Clinical trial NCT04188392
Conditions: Post-traumatic Stress Disorder Insomnia
Keywords: Post-traumatic Stress Disorder Insomnia
Sponsor: Baylor College of Medicine
Start date: 2020-01-06; Completion date: 2021-11-10
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This preliminary, open-label study assesses the feasibility of 34mg at bedtime for 6 weeks in Veterans with Posttraumatic Stress Disorder and insomnia.

Detailed description:
More treatments are needed to target insomnia in Veterans with Posttraumatic Stress Disorder. There is evidence to suggest that pimavanserin, a medication approved by the Food and Drug Administration for the treatment of psychosis in Parkinson's disease, may improve deep sleep and insomnia. This study preliminary assesses the feasibility of pimavanserin 34mg at bedtime for 6 weeks for the treatment of chronic insomnia in Veterans with Posttraumatic Stress Disorder.

Arms: arm 1: pimavanserin 34mg at bedtime for 6 weeks
Interventions: intervention 1: Pimavanserin
Intervention descriptions: intervention 1: pimavanserin tablet

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Pimavanserin for Insomnia in Veterans with 
Posttraumatic Stress Disorder (PIP) 
NCT04188392 
Protocol (includes Statistical Analysis) – version approved 08.20.2021 
Informed Consent Form – version approved 08.20.2021 
Melissa B. Jones, MD (PI) 
Staff Neuropsychiatrist, 
Michael E. DeBakey VA Medical Center 
Associate Director, 
Behavioral Neurology & Neuropsychiatry Fellowship 
Assistant Professor, 
Menninger Department of Psychiatry and Behavioral Sciences 
Baylor College of Medicine 
2002 Holcombe Blvd. 
Rm. 2B-122 (TBI-153) 
Houston, TX 77030 
713-791-1414 ext. 24747
melissa.jones2@bcm.edu
melissa.jones10@va.gov


 
The Feasibility of Pimavanserin for Insomnia in Veterans with Posttraumatic Stress Disorder 
 
