Suvorexant 3 - PE-PC

Suvorexant: Targeting Orexin to Augment Exposure Therapy in Veterans With PTSD and Insomnia

The goal of this clinical trial is to learn if combining suvorexant (a sleep medication) with a shorter form of prolonged exposure therapy called PE-PC works to treat PTSD symptoms and improve sleep in Veterans and military personnel with PTSD and insomnia, with and without mild-to-moderate traumatic brain injury (TBI). The main questions it aims to answer are:

Does suvorexant, when combined with PE-PC therapy, reduce PTSD symptoms more than PE-PC with a placebo (a look-alike substance that contains no drug)? Does suvorexant, when combined with PE-PC therapy, improve psychosocial and physical functioning more than PE-PC with a placebo?

Researchers will compare PE-PC combined with suvorexant to PE-PC combined with a placebo to see if adding suvorexant improves PTSD symptoms, sleep, and overall functioning in Veterans.

Participants will:

Receive weekly PE-PC therapy sessions for 8 weeks Take suvorexant (10-20 mg) or a placebo each night during the 8-week treatment period.

Complete repeated assessments of PTSD symptoms, sleep, and psychosocial and physical functioning throughout the study.

Study Overview

• Status: Not yet recruiting
• Conditions: Insomnia; TBI (Traumatic Brain Injury); PTSD - Post Traumatic Stress Disorder
• Intervention / Treatment: Drug: Suvorexant; Behavioral: Prolonged Exposure Therapy for Primary Care (PE-PC); Drug: Placebo

Detailed Description

Insomnia is the most prevalent symptom endorsed by PTSD patients and is highly prevalent in TBI, resulting in impairments in many domains of overall health and functioning. Prolonged exposure for primary care (PE-PC) is a shorter version of traditional PE that has demonstrated efficacy in the treatment of PTSD, related conditions (e.g., insomnia, depression), and improving functioning when compared to treatment as usual (e.g., PE, cognitive behavioral therapy for insomnia) in Veterans. However, challenges for PTSD interventions remain as some symptoms, particularly arousal and sleep-related difficulties, often fail to remit, with only 40-60% of Veterans showing clinically significant improvements following treatment, in addition to high attrition rates from these interventions. An integrated treatment that incorporates a pharmacological intervention that improves sleep during PE-PC may provide the greatest opportunity to facilitate recovery, by both increasing Veterans' engagement in treatment and supporting the extinction learning and consolidation mechanisms that promote recovery.

Hypothesis/Objective(s): The investigators aim to test whether integrating PE-PC with suvorexant, FDA-approved for the treatment of insomnia, will 1) promote the efficacy of PE-PC in improving sleep and PTSD symptoms in Veterans and military personnel with insomnia and posttraumatic stress disorder (PTSD) with and without mild-to-moderate traumatic brain injury (TBI); and 2) improve psychosocial and physical functioning.

Specific Aims: 1) To examine whether suvorexant facilitates PE-PC, seen as a greater reduction of PTSD symptoms over the course of treatment. 2) To examine whether suvorexant facilitates greater improvement in psychosocial and physical functioning compared to placebo over the course of treatment.

Study Design: The investigators propose an 8-week randomized, double-blind, placebo-controlled Phase IV clinical trial to examine the efficacy of augmenting PE-PC with suvorexant (10-20 mg) for the treatment of PTSD symptoms and improvement of functioning in Veterans with PTSD, insomnia, with and without TBI. The study design (N = 142) will involve repeated measures with two intervention arms, both of which include a standard course of weekly PE-PC therapy: 1) PE-PC+suvorexant (n = 71) compared to 2) PE-PC+placebo (n = 71).

Clinical Impact: This work aligns with the FY24 TBIPHRP CTA Research Level 2, Focus Area to Treat by examining repurposed interventions to improve outcomes of psychological health conditions and/or TBI through treatment and rehabilitation. The proposed intervention could promote sustained functional recovery following insomnia, PTSD, and TBI, as well as increased treatment engagement, retention, and success in those Veterans who would have otherwise not responded to treatment.

