Clinical trial NCT02849548
Conditions: Posttraumatic Stress Disorder
Sponsor: Howard University
Start date: 2017-01-03; Completion date: 2021-05-19
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine effects of blocking the orexin system with suvorexant after exposure-based intervention for posttraumatic stress disorder (PTSD) on sleep, PTSD symptoms, and intersession habituation.

Detailed description:
Cognitive behavioral therapies (CBT) that include exposure to trauma memories are considered first line treatments for PTSD. However, approximately 1/3 of patients who complete CBT for PTSD do not achieve remission, and hyperarousal symptoms including sleep disturbances are less responsive to CBT than other PTSD symptoms. Despite these limitations, CBT outcomes are generally superior to outcomes of pharmacotherapy. It is, therefore, imperative to identify strategies to improve effectiveness of treatments for PTSD, particularly hyperarousal symptoms.

Disturbed sleep is common in PTSD. Studies of PTSD and anxiety and mood disorders have shown that impaired sleep before psychotherapy predicted less favorable responses. Sleep has been implicated in learning processes that are a key to adaptive processing of trauma memories such as extinction learning and generalization of extinction. Our recent PTSD study showed that preserved slow-wave sleep (SWS), less increase in rapid-eye-movement (REM) density, and reduced wake after sleep onset (WASO) during sleep following an evening session of written narrative exposure (WNE: writing about one's traumatic experience) was associated with greater PTSD symptom reduction. These findings suggest that increased nocturnal arousal compromises sleep's benefits to emotional processing of trauma memories. Identifying strategies to reduce nocturnal arousal and promote sleep characteristics associated with emotional adaptation could enhance PTSD treatment outcomes.

Orexins are neuropeptides implicated in regulating both sleep/wakefulness and emotional behaviors, including anxiety. Inhibiting the orexin system promoted slow-wave patterns and reduced wake in animal models. The first orexin receptor antagonist (suvorexant) was recently approved for treatment of insomnia. Suvorexant reduced WASO and latency to persistent sleep and increased SWS and REM sleep in humans with insomnia. In addition, administrations of orexin-A increased anxiety-like behaviors in rodents, and administrations of an orexin receptor-1 antagonist to mice facilitated extinction of conditioned fear, an animal model of recovery from PTSD and anxiety disorders.

Objective: To examine effects of blocking the orexin system with suvorexant after WNE on sleep, PTSD symptoms, and intersession habituation.

The investigators will utilize the WNE paradigm in which participants with PTSD write about their traumatic experiences in the evening and morning sessions with intervening sleep. Suvorexant or placebo will be administered after the evening WNE, and sleep will be recorded.

The investigators hypothesize that 1) Suvorexant will promote the sleep characteristics that have been associated with more favorable treatment outcomes and emotional adaptation (e.g., increased SWS and REM sleep, reduced WASO) compared with placebo; 2) Participants given suvorexant will have greater PTSD symptom reduction and intersession habituation indexed by reduction of maximum pulse rate compared with participants given placebo; and 3) The greater PTSD symptom reduction and intersession habituation in the suvorexant group will be accounted for by effects of the medication on sleep.

Arms: arm 1: 10 to 20 mg to be administered after an evening written trauma narrative exposure session. arm 2: A pill without active ingredients
Interventions: intervention 1: suvorexant intervention 2: placebo
Intervention descriptions: intervention 1: First in class orexin antagonist approved by the FDA for the treatment of insomnia intervention 2: Pill with inactive ingredients

Protocol documents:
Prot_000.pdf: 
Study Protocol 
 
Official Title: Can Blocking the Orexin System Enhance Sleep's Benefits to Therapeutic 
Exposure for PTSD? 
NCT number: NCT02849548 
Date of the Document: July 7,2016 


