DSUVIA Early Evaluation of PAIN (DEEP) Trial
Phase: PHASE3
Conditions: Traumatic Injury
Sponsor: Frank Guyette

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Task Order 0008 
 
 
DSUVIA Early Evaluation of Pain (DEEP) Trial 
 
 
 
 
Protocol v3 1.12.2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Linking Investigations in Trauma and Emergency Services 

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Contents 
Protocol Synopsis .......................................................................................................................................... 4 
I. 
Objective and Specific Aims .................................................................................................................. 5 
II. 
Background and Significance ................................................................................................................ 6 
III. 
Study Design/Setting ............................................................................................................................ 7 
Study Population: ...................................................................................................................................... 7 
Inclusion Criteria ....................................................................................................................................... 7 
Exclusion Criteria....................................................................................................................................... 7 
Study Intervention: ................................................................................................................................... 8 
Study Intervention Arm......................................................................................................................... 8 
Standard Care Arm ................................................................................................................................ 8 
IV. Outcomes .............................................................................................................................................. 8 
Primary Outcome ...................................................................................................................................... 8 
Secondary Outcomes ................................................................................................................................ 8 
Secondary Outcome Definitions ........................................................................................................... 8 
Predefined Subgroups ............................................................................................................................. 10 
V. 
Screening and Enrollment ................................................................................................................... 10 
VI. Statistical Analysis Plan ....................................................................................................................... 10 
Random Assignment: .............................................................................................................................. 10 
Analyses: ................................................................................................................................................. 10 
Randomization of Ineligible Subjects ...................................................................................................... 12 
Non-adherence ....................................................................................................................................... 12 
Interim Analyses ..................................................................................................................................... 12 
Surveillance for Outcomes and Data Elements ...................................................................................... 13 
In-Hospital Resuscitation Elements .................................................................................................... 13 
Data Entry ............................................................................................................................................... 13 
Database Management ........................................................................................................................... 13 
VII. Clinical Coordinating Center (CCC) ..................................................................................................... 14 
VIII. Data Coordinating Center (DCC) ......................................................................................................... 14 
IX. Human Subjects .................................................................................................................................. 14 
Study Risks and Benefits: ........................................................................................................................ 14 
Institutional Review Board ...................................................................................................................... 14 
Training and Participating Site Coordination .......................................................................................... 14 

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X. 
Safety Monitoring ............................................................................................................................... 14 
Adverse Event and Non-compliance definitions ..................................................................................... 14 
Assessing and Reporting Adverse Events (AEs) and Non-compliance .................................................... 15 
Data Safety Monitoring Board (DSMB) ................................................................................................... 16 
XI. Quality Control, Assurance and Confidentiality.................................................................................. 17 
Protocol Compliance ............................................................................................................................... 17 
Protocol Deviations ................................................................................................................................. 17 
Privacy and Confidentiality ..................................................................................................................... 17 
Investigator Responsibilities ................................................................................................................... 17 
Time Table ............................................................................................................................................... 18 
XII. References .......................................................................................................................................... 18 
 
 
 

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Protocol Synopsis 
 
Protocol Title: 
DSUVIA Early Evaluation of Pain (DEEP) Trial 
Protocol Number: 
STUDY21100180 
NCT Number: 
NCT05288348 
Version # and Date: 
Version 3 1/12/2023 
Investigational Drug: 
DSUVIA as compared to standard care pain treatment  
Trial Sites: 
Clinical Coordinating Center 
• 
University of Pittsburgh, University of Pittsburgh Medical 
Center, Co-PI Jason Sperry, Co-PI Frank Guyette 
Additional Sites: 
• 
TBD 
Funding Agency 
Department of Defense 
Study Aims: 
Objectives for the study aims:  
(1) To conduct a prospective, randomized, interventional trial to 
examine effectiveness, safety, and acceptability of DSUVIA 
compared to standard care pain treatment in an emergency 
department (ED) setting in patients following traumatic injury 
with moderate to severe pain.  
 
