TNT/NW: Traumatic Nightmares Treated by NightWare (To Arouse Not Awaken)
Phase: NA
Conditions: Stress Disorders, Post-Traumatic, Combat Disorders, Ptsd, Nightmare, Nightmares, REM-Sleep Type, Nightmare Disorder With Associated Non-Sleep Disorder
Sponsor: NightWare

NightWare Digital Therapeutic  
NightWare INC. 
Protocol: NW101002 Version 1.1 
 
Page 1 of 43 
 
 
CLINICAL STUDY PROTOCOL 
 
 
TITLE: 
Traumatic Nightmares Treated by NightWare (To Arouse Not 
Awaken): A Randomized Controlled Trial 
 
 
 
NCT NUMBER: 
NCT04040387 
 
PRODUCT: 
NightWare Digital Therapeutic 
 
PROTOCOL NUMBER: 
NW101002 
 
STUDY SPONSOR: 
NightWare, INC. 
153 Ashley Road 
Hopkins, MN 55343 
 
ORIGINAL 
PROTOCOL: 
06 April 2023 
 
 
AMENDMENT DATE: 
Amendment 1: 27 Jun 2023 
VERSION: 
1.1 
CONFIDENTIALITY 
STATEMENT: 
This document is confidential. It contains proprietary information of 
NightWare INC. Any viewing or disclosure of such information that is 
not authorized in writing by NightWare INC. is strictly prohibited. Such 
information may be used solely for the purpose of reviewing or 
conducting this protocol.   
 
 
 
 
 
 

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Protocol: NW101002 Version 1.1 
 
Page 2 of 43 
 
 
 
SPONSOR PROTOCOL APPROVAL  
Traumatic Nightmares Treated by NightWare (To Arouse Not Awaken): A Randomized 
Controlled Trial 
 
Sponsor’s Approval: 
 
Brian Robertson 
 
 
06/27/2023 
Brian Robertson, MD 
Chief Medical Officer 
NightWare INC. 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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INVESTIGATOR SIGNATURE OF AGREEMENT  
Traumatic Nightmares Treated by NightWare (To Arouse Not Awaken): A Randomized 
Controlled Trial 
AGREEMENT 
I have read and understand this protocol. 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the 
study, without written authorization from the Sponsor. It is, however, permissible to provide 
the information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to my 
participation as an Investigator for this study to be terminated. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate my 
intention immediately in writing to the Sponsor. 
 
Principal Investigator’s Name:  
 
Principal Investigator’s Title: 
 
Institution Name: 
 
Address: 
 
 
 
Principal Investigator’s Signature: 
 
Date: 
 

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Table of Contents 
1. PROTOCOL SUMMARY 
7 
1.1. Synopsis 
7 
1.2. Schematic 
9 
1.3. Schedule of Activities 
10 
2. INTRODUCTION 
12 
2.1. Study Rationale 
12 
2.2. Background 
13 
2.3. NW System Description 
15 
3. OBJECTIVES AND OUTCOMES 
17 
4. STUDY DESIGN 
19 
4.1. Treatment Assignment 
19 
5. STUDY POPULATION 
19 
5.1. Inclusion Criteria 
19 
5.2. Exclusion Criteria 
20 
5.3. Screen Failures 
20 
6. STUDY METHODS 
21 
6.1. Pre-recruitment 
21 
6.2. Recruitment 
21 
6.3. Pre-Screening 
21 
6.4. Enrollment: Visit 1, Day 0 
22 
6.5. Calibration of System (Days 0-3, approximately) 
24 
6.6. Treatment Operation (Study Intervention, Post-Calibration, Daily Use 
Questionnaire ) 
24 
6.7. Day 1: Startup Phone Call 
24 
6.8. Days 2-6 and others if needed: Help Calls/Texts (Optional) 
25 

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6.9. Day 7: Checkup Phone Call 
25 
6.10. 
Day 14: Patient Questionnaire Assessment 
25 
6.11. 
Day 21: Checkup Phone Call 
25 
6.12. 
Day 30: Visit 2 -  In person follow up 
25 
6.13. 
Day 60: Visit 3 – Patient Questionnaire Assessment 
26 
6.14. 
Day 90: Visit 4 – Patient Questionnaire Assessment 
26 
6.15. 
Reimbursement Plan 
27 
7. Statistical Considerations 
28 
7.1. Randomization Procedure 
28 
7.2. Statistical Hypothesis Testing 
30 
7.3. Sample Size Determination 
31 
7.4. Interim Monitoring 
32 
7.5. Primary Safety Analyses 
32 
7.6. Secondary/Exploratory Analyses 
32 
7.7. Implementation 
33 
8. Subject Accountability 
33 
8.1. Withdrawal 
33 
8.2. Enrollment Controls 
34 
9. Safety 
34 
9.1. Risk/Benefit Assessment 
34 
9.1.1. Known Potential Risks 
34 
9.1.2. Known Potential Benefits 
34 
9.1.3. Assessment of Potential Risks and Benefits 
34 
9.2. Unanticipated Problems 
35 
9.2.1. Definition of Unanticipated Problems (UP) 
35 
9.2.2. Unanticipated Problem Reporting 
35 
9.2.3. Serious Adverse Event (SAE) Reporting 
36 

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9.2.4. Adverse Event Reporting 
36 
9.3. Death Reporting 
36 
10. 
Informed Consent 
36 
11. 
Protocol Deviations/Unexpected Problems Reports 
37 
12. 
Study Discontinuation and Closure 
37 
13. 
Data Management 
38 
13.1. 
Data Collection and Handling 
38 
13.2. 
Study Records Retention 
38 
14. 
Abbreviations 
39 
15. 
Statement of Compliance 
40 
16. 
References 
41 
17. 
Appendix A 
42 
 
 
 

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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Title: 
Traumatic Nightmares Treated by NightWare (To Arouse Not Awaken): A Randomized 
Controlled Trial 
Study Description: 
This is a double-blinded, sham-controlled, randomized controlled trial to establish the 
safety and efficacy of the NightWare (NW) digital therapeutic system (NW System) 
which is to be used for the treatment of sleep disturbances related to nightmares 
associated with post-traumatic stress disorder (PTSD). This system consists of a 
Smartphone, a Smartwatch, and a proprietary application. This study will compare the 
Active System, which monitors sleep and provides tactile stimulation to terminate 
nightmares, to the Sham System that while it does monitor sleep, does NOT provide 
intervention but is otherwise identical. This study seeks to determine the safety and 
efficacy in treating PTSD-related sleep disturbance with the NW System as well as 
delineating the impact of improved sleep when using the Active System versus the 
Sham System. 
The investigators hypothesize that the Active System will significantly improve sleep 
quality in subjects with PTSD-related sleep disorders who are suffering from 
nightmares and poor sleep quality, and that the magnitude of improvement will be 
greater than that observed in the subjects who receive a Sham System. 
Objectives: 
  
Primary Objectives:   
● Demonstrate that the Active System improves sleep quality as assessed by the 
Pittsburgh Sleep Quality Index (PSQI) in participants with PTSD 
● Demonstrate that improvement in sleep quality is greater for the Active System 
than the Sham System 
● Demonstrate that the Active System does not lead to worsening of daytime 
sleepiness as assessed by the Epworth Sleepiness Scale (ESS) 
● Demonstrate that there is not an increase in suicide risk as assessed by the 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Secondary Objectives:  
● Evaluate changes in the following measures between Day 0 (baseline) and Day 
30: 
- PTSD severity [PTSD Checklist (PCL-5)] 
- Sleep quality [PSQI Addendum for PTSD (PSQI-A)] 
- Subjective sleep quality [NW Likert Scale for Sleep Quality] 
- Quality of life [Functional Outcomes of Sleep Questionnaire (FOSQ-10) and 
Veterans Rand 12 Quality of Life instrument (VR-12)] 
- Nightmare severity/frequency [TRNS] 
- Depression symptoms [Patient Health Questionnaire-9 (PHQ-9)] 

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- Insomnia Severity Index (ISI) 
Outcomes: 
Primary Efficacy Outcomes: 
● Difference between PSQI score at baseline (Day 0) and average PSQI score at 
the post-treatment assessment (Day 30) [i.e., PSQI change] in the Active 
System. 
● Difference in average PSQI change scores between Active System and Sham 
System conditions. 
Primary Safety Outcomes:  
● No significant increase in ESS between baseline (Day 0) and Day 30 in the 
Active System. 
● No increase in C-SSRS severity score between Day 0 and Day 30 in the Active 
System. 
Observational Outcomes:  
● Improvement in sleep quality, nightmare frequency/intensity, quality of life, 
PTSD severity, and depression symptoms between Day 0 and Day 30 in the 
Active System. 
● Greater improvement in sleep quality, nightmare frequency/intensity, quality of 
life, PTSD severity, and depression symptoms in the Active System relative to 
the Sham System. 
Study Population: 
480 potential participants will be screened and 240 adults (120 in each arm), equal to or 
over the age of 22 years with symptoms indicative of PTSD and related nightmares will 
be enrolled into the study protocol. This is a multi-site study and will include active-
duty military members, military veterans, and military family members.  
Planned Number of 
Sites: 
This study will be conducted at WRNMMC and FBCH as the two DoD sites. It is also 
conducted at multiple VA Hospitals.  
Description of Study 
Intervention: 
Wearable digital therapeutic system that will measure physiologic data when worn 
during sleep to deliver a mild vibration via the watch (i.e., haptic feedback) to elicit an 
arousal thereby disrupting nightmares. This detection and stimulation sequence will be 
performed according to NW’s proprietary algorithm. 
Participant 
Duration: 
30 days in a randomized control trial followed by an additional 60-day open label 
extension.  
Data Banking 
De-identified data generated from this study will be saved for use in future studies. The 
site will transfer data to NightWare that does not contain individual identifiable 
information. 

