, benzodiazepines, or other drugs used for treating
insomnia, strong CYP3A inhibitors, or Digoxin

Prohibited:

- sedative-hypnotics

- benzodiazepines

- strong CYP3A inhibitors

- Digoxin

- Mood stabilizers, including:

- lithium

- carbamazepine

- valproate

- hypnotics

- neuroleptics or other drugs to treat insomnia will not be allowed because of
potential confounding of therapeutic effects

- Furthermore, CNS depressants (e.g., benzodiazepines, opioids, alcohol) increase the
risk of CNS depression when co-administered with suvorexant and will not be allowed
for safety reasons.

- Since metabolism by CYP3A is the major elimination pathway for suvorexant, concomitant
use of suvorexant with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole,
posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir,
indinavir, boceprevir, telaprevir, telithromycin and conivaptan), moderate CYP3A
inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem,
erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil), or
strong CYP3A inducers (e.g., rifampin, carbamazepine and phenytoin) will not be
allowed.

- All concomitant medication use will be monitored and documented