(2) 
To analyze pain treatment effectiveness outcomes including: 
a. 
Verbally administered Numeric Rating Scale (VNRS) 
for clinical pain measurement (0-100) 30 minutes 
after pain medication administration 
b. 
Adverse effects and events related to pain 
medication(s) including nausea/vomiting, headache, 
dizziness, hypoxia, hypotension, and need for 
advanced airway  
c. 
Verbally administered Numeric Rating Scale (VNRS) 
for clinical pain measurement (0-100) at 30-minute 
intervals until discharge from the ED (up to 120 
minutes) or rescue narcotic administration 
d. 
Patient Global Assessment (PGA) of Pain Control at 
30-minute intervals until discharge from the ED (up to 
120 minutes) or rescue narcotic administration 
e. 
Richmond Agitation-Sedation Scale score at 30-
minute intervals until discharge from the ED (up to 
120 minutes) or rescue narcotic administration 
f. 
Time-weighted summed pain intensity difference 
(SPID) at 30-minute intervals until discharge from the 
ED (up to 120 minutes) or rescue narcotic 
administration 

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g. 
Number of rescue doses of narcotic at 30 minutes and 
during ED stay (up to 120 minutes) 
h. 
Time to reduction of NRS pain score of 10 points 
i. 
Cognitive function assessment with the Six Item 
Screener (SIS) at 30 minutes 
j. 
Healthcare Professional Global Assessment (HPGA) 
of the Method of Pain Control at 30 minutes 
k. 
Acceptability to health care providers survey 
Study Design: 
Prospective, randomized, interventional trial 
Planned Sample Size:  
N= 150 total; 75 each arm 
Planned Study Duration: 
3 years 
Major Inclusion Criteria:  
1. Trauma activation (Level I, II or III)  
2. Age 18 years to 70 inclusive. 
3. Blunt or penetrating injury 
4. Need for pain treatment based upon an VNRS clinical pain 
measurement ≥ 50 
5. Estimated time in Emergency Department > 30 minutes 
following informed consent 
Major Exclusion Criteria: 
1. Advanced airway management prior to 1st dose 
administration 
2. Known allergy to fentanyl, sufentanil, or meperidine 
3. Known prisoner 
4. Known pregnancy 
5. ED pain treatment contraindicated per standard care  
6. Estimated BMI >40 
7. Significant respiratory depression 
8. Known or suspected gastrointestinal obstruction, including 
paralytic ileus 
Primary Outcome: 
Verbally administered Numeric Rating Scale (VNRS) for clinical 
pain measurement (0-100) at 30 minutes following randomized 
medication administration 
 
I. 
Objective and Specific Aims 
 
Our objective is to perform a prospective, randomized, interventional trial of Emergency Department 
(ED) administration of DSUVIA versus standard care pain management comparing pain treatment 
outcomes in injured patients with moderate to severe pain.  
AIM #1: To determine if, among injured patients with moderate to severe pain, treatment with DSUVIA 
compared to standard care pain treatment in the ED reduces the Verbally administered Numeric Rating 
Scale (VNRS) for clinical pain measurement (0-100) at 30 minutes. 
 