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1.2. Schematic 
 
 
 
 

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1.3. Schedule of Activities 
Study Activities Table: 
Study 
Activity 
Pre-
Tx 
Visit 
1 
Calib-
ration 
Start 
Up 
Call 
Help 
Calls 
Check 
Up Call 
1 
Assess
ment 
Call 
Check 
Up Call 
2 
Visit 2  Visit 3 
Visit 4 
Study Day 
Before 
Day 0 
Day 0 
Days 
0-3 
Day 1 
Days 
2-6 
(Opti
onal) 
Day 7  
Day 14 
(+/-3) 
Day 21 
(+/- 2) 
Day 30 
(+/- 7) 
Day 
60 (+/- 
7) 
Day 90 
(+/- 7)  
Recruitment 
X 
 
 
 
 
 
 
 
 
 
 
Chart Review 
X 
 
 
 
 
 
 
 
 
 
 
Phone Screen 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclu
sion 
X 
X 
 
 
 
 
 
 
 
 
 
ICF and HIPAA 
 
X 
 
 
 
 
 
 
 
 
 
Modified 
Dysken l 
 
Xa 
 
 
 
 
 
 
 
 
 
AUDIT 
 
Xb 
 
 
 
 
 
 
 
 
 
DAST-10  
 
Xc 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
Blood 
Pressure 
 
X 
 
 
 
 
 
 
X 
 
 
Med 
Reconciliation 
 
X 
 
 
 
 
 
 
X 
X 
X 
PSQI  
 
X 
 
 
 
 
X 
 
X 
X  
X  
PSQI-A 
 
X 
 
 
 
 
 
 
X 
 
 
ESS 
 
X 
 
 
 
 
 
 
X 
X 
X 
ISI 
 
X 
 
 
 
 
 
 
X 
X 
X 
PCL-5 
 
X 
 
 
 
 
X 
 
X 
X 
X 
CAPS-5 
 
X 
 
 
 
 
 
 
 
 
 
VR-12 (QOL) 
 
X 
 
 
 
 
 
 
X 
X 
X 
TRNS 
 
X 
 
 
 
 
 
 
X 
X 
X 

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FOSQ-10 
 
X 
 
 
 
 
 
 
X 
 
 
PHQ-9 
 
X 
 
 
 
 
X 
 
X 
X 
X 
C-SSRS 
Lifetime 
 
X 
 
 
 
 
 
 
X 
X 
X 
Blinding 
Assessment 
Questionnaire  
 
 
 
 
 
 
 
 
X 
 
 
NW Likert 
Scale 
 
X 
 
 
 
 
 
 
X 
X 
X 
Daily Use 
Questionnaire  
(Days 1-90) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Calculate 
Cutoffs/Eligible
? 
 
X 
 
 
 
 
 
 
 
 
 
Dispense NW 
Devices 
 
X 
 
 
 
 
 
 
 
 
 
Train Subject  
 
X 
 
 
 
 
 
 
 
 
 
Activate 
Devices 
 
X 
 
 
 
 
 
 
 
 
 
C-SSRS Since 
Last Contact 
 
 
 
 
 
 
 
 
X 
X 
X 
Payment of 
Subject(Bi 
weekly) 
See Reimbursement Section 6.15 
Start Up Call  
 
 
 
X 
 
 
 
 
 
 
 
Calibration  
 
 
X 
 
 
 
 
 
 
 
 
Active/Sham 
Treatment 
 
 
Post-
Calib.
f 
 
 
 
 
 
 
 
 
Help Calls 
Questionnaire 
(Optional) 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
Checkup Phone 
Call 
 
 
 
 
 
X 
 
X 
 
 
 
Sham Cross-
over to Active 
Treatment 
 
 
 
 
 
 
 
 
X 
 
 
 

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a—Administered DURING informed consent process to ensure subjects are capable of consent. Subjects must get all responses correct to be 
enrolled into the study, b-Exclude if score is equal to or greater than 8. c-Exclude if score is greater than 2. f-Only the Active System goes 
through calibration and on to Active Treatment. 
2. INTRODUCTION 
2.1. Study Rationale 
Nightmares are a common problem affecting around 2-8% of the general population and a higher 
proportion of clinical populations. The negative consequences of untreated nightmares are significant and 
include impaired quality of life, sleep deprivation (often resulting in increased intensity of nightmares), 
insomnia, daytime sleepiness, and fatigue. Untreated nightmares can also exacerbate the symptoms of 
underlying psychological dysfunction in subjects with depression and anxiety, leading to poor 
occupational and or social functioning.1,2 
 
Nightmares can be idiopathic or associated with the use (or withdrawal) of certain 
medications/substances, or associated with disorders including PTSD.2 
 
While nightmares are readily observed and recognized by subjects and their family members, nightmare 
physiology is still poorly understood. Despite a limited understanding of the mechanisms of nightmares, 
there are treatments that show variable efficacy. The American Academy of Sleep Medicine makes two 
recommendations for the treatment of nightmare disorder. One is pharmacological and the other is non-
pharmacological.3  
 
Prazosin, an alpha 1 antagonist antihypertensive, is a medication routinely used to treat nightmares and it 
is thought to mediate its effects by reducing the sympathetic outflow in the brain during sleep. While 
there has been evidence to support its efficacy in treatment of nightmares, common side effects include 
orthostatic hypotension and rebound hypertension with missed doses.3-6 Its interaction profile with other 
medications also limits use in clinical populations. 
 
Image Rehearsal Therapy, a modified cognitive behavioral therapy technique, is a non-pharmacological 
approach that appears to be effective. It requires the subject to write down the nightmares and THEN 
rehearse those nightmares (inserting a positive result) prior to sleep. However, studies demonstrate poor 
compliance with therapy. Moreover, rehearsing the nightmares immediately prior to bed carries the risk of 
re-exposing the subject to their traumatic nightmare and, thus, exacerbating the symptoms of nightmares 
as well as increasing the frequency of nightmares.3 
 
NightWare (Minneapolis, MN) has developed a novel approach to the treatment of nightmares. Through 
the use of a smartwatch-based application that senses physiologic parameters, the patient is aroused from 
sleep (without awakening the patient) so that the nightmare is interrupted prior to reaching a threshold of 
severity in which the patient would awaken in distress. Seconds later the patient returns to sleep without 
having experienced a nightmare. This approach avoids risk from pharmacological treatment, avoids 
exacerbation of symptoms from image rehearsal therapy and allows for a simple method with easily 
achieved adherence compared to existing treatments. 

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2.2. Background 
Approximately 80% of subjects with PTSD have nightmares that begin within the first 3 months of the 
trauma. Although up to 50% of subjects with PTSD have resolution of their nightmares within 3 months, 
a substantial proportion experience lifelong nightmares.2  
 
Despite their prevalence and distress, nightmares are frequently underreported and thereby undertreated. 
In a study published in 2015, more than 60% of subjects did not discuss clinically significant nightmares 
with their healthcare professional. 7 
 
Trauma related nightmares and accompanied sleep disturbances are thought to contribute to the 
development of PTSD as well as worsening symptom severity, functional impairment, distress and overall 
poor quality of life. 8,9,10 
 
Nightmares are categorized by whether they are due to a medication or substance, associated with a 
psychiatric disorder such PTSD, or idiopathic, meaning the cause is not readily known. 
 
The diagnosis of nightmares is made by a clinical history and examination. Laboratory tests are not 
routine unless there is suspicion for a drug use disorder. 
 
Sleep diagnostic testing using Polysomnography is not indicated for the diagnosis of nightmares, as 
nightmares tend to occur less frequently in a clinical sleep laboratory setting. 11 This is presumed to be 
due to the “first night effect” in which subjects’ sleep architecture may be different than in their natural 
home sleep environment. 
 
Formal Classification per the ICSD-3 
 
The following section is included as an indicator of the issues and severity that is commonly observed in 
subjects with trauma-related nightmares.  For a subject to actually receive a diagnosis of nightmare 
disorder 2 is exceedingly rare.  Having a diagnosis of nightmare disorder 2 is NOT a requirement for 
inclusion into this study. The third edition of the International Classification of Sleep Disorders states the 
following minimum criteria for nightmare disorder 2: 
1. Repeated occurrences of extended, extremely dysphoric, and well-remembered dreams that 
usually involved threats to survival, security, or physical integrity. 
2. On awakening from the dysphoric dreams, the person rapidly becomes oriented and alert. 
3. The dream experience, or the sleep disturbance produced by the awakening from it, causes 
clinically significant distress or mental impairment in social, occupational or other important 
areas of functioning as indicated by the report of at least one of the following: 
 
a. Mood disturbance (e.g., persistence of nightmares affects anxiety, dysphoria). 
b. Sleep persistence (e.g., bedtime anxiety, fear of sleep/subsequent nightmares). 
c. Cognitive impairments (e.g., intrusive, nightmare imagery, impaired    concentration, or 
memory.)  
d. Negative impact on caregiver or family functioning (e.g., nighttime disruption). 
e. Behavioral problems (e.g., bedtime avoidance, fear of the dark). 
f. Daytime sleepiness. 
g. Fatigue or low energy. 
h. Impaired occupational or educational function. 
i. 
Impaired interpersonal/social function. 

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While it is commonly thought that nightmares emerge from REM sleep, nightmares have also been 
observed to emerge from Non-REM sleep. In a cohort of 35 subjects that suffered from PTSD, an almost 
equal percentage of subjects were documented to have NREM and REM related nightmares. Heart rate 
and respiratory rate accelerations have been observed with subjects arising from nightmares. Motor 
behaviors preceding nightmare awakenings have been observed in stage N2 sleep.12 
 
Prazosin Pharmacologic Therapy 
 
Prazosin is an α1-adrenergic receptor antagonist. This medication was originally intended for use as an 
antihypertensive.4 It is believed that Prazosin can be effective in the treatment of nightmares related to 
post-traumatic stress disorder by reducing noradrenergic activity in the brain; which has been found to be 
elevated in people diagnosed with PTSD.6 While some evidence supports the efficacy of Prazosin in 
treatment of nightmares in PTSD subjects, that evidence is inconsistent, not strong, and there are common 
side effects that raise concern including: dizziness, headache, drowsiness, lack of energy, weakness, 
palpitations, and nausea.5 Even more concerning is the risk of orthostatic hypotension, and the potential 
for syncope-related injury. The American Academy of Sleep Medicine suggests that clinicians monitor 
patients for potential orthostatic hypotension when prescribing Prazosin for nightmares. 
 
Image Rehearsal Therapy 
 
Image rehearsal therapy is a form of cognitive behavioral therapy in which the subject later recalls a 
nightmare, then consciously imagines changes in the theme, storyline, ending, or any part of the dream, to 
a more positive and tolerable one. The intended outcome would be that when a subject has the rehearsed 
dream during sleep, they will replace the disturbing content with the positive and tolerable content 
imagined during the day. The subject will commonly practice the rehearsal of these dreams for 10 - 20 
minutes per day. While this has been demonstrated to be generally effective in the treatment of nightmare 
disorder in subjects with PTSD, reports have described increased nightmare frequency and exacerbation 
of PTSD symptoms during image rehearsal therapy.3 Likewise, sleep logs that subjects use to document 
the frequency and content of nightmares have been associated with subject reluctance to fill out the logs 
for fear of re-exposure 6. For these reasons, not to mention the specialized staff training and time for 
repeated clinic visits, image rehearsal therapy has low potential to have a large population-level impact on 
PTSD-related nightmares. 
 