Relevance to Military Health: PTSD affects one in four treatment-seeking U.S. Veterans returning from Iraq and Afghanistan and one in 10 VA healthcare users. Sleep disturbance was the most frequently reported symptom in Veterans with PTSD, with the prevalence of insomnia or nonrestorative sleep estimated between 60%-90% and up to 97.4% of combat Veterans with TBI. However, effective and readily available treatments for co-occurring PTSD, insomnia, and TBI are not readily available or successful outside of PTSD specialty clinics, leading to unmet healthcare needs and/or treatment dropout/non-response. The ultimate goal of this work is to improve treatment availability and options for Veterans and military personnel affected by PTSD and TBI. Increased effectiveness of PTSD treatment in Veterans has the potential to: 1) optimize performance; 2) preserve health across the full deployment life cycle; and 3) improve long-term physical, social, and occupational functioning.

• Study Type: Interventional
• Enrollment (Estimated): 142
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Sabra S Inslicht, PhD; Phone Number: 2-3341 415-221-4810; Email: sabra.inslicht@va.gov
• Study Contact Backup: Name: Bella S Benzaken, MA; Phone Number: 25116 415-221-4810; Email: Bella.Benzaken@ncire.org

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94121-1545
      • San Francisco VA Health Care System
      • Contact: Sabra Inslicht, PhD; Phone Number: 3341 415-221-4810; Email: Sabra.Inslicht@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults 18-75 years who are U.S. military Veterans; able to read/understand English and provide written informed consent;
2. Exposure to a DSM-5 Criterion A traumatic event;
3. Current PTSD, duration > 3 months, CAPS-5 total score ≥ 12
4. Insomnia diagnosis indicated by ISI score >14
5. If taking non-exclusionary psychotropics (e.g., SSRI/SNRI, tetracyclic antidepressants, tricyclics, antipsychotics, and mood stabilizers, insomnia medication, neuroleptics, anti-psychotics) must be on a dose stable ≥ 4 weeks before randomization.
6. If in supportive psychotherapy, stable ≥ 6 weeks before randomization (no concurrent exposure-based PTSD or CBT-I).
7. Women of childbearing potential: negative urine pregnancy test at screening; agree to use a medically acceptable contraception method during treatment.

Exclusion Criteria:

1. DSM-5 alcohol, marijuana, and/or other substance use disorder in the last 3 months. Mild alcohol and marijuana use not meeting criteria for disorder permissible;
2. Lifetime bipolar disorder I or II, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, or major depressive disorder with psychotic features;
3. Exposure to trauma in the last 3 months;
4. Prominent suicidal or homicidal ideation, any suicidal behavior in the past 3 months on the Columbia Suicide Severity Rating Scale (C-SSRS)83, or increased risk of suicide that necessitates additional therapy or inpatient treatment;
5. Pre-existing sleep apnea by type III device with AHI >15 in the absence of adherence to effective treatment (such as CPAP or oral device);
6. Night shift work or extreme morning or evening tendencies;
7. Neurologic disorder or systemic illness affecting CNS function;
8. Chronic or unstable medical illness (i.e., 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, and severe chronic obstructive pulmonary disease);
9. Severe cognitive impairment as assessed by the MoCA (or alternative validated threshold per site SOP)
10. Pregnancy or breastfeeding, or unwillingness to use effective contraception (women of childbearing potential).
11. Previous adverse reaction to a hypnotic;
12. Current use of sedative-hypnotics, benzodiazepines, moderate or strong CYP3A inhibitors, or strong CYP3A inducers or Digoxin;
13. Current participation in exposure-based PTSD or behavioral insomnia treatments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PE-PC + Suvorexant; PE-PC with suvorexant	Drug: Suvorexant; Suvorexant (10-20 mg) taken orally once nightly for 8 weeks, combined with weekly Prolonged Exposure for Primary Care (PE-PC) therapy sessions. Suvorexant is an FDA-approved orexin receptor antagonist indicated for the treatment of insomnia.; Behavioral: Prolonged Exposure Therapy for Primary Care (PE-PC); Prolonged Exposure for Primary Care (PE-PC) is a briefer version of traditional Prolonged Exposure (PE) therapy, delivered in weekly sessions over 8 weeks. PE-PC is designed to treat PTSD symptoms and related conditions such as insomnia and depression. All study participants will receive PE-PC therapy regardless of their assigned intervention arm (suvorexant or placebo).; Other Names: PE-PC
Placebo Comparator: PE-PC + Placebo; PE-PC with placebo	Behavioral: Prolonged Exposure Therapy for Primary Care (PE-PC); Prolonged Exposure for Primary Care (PE-PC) is a briefer version of traditional Prolonged Exposure (PE) therapy, delivered in weekly sessions over 8 weeks. PE-PC is designed to treat PTSD symptoms and related conditions such as insomnia and depression. All study participants will receive PE-PC therapy regardless of their assigned intervention arm (suvorexant or placebo).; Other Names: PE-PC; Drug: Placebo; A placebo pill taken orally once nightly for 8 weeks, combined with weekly Prolonged Exposure for Primary Care (PE-PC) therapy sessions. The placebo is a look-alike substance that contains no active drug and is used as a comparator to evaluate the efficacy of suvorexant.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in PTSD Symptom Severity as Assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at Week 4, Week 8, and 6 Months	The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a 30-item clinician-administered interview measuring the frequency and intensity of PTSD symptoms. Total scores range from 0 to 80, with higher scores indicating greater PTSD symptom severity.	Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks.
Change from Baseline in Overall Functioning as Assessed by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) at Week 4, Week 8, and 6 Months	The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a 36-item self-administered measure assessing functional ability across six domains. Summary scores range from 0 to 100, with higher scores indicating greater disability.	Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Insomnia Severity as Assessed by the Insomnia Severity Index (ISI) at Week 4, Week 8, and 6 Months	The Insomnia Severity Index (ISI) is a 7-item self-report measure of insomnia severity. Total scores range from 0 to 28, with higher scores indicating greater insomnia severity.	Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks
Change from Baseline in Objective Sleep Efficiency as Assessed by Wrist Actigraphy at Week 2, Week 4, Week 8, and 6 Months	Objective sleep efficiency will be assessed via wrist actigraphy worn continuously throughout the study. Sleep efficiency is calculated as the percentage of time in bed spent asleep, ranging from 0% to 100%, with higher values indicating better sleep efficiency. Sleep efficiency, sleep maintenance, total sleep time, and wake after sleep onset will be examined as secondary measures of sleep.	Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks
Change from Baseline in Subjective Sleep Efficiency as Assessed by Daily Sleep Diary at Week 2, Week 4, Week 8, and 6 Months	Subjective sleep efficiency will be assessed via daily self-reported sleep diary. Sleep efficiency is calculated as the percentage of time in bed spent asleep, ranging from 0% to 100%, with higher values indicating better sleep efficiency.	Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks
Change from Baseline in Psychosocial Functioning as Assessed by the Brief Inventory of Psychosocial Functioning (B-IPF) at Week 4, Week 8, and 6 Months	The B-IPF (Brief Inventory of Psychosocial Functioning) is a 7-item self-report measure assessing PTSD-related functional impairment in the past 30 days across seven functional domains, including romantic relationships, family relationships, work, friendships and socializing, parenting, education, and self-care.	Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks
Change from Baseline in Quality of Life as Assessed by the World Health Organization Quality of Life Assessment Brief Version (WHOQOL-BREF) at Week 4, Week 8, and 6 Months	The World Health Organization Quality of Life Assessment Brief Version (WHOQOL-BREF) is a 26-item instrument assessing quality of life across four domains: physical health, psychological health, social relationships, and environmental health. Items are scored 1-5 and transformed to a standardized scale of 0-100, with higher scores indicating better quality of life.	Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks
Change from Baseline in Engagement in Meaningful Activities as Assessed by the Engagement in Meaningful Activities Survey (EMAS) at Week 4, Week 8, and 6 Months	The Engagement in Meaningful Activities Survey (EMAS) is a 12-item scale assessing meaningful activity participation. Total scores range from 12 to 48, with higher scores indicating greater engagement in meaningful activities.	Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks

Collaborators and Investigators

• Sponsor: Northern California Institute of Research and Education
• Collaborators: Lowcountry Center for Veterans Research