Abbreviated Protocol – version 08/20/2021  
 
 
Background Information: 
Posttraumatic stress disorder (PTSD), a common and disabling condition in Veterans, is 
frequently accompanied by sleep disturbances that have grave consequences. In the general 
population, lifetime prevalence of PTSD is 8%.1 Rates of PTSD in military Veterans are even higher, 
as nearly 25% of former Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) 
servicemembers are affected.2 In PTSD patients, in general, sleep disturbances are the most 
common complaint, with 50-70% of patients having co-occurring sleep disorders.3 The most 
frequently reported sleep-related symptom in patients with PTSD is insomnia: impaired initiation 
and maintenance of sleep affect an estimated 41% and 47% of patients, respectively.4 
Posttraumatic nightmares, which occur in 70-90% of patients, are associated with greater disability 
and suicide risk.5 Patients with PTSD also frequently report disruptive nocturnal behaviors, such as 
running, kicking, and punching during sleep that result in violence and injury.4,6 
Current interventions are inadequate for PTSD-related sleep disturbances, which further 
confound response to otherwise effective treatments of PTSD. For example, sleep complaints in 
patients with PTSD persist even after completion of an evidence-based psychotherapy for PTSD.7 
Cognitive Behavioral Therapy for Insomnia (CBT-I) is a first-line treatment, but requires a trained 
clinician, which is not always available, and has high drop-out rates.3 Pharmacotherapies for 
insomnia, e.g., benzodiazepines, nonbenzodiazepine receptor agonists, atypical antipsychotics, 
and trazodone,8 all cause daytime sleepiness and other undesirable side effects due to their non-
selective mechanisms of action. The addiction potential of benzodiazepines and 
nonbenzodiazepine receptor agonists further limits their use, and pharmacotherapy for nightmares 
has limited efficacy.9 Finally, antidepressants commonly prescribed for PTSD may exacerbate 
dream enactment behaviors in susceptible individuals.10 Engagement in PTSD-specific 
psychotherapies could benefit from a pharmacological intervention that improves nocturnal sleep 
without causing adverse daytime effects and also avoids putative pathogenic risks associated with 
second-line pharmacotherapies used to treat PTSD and its specific symptoms, e.g., antidepressant 
and antipsychotic medications. 
Pimavanserin, a 5-HT2A inverse agonist approved by the FDA for Parkinson's Disease 
psychosis, is a promising candidate for the treatment of insomnia and other sleep disturbances. 5-
HT2A receptors are distributed in several brain regions known to regulate wakefulness, non-rapid 
eye movement (NREM) sleep, and rapid eye movement (REM) sleep.11 In healthy volunteers, 
pimavanserin increases the amount of slow wave sleep without causing daytime sleepiness.12 
Similarly, 5-HT2A receptor antagonists increase deep slow-wave sleep, decrease the duration of 
wake after sleep onset (WASO), and decrease the frequency of arousals and awakenings from 
sleep.13 Furthermore, studies on patients with Parkinson’s disease treated with pimavanserin 34mg 
reported improved sleep, with effects greatest in those with baseline sleep impairment and 
psychosis.14 
In patients with PTSD, we propose that pimavanserin will improve insomnia and other sleep 
disturbances by promoting slow-wave sleep and improving sleep maintenance. While PTSD lacks 
a polysomnographic “signature,” a meta-analytic review of 20 polysomnographic studies found 
increased stage 1 sleep and decreased slow wave sleep in patients with PTSD relative to those 
without PTSD.15 Evidence that pimavanserin selectively increases slow-wave sleep without causing 
daytime sleepiness suggests it would improve insomnia symptoms without causing the next-day 
hangover and other unwanted side effects of current pharmacological treatments for insomnia.12-14 
Other potential benefits of inverse agonism of 5-HT2A receptors include reduced intensity of 
nightmares, disruptive nocturnal behaviors, and overall PTSD symptomatology. 5-HT2A agonists 
are known to exert dream-like hallucinations that are similar in nature to affectively-laden and 
bizarre dreams.16 5-HT2A partial agonism may reduce the severity and intensity of nightmares in 
the same manner that it improves visual hallucinations. The pathophysiology of dream enactment 
behaviors reported by patients with PTSD are not completely understood but are similar in 
phenomenology to rapid eye movement sleep behavior disorder (RBD), a parasomnia known to be 
unmasked or exacerbated by serotonergic medications.10 As a 5-HT2A inverse agonist, 
pimavanserin may be a safer option for these patients, but the effects of such a medication on 


these disruptive nocturnal behaviors is unknown. Finally, as slow-wave sleep is required for 
memory consolidation and emotional processing,17 pimavanserin’s effects on sleep may improve 
overall PTSD severity. 
To address the critical need for pharmacotherapy targeting sleep disturbances in patients with 
PTSD, we propose a clinical trial of pimavanserin 34mg at bedtime for 6 weeks for insomnia in 
adult male and female Veterans with PTSD. We first propose a pilot, feasibility study to ensure 
adequate recruitment and retention rates prior to conducting a randomized, double-blind, placebo-
controlled trial. The primary endpoints of this initial study are the feasibility of recruitment, defined 
as the average number of subjects recruited into treatment per month, and the percentage of 
subjects who complete the protocol in its entirety. We also aim to preliminarily examine the effect of 
pimavanserin on sleep architecture as a possible therapeutic mechanism; the safety and 
tolerability of pimavanserin in our population; and the completion rates of key outcome measures 
of insomnia. Exploratory aims of this feasibility study are to preliminarily assess the change from 
baseline to week-6 in subjective and objective measures of insomnia; overall PTSD severity; 
disruptive nocturnal behaviors; and nightmare severity. The results of this study will inform on the 
feasibility of objective and subjective insomnia severity measures, as well as on the potential 
therapeutic mechanisms of pimavanserin on sleep, for a future double-blind, placebo-controlled 
trial. 
 
1. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder 
in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52(12):1048-1060.  
2. Fulton JJ, Calhoun PS, Wagner HR, et al. The prevalence of posttraumatic stress 
disorder in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans: a 
meta­ analysis. J Anxiety Disord. 2015;31:98-107.  
3. EI-Solh AA, Riaz U, Roberts J. Sleep Disorders in Patients With Posttraumatic Stress 
Disorder. Chest. 2018;154(2):427-439.  
4. Ohayon MM, Shapiro CM. Sleep disturbances and psychiatric disorders associated with 
posttraumatic stress disorder in the general population. Compr Psychiatry. 
2000;41(6):469-478.  
5. Waltman SH, Shearer D, Moore BA. Management of Post-Traumatic Nightmares: a 
Review of Pharmacologic and Nonpharmacologic Treatments Since 2013. Curr 
Psychiatry Rep. 2018;20(12):108. 
6. Insana SP, Hall M, Buysse DJ, Germain A. Validation of the Pittsburgh Sleep Quality 
Index Addendum for posttraumatic stress disorder (PSQI-A) in U.S. male military 
veterans. J Trauma Stress. 2013;26(2):192-200.  
7. Larsen SE, Fleming CJE, Resick PA. Residual symptoms following empirically 
supported treatment for PTSD. Psychol Trauma. 2018. 
8. Brownlow JA, Harb GC, Ross RJ. Treatment of Sleep Disturbances in Post-Traumatic 
Stress Disorder: A Review of the Literature. Curr Psychiatry Rep. 2015;17(6):41. 
9. Raskind MA, Peskind ER, Chow B, et al. Trial of Prazosin for Post-Traumatic Stress 
Disorder in Military Veterans. N Engl J Med. 2018;378(6):507-517.  
10. Postuma RB, Gagnon JF, Tuineaig M, et al. Antidepressants and REM sleep behavior 
disorder: isolated side effect or neurodegenerative signal? Sleep. 2013;36(11):1579-
1585. 11. Monti JM, Pandi Perumal SD, Warren Spence D, Torterolo P. The Involvement 
of 5-HT2A Receptor in the Regulation of Sleep and Wakefulness, and the Potential 
Therapeutic Use of Selective 5-HT2A Receptor Antagonists and Inverse Agonists for the 
Treatment of an Insomnia Disorder. In: Guiard BOG, G., ed. 5-HT2A receptors in the 
central nervous system. Vol 32. Humana Press, Cham; 2018.  
11. Ancoli-lsrael S, Vanover KE, Weiner DM, Davis RE, van Kammen DP. Pimavanserin 
tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by 
polysomnography in healthy adult volunteers. Sleep Med. 2011;12(2):134-141.  
12. Vanover KE, Davis RE. Role of 5-HT2A receptor antagonists in the treatment of 
insomnia. Nat Sci Sleep. 2010;2:139-150.  
13. Patel N, LeWitt P, Neikrug AB, Kesslak P, Coate B, Ancoli-lsrael S. Nighttime Sleep and 
Daytime Sleepiness Improved With Pimavanserin During Treatment of Parkinson's 
Disease Psychosis. Clin Neuropharmacol. 2018;41(6):210-215.  
14. Kobayashi I, Boarts JM, Delahanty DL. Polysomnographically measured sleep 
abnormalities in PTSD: a meta-analytic review. Psychophysiology. 2007;44(4):660-669.  
15. Kraehenmann R, Pokorny D, Vollenweider L, et al. Dreamlike effects of LSD on waking 


imagery in humans depend on serotonin 2A receptor activation. Psychopharmacology 
(Berl). 2017;234(13):2031-2046.  
16. Mellman TA, David D, Barza L. Nefazodone treatment and dream reports in chronic 
PTSD. Depress Anxiety. 1999;9(3):146-148. 
 
 
Purpose and Objectives 
 
Primary Objectives:  
To determine the feasibility of pimavanserin 34mg at bedtime for 6 weeks in Veterans with PTSD 
and insomnia, as measured by subject recruitment and retention rates. 
 
Secondary Objectives:  
1. Explore the effect of pimavanserin on the duration of slow wave sleep as a possible, 
therapeutic mechanism.  
2. Preliminarily examine the tolerability and safety of pimavanserin 34mg at bedtime in non-
elderly Veterans with PTSD and insomnia.  
3. To investigate the completion rate of subjective and objective measures of insomnia to 
inform on their feasibility in a definitive trial.  
4. Synthesize key outcome measures to assist with sample size estimation for a future, 
definitive trial. 
 