NightWare Digital Therapeutic 
 
For the purposes of this study, we will be using only the Apple (Cupertino, CA) 3rd generation 
smartwatch and the Apple iPhone. As described above, the NW System consists of a Smartphone (a 
functionality-limited iPhone), Smartwatch (a functionality-limited Apple Watch 3) and proprietary 
software application. NOTE: Since the phones and watches will be provided to research staff PRE-
IMAGED and with much of the functionality disabled, they will be referred to throughout this document 
as “research equipment, research phone, and/or research watch”. The NW System has been effective in 
focus groups when used on both Apple smartwatches and Motorola smartwatches. The NW System 
utilizes physiological markers obtained via the smartwatch to determine, by proprietary algorithm, 
whether a subject is in the early stages of a nightmare but has not yet awoken in distress. As directed by 
the algorithm, the smartwatch then applies varying degrees of vibratory stimulation to the wrist over 
variable lengths of time with the intention of arousing the subject from sleep without eliciting an 
awakening. 
 
 

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There are three levels of intervention: 
Low:  Vibration is least intense, of short duration. 
Medium: Vibration is slightly higher, duration is short (same as for “low”).  
High: Vibration level is the same as for “medium, duration is increased. 
 
The threshold for these interventions can be manually titrated, if needed, in response to a specific person’s 
symptoms. 
 
Background information regarding sleep patterns: Sleep architecture has been explored extensively by the 
use of EEG’s (Electroencephalography).  Normal sleep physiology includes micro-arousals.  These 
micro-arousals consist of EEG shifts of the brainwaves to a higher frequency and last from 3-10 seconds. 
They can be elicited through environmental stimuli such as noise. No definitive limits have been defined 
as to what is considered a pathologic frequency of micro-arousals. However, during routine clinical 
practice, micro-arousals of up to 15 times per hour are considered to be within normal limits. 
 
EEG shifts lasting ten seconds, or more are considered brief awakenings.  
 
The NW System cannot be used for detection of brain waves, therefore, no brainwave data (EEG) will be 
collected or analyzed. 
 
Every person has their own sleep pattern that is almost as unique as a fingerprint.  The NW System 
adjusts to a person’s usual sleep pattern by going through an observation-only calibration stage. Usual 
sleep information is gathered during the first 500 minutes of sleep after the person begins wearing the 
NW System.  The system then calculates an individual “arousal index” based on that sleep information 
for each subject. Once this arousal index has been calculated, the NW System goes into Active Treatment 
mode.  Every time the arousal index for that person is exceeded, the system will intervene by applying a 
vibration through the smartwatch.  The system uses only enough intervention (see intervention levels, 
above) to generate a micro-arousal and bring the person out of the nightmare. 
 
In a 2004 study measuring EEG sleep changes elicited by vibratory tactile plus simultaneous auditory 
stimuli, microarousals were significantly more frequent than awakenings. This suggests that non-painful 
tactile stimuli can be used to elicit arousals and shift sleep stages without awakening subjects.13 
 
The vibrations (0-3 seconds) being delivered by the NW System are intended to be brief enough that they 
reduce the chances of awakenings and the subsequent memories of the stimulation. The subject continues 
sleeping, and the smart watch arousal derails the generation and processing of the potential nightmare. 
Even in the uncommon event that the subject is awakened briefly, nightmare processing should still be 
curtailed.  
 
Our hypothesis is that by abating these nightmare events people can improve the sleep quality and overall 
quality of their lives without major adverse consequences. 
2.3. NW System Description  
The NW System’s proprietary application directs the smartwatch to monitor the wearer’s movements and 
heart rate during sleep to detect the onset of a nightmare.  When physiologic symptoms of a nightmare are 
detected (increased movements, fast movements, increased heart rate), the smartwatch provides gentle 
stimulation to minimally arouse but not fully awaken the wearer and therefore prevent the nightmare from 
fully developing and causing significant awakenings and/or sleep disturbance.   

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Once the smartwatch has been properly fitted to the individual and activated the Active System goes 
through a learning phase/calibration period. During this time the system monitors the subject’s 
movements and heart rate to delineate the usual low, medium, and high-stress points, termed the “stress 
index” (threshold) (i.e. system determines the wearer’s usual sleep patterns).  The application then 
calculates the “stress index” (threshold) for that individual. When the upper end of this “stress index” 
(threshold) is exceeded, the system is activated and directs the smartwatch to gently vibrate leading to a 
slight arousal of the subject to interrupt the development of the nightmare without waking them and allow 
for a more restful sleep. The Sham System monitors the wearers’ sleep patterns and calculates a “stress 
index” (threshold) but does NOT provide any interventions.  The calculated “stress index” (threshold) 
will be used for subsequent data analysis only.  The stress index (threshold) will be set manually on the 
Sham System to be so high that it will NEVER be activated. Data is collected throughout, and a stress 
threshold is initially calculated during the initial phase, though the subject isn’t aware of this or shown it 
in any way. The stress threshold is continually calculated in both groups. The sham group never receives 
treatments regardless of stress threshold 
 
Graphically, this learning/intervention strategy for nightmares is shown below (Active System, only). 
 
Figure 2: NightWare User Interface and Data Flow 
 
 
 
 

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Active Intervention Description 
 
The Active System captures heart rate and movement data from the wearer via sensors in the smartwatch 
(gyroscope, accelerometer, and heart rate monitor). This data is transmitted to the smartphone where the 
proprietary NW application algorithms calculate the individual’s stress index (threshold) and learn how 
best to intervene in that person’s nightmare development.  This data is also transmitted by the smartphone 
to the secure NW server.  This data is accessible only to NW Study staff and is used to monitor each 
subject.  Monitoring will be used to ensure that each subject is wearing the NW System every night and to 
manually change the titration threshold and intervention strength parameters as necessary to provide the 
best sleep possible. If the subject is not wearing the NW System every night, the subject will be contacted 
to ask why the NW System is not being utilized. The Sham System will also be monitored to ensure that 
the system is being used nightly, but as the system is NOT active, no changes to the parameters will be 
made.  
  
Sham Intervention Description 
 
Subjects randomized to the Sham System will receive a research phone and research watch (as did those 
randomized to the Active System) and a version of the NW Application that has the threshold set 
extremely high (so high that it will NEVER be activated) will be installed.  The Sham System will have 
the same user interface on the smartwatch (start button is enabled and is indistinguishable from the user 
interface present in active mode). The Sham System (as well as the Active System) will vibrate whenever 
the subject hits the “START” button.  The Sham System will monitor the wearer’s sleep pattern, as the 
active system does but will not provide any interventions during the night. 
 
3. OBJECTIVES AND OUTCOMES 
OBJECTIVES 
OUTCOMES 
JUSTIFICATION FOR 
OUTCOMES 
Primary Efficacy 
  
  
To demonstrate that the 
NW digital therapeutic 
improves sleep quality in 
subjects with PTSD 
Difference between average PSQI 
score at baseline (Day 0) and 
average PSQI score at post-
treatment (Day 30) assessment  
The NW digital therapeutic is 
expected to improve sleep 
quality.  PSQI is a validated 
measure of subject-reported 
sleep quality 
Primary Safety 
  
  
To assess the potential 
risk of worsening sleep 
quality 
Difference between average 
Epworth Sleepiness Scale (ESS) at 
baseline (Day 0) and ESS at Day 
30.  
The Epworth Sleepiness Scale is 
a validated measure of daytime 
somnolence.  

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To assess the potential 
worsening of suicidal risk 
Difference between the average 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) at baseline (Day 
0-Lifetime and Recent version) 
and C-SSRS at Day 30 (Since 
Previous Contact version)  
The Columbia-Suicide Severity 
Rating Scale is a validated 
measure of suicide risk.  
Secondary: 
Observational 
  
  
To evaluate changes in 
subjective sleep quality. 
Difference in PSQI-A and NW 
Likert Scale for Sleep Quality 
between baseline (Day 0) and 
post-treatment (Day 30) in the 
Active System.  
May show improved sleep 
quality on scales other than 
PSQI. 
To evaluate changes in 
PTSD and/or depression 
symptoms. 
  
Difference in PCL-5 and PHQ-9 
between baseline (Day 0) and 
post-treatment (Day 30) in the 
Active System. 
The NightWare digital 
therapeutic may improve PTSD 
and/or depression symptoms. 
Therefore, this is an 
observational endpoint. 
To evaluate changes in 
quality of life 
Difference in FOSQ-10 and VR-12 
between baseline (Day 0) and 
post-treatment (Day 30) in the 
Active System. 
Improved sleep quality may 
improve quality of life 
To evaluate changes in 
nightmare severity and 
frequency 
Difference in TRNS between 
baseline (Day 0) and post-
treatment (Day 30) in the Active 
System. 
The TRNS is a validated 
measure of nightmare frequency 
and severity. 
To evaluate changes in 
insomnia symptoms 
Difference in ISI between baseline 
(Day 0) and post-treatment (Day 
30) in the Active System 
Decreased sleep latency and 
reduced sleep disturbance were 
noted as major areas of 
improvement in sleep quality on 
interim and secondary analyses 
of current data. Treatment of 
nightmares may improve 
insomnia symptoms. 

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4. STUDY DESIGN 
This is a prospective, randomized, controlled, multi-center clinical trial to evaluate the effectiveness and 
safety of the NW System for the treatment of nightmare disorder secondary to post-traumatic stress 
disorder. 
4.1. Treatment Assignment 
Any subject meeting all inclusion and no exclusion criteria is eligible for enrollment in the study. Subjects 
are considered enrolled in the study once the informed consent form (ICF) and Health Insurance 
Portability and Accountability Act (HIPAA) form have been executed. 
  