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Hypothesis #1: Null Hypothesis:  There will be no difference in the pain score at 30 minutes of patients 
who received DSUVIA as compared to standard care pain medicine in trauma patients  
AIM #2: To determine if, among injured patients with moderate to severe pain, treatment with DSUVIA 
compared to standard care pain treatment in the ED reduces adverse effects and events related to pain 
medication(s) including nausea/vomiting, headache, dizziness, hypoxia, hypotension, and need for 
advanced airway.  
Hypothesis #2: Null Hypothesis: There will be no difference in the rate of adverse events of 
nausea/vomiting, headache, dizziness, hypoxia, hypotension and need for advanced airway in patients 
who received DSUVIA as compared to standard care pain medicine in trauma patients.  
AIM #3: To determine if, among injured patients with moderate to severe pain, treatment with DSUVIA 
compared to standard care pain treatment in the ED improves pain treatment effectiveness including serial 
VNRS scores (every 30 minutes), the need for rescue narcotic administration, the time needed to reduce 
the VNRS pain score by 10 points, time-weighted summed pain intensity difference, patient global 
assessment (PGA), Six Item Screener (SIS) cognitive assessment and Richmond Agitation-Sedation Scale 
scores. 
Hypothesis #3: Null Hypothesis: There will be no difference in the pain treatment effectiveness, need for 
rescue narcotic administration, time to reduction of 10 points of VNRS pain score by 10 points, the time-
weighted summed pain intensity difference, patient global assessment, Six-Item Screener and the 
Richmond Agitation-Sedation Scale scores in patients who received DSUVIA as compared to standard 
care pain medicine in trauma patients.  
AIM #4: To determine if, among injured patients with moderate to severe pain, treatment with DSUVIA 
compared to standard care pain treatment in the ED improves Healthcare Professional Global Assessment 
(HPGA) of the Method of Pain Control and health care provider survey scores. 
Hypothesis #4: Null hypothesis: There will be no difference in the Healthcare Professional Global 
Assessment (HGPA) of the method of pain control and healthcare provider survey scores in patients who 
received DSUVIA compared to standard care pain medication in trauma patients.  
II. 
Background and Significance 
The management of pain following an acute injury is an essential part of caring for a trauma victim in 
both the military and civilian systems.1 Providing analgesia as soon as practicable is humane, reduces 
suffering, moderates physiologic complications of trauma, and may mitigate the incidence of long-term 
sequelae such as chronic pain and PTSD.2,3 Reviews of pain management demonstrate high variability 
and inconsistency in the reporting, assessment, and treatment of pain.4,5 Pain management is further 
complicated by fears and misconceptions of adverse events, chemical dependency, and implicit bias.6 
Current prehospital pain management strategies rely on parenteral medications to provide rapid relief 
because oral medications are slow in onset and absorption from intramuscular injections is unpredictable.7 
In combat, only 7% of casualties had a pain score recorded and only 15% received any analgesic.5 In less 
austere environments, providers only assess pain in 2/3 of patients. Pain following traumatic injury is 
common (81%), severe (73%), infrequently treated (47%), and the management inadequate (25%).8 
Guidelines from the National Association of EMS Physicians (NAEMSP) recommend assessing pain in 
all patients, using a self-reported pain score (NRS), using opioid analgesics (morphine or fentanyl), 
reassessing pain and adverse effects frequently, and redosing analgesia if significant pain remains.4 
Greater granularity in pain assessment is achieved with a verbally administered NRS which has been 
extensively applied in ED settings during the assessment of acute pain.9-11  

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The NAEMSP guidelines focus on intravenous (IV) fentanyl and morphine because of wide availability 
among American EMS services. Use of IV opioids is limited by the need to obtain IV access, which can 
be time consuming, is associated with a significant failure rate, and may lead to increased exposure in a 
tactical environment.12 The US military uses oral transmucosal fentanyl citrate (OTFC) which can be 
administered without IV access, but has slow absorption.  Furthermore, safety data on OTFC, outside of 
long-term analgesia for cancer patients, is not well described.7 Given these significant limitations, an 
alternative to IV opioid analgesics in necessary. The ideal agent has robust stability, easy delivery, rapid 
onset, minimizes altered mental status and has a wide therapeutic index.13 In addition, the ideal agent 
would have a longer duration of action and an improved side effect profile as compared to the current 
standard care. 
Sufentanil is a potent opioid analgesic derived from fentanyl with no active metabolites, rapid onset, and a 
therapeutic index superior to morphine and fentanyl.14 Sufentanil is highly lipophilic and rapidly achieves 
equilibrium in the brain; the time to analgesia is similar to IV morphine.15 When administered 
sublingually, sufentanil is 53% of the IV bioavailability within one minute and provides analgesia within 
15 minutes.15,16  Sufentanil has a low incidence of side effects, with nausea, headache, dizziness, and 
vomiting being the most common.15 As with any opioid, respiratory depression and hypoxia can occur but 
was observed to be <1%.17 Similar studies found no clinically significant changes in vital signs after the 
administration of sublingual sufentanil in post-operative patients.18,19 Sufentanil was effective in a cohort 
of patients with painful injuries presenting to the ED with pain reduction seen in less than 15 minutes and 
persisting for 2 hours.17 
These data suggest that in this cohort of injured patients with moderate to severe pain, sublingual 
sufentanil (DSUVIA) may provide similar analgesia to IV opioids. Similar to standard care with IV 
fentanyl or morphine, sufentanil (DSUVIA) is effective, rapid in onset, and has a favorable side effect 
profile. DSUVIA has the advantage of sublingual administration, precluding the need for IV access while 
providing rapid analgesia. In addition, sublingual administration of sufentanil provides longer duration of 
analgesia compared to IV fentanyl and more rapid absorption and analgesia then OTFC.  The current 
management of pain in this injured cohort is inadequate and demonstrates the need to determine the 
efficacy and safety of DSUVIA (sublingual sufentanil) as compared to standard care for pain management 
in the prehospital setting. 
III. 
Study Design/Setting 
The current proposed study will be a 3-year, multi-center, open label, randomized trial utilizing 2-4 level-
1 trauma centers from within the LITES network and will enroll approximately 150 patients. The 
University of Pittsburgh will be the Clinical Coordinating Center and the Data Coordinating Center for 
the study. 
Study Population: Blunt or penetrating injured patients who require pain management in the 
Emergency Department phase of care. 
Inclusion Criteria 
1. Trauma activation (Level I, II or III) 
2. Age 18-70 years inclusive. 
3. Need for pain treatment based upon an NRS (0-100) clinical pain measurement ≥ 50 
4. Estimated time in Emergency Department > 30 minutes following informed consent 
  