Approach 
Study Team: The highly qualified interdisciplinary study team has significantly 
contributed to the proposal and will continue to guide the candidate. Thomas Mellman, M.D., 
primary mentor, is an expert in sleep, PTSD, and pharmacological trials for PTSD and insomnia 
and advises on all aspects of the clinical trial. Larry Sanford, Ph.D., co-mentor, contributes his 
expertise in neurophysiology and animal models of PTSD and sleep and advises on all aspects 
of the animal pilot study. Patrick Forcelli, Ph.D., co-mentor, contributes his expertise in 
neurophysiology and optogenetic methods and supervises the implementation of the animal 
pilot study. John Kwagyan, Ph.D., collaborator, contributes his expertise in biostatistics. Akihiro 
Yamanaka, Ph.D., consultant, contributes his expertise in optogenetic manipulations of orexin 
neurons using transgenic mice.  
Clinical Study Approach: AIM 1: To examine effects of pharmacologically blocking the orexin 
system after WNE on sleep, PTSD symptoms, and intersession habituation.  
Participants: Participants will be physically healthy adults (1:1 gender ratio) (age 18 – 
55) who meet DSM-5 criteria for PTSD57 with index trauma exposure within the previous 5 
years. Justifications for this include a greater likelihood of remembering the details of the event 
and our prior finding indicating changes in sleep characteristics over the duration of PTSD.58 
Exclusion criteria include: 1) medical or psychiatric conditions that require consistent use of 
medication, except for hormonal contraceptives; 2) medical condition that affects sleep; 3) 
inability to remember most details of the index event; 4) body mass index ≥ 40 (due to very high 
comorbidity rates of sleep apnea59); 5) diagnosis of a sleep disorder other than insomnia 
including PSG findings of apnea/hypopnea index > 10/hour; 6) consumption of more caffeine 
than 5 cups of coffee/day equivalent; 7) smoking > 20 cigarettes/day; 8) habitual bedtimes after 
2AM, habitual rise times after 9AM, or habitual napping > 1 hour/day; 9) moderate or severe 
alcohol or drug use disorders within the past year; 10) positive urine toxicology for illicit drugs 
including cannabis; 11) a diagnosis of psychotic disorders, bipolar disorder, or depression that 
preceded the onset of PTSD; 12) suicidal ideation with intent to act or with specific plan and 
intent in the past 6 months [Type 4 – 5 ideation on the Columbia Suicide Severity Rating Scale 
(C-SSRS)] or history of a suicide attempt; 13) completion of exposure-based therapy targeting 
the index trauma; 14) pregnancy or breast feeding (All female participants will be required to 
complete an urine pregnancy test. Sexually active female participants will be required to use a 
medically acceptable form of birth control); 15) known sensitivity or allergy to an orexin receptor 
antagonist; and 16) limited ability to read or write English. 
Design and Overview (Table 3): This is a randomized, double-blind, placebo-controlled 
trial examining the effects of suvorexant (Merck & Co., Kenilworth, NJ), a dual orexin receptor 
antagonist that is FDA approved for insomnia, on sleep and PTSD symptom reduction following 
WNE. We will employ our successful recruitment strategies, including flyers, outreach activities, 
and referral from previous participants. Potential 
participants will initially be screened over the phone 
or in person, and those who meet initial criteria will 
be invited to the Clinical Research Unit (CRU) at 
Howard University to complete a consent procedure, 
questionnaires, a clinical interview, a physical 
examination, and urine tests. Participants who meet 
the selection criteria will be invited to complete two 
pairs of 30-minute WNE sessions and four overnight 
PSG recordings [screening, baseline, between WNE 
sessions (twice)]. Both pairs of WNE sessions will 
occur at 8PM and 8AM in the following morning with 
intervening sleep. The second pair will occur one 
week after the first pair. Four WNE sessions are 