Publications and helpful links

General Publications

• Neylan TC, Marmar CR, Metzler TJ, Weiss DS, Zatzick DF, Delucchi KL, Wu RM, Schoenfeld FB. Sleep disturbances in the Vietnam generation: findings from a nationally representative sample of male Vietnam veterans. Am J Psychiatry. 1998 Jul;155(7):929-33. doi: 10.1176/ajp.155.7.929.
• Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, Krystal AD, Walsh JK, Benca RM, Rosenberg R, Sangal RB, Budd K, Hutzelmann J, Leibensperger H, Froman S, Lines C, Roth T, Michelson D. Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials. Biol Psychiatry. 2016 Jan 15;79(2):136-48. doi: 10.1016/j.biopsych.2014.10.003. Epub 2014 Oct 23.
• Kobayashi I, Mellman TA, Cannon A, Brown I, Boadi L, Howell MK, Lavela P, Sandhu I. Blocking the orexin system following therapeutic exposure promoted between session habituation, but not PTSD symptom reduction. J Psychiatr Res. 2022 Jan;145:222-229. doi: 10.1016/j.jpsychires.2021.12.027. Epub 2021 Dec 14.
• Rauch SAM, Kim HM, Acierno R, Ragin C, Wangelin B, Blitch K, Muzzy W, Hart S, Zivin K. Improving function through primary care treatment of posttraumatic stress disorder study outcomes: A randomized controlled trial of prolonged exposure for primary care in veterans. Fam Syst Health. 2023 Dec;41(4):502-513. doi: 10.1037/fsh0000823. Epub 2023 Aug 31.
• Gilbert KS, Kark SM, Gehrman P, Bogdanova Y. Sleep disturbances, TBI and PTSD: Implications for treatment and recovery. Clin Psychol Rev. 2015 Aug;40:195-212. doi: 10.1016/j.cpr.2015.05.008. Epub 2015 Jun 3.
• Wisco BE, Nomamiukor FO, Marx BP, Krystal JH, Southwick SM, Pietrzak RH. Posttraumatic Stress Disorder in US Military Veterans: Results From the 2019-2020 National Health and Resilience in Veterans Study. J Clin Psychiatry. 2022 Feb 22;83(2):20m14029. doi: 10.4088/JCP.20m14029.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): August 30, 2029

Study Registration Dates

• First Submitted: June 1, 2026
• First Submitted That Met QC Criteria: June 29, 2026
• First Posted (Actual): July 7, 2026

Study Record Updates

• Last Update Posted (Actual): July 7, 2026
• Last Update Submitted That Met QC Criteria: June 29, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: PTSD; Veterans; Sleep; Insomnia; TBI; Stress Disorders, Post-Traumatic; Sleep Initiation and Maintenance Disorders; suvorexant; Prolonged Exposure Therapy for Primary Care (PE-PC); Orexin Receptor Antagonists; Dual Orexin Receptor Antagonists (DORA)
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Wounds and Injuries; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Stress Disorders, Traumatic; Brain Injuries, Traumatic; Sleep Initiation and Maintenance Disorders; Stress Disorders, Post-Traumatic; Combat Disorders; Health Services Administration; Patient Care Management; Comprehensive Health Care; suvorexant; Primary Health Care
• Other Study ID Numbers: 1874261; HT94252510779 (Other Grant/Funding Number: DOD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie the results reported in publications will be shared, including data on primary and secondary outcome measures (PTSD symptom severity, psychosocial and physical functioning, sleep outcomes, and quality of life). Data will be de-identified prior to sharing to protect participant confidentiality. Demographic and clinical characteristics used to describe the study sample will also be made available.
• IPD Sharing Time Frame: De-identified IPD and supporting information will be available beginning 12 months after the publication of primary study results and will remain available for a minimum of 5 years following the end of the study.
• IPD Sharing Access Criteria: De-identified IPD will be available to researchers who provide a methodologically sound proposal and agree to the terms of a data use agreement. Requests for data access should be submitted to the principal investigator. Data will be shared in a secure manner consistent with applicable federal regulations and institutional policies governing research data sharing.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• 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.: No