Exclusion Criteria 
 
1. Advanced airway management prior to 1st dose administration 

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2. Known allergy to fentanyl, sufentanil, or meperidine 
3. Known prisoner 
4. Known pregnancy 
5. ED pain treatment contraindicated 
6. Estimated BMI >40 
7. Significant respiratory depression 
8. Known or suspected gastrointestinal obstruction, including paralytic ileus 
 
Study Intervention:  The study intervention will be the administration of 30 micrograms of DSUVIA 
in tablet form utilizing a sublingual applicator following informed consent for participation.  
 
Study Intervention Arm: Patients randomized to the study intervention arm will receive DSUVIA via 
approved applicator as soon as feasible after randomization. A single dose of DSUVIA will be provided 
as directed on the package insert. Pre-randomization pain treatment will not be prohibited for study 
participation and dosage and narcotic type will be documented and recorded. 
 
Standard Care Arm: Patients randomized to the standard care arm will receive standard care pain 
management. Dose administered and the respective narcotic will be recorded. Pre-randomization pain 
treatment will not be prohibited for study participation and dosage and narcotic type will be documented 
and recorded. 
 
Randomization and Masking: Individual patients meeting all inclusion and no exclusion criteria in the 
emergency department will be randomized and assigned according to a 1:1 ratio of DSUVIA or standard 
care pain treatment using a permuted block design with variable block sizes of 4 and 6. A predefined 
randomization assignment will be utilized. The arm assignment will be provided in real time at the 
individual patient level. Trauma attending and ED physicians will not be masked to treatment assignment 
as the study intervention will not be blinded. Arm assignment will be concealed to all outcome assessors 
for follow up.  
 
IV. 
Outcomes  
 
Primary Outcome: The primary outcome for the pilot trial will be the Verbally administered Numeric 
Rating Scale (VNRS) for clinical pain measurement (0-100) at 30 minutes following randomized 
medication administration. 9-11 
 
Secondary Outcomes: Secondary outcomes will include adverse events including hypoxia needing 
supplemental oxygen (SpO2 < 90%); hypotension (systolic blood pressure < 90mmHg); advanced airway 
or bag mask ventilation; incidence of nausea/vomiting/headache/dizziness requiring treatment; serial (30 
minute intervals until ED discharge, up to 120 minutes or rescue narcotic administration) measurements 
of a) VNRS for clinical pain (0-100), b) Patient Global Assessment (PGA) of Pain Control, c) Richmond 
Agitation-Sedation Scale (RASS) scores, and d) time-weighted Summed Pain Intensity Difference 
(SPID); number of rescue narcotic doses at 30 minutes and during ED stay (up to 120 minutes); time to a 
reduction in VNRS pain score of 10 points; patient cognitive function as assessed by the Six Item 
Screener (SIS) at 30 minutes; Healthcare Professional Global Assessment (HPGA) of the method of pain 
control at 30 minutes; and acceptability of pain treatment to health care providers. 
 
Secondary Outcome Definitions:  
 

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Hypoxia, hypotension or need for advanced airway: The principal safety outcome for the trial 
will be the incidence of serious adverse events following the first dose of analgesic following 
randomization including hypoxia (SpO2 < 90%), hypotension (SBP < 90 mmHg) or the need for 
advanced airway management (placement of an endotracheal tube, supraglottic airway or bag 
mask ventilation) until ED discharge (up to 120 minutes), when feasible. 
 