All subjects will receive a NW System (research phone, research watch, and NW proprietary application-
set to either an active mode or a sham mode). 240 subjects will be enrolled into the study.  Subjects will 
be randomly assigned to receive either the Active System or Sham System. There will be 120 subjects in 
each arm.  None of the subjects will be aware of whether they have received an Active System or a Sham 
System.  For further details of treatment assignment procedures, go to the “Randomization” section of this 
protocol. 
5. STUDY POPULATION 
Veterans and active-duty service members that meet the inclusion and exclusion criteria will be enrolled 
in the study. 
5.1. Inclusion Criteria 
Inclusion Criteria 
● Either Diagnosis of PTSD via American Psychiatric Association PTSD diagnostic criteria in the 
fifth edition of its Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or having 
symptoms consistent with PTSD (subject must score at least 25 on the PTSD Checklist-5 to 
qualify for the study).  
● Equal to or older than 22 years of age. 
● Proficient in both reading and writing in the English language.  
● Pittsburgh Sleep Quality Index (PSQI). Potential participants would need to score 10 or more to 
qualify.   
● ESS: On question #8 any score above “0” will prompt an additional question: 
○ Do you drive (“get behind the wheel”) when you are drowsy?  
■ Answer must be “No” to be enrolled in the study due to safety concerns.  
● Have repetitive nightmares contributing to disrupted sleep as reported by the subject 
● Wireless Internet and two power outlets where they sleep 
● Prazosin use; if yes, subject may be included if willing to be tapered by prescribing provider.  
○ Taper must be completed, and the subject must be off prazosin for 2 weeks prior to 
enrollment. 
● Alpha blocker use; if yes, subject may be included if willing to be tapered by prescribing 
provider. Taper must be completed, and the subject must be off all alpha blockers for 2 weeks 
prior to enrollment.  

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5.2. Exclusion Criteria 
● Patient Health Questionnaire-9 (PHQ-9) score greater than or equal to 20 indicates that the 
subject is too depressed to be included in this study. 
○ Score of 1 or more on the suicide ideation item (question #9) of the PHQ-9 will trigger a 
risk assessment by the principal investigator or qualified co-investigator. 
● Responses on the C-SSRS that indicate High Suicide Risk. 
○ Study staff will contact a licensed Behavioral Health Provider to assess any subject who 
reports any symptoms that fall into the High-Risk categories or are having current (within 
the last month) suicidal ideation. 
● Uncontrolled atrial fibrillation 
● Current use of varenicline 
● Current use of beta-blockers (unless ophthalmic solutions). See “Excluded Medications List” in 
Appendix A. 
● Current use of non-dihydropyridines. See “Excluded Medications List” in Appendix A.  
● Current use of Prazosin for the treatment of nightmares (can include subjects 2 weeks post-taper 
and discontinuation). This would be coordinated with the prescribing provider. 
● Current use of alpha blockers (can include subjects 2 weeks post-taper and discontinuation under 
guidance from prescribing provider). 
● Circadian rhythm disruption on a regular basis (shift work)  
○ Including regularly scheduled overnight care of very young, elderly, or sickly family 
members 
● Known diagnosis of OSA 
● Diagnosis of an active disorder of arousal from non-rapid eye movement sleep 
● Diagnosis of rapid eye movement sleep behavior disorder 
● Diagnosis of narcolepsy 
● Alcohol Use Disorders Inventory Test (AUDIT) (score equal to 8 or higher) 
● Drug Abuse Screening Test-10 (DAST-10) (score greater than 2) 
● Suspicion of nightmares being secondary to substance abuse or withdrawal 
● Diagnosis or suspicion of dementia 
● Previous or foreseeable legal proceedings involving nightmares or trauma 
● Nocturia that causes awakening from sleep 
● Known sleep walking 
● Wrist tattoos on the both  arms where the watch will be worn, that prevent detection of heart rate 
by the device watch. 
5.3. Screen Failures 
Subjects that are screened but do not meet inclusion or exclusion criteria will not be enrolled or followed 
in the trial. Screen failures will be informed of other possible treatments available. Persons that failed 
screening due to Suicidal Ideation or having Moderate- to High-Risk on the C-SSRS will be assessed by 
the PI and, if deemed necessary, referred to a qualified Behavioral Health Provider immediately and 
provided appropriate referrals for emergency or outpatient treatment as indicated by risk assessment. 

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6. STUDY METHODS 
6.1. Pre-recruitment 
We will request a HIPAA Waiver and a Waiver of the Informed Consent Form (ICF) for purposes of 
recruitment. Note that no participants will be enrolled in the study without full written consent.  The 
HIPAA Waiver will allow us to request that a computer search be done so that veterans and active-duty 
service members who meet the basic inclusion/exclusion criteria can be found. The Waiver of Informed 
Consent will also allow us to call and speak to the possible subject and to conduct a phone screen.  
6.2. Recruitment 
1. Subjects will be recruited using fliers and referrals from areas like the PTSD Clinic, VA Hospital 
CBOCs, Non Clinical counseling veteran centers, and mental health and behavior health clinics. 
Invitation letters will be sent to all veterans and active-duty service members compiled from the 
computer search, asking them to call the study coordinator if they are interested in study 
participation.  
2. If the subject has not contacted study staff within two weeks after the recruitment letter is mailed, 
the subject may be called and/or texted by study staff.  
a. Study Staff has requested a IRB-Approved Cell Phone to assist in contacting and 
interacting with potential/enrolled subjects. (See Cell Phone/Text message content 
document submitted with this protocol). 
3. Recruitment letters/Fliers will specify that if the veteran calls and either speaks to study staff or 
leaves a voicemail (secured) expressing interest, that their medical charts will be checked to 
determine eligibility. 
4. If study staff answer the phone when the veteran calls, the veteran will be told about the study 
requirements and, if interested, phone screened.  
5. Based on the phone screen results, those veterans and active-duty service members who appear to 
qualify will be told that their chart will be checked to make the final determination of their 
eligibility.  
6.  Study staff will call and/or text veterans and active-duty service members who leave messages 
after their chart has been checked for inclusion/exclusion criteria.  If the veteran and active-duty 
service member appears to qualify, the phone screen will be conducted, and the veteran and 
active-duty service member will know his/her eligibility at the end of the call.   
7. Veterans and active-duty service members that pass both chart review and phone screening will 
be invited to come in for an enrollment visit.  
8. Veterans and active-duty service members and active-duty service members who do not qualify 
for the study will be told of other treatment options. These options are on the Handout “Post-
Study Resources for Participants”. Contents of Handout may be read to the veteran and active-
duty service member over the phone and/or the Handout mailed to the veteran and active-duty 
service member as requested. 
6.3. Pre-Screening 
A trained study staff member will pre-screen interested veterans and active-duty service 
members for basic eligibility requirements (see above for inclusion criteria and exclusion 
criteria) and schedule consent and eligibility/baseline assessment appointments with site 
RA. (See Phone Screen submitted with this protocol for details.) 

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Based on the answers to this phone screen questionnaire, this subject: 
1. Subject does not qualify. 
a. Subject will be thanked for their time and the phone call terminated.  
b. If the subject did not qualify due to recent suicidal ideation, if deemed necessary 
by the PI (a licensed Neurologist), a licensed Behavioral Health Provider will be 
contacted to provide appropriate follow up care. 
c. Subject will be informed of other options for care. These options are on the 
Handout “Post-Study Resources for Participants”. Handouts may be read to 
veteran and active-duty service members over the phone and/or mailed to the 
veteran and active-duty service member if requested. 
2. Subjects who do not clearly fail, or meet, the study criteria will be told that the rest of 
the study team will need to be contacted to determine if the subjects are eligible or not. 
Subject will then be contacted to be told the team’s decision. 
3. Veterans and active-duty service members who pass the phone screening will be 
asked to come in for an enrollment visit. 
6.4. Enrollment: Visit 1, Day 0 
Those who pass the telephone pre-screening will be scheduled for an Enrollment Visit (Visit 1, Day 0).   
 
Procedures to be done at this visit include: 
1. Re-check of inclusion/exclusion criteria prior to signing enrollment forms.  
2. Signing of Informed Consent Form (ICF) and HIPAA 
3. Completion of a Demographics Form 
4. Baseline Psychometric Instruments: 
a. Pittsburgh Sleep Quality Index (PSQI) 
b. PSQI Addendum for PTSD (PSQI-A) 
c. PCL-5 Checklist (past 1 month) 
d. Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) 
e. Patient Health Questionnaire-9 past 1-month version (PHQ-9) (Score greater than or 
equal to 20 indicates severity of depression too great for this study. Score of 1 or more on 
the suicide ideation item [question #9] to trigger a risk assessment by PI and a licensed 
Behavioral Health Provider.) 
f. Epworth Sleepiness Scale ESS: On question #8 any score above “0” will prompt an 
additional question: 
1. Do you drive (“get behind the wheel”) when you are drowsy? 
a. Answer must be “No” to be enrolled in the study due to safety 
concerns. 
g. DAST-10: Exclude if score is greater than two (2). 
h. AUDIT: Exclude if score is equal to, or greater than, eight (8).  
i. 
Functional Outcomes of Sleep Questionnaire (FOSQ) 
j. 
Insomnia Severity index (ISI) 
k. Trauma Related Nightmare Scale (TRNS) 

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l. 
VR-12 Quality of Life (VR-12) 
m. NW Likert Scale for Sleep Quality (NW Likert) 7-day 
n. Columbia-Suicidality Severity Rating Scale, Lifetime and Recent version (C-SSRS) 
(responses in the High-Risk range will make the subject ineligible).  
i. 
After further assessment with the PI, Study Staff will contact the healthcare 
provider that has been trained to perform a suicide assessment for all subjects 
with a rating greater than “LOW”. 
o. RedCAP collection questionnaire: What type or types of traumas led to your PTSD?  
(Choose the primary type of trauma that applies) 1) Combat/blast trauma 2) Sexual 
Trauma/Rape/Sexual Assault 3) Natural Disaster 4) Childhood physical abuse 5) 
Accident, such as a car accident 6) Other (a secondary choice would appear for free text). 
5. Baseline health assessments 
a. Blood Pressure-Blood pressures should be taken while the patient is in a sitting position 
with their feet flat on the ground after at least 5 minutes of rest. A minimum of 2 blood 
pressures should be taken 30-60 seconds apart. The average of these two blood pressures 
should be recorded. 
b. Height and Weight to calculate BMI 
c. Complete a Health Questionnaire 
d. Medication Reconciliation (compare to EHR, add any over the counter medications) 
6. Determination of subject’s eligibility for randomization: 
a. Based on each subject’s scores and answers to the previous questionnaires/questions the 
subject will either be: 
i. 
Randomized. 
1. The enrollment visit will continue.  
ii. 
Told that he/she does not qualify.   
1. Enrollment visit ends.   
2. Subjects are reimbursed for their time/assessments. 
3. Subject given contact information for behavioral health services.  
4. No further contacts/visits will be scheduled.  
7. Randomization.   
a. Eligible subjects with scores equal to or more than 16 (PSQI High stratum), will be 
randomized separately from subjects whose scores were equal to a minimum of 10 to a 
maximum of 15 (PSQI Low stratum).  
i. 
Both the 16 and over scoring group and the 15 and under scoring group will have 
50% of their group given the Active System and 50% will get the Sham System.  
b. PSQI Low stratum subjects will have assigned ID #’s ending in 001 to 499. 
c. PSQI High stratum subjects will have ID #’s ending in 500 to 999. 
8. NW System provided to subject 
a. Systems will be pre-prepared by NW Corporate.  
b. Pre-prepared Systems will be labeled with the study ID number used. 
c. Subjects will then be randomized using the randomization procedure delineated in section 
6.1. 
d. Once the subject is randomized, the system will be set to sham or active mode by NW 
technical staff. 
i. 
These staff are not located at the study site. 
ii. 
Neither the subject nor the study staff will have access until data is unblinded. 
9. Subject training on NW System: 
a. Subjects will be instructed on the proper use and care of the phone and watch.  
b. Subjects will be shown how to Access and Use the NW Application. 

