Pimavanserin for Insomnia in Veterans With Posttraumatic Stress Disorder: Proof of Concept

Inclusion Criteria:

• Male and female Veterans, aged 18-64
• Determined to meet criteria for current posttraumatic stress disorder, as per theClinician Administered PTSD Scale for the DSM-5 (CAPS-5) and a total score of ≥33 onthe PTSD Checklist (PCL-5)
• Meets DSM-5 standards of chronic insomnia disorder, as follows: a. Complains ofdissatisfaction with nighttime sleep in the form of difficulty falling asleep (subjective sleep onset latency ≥30 minutes), difficulty staying asleep (subjectivetime 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. b. Insomnia frequency of ≥3 times per week c. The duration of theinsomnia complaint is ≥3 months d. Associated with complaint of daytime impairment
• Insomnia Severity Index total score ≥15 (moderate insomnia)
• Willing and able to comply with all aspects of the protocol
• Willing to not start a concurrent behavioral or other treatment program for insomnia,PTSD, or other psychiatric disorders during the participation in the study
• If female subjects nor their partners are surgically sterile, and if they are notpost- menopausal (absence of menses for at least 12 months), female subjects areconsidered to be of child-bearing potential. It is required that women ofchild-bearing potential who are sexually active agree to either refrain from sexualactivity or use a two methods of contraception for the duration of the study (i.e.,beginning 30 days prior to drug initiation and extending to 30 days after the lastdose of study drug). The two methods should include: 1) A barrier method (e.g., condomwith spermicidal gel, diaphragm with spermicide, intrauterine devices, cervical cap),and 2) One other method, including hormonal contraceptives (e.g., oral contraceptives,injectable contraceptives, contraceptive implant) or another barrier method.

Exclusion Criteria:

• Current or a history of a primary psychotic disorder (i.e., schizophrenia,schizoaffective or bipolar disorder)
• Active suicidal or homicidal ideation requiring crisis intervention
• Current moderate or severe alcohol or marijuana/cannabis use disorder, or otherillicit use disorder of any severity
• A history of moderate or severe traumatic brain injury or other neurological illness (i.e., stroke, epilepsy, multiple sclerosis)
• Caffeine use that is deemed excessive and is contributing to the insomnia per theopinion of the investigators (i.e. caffeinated beverages consumed after 18:00 3times/week or more and/or that correlates with the timing of the insomnia complaints)
• Tobacco use before bedtime that is contributing to the insomnia per the opinion of theinvestigators or that would interfere with completing an overnight polysomnogram
• Previous diagnosis of periodic limb movement disorder, restless legs syndrome,circadian rhythm sleep disorder, narcolepsy, RBD, or other sleep disorders (exceptobstructive sleep apnea) that may confound, per the opinion of the investigators, theassessment of insomnia
• Previous diagnosis of moderate to severe obstructive sleep apnea (defined as an AHIequal to or greater than 15)
• Participants deemed to be at high risk of moderate to severe obstructive sleep apneaper the Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age,Neck circumference, and male Gender questionnaire (STOP-BANG). Subjects with aSTOP-BANG score of 5 or greater, or STOP score of 2 or greater plus (body mass indexgreater than 35 kg/m2 or male or neck circumference greater than 40 cm), areconsidered to be high-risk and will be referred to clinical treatment
• Participants identified as having moderate to severe obstructive sleep apnea duringthe screening polysomnogram. These participants will be referred to clinical treatment
• Periodic limb movement arousal index 15 or greater or other sleep disorders capturedduring the screening polysomnogram that may confound, per the opinion of theinvestigators, the assessment and treatment of insomnia
• A prolonged QT interval, corrected for heart rate (QTc), at the screeningelectrocardiogram. A prolonged QTc is defined as 470 milliseconds for males and 480milliseconds for females
• Engagement in an evidence-based psychotherapy within 1-week prior to enrollment thatin the opinion of the investigators, may confound the assessment of insomnia (ex. CBTfor insomnia)
• Current evidence of clinically significant cardiac, respiratory, gastrointestinal,renal, neurological, hepatic, and/or chronic pain that in the opinion of theinvestigator(s) could affect the participant's safety or interfere with the studyassessments
• Females who are breastfeeding or pregnant at screening; 16. Females of childbearingpotential who are not practicing acceptable pregnancy prevention methods (NOTE: Allfemales will be considered to be of childbearing potential unless they arepostmenopausal or have been sterilized surgically)
• Patients with cardiac conditions that in the opinion of the investigators may increasethe risk of torsades de pointes and/or sudden death (ex. symptomatic bradycardia,congenital prolongation of the QT interval)
• Current use of a prohibited medications: Hypnotic or sedating medications taken atbedtime for insomnia; antipsychotics and antidepressants with known 5HT2A antagonistactivity; medications that increase or decrease the metabolism of pimavanserin;medications that increase the risk of QTc prolongation