Composite outcome of nausea, vomiting, headache, and/or dizziness requiring treatment: 
The incidence of nausea, vomiting, headache, and/or dizziness requiring treatment will be 
recorded for initial 30 minutes, when feasible. 
  
Verbally administered Numeric Rating Scale (VNRS) pain measurements (0-100) at 30-
minute intervals:  VNRS for clinical pain (0-100) measurements at approximate 30-minute 
intervals until discharge from the ED (up to 120 minutes) or rescue narcotic administration, will 
be obtained when feasible. 
              
Patient Global Assessment (PGA) of Pain Control at 30-minute intervals: The PGA of the 
method of pain control at approximate 30-minute intervals until discharge from the ED (up to 120 
minutes) or rescue narcotic administration, will be obtained when feasible. The research team will 
read the following statement aloud to the subject and the response will be recorded: "Overall, 
would you rate this method of pain control during the last 30 minutes/hours as being poor (1), fair 
(2), good (3), or excellent (4)?20” 
 
Richmond Agitation-Sedation Scale (RASS) score at 30-minute intervals: 
A RASS score at approximate 30-minute intervals until discharge from the ED (up to 120 
minutes) or rescue narcotic administration, will be obtained when feasible. (-5 to 4+; 10-point 
scale).21 
 
Time-weighted Summed Pain Intensity Difference (SPID) at 30-minute intervals: 
Time-weighted SPID measurements will be calculated at approximate 30-minute intervals until 
discharge from the ED (up to 120 minutes) or rescue narcotic administration, will be determined 
when feasible.22 Essentially, the SPID represents serial assessments of pain intensity over time, 
weighted by time differences. SPID will be calculated using values from a 101-point continuous 
pain intensity scale (0 = no pain to 100= worst pain imaginable). The Pain Intensity Difference 
(PID) (e.g., raw differences in pain intensity) is calculated by subtracting the pain intensity at 
each time point from the pain intensity at time 0. The SPID is then calculated by multiplying the 
PID score at each post dose time point by the duration (in hours) since the preceding time point 
and then summing the values over the relevant time period.11 If patients did not complete the full 
120 minutes, the last pain observation was carried forward.23 
 
Number of rescue doses of narcotic at 30 minutes and until ED discharge (up to 120   
minutes): The number of doses of standard care pain treatment given within 30 minutes 
following randomly assigned intervention and total until ED discharge (up to 120 minutes), when 
feasible. 
              
Time to reduction of VNRS pain score of 10 points (up to 120 minutes) 
The time in minutes will be determined for the VNRS pain score (0-100) to be reduced by 10 
points following randomized assignment administration for patients, when feasible. 
 
Cognitive function at 30 minutes using Six Item Screener (SIS): The SIS24 will be used to 
detect cognitive impairment (e.g., sleepiness, confusion, memory impairment and reaction time) 

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at 30 minutes. Using a cutoff of ≤ 4 (out of 6) to reflect cognitive impairment has been proposed 
for ED use25 and has been used in prior studies of treatment of acute pain with sufentanil in the 
ED.22 
 
Healthcare Professional Global Assessment (HPGA) of the Method of Pain Control at 30 
minutes: The HPGA of the method of pain control will also be reported by the healthcare 
professional (primarily nurses) at the 30-minute time period as the PGA above.26 
 
Acceptability to health care providers survey: An acceptability to health care providers score 
will be requested of health care providers in the ED including ED nurse, ED trauma team member 
and/or trauma surgery team member at 30 minutes or when feasible. The score (-2 to +2; 5-point 
scale) ratings will be from; very dissatisfied, dissatisfied, neither satisfied nor dissatisfied, 
satisfied, very satisfied, and will document providers assessment regarding the individual 
patient’s pain management process, ease and acceptability relative to past experiences, when 
feasible. 
 
Predefined Subgroups: Predefined subset analyses will be performed on: sex (male/female), Injury 
Severity Score (ISS < or ≥ 16), age (< or ≥ 50), blunt versus penetrating injury, history of pre-injury 
opioid use (Y/N), air versus ground prehospital transport, transport origin (scene versus outside ED). 
 
