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

Primary Purpose

Sleep Initiation and Maintenance Disorders, Stress Disorders, Posttraumatic

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Suvorexant
Placebo
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sleep Initiation and Maintenance Disorders focused on measuring Sleep Initiation and Maintenance Disorders, Stress Disorders, Posttraumatic, Suvorexant, Veterans

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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
  • PTSD symptoms >3 months duration as indexed by a CAPS-5 12 and a partial PTSD diagnosis at screening
  • 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
  • Sleep apnea score 30; if screening indicates mild or moderate sleep apnea (score between 5 and 30), referral will be provided

Exclusion Criteria:

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

    • Mild alcohol use not meeting criteria for moderate or severe use disorder may be allowed on a case-by-case basis
    • Mild or moderate marijuana use disorder may be allowed on a on a case-by-case basis
  • Manic or psychotic episode in the last 5 years
  • Exposure to trauma in the last 3 months
  • 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 severe sleep apnea (score >30) in the absence of adherence to effective treatment (such as CPAP or oral device) or positive screen for severe sleep apnea by type III device (score > 30)
  • 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 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)
  • Narcolepsy
  • Previous adverse reaction to a hypnotic
  • Current use of benzodiazepines, strong CYP3A inhibitors, or Digoxin

Prohibited:

  • benzodiazepines
  • strong CYP3A inhibitors
  • Digoxin
  • 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

Sites / Locations

  • San Francisco VA Medical Center, San Francisco, CARecruiting
  • Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NCRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Suvorexant

Identical Placebo

Arm Description

Suvorexant is a dual orexin receptor antagonist that is FDA approved to treat insomnia.

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.

Outcomes

Primary Outcome Measures

Insomnia Severity Index (ISI)
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.
Clinician Administered PTSD Scale for DSM-5 (CAPS-5)
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

Wrist Actigraphy
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.
Pittsburgh Sleep Quality Index-PTSD Addendum (PSQI-A)
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.

Full Information

First Posted
August 20, 2018
Last Updated
November 10, 2022
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT03642028
Brief Title
Suvorexant: A Dual Orexin Receptor Antagonist for Treating Sleep Disturbance in Posttraumatic Stress
Official Title
Suvorexant: A Dual Orexin Receptor Antagonist for Treating Sleep Disturbance inPosttraumatic Stress
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
August 30, 2019 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sleep Initiation and Maintenance Disorders, Stress Disorders, Posttraumatic
Keywords
Sleep Initiation and Maintenance Disorders, Stress Disorders, Posttraumatic, Suvorexant, Veterans

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
144 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Suvorexant
Arm Type
Experimental
Arm Description
Suvorexant is a dual orexin receptor antagonist that is FDA approved to treat insomnia.
Arm Title
Identical Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Suvorexant
Other Intervention Name(s)
Belsomra
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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 Measure Information:
Title
Insomnia Severity Index (ISI)
Description
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.
Time Frame
Change from baseline to week 12
Title
Clinician Administered PTSD Scale for DSM-5 (CAPS-5)
Description
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.
Time Frame
Change from baseline to week 12
Secondary Outcome Measure Information:
Title
Wrist Actigraphy
Description
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.
Time Frame
Change from 1 week at baseline, and weeks 4, 8, and 12
Title
Pittsburgh Sleep Quality Index-PTSD Addendum (PSQI-A)
Description
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.
Time Frame
Change in PTSD-related nightmares across the 12 week trial
Other Pre-specified Outcome Measures:
Title
Clinical Global Impression (CGI)
Description
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").
Time Frame
Change across the 12 week trial

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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 PTSD symptoms >3 months duration as indexed by a CAPS-5 12 and a partial PTSD diagnosis at screening 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 Sleep apnea score 30; if screening indicates mild or moderate sleep apnea (score between 5 and 30), referral will be provided Exclusion Criteria: DSM-5 alcohol, marijuana, and/or other drug use disorder in the last 3 months Mild alcohol use not meeting criteria for moderate or severe use disorder may be allowed on a case-by-case basis Mild or moderate marijuana use disorder may be allowed on a on a case-by-case basis Manic or psychotic episode in the last 5 years Exposure to trauma in the last 3 months 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 severe sleep apnea (score >30) in the absence of adherence to effective treatment (such as CPAP or oral device) or positive screen for severe sleep apnea by type III device (score > 30) 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 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) Narcolepsy Previous adverse reaction to a hypnotic Current use of benzodiazepines, strong CYP3A inhibitors, or Digoxin Prohibited: benzodiazepines strong CYP3A inhibitors Digoxin 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sabra S Inslicht, PhD
Phone
(415) 221-4810
Ext
3341
Email
sabra.inslicht@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sabra S Inslicht, PhD
Organizational Affiliation
San Francisco VA Medical Center, San Francisco, CA
Official's Role
Principal Investigator
Facility Information:
Facility Name
San Francisco VA Medical Center, San Francisco, CA
City
San Francisco
State/Province
California
ZIP/Postal Code
94121
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sabra S Inslicht, PhD
Phone
415-221-4810
Ext
3341
Email
sabra.inslicht@va.gov
First Name & Middle Initial & Last Name & Degree
Sabra S Inslicht, PhD
Facility Name
Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
City
Salisbury
State/Province
North Carolina
ZIP/Postal Code
28144
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Robin Hurley, MD
Phone
704-638-9000
Ext
14455
Email
robin.hurley@va.gov
First Name & Middle Initial & Last Name & Degree
Amy Morris
Phone
7046389000
Ext
14392
Email
amy.morris3@va.gov

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://studypages.com/s/are-you-a-veteran-with-sleeping-problems-and-posttraumatic-stress-participate-in-a-clinical-research-study-from-home-601539/
Description
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Suvorexant: A Dual Orexin Receptor Antagonist for Treating Sleep Disturbance in Posttraumatic Stress

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