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

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ClinicalTrials.gov Identifier: NCT03642028
Recruitment Status : Recruiting
First Posted : August 22, 2018
Last Update Posted : September 5, 2019
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
Post-traumatic stress disorder (PTSD) is a common consequence of combat that can result in trauma-related hyperarousal and sleep disturbances. Poor sleep, one of the most common complaints in Veterans with PTSD, can be distressing, impair concentration and memory, and contribute to physical health conditions, such as metabolic syndrome, inflammation, and cardiovascular disease. The orexin neuropeptide system underlies both sleep and stress reactivity. Suvorexant, a drug that reduces orexin, improves sleep in civilians, but has not yet been tested in Veterans with PTSD. This study will test whether suvorexant can improve sleep disturbances and PTSD symptoms in Veterans. Suvorexant may benefit Veterans by improving sleep quickly while also reducing PTSD symptoms over the long term, and with fewer side effects that were common in previous medications used to treat these conditions. Improving Veterans' sleep and PTSD symptoms could lead to better emotional and physical well-being, quality of life, relationships, and functioning.

Condition or disease Intervention/treatment Phase
Sleep Initiation and Maintenance Disorders Stress Disorders, Posttraumatic Drug: Suvorexant Other: Placebo Phase 4

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The blind will be maintained through completion of the entire study at both sites and will only be broken once data are cleaned to an acceptable level of quality, except for medical necessity.
Primary Purpose: Treatment
Official Title: Suvorexant: A Dual Orexin Receptor Antagonist for Treating Sleep Disturbance inPosttraumatic Stress
Actual Study Start Date : August 30, 2019
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : September 30, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Suvorexant

Arm Intervention/treatment
Experimental: Suvorexant
Suvorexant is a dual orexin receptor antagonist that is FDA approved to treat insomnia.
Drug: Suvorexant
Suvorexant, a dual orexin receptor antagonist, is the first in a new class of drugs with great promise of addressing insomnia in Veterans with PTSD. Suvorexant targets the orexin neuropeptide system and has been shown to be highly successful in treating insomnia.
Other Name: Belsomra

Placebo Comparator: Identical Placebo
Visibly matched, equally weighted placebo tablets. In addition to matching in appearance and weight, they will have identical packaging and labeling as randomized, blinded study medication.
Other: Placebo
Visibly matched, equally weighted placebo tablets. In addition to matching in appearance and weight, they will have identical packaging and labeling as randomized, blinded study medication.




Primary Outcome Measures :
  1. Insomnia Severity Index (ISI) [ Time Frame: Change from baseline to week 12 ]
    The ISI is a specific index of perceived insomnia severity. Areas assessed include problems with sleep onset, sleep maintenance, and early morning awakening; dissatisfaction with sleep; interference with daily functioning; impact on quality of life; and worry about sleep problems.

  2. Clinician Administered PTSD Scale for DSM-5 (CAPS-5) [ Time Frame: Change from baseline to week 12 ]
    The CAPS-5 is a 30-item interview that is the gold standard assessment for PTSD. The CAPS-5 provides a dimensional and categorical measure of PTSD, and incorporates frequency and intensity of symptoms into a single severity score. The CAPS-5 will determine a threshold for PTSD severity (past week) at baseline (excluding change in item #20 falling and staying asleep). Possible scores range from 0 to 80. All trained and certified CAPS-raters will function independently and will not be involved in recruitment, study coordination, or evaluation of side effects.


Secondary Outcome Measures :
  1. Wrist Actigraphy [ Time Frame: Change from 1 week at baseline, and weeks 4, 8, and 12 ]
    Sleep wake schedule will be monitored with wrist actigraphy (Micro Motionlogger, Ambulatory Monitoring, Inc.). The actigraph provides continuous activity data using a battery-operated wristwatch-size microprocessor that senses motion with a three axis accelerometer. High-resolution data will be down-sampled to one-minute sample intervals for conventional actigraphic sleep-wake estimation and analyzed using ActionW-2 (Ambulatory Monitoring, Inc.) software. Sleep efficiency, sleep maintenance, total sleep time and wake after sleep onset will be used as secondary measures of sleep.

  2. Pittsburgh Sleep Quality Index-PTSD Addendum (PSQI-A) [ Time Frame: Change in PTSD-related nightmares across the 12 week trial ]
    PSQI-A will be used to assess disruptive nocturnal behaviors related to PTSD, including nightmares, hot flashes and episodes of terror during sleep. Scores ranges from 0 (normal) to 21 (severe). The investigators plan to evaluate nightmares as a secondary outcome.


Other Outcome Measures:
  1. Clinical Global Impression (CGI) [ Time Frame: Change across the 12 week trial ]
    The Clinician and patient reports of improvement on the CGI (depression, mood, vigor, suicidality, daytime somnolence, and functional disability rating scales.) The CGI measures psychiatric treatment response by evaluating global severity of illness and change in the clinical condition over time. It consists of 3 global subscales: Severity of Illness, Global Improvement, and Efficacy Index. Item 1 is rated on a seven-point scale (1=normal to 7=extremely ill); item 2 on a seven-point scale (1=very much improved to 7=very much worse); and item 3 on a four-point scale (from 'none' to 'outweighs therapeutic effect'). The CGI will be used as a secondary measure of remission (i.e., CGI-I of 1 "very much improved" or 2 "much improved").



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03642028


Contacts
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Contact: Sabra S Inslicht, PhD (415) 221-4810 ext 3341 sabra.inslicht@va.gov

Locations
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United States, California
San Francisco VA Medical Center, San Francisco, CA Recruiting
San Francisco, California, United States, 94121
Contact: Sabra S Inslicht, PhD    415-221-4810 ext 3341    sabra.inslicht@va.gov   
Principal Investigator: Sabra S Inslicht, PhD         
United States, North Carolina
Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC Not yet recruiting
Salisbury, North Carolina, United States, 28144
Contact: Robin Hurley, MD    704-638-9000 ext 14455    robin.hurley@va.gov   
Contact: Amy Morris    7046389000 ext 14392    amy.morris3@va.gov   
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Sabra S Inslicht, PhD San Francisco VA Medical Center, San Francisco, CA

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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT03642028     History of Changes
Other Study ID Numbers: MHBB-009-17F
1I01CX001814-01 ( U.S. NIH Grant/Contract )
First Posted: August 22, 2018    Key Record Dates
Last Update Posted: September 5, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by VA Office of Research and Development:
Sleep Initiation and Maintenance Disorders
Stress Disorders, Posttraumatic
Suvorexant
Veterans
Additional relevant MeSH terms:
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Dyssomnias
Sleep Wake Disorders
Parasomnias
Sleep Initiation and Maintenance Disorders
Disease
Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Pathologic Processes
Trauma and Stressor Related Disorders
Mental Disorders
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Sleep Disorders, Intrinsic
Suvorexant
Orexin Receptor Antagonists
Sleep Aids, Pharmaceutical
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action