 
Design/Procedure: 
 
This is an open-label, feasibility, fixed-dose design of pimavanserin 34mg at bedtime for 6 
weeks in Veterans with PTSD and insomnia. After an initial screening visit, participants will 
complete 7 days of actigraphy monitoring and sleep diaries. Screening and baseline 
polysomnograms will be completed prior to receiving the study drug. Participants will then receive 
a fixed dose of pimavanserin 34mg (the recommended dosing for adults) at bedtime for 6 weeks. 
A duration of 6-weeks was chosen based on the pivotal, phase 3 study of pimavanserin in patients 
with Parkinson ls Disease psychosis, where a statistically significant improvement in sleep was 
not seen until week-4 and week-6 of the study. Safety will be assessed via questionnaires 
completed in-person at the baseline, midpoint, and end of the study. Between in-person visits, 
safety will also be assessed via phone calls from a research coordinator using the same 
questionnaires. Actigraphy and sleep diaries will again be performed during the final week of the 
study. A final polysomnogram and exit visit will conclude the study. 
 
Inclusion Criteria: 
1. Male and female Veterans, aged 18-64;  
2 . Determined to meet criteria for current PTSD, as per a total score of ≥ 33 on the PTSD 
Checklist (PCL-5) and Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition 
(DSM-5) criteria for PTSD;  
3 .  At the initial enrollment visit, meets DSM-5 standards of chronic insomnia disorder, as 
follows: a. 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. b. 
Insomnia frequency of ≥3 times per week c. The duration of the insomnia complaint is ≥3 
months d. Associated with complaint of daytime impairment;  
4. Insomnia Severity Index total score ≥15 (moderate insomnia);  
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 use two 
methods of contraception for the duration of the study and extending to 30 days after the last 
dose of study drug. The two methods should include: 1) A barrier method (e.g., condom with 
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: 
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 marijuana/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 (i.e. caffeinated beverages consumed after 18:00 3 times/week or more 
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, RBD, 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 AHI ≥ 
15);  
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 of ≥ 5 or STOP score of ≥ 2 plus (body mass index greater than 35 
kg/m2 or male or neck circumference greater than 40 cm), are considered to be high-risk 
and will be referred to clinical treatment; 
10. Participants identified as having moderate to severe obstructive sleep apnea 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 an evidence-based psychotherapy for 1- week prior to enrollment that in 
the opinion of the investigators, may confound the assessment of insomnia (ex. CBT for 
insomnia);  
14. Current evidence of clinically significant cardiac, respiratory, gastrointestinal, renal, 
neurological, hepatic, and/or chronic pain 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 cardiac conditions that in the opinion of the investigators may increase the 
risk of torsades de pointes and/or sudden death (ex. symptomatic bradycardia, congenital 
prolongation of the QT interval). 
 
Permitted medications: 
1. Selective serotonin reuptake inhibitors (SSRls), serotonin norepinephrine reuptake inhibitors 
(SNRls), bupropion, and anticonvulsants (excluding strong CYP3A4 inhibitors or inducers) for 
1 month prior to enrollment;  
2. Medications taken for other medical conditions (i.e., hypothyroidism, diabetes) at doses 
stable for 1 month prior to enrollment. 
 
Prohibited medications: 
1. 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 tricyclics, antihistamines, opioids, muscle relaxants) 
must be discontinued for 1 week prior to enrollment;  
2. Antipsychotics and antidepressants with known 5HT2A antagonist activity (ex. quetiapine, 
olanzapine, mirtazapine, trazodone) must be discontinued for 1 week prior to enrollment;  
3. Strong CYP3A4 inhibitors (ex. itraconazole, ketoconazole, clarithromycin, indinavir) that 
may increase the levels of pimavanserin; 
4. Patients taking strong CYP3A4 inducers (ex. rifampin, carbamazepine, phenytoin, St. 
John’s wort) that may reduce the levels of pimavanserin;  
5. Concurrent use of medications known to increase the QT interval, such as Class 1A 
antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., 
amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, 
thioridazine), and certain antibiotics (e.g., gatifloxacin, moxifloxacin). 
 