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c. Verify that participant understands how to use the NW System 
d. Send participant home with directions “Home Instruction Sheet”  
i. 
The Contact Number for Study Staff is included in the Home Instruction Sheet, 
so if there is/are any issue(s) prior to the Checkup Call the subject may obtain 
help solving the issue(s) 
10. Complete the NW Call and Visit Schedule (included in this submission). 
a. Subjects will fill-in their own copy of the form and take it home with them.  
11. Stress to subject that ANY ISSUES with the phone and/or watch must be reported promptly to 
Study Staff so that they can be corrected. 
12. Inform subjects that Study Staff may call DAILY from days 2-6 (optional—dependent on subject 
understanding, connectivity issues, etc.). These calls have been named “Help Calls”. 
13. Enrollment status and subject ID will be placed into a spreadsheet that indicates  Study ID #, 
name, last 4, contact phone, address, and the serial number of the pre-prepped System that was 
provided to the subject.  
a. This spreadsheet will NOT be shared with NightWare personnel as it contains PHI.  
14. A second spreadsheet will keep track of all pre-prepared phones and watches received from NW.  
a. Phone and watch passcodes as well as the NW Application log-in key code will be 
tracked upon receipt. 
6.5. Calibration of System (Days 0-3, approximately)  
Once the NW Active System has been installed on the watches of those participants randomized to 
receive study intervention, a calibration period consisting of the recording of approximately 500 minutes 
of normal (non-intervention) sleep will occur. This calibration allows for a Stress Index (Threshold) to be 
assigned for the participant. Sham Systems will not go through a calibration phase, nor will they ever 
provide study interventions. 
6.6. Treatment Operation (Study Intervention, Post-Calibration, Daily 
Use Questionnaire )  
After the calibration period, the Active System enters active treatment (study intervention) on 
approximately days 2-3. The Sham System will never go into this mode.  
Subjects will also receive a daily use questionnaire Deployed via RedCAP 
1. RedCAP deployed Daily Use questionnaire (Day 1-90) 
a. How was your sleep quality?  0 = Refreshing, 1 = Average, 2 = Poor 
b. Was the device disruptive?  0 = Did not feel it, 1= Mildly disruptive, 2 = Uncomfortable 
c. How many nightmare-related awakenings? 0 = none, 1 = 1-2, 2 = 3 or more 
6.7. Day 1: Startup Phone Call  
This call will be to see if subjects have gotten the NW System connected to their home WiFi and were 
able to set things up and use the system during the night  
Administer: 
1. NW Start up Call Questionnaire. 
 
Any issues that arise will be dealt with by Study Staff (help with calling participant’s internet service 
provider to get the System synced with the participant’s home WiFi, additional education on how to wear 
the watch and use the application, etc.). 

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6.8. Days 2-6 and others if needed: Help Calls/Texts (Optional) 
After doing the Start Up Call on Day 1, research staff will conduct additional calls/texts on days 2-6, and 
on other days, as needed.  During these calls/texts, research staff will address any issues arising with WiFi 
connectivity, misunderstandings and the proper use of the devices, as well as any other issues that may 
arise. Administer the following questionnaire (as needed): Help Calls.  
6.9. Day 7: Checkup Phone Call  
Study staff will call on Day 7 (+/- 2 days) to determine how the participant is doing with the NW System. 
Administer: 
a. NW Help Calls Questionnaire 
6.10. Day 14: Patient Questionnaire Assessment 
Participants will complete questionnaires on Day 14 (+7 days). Study coordinator will contact participants 
on Day 16 if the questionnaires have not yet been completed.  Questionnaires to be completed:  
a. Administer the PCL-5. 
b. Administer the PHQ-9 
c. Pittsburgh Sleep Quality Index (PSQI) 
6.11. Day 21: Checkup Phone Call  
Study staff will call on Day 21 (+7 days) to determine how the participant is doing with the NW System.  
Administer: 
a. NW Help Calls Questionnaire 
6.12. Day 30: Visit 2 -  In person follow up 
The following events/assessments will occur at the in-person 30-day (+ 7 days) visit.  
Health assessments 
2. Psychometric Instruments: 
a. Pittsburgh Sleep Quality Index (PSQI) 
b. PSQI Addendum for PTSD (PSQI-A) 
c. PCL-5  
d. Insomnia Severity Index (ISI) 
e. (PHQ-9) (Score of 1 or more on the suicide ideation item [question #9] to trigger a risk 
assessment by a licensed Behavioral Health Provider if deemed necessary by the PI.) 
f. Epworth Sleepiness Scale ESS  
g. Functional Outcomes of Sleep Questionnaire (FOSQ) 
h. Trauma Related Nightmare Scale (TRNS) 
i. 
VR-12 Quality of Life (VR-12) 
j. 
NW Likert Scale for Sleep Quality (NW Likert)  
k. Columbia-Suicidality Severity Rating Scale, Since Last Contact version (C-SSRS)  
i. 
If deemed necessary by the PI, Study Staff will contact a healthcare provider that 
has been trained to perform a suicide assessment if there is any risk of suicide. 
l. 
Blinding Assessment Questionnaire  
3. Health assessments 

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a. Blood Pressure- Blood pressures should be taken while the patient is in a sitting position 
with their feet flat on the ground after at least 5 minutes of rest. A minimum of 2 blood 
pressures should be taken 30-60 seconds apart. The average of these two blood pressures 
should be recorded. 
b. Height and Weight to calculate BMI 
c. Medication Reconciliation  
 
Every effort will be made to get the subject to the Study Site for an in-person visit.  However, if the 
participant absolutely cannot come in, the assessments can be made by phone or mail and a deviation 
recorded. Blood pressure and BMI assessments will not be able to be done. 
6.13. Day 60: Visit 3 – Patient Questionnaire Assessment 
Participants will complete questionnaires on Day 60 (+7 days). Study coordinator will contact 
participants on Day 62 and after if the questionnaires have not yet been not completed.  
Procedures to be done during the call: Questionnaires to be completed:  
1. Psychometric Instruments: 
a. Pittsburgh Sleep Quality Index (PSQI) 
b. PCL-5  
c. (PHQ-9) (Score of 1 or more on the suicide ideation item [question #9] to trigger a risk 
assessment by the PI, and if necessary, a licensed Behavioral Health Provider.) 
d. Epworth Sleepiness Scale ESS  
e. Trauma Related Nightmare Scale (TRNS) 
f. Insomnia Severity index (ISI) 
g. VR-12 Quality of Life (VR-12) 
h. NW Likert Scale for Sleep Quality (NW Likert)  
i. 
Columbia-Suicidality Severity Rating Scale, Since Last Contact version (C-SSRS)  
i. 
Study Staff will immediately contact the PI, and if necessary, a healthcare 
provider that has been trained to perform a suicide assessment if there is any risk 
of suicide. 
6.14. Day 90: Visit 4 – Patient Questionnaire Assessment 
Participants will complete questionnaires on Day 90 (+7 days). The study staff will contact 
participants on Day 92 and after if the questionnaires have not yet been completed. When all 
questionnaires are completed, the study staff will call or text the participants to confirm that their 
involvement in the study is complete and to reiterate the instructions on returning the study 
device.  
Questionnaires to be completed:  
Health assessments 
1. Psychometric Instruments: 
a. Pittsburgh Sleep Quality Index (PSQI) 
b. PCL-5  
c. Insomnia Severity index (ISI) 
d. (PHQ-9) (Score of 1 or more on the suicide ideation item [question #9] to trigger a risk 
assessment by the PI, and if necessary, a licensed Behavioral Health Provider.) 
e. Epworth Sleepiness Scale ESS  
f. Trauma Related Nightmare Scale (TRNS) 

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g. VR-12 Quality of Life (VR-12) 
h. NW Likert Scale for Sleep Quality (NW Likert)  
i. 
Columbia-Suicidality Severity Rating Scale, Since Last Contact version (C-SSRS)  
i. 
Study Staff will immediately contact the PI, and if necessary, a healthcare 
provider that has been trained to perform a suicide assessment if there is any risk 
of suicide. 
 
Subjects will be allowed to keep the device at the end of the study, but will be given a $100 
reimbursement if they return it. The device can only be used for NightWare. No other applications are 
enabled on the device.  
6.15. Reimbursement Plan 
Subjects will receive $50 for enrolling and completing study-related surveys at their baseline visit.  
 
At each two-week interval during the Study (Day 15, 30, 45, 60, 75, & 90) study participants will receive 
$25 for continuing to participate in the study.  
Study participants will also receive an additional $25 every two weeks (Day 
15, 30, 45, 60, 75, & 90) for wearing the device for ≥70% or 10 of the 15 nights 
in a two-week period.  
 
Subjects will also receive $100 upon returning the device and completing study-related surveys.  
 
In total, participants will receive between $200-$450 for participating in the Study, which averages up to 
$5/day.  
 
Study participants will also be reimbursed for any travel expenses if required.  
 
