Suvorexant 3 - PE-PC

Official title

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

Overview

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.

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.

Interventions

• 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.
• 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.
• 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).

Primary outcome measures

• 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 [Time frame: 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 [Time frame: Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks]

Secondary outcome measures (6)

• Change from Baseline in Insomnia Severity as Assessed by the Insomnia Severity Index (ISI) at Week 4, Week 8, and 6 Months [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: Baseline (Week 0), Week 4 (Mid-Treatment), Week 8 (End of Treatment), and 6 months post-treatment; up to 32 weeks]

Eligibility criteria

Inclusion criteria

• Adults 18-75 years who are U.S. military Veterans; able to read/understand English and provide written informed consent;
• Exposure to a DSM-5 Criterion A traumatic event;
• Current PTSD, duration > 3 months, CAPS-5 total score ≥ 12
• Insomnia diagnosis indicated by ISI score >14
• 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.
• If in supportive psychotherapy, stable ≥ 6 weeks before randomization (no concurrent exposure-based PTSD or CBT-I).
• Women of childbearing potential: negative urine pregnancy test at screening; agree to use a medically acceptable contraception method during treatment.

Exclusion criteria

• 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;
• 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;
• 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;
• 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);
• Night shift work or extreme morning or evening tendencies;
• Neurologic disorder or systemic illness affecting CNS function;
• 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);
• Severe cognitive impairment as assessed by the MoCA (or alternative validated threshold per site SOP)
• Pregnancy or breastfeeding, or unwillingness to use effective contraception (women of childbearing potential).
• Previous adverse reaction to a hypnotic;
• Current use of sedative-hypnotics, benzodiazepines, moderate or strong CYP3A inhibitors, or strong CYP3A inducers or Digoxin;
• Current participation in exposure-based PTSD or behavioral insomnia treatments.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• San Francisco VA Health Care System — San Francisco

Publications

• 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. PMID 25526970
• 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. PMID 34933185
• 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. PMID 37650808
• 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. PMID 26164549
• 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. PMID 35192748
• 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. PMID 9659859

Identifiers

NCT: NCT07686731 · 1874261 · HT94252510779

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