V. 
Screening and Enrollment 
Subjects will be identified prospectively in the ED by research personnel that are trained and familiar with 
the inclusion and exclusion criteria. Those patients who meet all inclusion and no exclusion criteria will 
be approached for informed consent, and once obtained, randomized to DSUVIA or standard care based 
upon the predetermined randomization assignment. Subjects will be paid $25.00 in a Vincent Pay card 
upon completion of the study.  
 
VI. 
Statistical Analysis Plan 
 
Random Assignment:  Participants will be randomly assigned in a 1:1 ratio to either DSUVIA or 
standard of care, stratified by site.  Within each stratum, random assignment will be blocked, with random 
block size of two and four.  
 
Analyses:  All analyses will be carried out based on the intention-to-treat principle.  Of those randomly 
assigned, the analyses will begin by describing the overall characteristics of the study population at the 
time of random assignment.  Baseline characteristics will be described overall using summary statistics 
(e.g., means, standard deviation, percentages) and graphical techniques (e.g., histograms, box plots).  
Baseline characteristics between the two groups will be compared using t-tests or Wilcoxon tests for 
continuous variables and a chi-square tests for discrete variables.  
 
The analyses for each aim are presented below.   
 
AIM #1: To determine if, among injured patients with moderate to severe pain, treatment with DSUVIA 
compared to standard care pain treatment in the ED reduces the Verbally Administered Numeric Rating 
Scale (VNRS) for clinical pain measurement (0-100) at 30 minutes.  
 
A t-test will be used to compare the mean VNRS scores between the two treatment groups.  A 
multivariable regression model will be used to compare the means after adjusting for stratification 

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variables (i.e., site) and baseline characteristics not balanced through random assignment.  All 
assumptions of the analyses will be tested (e.g., normality of residuals).  If any assumptions are violated, 
transformations of the data will be investigated and the transformed data will be analyzed and evaluated.  
If an adequate transformation cannot be identified, nonparametric methods will be used.  
 
AIM #2: To determine if, among injured patients with moderate to severe pain, treatment with DSUVIA 
compared to standard care pain treatment in the ED reduces adverse effects and events related to pain 
medication(s) including nausea/vomiting, headache, dizziness, hypoxia, hypotension, and need for 
advanced airway.  
 
The adverse events will be analyzed in composite (any of them) and individually.  For each, a chi-square 
test will be to compare the proportion of events between the two treatment groups.  A multivariable 
logistic regression model will be used to compare the proportions after adjusting for stratification 
variables (i.e., site) and baseline characteristics not balanced through random assignment  
 
AIM #3: To determine if, among injured patients with moderate to severe pain, treatment with DSUVIA 
compared to standard care pain treatment in the ED improves pain treatment effectiveness including serial 
VNRS scores (every 30 minutes), the need for rescue narcotic administration, the time needed reduce the 
VNRS pain score by 10 points, time-weighted Summed Pain Intensity Difference, Patient Global 
Assessment (PGA), Six Item Screener (SIS) cognitive assessment, and Richmond Agitation-Sedation 
Scale scores. 
 
The analysis plan will vary based on the time of outcome variable.  For binary outcomes (e.g., need for 
rescue narcotic administration), analyses identical to those described for Aim 2 will be carried out.  For 
longitudinal data with repeated measures (e.g., VNRS scores every 30 minutes), a mixed-effect regression 
model will be used to compare the average scores over time.  Main effects will include an indicator of 
treatment group, site, and baseline characteristics not balanced through random assignment.  Random 
effect will include intercept and slope.  For time to event analyses (e.g., time to reduce VNRS pain by 10 
points, a Kaplan-Meier curve will be used to describe the distribution of time to event between the two 
treatment groups and a Log-Rank test will be used to test for differences between the two curves.  A Cox 
Proportional-hazards model will be used to compare the distribution, after controlling for site and baseline 
characteristics not balanced through random assignment.  For ordinal discrete outcomes (e.g., RASS), a 
Wilcoxon test will be use do compare scores between the two treatment groups.  A nonparametric 
regression approach will then be used to examine for differences between the two treatment groups after 
adjusting for site and baseline characteristics not balanced through random assignment. 
 