 
 

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Compensation Table 
Study Day 
Base 
Amount  
Incentive 
Amount 
Condition 
of 
incentive 
Amount 
1 
$50 
 
 
15 
$25 
$25 
Study 
device use 
in 10 of 
last 15 
days 
30 
$25 
$25 
45 
$25 
$25 
60 
$25 
$25 
75 
$25 
$25 
90 
$25 
$25 
Return of 
study 
device 
 
$100 
 
TOTAL 
$200 
$250 
 
7. Statistical Considerations 
7.1. Randomization Procedure 
The study will use stratified randomization based on study site and whether the participant has a baseline 
PSQI score equal to or less than 15 versus scores that are equal to 16 or more. This will result in four 
study strata (groups). See Table #2, below. 
 
 
 

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Table #2:  Assigned ID numbers for different strata-schema 
 
NW RCT 
Assigned ID’s 
Study 
Protocol 
# 
Site 
Number 
1st ID for 
stratum 
(low/high 
PSQI score) 
Last ID for 
stratum 
Final ID assigned 
numbers by stratum 
Minneapolis 
(Mpls) Low 
PSQI 
2 
1 
001 
499 
21001-21499 
Mpls High 
PSQI 
2 
1 
500 
999 
21500-21999 
Tampa Low 
PSQI 
2 
2 
001 
499 
22001-22499 
Tampa High 
PSQI 
2 
2 
500 
999 
22500-22999 
Walter Reed 
Low PSQI 
2 
3 
001 
499 
23001-23499 
Walter Reed 
High PSQI 
2 
3 
500 
999 
23500-23999 
Cleveland Low 
PSQI 
2 
4 
001 
499 
24001-24499 
Cleveland 
High PSQI 
2 
4 
500 
999 
24500-24999 
Low PSQI 
2 
n 
001 
499 
2n001-2n499 
High PSQI 
2 
n 
500 
999 
2n500-2n999 
 
 
As explained below, throughout the study the Active and Sham Systems will be well balanced in the 
number of participants from each study stratum. The rationale for imposing balance (equal numbers of 
participants in each stratum as delineated in table #2, above) based on baseline PSQI score, is that 
participants with a higher baseline PSQI will have a greater potential for PSQI-score reduction during 
follow-up, while participants that begin the study with lower scores, will have a correspondingly lower 
potential for PSQI-score reduction.  If these strata were NOT imposed there is a real risk that a higher 
proportion of participants with LOW starting PSQI-scores would be given the Active System and the 
HIGH starting PSQI-scores would receive the Sham System.  Upon analysis of the strata in this example, 
any effect that was due to having the Active System would be severely blunted.  This would make it seem 
that the NW System is not as effective as it really is. If, conversely, the Active System was assigned to 
more baseline HIGH PSQI-scorers, the effect of the NW System could show a much-greater effect than 
there really is.  As explained in the journal JAMA17: 
 

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The permuted block technique randomizes patients between groups within a set of study 
participants, called a block. Treatment assignments within blocks are determined so that 
they are random in order but that the desired allocation proportions are achieved exactly 
within each block. In a 2-group trial with equal allocation and a block size of 6, 3 patients in 
each block would be assigned to the control and 3 to the treatment and the ordering of those 
6 assignments would be random. For example, with treatment labels A and B, possible 
blocks might be: ABBABA, BABBAA, and AABABB. As each block is filled, the trial is 
guaranteed to have the desired allocation to each group. 
 
Participant ID’s will be linked to a randomization schedule to be accessed by the unblinded NightWare 
programmers (who keep the randomization results secret) so that each participant's NW System may be 
remotely programmed accordingly as either Active or Sham.  This remote programming will occur before 
the subject arrives home with the study device. 
 
The randomization schedule for each of the four study strata will be generated randomly using permuted 
blocks (as described above) of size two, four, or six. When, for example, a block size of two is used, one 
participant will be assigned Active and the other will be assigned Sham; for a block size of four, two will 
be assigned Active and two will be assigned Sham; and for a block size of six, three will be assigned 
Active and the other three will be assigned Sham. The assignment order within the block will be 
randomly chosen with equal probability. For example, the assignment order for a block size of two may 
be Active, then Sham or Sham, then Active; whereas for a block of four the assignment order is realized 
in six possible ways, and for a block of six the assignment order is realized in twenty possible ways. Due 
to the many possible randomization schemes possible it will be difficult to predict the next arm 
assignment, even for someone who is unblinded to the previous assignments and strata information.  After 
each block of participants has been enrolled in a particular study stratum, the two arms will necessarily 
have the same number of participants from that study stratum. To generate the randomization schedule for 
each stratum, a string of block sizes, along with their assignment order, will be randomly selected using 
the software statistical package R v 3.5.1 and subsequently imported into the randomization document to 
be accessed by the unblinded NightWare programmers as needed.  
7.2. Statistical Hypothesis Testing 
The primary hypothesis is that NW will improve sleep quality as measured by the Pittsburgh Sleep 
Quality index (PSQI) relative to sham. On average, compared to the sham, NW will provide a greater 
reduction in PSQI score measured on day 30 relative to baseline on day 0 
  
Let Yij denote the PSQI score for the i-th participant at their j-th assessment, j=0,1,2, where j=0 denotes 
baseline, and i=1,…,n. Let Di = Yi0 – Yi1/2, i.e., the difference between the i-th participant’s PSQI score at 
baseline (Yi0) and their average PSQI score across the post-treatment initiation assessment (Yi1). The trial 
will test the hypotheses  
  
H0: µActive≤ µSham versus HA: µActive > µSham, 
 
where µActive and µSham respectively reflect the average difference with NW and sham. 
 
We will evaluate the statistical hypotheses using an equal-variances, two sample t-test. If the equal 
variance assumption is untenable, we instead will use an unequal-variances, two sample t-test, i.e., 
Welch’s t-test. We will reject the null hypothesis (H0) that change in PSQI from baseline to day 30 
resulting from the active NW system is no better than sham when the two-sided p-value is less than or 

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equal to 0.05 and the direction of the difference favors NW over sham. In this way, the proposed test 
controls the one-sided type I error rate at 2.5%. 
 
Data will be presented as mean(standard deviation) or median (interquartile range), as appropriate for 
continuous variables. Categorical variables will be presented as frequency (percentage). Continuous 
data will be assessed for normality, and transformed as appropriate (e.g. log transformation, square 
root transformation, etc.). Patient demographics and characteristics will be listed and compared. 
Continuous 
variables will be analyzed by category, intervention vs control, by two-sided t-test or Mann-U Whitney, 
as appropriate. Categorical variables will be compared by Chi-Square test or Fisher’s Exact test as 
appropriate. The change in PSQI score from baseline to day 30 will be tested via repeated measures 
tests as determined appropriate by a trial statistician. 
Time-to-event analyses will be conducted to determine time to a reduction of PSQI over the longevity of 
the study (baseline, visit 2, day 30, day 60, day 90). These analyses may be Kaplan Meier survival curves 
to determine the time to the median population attaining the 3 point decrease. If appropriate, 
 
univariate cox regression models will be used to determine the hazard ratios of PSQI scores. Additionally 
multivariable, adjusted, models will be evaluated. All analyses will be conducted at = 0.05 to alleviate 
type II errors. 
7.3. Sample Size Determination 
A total of 240 veterans and active-duty service members will be enrolled (consented) into the study so 
that even with attrition of up to 50% of study subjects, we can ensure that the study is completed by a 
MINIMUM of n = 120 participants (60 in each arm) to reach 90% power for rejecting the null hypothesis 
under the targeted benefit of δ = µActive - µSham = 3 points with an equal standard deviation of σ = 5 points in 
each of the two arms. Figure 1 (see below) depicts the power of the trial as a function of the true 
standardized reduction (δ/σ) in the population assuming we enroll and retain a MINIMUM of 60 
participants in each arm of the proposed trial. If we get more than 60 participants (i.e. less than a 50% 
attrition rate) this will just make the study results even more powerful. 
 
Figure 4: Power Curve (total completers- n=120, 50% for each arm) 
 
 

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The rationale for powering the trial to detect a 3-point reduction is two-fold. First, a 3-point reduction 
constitutes a clinically relevant benefit as this may reflect, for example, a change from 3 (most severe) to 
0 (least severe) on a particular item of the PSQI, or a 1-point reduction on three items of the PSQI. 
Second, assuming a 5-point standard deviation, the targeted 3-point reduction is equivalent to a 0.6 
standardized effect, which is plausible as evidenced by a meta-analysis20 for the observed benefit in 
previous clinical trials evaluating cognitive behavioral therapies for treating nightmare disorder using the 
difference between PSQI score at baseline and post-treatment follow-up assessment in which the 
estimated standard effect size was estimated to be 0.68 (0.34, 1.03). Furthermore, a more recent open-
label trial21 reported a standardized effect size of 1.06. Therefore, the targeted 3-point reduction or 0.6 
standardized effect constitutes both a plausible and clinically meaningful benefit in this context.  
7.4. Interim Monitoring 
The trial will incorporate two interim analyses after 20 and 40 participants in each arm have completed 
the first 30 days of the trial. Statistical monitoring guidelines will be based on two-sided O’Brien-Fleming 
boundaries. This conservative interim monitoring plan demands a negligible increase in sample size, so 
with a MINIMUM of 120 total participants completing, the trial will still be powered at 90% for the 
targeted benefit. The interim analyses will assess only patient demographics and primary endpoint. 
7.5. Primary Safety Analyses  
The hypothesis for the primary safety endpoint is that the Active NW System will not lead to worsening 
of daytime sleepiness as measured by the Epworth Sleepiness Scale, which provides a score between 0 
and 24 with higher values indicating a higher degree of sleepiness. Specifically, the hypothesis is that on-
average a user of NW will have a mean ESS score measured at 30 days following the start of NW digital 
therapeutic system use that is not higher than their ESS score measured at baseline. This hypothesis will 
be tested similarly to the primary efficacy hypothesis using a one sample t-test.   
The hypothesis for the secondary safety endpoint is that the Active NW System will not lead to an 
increase in suicide risk as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) from baseline 
(Day 0) to Day 30. C-SSRS has ratings of “none”, “low”, “moderate”, and “high”. Those possible 
participants rated as “high” on the C-SSRS at Visit 1 will NOT qualify for the study and, if deemed 
necessary by the PI, will be given immediate assessment by a licensed Mental Health Provider, who will 
determine the next therapeutic steps. This hypothesis will be tested similarly to the primary efficacy 
hypothesis using a one sample t-test.  
7.6. Secondary/Exploratory Analyses  
Secondary and Exploratory analyses will be carried out with appropriate regression modeling techniques 
and hypothesis tests. In particular, we will use longitudinal data analysis methods, such as generalized 
estimating equations and generalized linear mixed models, to assess temporal variation in the longitudinal 
outcome measures, and we will carry out two sample t-tests of the secondary hypotheses. 
 