needed because the majority of participants in the preliminary study did not achieve remission 
until after completing the second pair of WNE. Participants will be stratified by gender and 
randomly assigned to either suvorexant or placebo. After the 1st evening WNE, a 10 mg tablet of 
suvorexant or placebo will be administered orally 30 minutes before bedtime. If the medication 
is well tolerated, the dose will be increased to 20 mg at the 2nd administration after the 3rd 
WNE. The recommended dose is 10mg, and the maximum recommended dose is 20mg.60 The 
1-week CAPS will be administered before the 1st and 3rd sessions and at 1-week follow-up. 
Feasibility: The primary mentor’s lab has been successfully recruiting, on average, one 
trauma-exposed participant/week. A pilot study will be conducted during the current KL2 to 
address potential barriers for recruitment and retention of participants. In the R21 funded study, 
approximately a half of participants met inclusion criteria and completed at least first two WNE 
sessions (Fig. 2). Therefore, we expect to enroll 140 participants during the 40-month K01 
recruitment period (3.5/month), and ~70 of them would complete at least first two WNE 
sessions. Based on the previous retention rate, we estimate that 54 participants (27 in each 
group) would complete the entire protocol. Reasons for dropouts from the R21 study included 
time conflicts and a family emergency. No participants reported distress related to WNE as a 
reason for withdrawal.  
Assessment: Screening and self-report measures. The initial phone screening will 
include questions about excluded conditions, trauma exposure, and PTSD symptoms (using the 
Primary Care PTSD screen,61 a 4-item screener). The questionnaire package includes a 
demographic questionnaire, the Life Event Checklist (LEC) 55 to determine the most stressful 
event (the index trauma), and a sleep questionnaire developed in the mentor’s lab to assess 
habitual sleep schedule and signs of possible narcolepsy.  
Medical/physical tests. Vital signs, height, and weight will be measured, and a physical 
examination will be performed by a physician or a nurse practitioner. Urine toxicology screening 
(all participants) and a urine pregnancy test (all female participants) will be conducted by a 
nurse at the CRU.  
Clinical interviews. Structured interviews will be conducted by clinically trained staff and 
will be reviewed weekly in a consensus conference with the candidate (a licensed psychologist) 
and the primary mentor (a board certified psychiatrist). The CAPS55 will be administered to 
assess current (past month and past week) and lifetime PTSD diagnosis and severity 
associated with the index trauma. The Structured Clinical Interview for DSM-5 (SCID)62 will be 
administered to assess current and lifetime psychiatric diagnoses and confirm inclusion criteria. 
The C-SSRS63 will be administered at the initial visit to assess suicidal ideation and behaviors in 
lifetime and past 6 months and at subsequent visits to assess any changes since the previous 
visit. The PI will be immediately notified if a participant indicates concerning suicidal ideation or 
behaviors. 
Sleep recordings. PSG recordings in the CRU will use a Natus/Embla (Pleasanton, CA) 
Titanium PSG unit including two central, frontal, and occipital EEG leads, two 
electrooculograms, chin and limb electromyograms, and an electrocardiogram. Participants will 
be instructed to go to bed at their habitual bedtime and wake up at 8 AM. Screening for sleep 
disordered breathing will be performed using the screening night data. Visual scoring of sleep 
records will be done following the American Academy of Sleep Medicine Manual, Version 2.3.64 
We will calculate standard PSG sleep parameters including total sleep time, WASO, the 
percentage and the duration of each sleep stage, and REM density using the REMLogic 
software (Natus/ Embla). Sleep changes from baseline to post-WNE will be computed by 
subtracting baseline measures from respective measures obtained during sleep following the 1st 
and 3rd WNE sessions. 
Alertness visual analogue scale (VAS). Participants will complete an alertness VAS upon 
awakening in the morning after PSG recordings. The VAS is a 100 mm horizontal line with a 
label “very sleepy” on the left end and “very alert” on the right end. Participants will be place a 