AIM #4: To determine if, among injured patients with moderate to severe pain, treatment with DSUVIA 
compared to standard care pain treatment in the ED improves Healthcare Professional Global Assessment 
(HPGA) of the Method of Pain Control and health care provider survey scores. 
Scores to the HPGA will be based on a four-point scale.  A 2x4 chi-square test will be used to compare 
the distribution of scores across the two treatment groups.  An ordinal polytomous logistic regression 
model will be used to compare the distribution of proportions after controlling for stratification (sites) and 
baseline characteristics not balanced through random assignment.  The same analysis will be repeated on 
the health care provider survey scores, with the modification to account for a five-level outcome. 
 
Sample Size:  The sample size calculations are based on the analyses of the primary aim (Aim 1) of the 
study.  To detect a minimum effect size of 0.45, a sample size of 150 subject is needed (75 per group), 
assuming a type I error of 0.05, a two-sided alternative hypothesis, and 80% power.  Thus, assuming a 
standard deviation of 21 (Karcioglu, 2003), a difference of 7.1 can be detected between the mean VNRS 
scores. 

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Missing data:  Every attempt will be made to minimize the amount of missing data.  Give the short time-
window to collect data, missing data should be minimal.  However, in the event that there is missing data 
for the outcomes, the pattern of missingness will be evaluated.  Assuming that the data will be missing at 
random, multiple imputation techniques will be used to impute data and carry out the proposed analyses. 
 
Subgroup:  Analyses will be carried out for pre-defined subgroups, specifically: sex (male/female), 
Injury Severity Score (ISS < or ≥ 16), age (< or ≥ 50), blunt versus penetrating injury, history of prior 
opioid use (Y/N), air versus ground prehospital transport, transport origin (scene versus outside ED).  For 
all subgroup analyses, regression models will be used to assess if there is a differential treatment effect by 
subgroup.  Regression models will include main effects for treatment and the indicator of the subgroup, as 
well as the two-way interaction between treatment and the subgroup indicator.  A statistically significant 
interaction will indicate a differential treatment effect. 
      
Randomization of Ineligible Subjects: It is anticipated that there will be a small proportion of 
patients enrolled who receive DSUVIA or standard care that in retrospect will not have met the entry 
criteria and are thus ineligible. In this circumstance, patients will be analyzed according to the group to 
which they were randomized. Subgroup analyses based on eligibility criteria will be performed if the 
number of patients so affected is large. However, based on the relatively limited inclusion and exclusion 
criteria it is anticipated that the frequency of this event will be low.   
 
Non-adherence: In some circumstances, patients may receive standard care instead of the DSUVIA 
intervention when randomized to DSUVIA. Non-adherence is most likely to occur in the case of the 
patient who requires intervention and despite DSUVIA being available, is unable to be provided. In the 
event of inappropriate handling or unsuccessful administration of the DSUVIA, a second dose of 
DSUVIA may not be administered. Once a physician has assessed the subject, if appropriate, the subject 
may receive a dose of standard care pain medication and continue in the DEEP study. Fortunately, this 
event is relatively rare. In keeping with the intention-to-treat analytic design, these patients will be 
analyzed with the group to which they were randomized. 
 
Interim Analyses: Throughout the course of the study, the DSMB will review recruitment, retention, 
adherence to assigned intervention, data completeness, protocol deviations, and adverse events. Safety 
data will be examined on an ad hoc basis in the event that unexpected safety concerns arise from study 
data or from external research or literature.  
The DSMB will review the primary and secondary outcomes bi-annually. Prior to initiation of the trial, 
the final monitoring plan will be developed to serve as the guide to the DSMB’s decision-making process 
concerning early stopping of the trial. The interim analysis will consist of two components, efficacy 
evaluation and futility evaluation. The purpose of the efficacy evaluation is to detect early sign of 
treatment effect early in the study. The purpose of the futility analysis is to assess if the study is unlikely 
to achieve a statistically significant effect. In making the decision to recommend termination of the study, 
the DSMB shall be guided by several types of information: (i) a formal stopping rule based on the 
primary analysis (comparison of treatment groups on the primary outcome), (ii) information on safety 
outcomes by treatment group, (iii) consistency between results for primary and secondary outcomes, (iv) 
consistency of treatment effects across subgroups, and (v) conditional power. 
We have designed this trial with one-interim analyses before the final analysis. The number of interim 
analyses will be finalized in discussion with the DSMB prior to the initiation of the study. The interim 
analysis plan is based on the Lan and Demets approach utilizing an O'Brien-Fleming spending function to 