At the conclusion of the trial, the data will be assessed as both intention to treat (ITT) and per protocol. 
The effect sizes at the conclusion of the analyses will be compared using standard techniques. If the 
effect size of the per protocol analysis is greater than 10%, data will be reported as intention to treat to 
decrease probability of type I errors. Both analyses will follow the outline below: 
 
Secondary outcomes, data will be presented as mean(standard deviation) or median (interquartile 
range), as appropriate for continuous variables. Categorical variables will be presented as frequency 

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(percentage). Continuous data will be assessed for normality, and transformed as appropriate (e.g. log 
transformation, square root transformation, etc.). Patient demographics and characteristics will listed an 
compared. Continuous variables will be analyzed by category, intervention vs control, by two-sided t- 
test or Mann-U Whitney, as appropriate. Categorical variables will be compared by Chi-Square test or 
Fisher’s Exact test as appropriate. Longitudinal data will be analyzed by repeated measures tests as 
appropriate for the variables. 
 
Repeated measure ANOVA will be used to determine the difference in responses at the time points 
between groups for all survey types and questions, as appropriate. If determined inappropriate Poisson 
regression models will be used to determine the univariate, univariable, effect size. 
 
Upon secondary outcomes analysis , multivariable, adjusted, models will be used to determine 
controlled effect sizes. Each variable with a p-value of 0.25 or less in standard distribution test will be 
included in the model. Backward stepwise regression modeling may be used to best fit the model. 
 
Time-to-event analyses will be conducted to determine time to survey effects over the longevity of the 
study (baseline, visit 2, day 30, day 60, day 90) for all survey results within the secondary outcomes. 
Univariate Cox regression models may be used to determine hazard ratios for the survey scores if 
appropriate. 
 
Correlation coefficients (i.e. Spearman, Pearson) may be used to determine the inter-survey reliability. If 
determined to be reliable, multivariate analyses may be conducted for surveys. 
7.7. Implementation 
All statistical analyses will be carried out by the Principal Investigator and/or a PhD Biostatistician. 
8. Subject Accountability 
Subjects who meet the eligibility criteria and agree to participate will be given written informed consent 
approved by the center’s Institutional Review Board (IRB). 
 
All subjects who meet eligibility criteria and complete the informed consent form are considered enrolled 
in the study.  Screening tests that are part of Standard of Care (SOC) can be used to determine pre-
eligibility. Subjects enrolled in this investigation must be followed per this investigational protocol.   
8.1. Withdrawal 
All subjects enrolled in the clinical study, including those withdrawn from the clinical study or lost to 
follow-up, shall be accounted for and documented. If a subject withdraws from the clinical investigation, 
the reason(s) shall be reported. Reasons for withdrawal include, but are not limited to: 
 
● Subject found not to meet eligibility criteria 
● Subject choice to withdraw consent 
● Investigator discretion 
● Enrollment ceiling met 
● Lost to follow-up, despite best efforts to locate the subject 
● Death (see Section 8.3 for reporting requirements) 

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If a subject withdraws from the clinical investigation, the reason(s) shall be reported in a study data 
collection system. Data up to the point of withdrawal will be collected. All open adverse events should be 
closed or documented as chronic. 
8.2. Enrollment Controls 
Investigational sites will monitor the number of subjects enrolled and will notify NW when the 
enrollment goal is close to being reached. Once enrollment ceiling is reached, site staff shall discontinue 
study enrollments.  
9. Safety 
9.1. Risk/Benefit Assessment   
9.1.1. Known Potential Risks   
There are no predicate devices used specifically to treat nightmares.  However, there are many variations 
of over-the-counter applications and wearable devices that vibrate to signal the wearer.  The same risks 
known to over-the-counter wearable fitness devices apply to this device.  
The NW digital therapeutic is designed to interrupt during a nightmare, but not awaken the individual.  
The device may instead awaken, or incorrectly diagnose a nightmare and alarm (false positive).  
Therefore, worsening sleep quality is a potential risk of this device intervention.  
9.1.2. Known Potential Benefits 
Potential benefits are currently unknown. Uninterrupted sleep due to interrupting nightmares by arousing 
the subject without waking them, resulting in a more restful sleep, as measured by the PSQI.  Improved 
sleep quality and duration can improve overall psychological effects of sleep deprivation. 
9.1.3. Assessment of Potential Risks and Benefits 
Study inclusion and exclusion criteria were designed to only include subjects already suffering from sleep 
disorder and therefore most likely to benefit from the intervention.  
  
Since the intervention is delivered through a non-invasive smartwatch, study participants may simply 
discontinue wearing the watch if the intervention is contributing to deteriorating sleep quality.   
 
The trial includes a primary safety endpoint designed to evaluate worsening sleep quality: 
1. Epworth Sleepiness Scale 
 
The trial also includes a secondary safety endpoint designed to evaluate worsening suicidal risk: 
1. Columbia-Suicide Severity Rating Scale (C-SSRS LT) will be administered at the beginning and 
end of the study. 
a. The Lifetime and Recent version will be used to determine if the subject is suitable for 
this study. 
i. 
Potential Subjects that have a rating of “High” will be excluded from this 
study.  

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ii. 
Since a “High” rating is an imminent safety risk, study staff will immediately 
call/page the PI, and if needed, a licensed staff member to conduct a safety 
assessment.  
1. If there isn’t a licensed staff person available, the subject will be 
TAKEN to the Hospital Emergency Room. 
b. At the 30, 60, and 90 day visits(+7 days), the subject will take another C-SSRS, the Since 
Last Contact version. 
i. 
Either an increase in or a “High” score is an imminent safety risk, so study 
staff will immediately call/page licensed staff member to conduct a safety 
assessment.  
1. If there isn’t a licensed staff person available, the subject will be 
TAKEN to the Hospital Emergency Room. 
9.2. Unanticipated Problems  
9.2.1. Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
  
● Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
● Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
● Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
  
This definition could include an unanticipated adverse device effect, any serious adverse effect on health 
or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)). For this clinical trial, unanticipated problems include, but are not limited to, 
significant changes in the sleep environment which may impact sleep quality.   
9.2.2. Unanticipated Problem Reporting 
The principal investigator (PI) will report unanticipated problems (UPs) to the site Institutional Review 
Board (IRB) and to the sponsor. The UP report will include the following information: 
  
● Report date, IRB Study number, Study Title, Study Staff Contact Information, Date UP occurred, 
and date PI was notified about the UP. 
● Description of the Unanticipated Problem which occurred during the conduct of the research. 
● Provide an explanation for why this Unanticipated Problem occurred. 
● Characterize the impact of the Unanticipated Problem on the study. 

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● Describe the steps which have been taken to resolve the reported occurrence. 
● Describe the plan implemented to avoid or prevent future occurrences. 
● Inform other study participants as necessary. 
● Name all other entities to which this UP has been reported. 
● Determine if the UP will require modification of the currently approved study and/or consent 
form. 
9.2.3. Serious Adverse Event (SAE) Reporting 
A Serious Adverse Event (SAE) is an untoward occurrence in human research that results in death, a life-
threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant 
disability or incapacity, congenital anomaly, or birth defect, or that requires medical, surgical, behavioral, 
social, or other intervention to prevent such an outcome (VHA Handbook 1058.01§4.r and 21 CFR 
312.32(a)).  
 
Only adverse events and deaths occurring at the site that are 1. serious and 2. unanticipated and 3. related 
or probably related to the research need to be reported to the IRB (VHA Handbook 1058.01 §6.a. & 6.b.) 
 
If the event satisfies ALL three of these criteria the event must be reported to the IRB within 5 business 
days of learning of the event. The study sponsor will also be notified within the same time frame. 
9.2.4. Adverse Event Reporting 
Adverse Events are unfavorable changes in health that occur in trial participants during the clinical trial or 
within a specified period following the trial. 
For this clinical trial, adverse events include any adverse event that occurs as a result of the use or 
potential use of the study device. An investigator shall submit to the sponsor and to the reviewing 
Institutional Review Board (IRB) a report of any unanticipated adverse events, no later than 10 working 
days after the investigator first learns of the effect (21 CFR 812.150(a)(1)). A sponsor who conducts an 
evaluation of an unanticipated adverse device effect under 812.46(b) shall report the results of such 
evaluation to the Food and Drug Administration (FDA) and to all reviewing IRB's and participating 
investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the 
sponsor shall submit such additional reports concerning the effect as FDA requests (21 CFR 
812.150(b)(1)).   
 
9.3. Death Reporting 
Death is reported as is stated in section 8.2.3 Serious Adverse Event (SAE) Reporting.  
A death that meets all three criteria for an SAE, as above, shall be reported by Study Staff to the IRB 
within 5 business days of learning of the death.  
A detailed narrative or death letter may be requested by the sponsor including date of death, place, 
circumstances, cause of death, and whether the death was witnessed or not. 
10. Informed Consent 
Subject participation in this clinical study is voluntary.  Formal Consent is required from each subject and 
consists of a signed IRB-Approved ICF and signed IRB-Approved HIPAA. The Investigator is 

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responsible for ensuring that such Formal Consent is obtained prior to the use of any investigational 
devices, study-required procedures and/or testing, or data collection. 
  
The obtaining and documentation of Informed Consent must be in accordance with the principles of the 
Declaration of Helsinki, ISO 14155, any applicable national regulations, and local IRB. The ICF must be 
accepted by the sponsor and approved by the site’s IRB. 
  
The IRB will provide a template of both the ICF and HIPAA documents to investigators participating in 
this study. Study staff will complete the templates incorporating study-specific information. 
  
The process of obtaining Informed Consent shall at a minimum include the following steps, as well as any 
other steps required by applicable laws, rules, regulations and guidelines: 
● be conducted by the Principal Investigator or designee authorized, 
● include a description of all aspects of the clinical study that are relevant to the subject’s decision 
to participate throughout the clinical study, 
● avoid any coercion of or undue influence of subjects to participate, 
● not waive or appear to waive subject’s legal rights, 
● use native language that is non-technical and understandable to a subject that has the equivalent 
of a high-school education, 
● provide ample time for the subject to consider participation and ask questions, if necessary, 
● ensure important new information is provided to new and existing subjects throughout the clinical 
study. 
● The subject will be made aware that they may be in the sham arm of the trial and not receive 
treatment. 
11. Protocol Deviations/Unexpected Problems Reports 
A protocol deviation is any noncompliance with the clinical trial protocol.  It is the responsibility of the 
site investigator to use continuous vigilance to identify and report deviations within 10 working days of 
identification of the protocol deviation, or within 3 working days of the scheduled protocol-required 
activity (if the deviation/UP is discovered immediately).  All deviations must be addressed in study 
source documents.  Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) 
per their policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. 
  