Procedure: 
 
Prior to the baseline visit, additional screening for the inclusion and exclusion criteria will take 
place over the phone and via chart review. If eligibility is likely, participants will be evaluated at a 
screening visit. See Table 1 for a schedule of visits and procedures, as well as the estimated times 
to complete visits and phone calls, and Table 2 for the subject reimbursement schedule. 
At the screening visit, participants complete questionnaires and a clinical interview to 1) 
confirm the presence of insomnia symptoms of sufficient severity and frequency to meet criteria for 
chronic insomnia disorder per the DSM-5 and 2) confirm the subject meets DSM-5 criteria for 
current PTSD. Subjects will undergo a complete history, including sleep history; vital sign 
measurement (heart rate, blood pressure, temperature, respiratory rate, weight and height for body 
mass index, neck circumference); screening laboratory tests (complete metabolic panel, complete 
blood count with differential, magnesium level, urine toxicology screen, pregnancy test where 
appropriate); and baseline electrocardiograms (EKG). 
For those subjects with comorbid obstructive sleep apnea, PAP device adherence is 
confirmed via data card download. If subjects have not completed a semi-structured or structured 
psychiatric diagnostic interview within 30 days of the initial screening phase, the Structured Clinical 
Interview for the DSM-5 (SCID-5) will be performed to assess for comorbid psychiatric conditions. 
Eligible participants wear an actigraphy watch on their non-dominant wrist and complete 
nightly sleep diaries for 7 days prior to receiving the study drug. The actigraphy watch provides 
objective, home-based data to compare with subjective and polysomnographic measures of 
insomnia. To interpret the actigraphy data, and in accordance with proposed research standards for 
insomnia, participants will complete nightly sleep diaries while wearing the actigraphy watch. 
Specifically, the Spectrum PRO (Patient Reported Outcome) actigraphy watch has the capability to 
remind participants to complete the sleep diary up to twice daily at a prespecified time set by the 
investigator. Summary variables generated from actigraphy include total sleep duration, sleep 
efficiency, and number of awakenings per night. The sleep diary collects self-reported information on 
bed and wake times, sleep onset, time awake after sleep onset, naps, actigraphy removal or other 
events. 
Subjects then complete two consecutive polysomnograms prior to receiving the study drug. 
The purpose of the first polysomnogram is to screen out participants with confounding and untreated 
obstructive sleep apnea or periodic limb movement disorder, as well as to prevent the “first night 
effect” from confounding the assessment of insomnia and sleep architecture. Attended 
polysomnography is performed overnight at the MEDVAMC utilizing the standard montage 
recommended by the American Academy of Sleep Medicine (AASM). Subjects sleep in private 
rooms with video monitoring. Polysomnogram tracings are scored according to current AASM 
standards. 
Subjects diagnosed with moderate to severe obstructive sleep apnea during the screening 
polysomnogram may undergo PAP titration, where possible, and are referred for clinical treatment. 
Subjects with sleep disorders that may, per the opinion of the investigators, confound the 
assessment and treatment of insomnia (e.g., periodic limb movement disorder, suspected 
narcolepsy) are excluded and referred to clinical treatment. 
Following the baseline polysomnogram, subjects start open-label, fixed-dose pimavanserin 
34mg at bedtime for 6 weeks. Although pimavanserin is usually taken in the daytime, we predict the 
medication half-life (57 hours) is sufficiently long enough to enable nighttime dosing. Safety and 


