Pimavanserin for Insomnia in Veterans With PTSD (PIP-II)

Pimavanserin for Insomnia in Veterans With Post-traumatic Stress Disorder

This is a preliminary randomized, double-blind, placebo-controlled trial comparing pimavanserin 34mg at bedtime vs. placebo for the treatment of insomnia associated with post-traumatic stress disorder.

Study Overview

• Status: Recruiting
• Conditions: Insomnia; Post-traumatic Stress Disorder
• Intervention / Treatment: Drug: pimavanserin; Other: Placebo

Detailed Description

Veterans with post-traumatic stress disorder (PTSD) frequently have insomnia (trouble falling or staying asleep). Untreated insomnia carries grave health consequences. Early evidence suggests that pimavanserin (Nuplazid), a medication approved by the Food and Drug Administration for the treatment of psychosis (hallucinations and delusions) in Parkinson's Disease, may treat insomnia. In this preliminary study, Veterans with insomnia and PTSD will receive either pimavanserin 34mg or placebo at bedtime for 8 weeks, and sleep quality will be compared pre- and post-treatment. Veterans will also complete sleep studies and wear actigraphy watches so we may better appreciate how pimavanserin impacts sleep. Overall, this study will help us understand pimavanserin's potential benefit for treating PTSD-related insomnia and prepare for a larger, future trial.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Melissa B Jones, MD; Phone Number: (713) 794-1414; Email: Melissa.Jones10@va.gov
• Study Contact Backup: Name: Ricardo E Jorge, MD; Phone Number: (713) 791-1414; Email: Ricardo.Jorge@va.gov

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030-4211
      • Recruiting
      • Michael E. DeBakey VA Medical Center, Houston, TX
      • Principal Investigator: Melissa B Jones, MD
      • Contact: Ricardo E Jorge, MD; Phone Number: (713) 791-1414; Email: Ricardo.Jorge@va.gov
      • Contact: Melissa B Jones, MD; Phone Number: 713-794-1414; Email: Melissa.Jones10@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult, male and female Veterans, aged 18-64;

2. At the initial enrollment visit, meets DSM-5 standards of chronic insomnia disorder, as follows:

   1. Complains of dissatisfaction with nighttime sleep in the form of difficulty falling asleep (subjective sleep onset latency 30 minutes), difficulty staying asleep (subjective time awake after sleep onset 30 minutes), and/or awakening earlier in the morning ( 30 minutes before scheduled wake time and before a total sleep time of 6.5 hours) than desired;
   2. Insomnia frequency of 3 times per week
   3. The duration of the insomnia complaint is 3 months
   4. Associated with complaint of daytime impairment;
3. Insomnia Severity Index (ISI) total score 15 (moderate insomnia);
4. Determined to have clinically significant PTSD symptoms as per the PTSD Checklist (PCL-5); a total score of 33 is a recommended cutoff for a diagnosis of PTSD;
5. Willing and able to comply with all aspects of the protocol;
6. Willing to not start a concurrent behavioral or other treatment program for insomnia, PTSD, or other psychiatric disorders during the participation in the study;
7. It is required that women of child-bearing potential who are sexually active agree to either refrain from sexual activity or use a method of contraception for the duration of the study (i.e., beginning 30 days prior to drug initiation and extending to 30 days after the last dose of study drug). Acceptable methods of contraception include: 1) hormonal contraceptives (e.g., oral contraceptives, injectable contraceptives, contraceptive implant) or a non-hormonal intrauterine device;
8. Subjects are permitted to remain on serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, anticonvulsants (excluding strong CYP3A4 inhibitors or inducers), and other non-prohibited, psychiatric medications taken at stable doses for at least 1 month prior to study entry.

Exclusion Criteria:

1. Current or a history of a primary psychotic disorder (i.e., schizophrenia, schizoaffective or bipolar disorder);
2. Active suicidal or homicidal ideation requiring crisis intervention;
3. Current moderate or severe alcohol or cannabis use disorder, or other illicit use disorder of any severity;
4. A history of moderate or severe traumatic brain injury or other neurological illness (i.e., stroke, epilepsy, multiple sclerosis);
5. Caffeine use that is deemed excessive and is contributing to the insomnia per the opinion of the investigators (e.g., caffeinated beverages consumed after 18:00 3 times/week and/or that correlates with the timing of the insomnia complaints);
6. Tobacco use before bedtime that is contributing to the insomnia per the opinion of the investigators or that would interfere with completing an overnight polysomnogram;
7. Previous diagnosis of periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder, narcolepsy, rapid eye movement sleep behavior disorder, or other sleep disorders (except obstructive sleep apnea) that may confound, per the opinion of the investigators, the assessment of insomnia;
8. Previous diagnosis of moderate to severe obstructive sleep apnea (defined as an apnea hypopnea index equal to or greater than 15 on home sleep test or attended polysomnography);
9. Participants deemed to be at high risk of moderate to severe obstructive sleep apnea per the Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and male Gender questionnaire (STOP-BANG). Subjects with a STOP-BANG score 5, or STOP score of 2 plus (body mass index > 35 kg/m2 or male or neck circumference >40 cm), are considered to be high risk and will be referred to clinical treatment;
10. Participants identified as having an apnea hypopnea index (AHI) 15 during the screening polysomnogram. These participants will be referred to clinical treatment;
11. Periodic limb movement arousal index 15 or other sleep disorders captured during the screening polysomnogram that may confound, per the opinion of the investigators, the assessment and treatment of insomnia;
12. A prolonged QT interval, corrected for heart rate (QTc), at the screening electrocardiogram. A prolonged QTc is defined as 470 milliseconds for males and 480 milliseconds for females;
13. Engagement in CBT-I, prolonged exposure or cognitive processing therapy for 1-week prior to enrollment that in the opinion of the investigators may confound the assessment of insomnia and/or PTSD;
14. Current evidence of clinically significant cardiac, respiratory, gastrointestinal, renal, hepatic, neurological, or other medical illness that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments;
15. Females who are breastfeeding or pregnant at screening;
16. Females of childbearing potential who are not practicing acceptable pregnancy prevention methods (NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically);
17. Patients with conditions known to increase the risk of torsades de pointes and/or sudden death, such as symptomatic bradycardia and congenital prolongation of the QT interval;
18. Hypnotics or other sedating medications that are being taken at bedtime for sleep (ex. melatonin, melatonin receptor agonists, zolpidem, eszopiclone, benzodiazepines, trazodone, mirtazapine, low-dose tricyclic antidepressants, antihistamines, opioids, etc.) must be discontinued for 1 week prior to enrollment;
19. Antipsychotics and antidepressants with known 5-HT2A antagonist activity (ex. quetiapine, olanzapine, mirtazapine, trazodone) must be discontinued for 1 week prior to enrollment;
20. Strong CYP3A4 inhibitors (ex. itraconazole, ketoconazole, clarithromycin, indinavir) that may increase the levels of pimavanserin are prohibited;
21. Strong CYP3A4 inducers (ex. rifampin, carbamazepine, phenytoin, St. John's wort) that may reduce the levels of pimavanserin are prohibited;
22. Concurrent use of medications known to increase the QTc interval, such as Class 1A antiarrhythmics (e.g., quinidine, procainamide), Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics (e.g., gatifloxacin, moxifloxacin) are prohibited.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pimavanserin 34mg PO at bedtime; Pimavanserin 34mg is taken by mouth at bedtime for 8 weeks .	Drug: pimavanserin; pimavanserin 34mg PO at bedtime; Other Names: Nuplazid
Placebo Comparator: Placebo PO at bedtime; The active study medication listed above will be compared with a placebo, which is a pill that looks like a study medication but has no medication in it	Other: Placebo; The placebo is a pill that looks like a study medication but has no medication in it

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insomnia Severity Index (ISI)	Mean change in ISI total score at 8-weeks in active vs. placebo groups	8 weeks post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PTSD Checklist for DSM-5	Mean change in PCL-5 at 8-weeks in active vs. placebo groups	8 weeks post-randomization
Pittsburgh Sleep Quality Index (PSQI)	Mean change in PSQI at 8-weeks in active vs. placebo groups	8 weeks post-randomization

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: ACADIA Pharmaceuticals Inc.
• Investigators: Principal Investigator: Melissa B Jones, MD, Michael E. DeBakey VA Medical Center, Houston, TX

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2023
• Primary Completion (Estimated): July 12, 2027
• Study Completion (Estimated): July 12, 2027

Study Registration Dates

• First Submitted: June 28, 2022
• First Submitted That Met QC Criteria: June 28, 2022
• First Posted (Actual): July 1, 2022

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Stress Disorders, Post-Traumatic; Sleep Initiation and Maintenance Disorders
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Stress Disorders, Traumatic; Sleep Initiation and Maintenance Disorders; Stress Disorders, Post-Traumatic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Neurotransmitter Agents; Tranquilizing Agents; Psychotropic Drugs; Antiparkinson Agents; Anti-Dyskinesia Agents; Serotonin Antagonists; Serotonin Agents; Antipsychotic Agents; Serotonin 5-HT2 Receptor Antagonists; pimavanserin
• Other Study ID Numbers: MHBP-001-21F; IK2CX002363-01A1 (U.S. NIH Grant/Contract: VA CSR&D; Acadia Pharmaceuticals (medication only))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: Yes