Protocol deviations must also be reported in the study data collection system. 
12. Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to the principal investigator and study sponsor (if sponsor is NOT 
the terminating party). If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, and, as necessary, the Institutional Review Board (IRB), and/or 
the sponsor and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to their study visit schedule. 
 terminate 
Circumstances that may warrant termination or suspension include, but are not limited to: 

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● Determination of unexpected, significant, or unacceptable risk to participants 
● Demonstration of efficacy that would warrant stopping   
● Insufficient compliance to protocol requirements 
● Data that are not sufficiently complete and/or evaluable 
● Determination that the primary endpoint has been met 
● Determination of futility 
  
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
13. Data Management 
13.1. Data Collection and Handling 
Subject data will be recorded on REDCap electronic case report forms. MyCAP, a companion application 
for REDCAP, will be installed on study device phones and used by the participants to complete 
questionnaires throughout this study. Data will be entered with a de-identified subject indicator, with a 
crosswalk file to the subject identifier to be maintained by the investigating site. The electronic files will 
be maintained as the original study documents. All paper forms will be maintained in a locked office 
before being entered in the database.  Once entered, the paper files will be destroyed.  
 
De-identified data will be entered from REDCap into an SPSS database to perform data analysis.   
13.2. Study Records Retention 
The Office of Research Development/ Office of Research Oversight (ORD/ORO” Records Control 
Schedule Guideline (DAA-0015-2015-0004) states: 
All Protocol Files related to the review and oversight of human subjects’ research 
protocols submitted by principal investigators to the IRB shall have a cutoff at the end of 
the fiscal year after the research project has been completed or terminated.  Records will 
be retained for 6 years after the cutoff.  
Records include, but are not limited to, the application to the IRB; research protocol and 
amendments; case reports forms; informed consent template and HIPAA Authorization 
template; reports of adverse events, complaints, and deviations from IRB-approved 
protocol; data and safety monitoring reports; research findings to date; and all relevant 
documents and related correspondences between the  IRB and the investigators in the 
review of an associated protocol.  
No records will be destroyed without the written consent of the sponsor, if applicable. 
 
 
 
 
 
 

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14. Abbreviations 
The list below includes abbreviations utilized in this protocol.   
  
Abbreviation 
Description 
AUDIT 
Alcohol Use Disorders Identification Test 
 BMI 
Body Mass Index 
C-SSRS (LT) 
Columbia-Suicide Severity Rating Scale-Lifetime 
C-SSRS (SLC) 
Columbia-Suicide Severity Rating Scale-Since Last Contact  
DAST-10 
Drug Abuse Screening Test - 10 
DCC 
Data Coordinating Center 
EEG 
Electroencephalogram 
EHR 
Electronic Health Record 
ESS 
Epworth Sleepiness Scale 
FOSQ-10 
Functional Outcomes of Sleep Questionnaire 
Ha 
Alternate hypothesis 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
Ho 
Null hypothesis 
ICF 
Informed Consent Form 
ICSD-3 
International Classification of Sleep Disorders – 3rd Edition 
IRB 
Institutional Review Board 
IRT 
Image Rehearsal Therapy 
ISI 
Insomnia Severity Index 
NCT 
National Clinical Trial 
N-T-F 
Note-to-file 
NW 
NightWare 
OSA 
Obstructive Sleep Apnea 

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PCL-5 
PTSD Checklist -5 
PHQ-9 
Patient Health Questionnaire - 9 
PI 
Principal Investigator 
PSQI 
Pittsburgh Sleep Quality Index 
PSQI-A 
PSQI-Addendum for PTSD 
PTSD 
Post-Traumatic Stress Disorder 
VR-12 
Veterans Rand 12 health and quality of life survey 
REM 
Rapid Eye Movement 
SOC 
Standard of Care 
SPSS 
Statistical Package for the Social Sciences 
TNT 
Traumatic Nightmares Treated 
TRNS 
Trauma-Related Nightmare Survey 
UP 
Unanticipated Problem 
UPR 
Unanticipated Problem Report 
δ 
Delta (gr) – change in measurement (i.e.:  PSQI) 
σ 
Sigma (gr) – variability (i.e.:  variance) 
 
15. Statement of Compliance 
The trial will be conducted in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and applicable United States (US) Code of Federal Regulations (CFR). The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the Institutional Review Board (IRB), except 
where necessary to eliminate an immediate hazard(s) to the trial participants. 
  
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
 

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16. References 
1.  
Li SX, Zhang B, Li AM, Wing YK. Prevalence and correlates of frequent nightmares: a 
community-based 2-phase study. Sleep. 2010;33(6):774-780. doi:10.1164/ajrccm.161.3.9805008 
2.  
Kilpatrick D, Resnick H, Freedy J, et al. Posttraumatic Stress Disorder Field Trial: Evaluation of 
PTSD Construct Criteria A through E. In: Widiger T, Frances A, Pincus H, et Al., Eds. DSM-IV 
Sourcebook. Vol 4. Washington, D.C: American Psychiatric Press; 1994. 
3.  
International Classification of Sleep Disorders, 3rd Edition: Diagnostic and Coding Manual. 
Westchester, IL: American Academy of Sleep Medicine; 2014. 
4.  
Schoenfeld FB, Deviva JC, Manber R. Treatment of sleep disturbances in posttraumatic stress 
disorder: a review. J Rehabil Res Dev. 2012;49(5):729-752. doi:10.9740/mhc.n190104 
5.  
Aurora RN, Zak RS, Auerbach SH, et al. Best practice guide for the treatment of nightmare 
disorder in adults. J Clin Sleep Med. 2010;6(4):389-401. 
6.  
Thompson CE, Taylor FB, McFall ME, Barnes RF, Raskind MA. Nonnightmare distressed 
awakenings in veterans with posttraumatic stress disorder: response to prazosin. J Trauma Stress. 
2008;21(4):417-420. doi:10.1002/jts.20351 
7.  
Pfizer. “Minipress Prescribing Information” (PDF). United States Food Drug Adm. 
2015:Retrieved 3 June 2016. 
8.  
Cranston CC, Davis JL, Rhudy JL, Favorite TK. Replication and expansion of “best practice guide 
for the treatment of nightmare disorder in adults.” J Clin Sleep Med. 2011;7(5):549-553. 
doi:10.5664/JCSM.1330 
9.  
Krakow B, Hollifield M, Johnston L, et al. Imagery rehearsal therapy for chronic nightmares in 
sexual assault survivors with posttraumatic stress disorder: a randomized controlled trial. JAMA. 
2001;286(5):537-545. doi:10.1001/jama.286.5.537 
10.  
Nadorff MR, Nadorff DK, Germain A. Nightmares: Under-reported, undetected, and therefore 
untreated. J Clin Sleep Med. 2015;11(7):747-750. doi:10.5664/jcsm.4850 
11.  
Mellman TA, Hipolito MMS. Sleep disturbances in the aftermath of trauma and posttraumatic 
stress disorder. CNS Spectr. 2006;11(8):611-615. 
12.  
Kobayashi I, Sledjeski EM, Spoonster E, Fallon WF, Delahanty DL. Effects of early nightmares 
on the development of sleep disturbances in motor vehicle accident victims. J Trauma Stress. 
2008;21(6):548-555. doi:10.1002/jts.20368 
13.  
Koffel E, Khawaja IS, Germain A. Sleep disturbances in posttraumatic stress disorder: Updated 
review and implications for treatment. Psychiatr Ann. 2017;46(3):173-176. 
doi:10.3928/00485713-20160125-01.Sleep 
14.  
Woodward SH, Bliwise DL, Friedman MJ, Gusman FD. First night effects in post-traumatic stress 
disorder inpatients. Sleep. 1996;19(4):312-317. doi:10.1093/sleep/19.4.312 
15.  
Phelps AJ, Kanaan RAA, Worsnop C, Redston S, Ralph N, Forbes D. An Ambulatory 
Polysomnography Study of the Post-traumatic Nightmares of Post-traumatic Stress Disorder. 
Sleep. 2018;41(1):1-9. doi:10.1093/sleep/zsx188 
16.  
Kato T, Montplaisir JY, Lavigne GJ. Experimentally induced arousals during sleep: A cross-
modality matching paradigm. J Sleep Res. 2004;13(3):229-238. doi:10.1111/j.1365-
2869.2004.00409.x 
17.  
Broglio K. Randomization in Clinical Trials: Permuted Blocks and Stratification. JAMA. 
2018;319(21):2223-2224. doi:10.1001/jama.2018.6360 
 
 
 

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17. Appendix A 
 
Excluded Medications 
Use 
Verenicline 
Anti-Smoking 
  
  
Non-dihydropyridines 
  
verapamil 
Calcium channel blockers --affect the heart. 
Reduce Heart Rate. 
Diltiazem 
Calcium channel blockers --affect the heart. 
Reduce Heart Rate. 
  
  
Beta-Blockers (not ophthalmic) 
Reduce blood pressure, slows heart rate. 
  
Treats: Heart Failure, anxiety, migraines 
  
May cause: Headache, depression, confusion, 
dizziness, NIGHTMARES, Hallucinations.  
acebutolol (Sectral) 
  
atenolol (Tenormin) 
  
betaxolol (Kerlone) 
  
betaxolol (Betoptic S) 
  
bisoprolol fumarate (Zebeta) 
  
carteolol (Cartrol, discontinued) 
  
carvedilol (Coreg) 
  
esmolol (Brevibloc) 
  
labetalol (Trandate [Normodyne - discontinued]) 
  
metoprolol (Lopressor, Toprol XL) 
  
nadolol (Corgard) 
  

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NightWare INC. 
Protocol: NW101002 Version 1.1 
 
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nebivolol (Bystolic) 
  
penbutolol (Levatol) 
  
pindolol (Visken, discontinued) 
  
propranolol (Hemangeol, Inderal LA, Inderal XL, 
InnoPran XL) 
  
sotalol (Betapace, Sorine) 
  
Timolol (Blocadren, discontinued) 
 
Alpha Blockers 
MUST Taper then be off med for at least 2 
weeks before enrolling.