slash mark on the scale to indicate their alertness at the moment. A morning WNE session will 
not begin until the participant’s alertness level reaches the level he/she indicated in the morning 
after the baseline PSG recording. 
Adverse event assessment. Participants will be queried regarding the presence of any 
symptoms or concerns before and after the medication administration. 
Pulse rate. The pulses will be continuously recorded during the 5-min baseline and the 
30-min WNE through a finger pulse transducer of the PowerLab system (ADInstruments, 
Colorado Springs, CO). Data will be visually inspected using the LabChart software 
(ADInstruments), and segments with artifacts will be excluded. The average pulse rates for the 
5-min baseline and each 2-minute epoch during WNE will be computed. A baseline-corrected 
highest average pulse rate for each session will be computed by subtracting the session’s 
average baseline pulse rate from the highest average pulse rate in the session. The baseline 
correction will be performed to correct for circadian influences on pulse rates.65-67   
Study Medication: Suvorexant, a dual orexin receptor antagonist, is the first and only 
FDA-approved agent in this class for treatment of insomnia. Over 2,000 patients with insomnia 
have been exposed to suvorexant in one 4-week Phase IIB, two 3-month Phase III, and one 1-
year Phase III trials.48,49,68 Suvorexant (both 10 mg and 20 mg) reduced PSG-measured WASO 
and increased total sleep time, sleep efficiency, and REM sleep on the first night and at 4-week 
follow-up. In the largest trial, 20 mg (non-elderly)/15 mg (elderly) suvorexant increased SWS on 
the first night in patients with insomnia, and the effect was greater with a higher dose, 40/30 
mg.50 No gender differences were found in its effects on self-reported or PSG outcomes or its 
safety.48,60,69 The most common adverse effect was somnolence which occurred in 7% of 
insomnia patients receiving 20/15 mg, daily for 3 months compared with 3% receiving placebo. 
Other adverse events included nasopharyngitis (5%) and headache (7%), although these rates 
were comparable to the rates for those receiving placebo. Only 3% of the 3-month trial 
participants receiving suvorexant discontinued treatment due to adverse effects, which was 
comparable to the rate for those receiving placebo. The recommended dose is 10 mg, once 
daily, and the maximum recommended dose is 20 mg. The prescription information provided by 
Merck instructs to take the medication within 30 minutes of going to bed and stay in bed for at 
least 7 hours.60 Given that suvorexant’s effects on SWS were stronger with the higher doses, in 
this study, the dose will be increased from 10 mg at the 1st administration to 20 mg at the 2nd 
administration if the participant tolerated the lower dose well. The 2nd dose will remain at 10 mg 
if the participant had mild to moderate sedation in the morning after the 1st administration. If the 
participant had significant adverse events (that is rare), he/she will not have the 2nd 
administration. The CRU nurse and the study staff will monitor participants’ alertness level in the 
following morning, and those who remain at a low alertness level will be prohibited from driving 
themselves.  
Study Medication Administration: Participants will be stratified for gender and randomly 
assigned to either suvorexant or placebo before the 1st WNE. Suvorexant or placebo will be 
administered orally after the 1st and 3rd WNE, 30 minutes before the participant’s habitual 
bedtime. If the participant well tolerates 10mg, the dose will be increased to 20mg at the 2nd 
administration. Participants will have continuous access to research nurses during the sleep 
recording. In the following morning, a nurse will assess possible adverse effects.   
Written Narrative Exposure (WNE): We will use a procedure similar to the one used in 
the R21 study. Sessions will begin at 8PM and approximately 8AM. The morning sessions will 
not start until the participant’s alertness level reaches the level he/she indicated in the morning 
after the baseline PSG recording. The participant will sit at a desk in a private room with a 
facilitator, and a pulse transducer will be attached to the distal of the middle finger of his/her 
non-dominant hand placed on the desk. After a 10-minute acclimatization period, a 5-minute 
baseline pulse recording will begin. At the end of the baseline, the facilitator will provide 
instructions to write in as much detail as possible about his/her index trauma including what 