medication adherence will be evaluated in-person via questionnaire at week-3 (midpoint visit) and 
week-6 (closeout visit). For the remaining weeks, safety and adherence will be assessed via weekly 
phone calls. To monitor treatment progress, measures of insomnia, PTSD severity, and mood are 
performed at the 3-week, treatment midpoint visit. 
During the final week of the treatment phase, actigraphy and sleep-diary measures are 
repeated to compare to pre­ treatment values. Participants will also complete a post-treatment 
polysomnogram to assess the effects of pimavanserin on the duration of stage 3 sleep from 
baseline to week-6 post-drug and to compare objective and subjective measures of insomnia. 
Where applicable, PAP data card download will be performed to re-assess adherence. At the exit 
visit, subjects will again complete questionnaires assessing insomnia severity, PTSD, and mood. At 
this time, pimavanserin will be discontinued, and subjects will be referred for clinical care if 
indicated. Subjects receive a follow up phone call 2 weeks after pimavanserin’s discontinuation to 
re-assess subject safety and to refer for clinical care if indicated. 
 
 
 
Sample Size/Data Analysis: 
 
Sample Size 
We hypothesize that pimavanserin 34mg at bedtime for 6 weeks is a feasible intervention for 
the treatment of insomnia symptoms in Veterans with PTSD. Specifically, we hypothesize that, after 
exits for exclusion criteria, a total of 6 participants will be enrolled into open-label treatment during 
the recruitment period, and that at least 75% of these participants (approximately n=5) will complete 
the study protocol. We estimate that 6 subjects enrolled into treatment will provide preliminary 
information on the feasibility of the protocol given budgetary constraints. 
Data Analysis 
Primary Endpoint 1. The feasibility of the protocol, as measured by the average monthly rate 
of subjects recruited into treatment and the percentage of participants completing the protocol in its 
entirety. 
Secondary Endpoint 1. Mean change in duration of stage 3 sleep from baseline to week-6 
polysomnogram; 2. The number of subjects who discontinue the protocol due to adverse effects; 3. 
Completion rates of key outcome measures, including sleep diaries, actigraphy, and attended 
polysomnography. 
Statistical analyses will be conducted with an alpha level of 0.05. We will derive point 
estimates and 95% confidence intervals for the quantities of interest, such as the recruitment rate, 
retention rate, the mean change in duration of stage 3 sleep from baseline to week-6, and rates of 
treatment discontinuation and completion. Repeated measures analysis and paired t-tests using 
baseline and subsequent scores will be used to assess for within patient time effects. The underlying 
assumptions of all analytic procedures will be carefully examined. If violation of any assumption is 
detected, we will implement alternative robust procedures, such as the Wilcoxon’s signed-rank test 
for the change from baseline to endpoint. As appropriate, McNemar's test or its generalized version 
will be used to compare categorical variables. 
 
 
 
Consent Procedures: 
 
All recruitment materials, consent forms, and Health Insurance Portability and Accountability 
Act of 1996 form will be approved by the MEDVAMC Research and Development Committee and 
the IRB prior to the beginning of the protocol. The study personnel will have certification of Human 
Subjects Research Training. Informed consent will be obtained prior to conducting any study 
procedures. 
Recruitment will occur via referral from staff members and services at the MEDVAMC. The 
referring staff members will ask eligible subjects if they are interested in hearing more about this 
study. If the veteran agrees or expresses interest in the study,the Pl or study coordinator will 
approach or contact the subject to explain, in detail, the characteristics of the study, including 
potential benefits and risks. Veterans will receive a brochure summarizing this information and 
describing the way in which Veterans may contact the research team. Brochures that describe the 
study and provide contact information for the research team will also be distributed to clinics and 


staff members to be provided to interested veterans, who then may contact the Pl or research 
coordinator. 
We will also review the charts of patients enrolled in clinics at the Michael E. DeBakey 
Medical Center for eligibility, including the PTSD clinic, General Mental Health Clinic, post-
deployment clinic, and sleep medicine clinics. Potentially eligible participants will be mailed a letter. 
If we do not receive a contrary response within 14 days, we will contact the patient by phone to 
inform them of the study. By pre-screening patients in CPRS, the research team can focus 
recruitment efforts on Veterans who are more likely to qualify for the study. Pre-screening involves 
reviewing the patient's medical record to check for inclusion/exclusion criteria. (Veterans who are 
referred or recruited through flyers may be pre-screened through CPRS chart review or over the 
phone. If pre-screening over the phone, a verbal consent script will be read before asking any 
questions).