happened, how s/he felt, and what s/he perceived and thought and to use the entire 30 minutes. 
The facilitator will also instruct the participant to orally report an overall level of distress on a 
scale from 0 – 100 [subjective units of distress scale (SUDS)] at baseline, every 10 minutes, 
and at the end of the writing period. The facilitator will remain in the same room during the 
writing to obtain SUDS scores and to assist and encourage the participant if necessary. At the 
end of the writing period, if warranted, the facilitator will instruct the participant in relaxation 
techniques for ≤10 minutes. Participants will not be dismissed until distress is minimal.  
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
Official Title: Can Blocking the Orexin System Enhance Sleep's Benefits to Therapeutic 
Exposure for PTSD? 
NCT number: NCT02849548 
Date of the Document: July 7,2016 


Data Analysis Plan: Initially, data will be pre-screened for errors, outliers, normality of 
distributions, and any necessary modifications such as transformation will then be conducted. 
The suvorexant and placebo groups will be compared on demographics and baseline measures 
using t-tests or chi-squared tests to examine group comparability. Fig. 1 describes each 
hypothesis. Hypothesis 1a: The primary comparison will be between the 2 groups (suvorexant 
vs. placebo) and sleep parameters measured at 3 time points (baseline, post-Session 1, and 
post-Session 3). A repeated-measures ANOVA will be performed to examine whether there is a 
Group x Time interaction effect on each sleep parameter of interest (i.e., N3, WASO, and REM 
sleep). If a significant interaction effect is found, group comparisons will be performed at each 
time point. Hypothesis 1b: A repeated-measures ANOVA will be performed to examine 
whether there is a Group x Time interaction effect on CAPS scores. In 
addition, 2(Group) x 2(Time) ANOVAs will be performed to examine if 
there is an interaction effect on intersession habituation between 
Session 1 & 2 and between Session 3 & 4, using a baseline-corrected 
highest average pulse rate as a dependent variable. Hypothesis 1c: 
To examine indirect effects of suvorexant on PTSD through the 
mediator, post-WNE sleep change, a path analysis using bootstrapping 
procedures will be performed for each sleep parameter of interest using 
SPSS macros developed by Preacher & Hayes.70 Baseline CAPS 
scores will be included as a covariate. The same method will be used to examine indirect effects 
of suvorexant on intersession habituation.  
Power considerations. G*Power71 was used to perform power analysis. α = .05 was 
applied in all analyses. We estimate that 54 participants (27 in each group) will complete 
protocol (see the Feasibility section). Hypothesis 1a: The primary outcomes for power 
evaluation are WASO and REM sleep. The prior studies suggest small effects of suvorexant on 
N3; therefore, it was not considered for power evaluation. Herring et al’s clinical trials48,50 
showed that effect sizes of one night of 20/15mg suvorexant on WASO and REM sleep 
(minutes and %) were f = -0.37, 0.32, and 0.22, respectively. A total of 16, 22, and 50 
participants are needed to detect a Group x Time effect on WASO and REM sleep in minutes 
and percentage, respectively, with 80% power. Since no studies have examined effects of 
suvorexant on PTSD, power analysis for Hypothesis 1b is based on effect sizes found in Taylor 
et al’s’44 clinical trial of prazosin in civilian outpatients with PTSD. 12 participants are needed to 
detect the effect size found in this trial (f = 0.40). Hypothesis 1c: Sizes of the indirect effects of 
suvorexant on PTSD and intersession habituation through post-WNE sleep change are 
unknown. We selected the bootstrapping procedure as it is more powerful than Sobel test.72  
The proposed study also includes comparisons of several other variables. The relative 
sample size required for multiple comparisons of variables (between 10-20) allowing for 
Bonferroni-adjusted test to achieve 80% power relative to the sample size required for a 
nominal is only 3.73 The proposed sample size of 54 will, therefore, have adequate power to 
detect medium to large effects in our planned analyses. Statistical significance of effects and 
their clinical importance will be carefully considered in data interpretation to inform the 
development of subsequent grant applications.