13 
 
determine alpha spending and test boundaries.  A formal interim analysis of efficacy will be performed 
when 50% of the randomly assigned participants have completed the assessment of the primary outcome. 
We will use a t-test to test for difference. The level of significance will maintain an overall p-value of 
0.05 according to O’Brien-Fleming stopping boundaries leaving a p value of 0.003 and 0.049 for the 
interim and final analyses, respectively.  This translates to a two-sided z-value for the interim and final 
analyses of +/-2.96 and +/-1.97, respectively.  
In addition, the futility of the study will be evaluated at the time an interim efficacy test is conducted. 
Specifically, the conditional power will be calculated. If the condition power is less than value pre-
specified by the DSMB (e.g., <20%), we can conclude that it would be futile to continue with the 
investigation. 
Surveillance for Outcomes and Data Elements: Data will be collected prospectively as patient 
care progresses. This will include a review of the prehospital patient care report(s), ED and electronic/ 
paper hospital records. 
 
In-Hospital Resuscitation Elements: Demographics, prehospital assessments and narcotic treatments, 
injury mechanism and characteristics, ED vitals, ED procedures/interventions, injury severity, injury 
severity scoring and assessment, ICU days and length of stay. 
 
Data Entry: The DCC will create web-based HTML forms to collect necessary information from all 
participating sites. Web entry forms will have dynamic features such as edit and data type checks. Details 
and clarification about data items will be provided using pop-up windows. Data encryption and 
authentication methods will be used. Additional features will be built into the web entry forms including: 
forms transmission history, access to past forms, tracking of data corrections, and the capability to save 
and re-load incomplete forms. The subjects will be identified by a study number only. All clinical 
interventions will become part of the patient’s medical records. All hard copy source documentation will 
be kept in a secured, locked cabinet in the site’s research coordinator’s office. All study documents will 
be maintained in a secure location for the time frame designated by each participating site’s requirements. 
The electronic data will be entered and maintained on a password protected SSL website designed for this 
trial. 
The data entered for the DEEP trial will be maintained by the DCC on a relational database. The database 
would be housed in a virtual environment so in the event of a hardware failure it would migrate to a new 
host. The data will be backed on a regular schedule with full transaction log files in use and copies of the 
data will be stored offsite with a secure service. In addition to the data server, the production web server 
will also be backed up routinely and as a virtual machine can be transitioned to different hardware 
automatically in case of hardware failure.  All Servers are behind an enterprise firewall and access has to 
be granted through the firewall even within the University Network.   
Database Management: A two-tiered database structure will be created. A front-end database will 
serve the web entry needs, using a database management system well-suited to handling updates from 
multiple interactive users. The data from this database will be transferred on a regular schedule to a data 
repository that can be used by statistical software packages. These datasets will be the basis for data 
queries, analyses and monitoring reports. Various versions of this database will be kept as needed, e.g. for 
quarterly performance reports. Access to data will be limited to those who need access to perform their 
tasks. The database management system is able to manage large quantities of data, to merge data from 

14 
 
multiple databases as required, to handle complex and possibly changing relationships, and to produce 
analysis datasets that can be imported into a variety of statistical analysis packages. 
 
VII. Clinical Coordinating Center (CCC) 
Clinical Coordination specific to the DEEP study will be performed by the LITES Network Coordinating 
Center and their dedicated research team at the University of Pittsburgh, including all regulatory 
requirements, provider and coordinator training and monitoring. 
VIII. Data Coordinating Center (DCC) 
Data Coordination specific to the DEEP study will be performed by the DCC and led by Dr. Wisniewski 
at the Graduate School of Public Health at the University of Pittsburgh. The DCC will coordinate all data 
collection and entry, management, security and confidentiality, data archiving, quality control and 
electronic medical record biomedical informatics as needed, as well as plan, coordinate and assist with all 
statistical analyses. 
IX. 
Human Subjects 
We anticipate that this study will be conducted utilizing a written informed consent while the patient 
resides in the ED. 
Study Risks and Benefits: Risks associated with pain management include allergic reaction, hypoxia 
requiring oxygen, (SPO2 < 90%), hypotension (SBP < 90 mmHg), or need for advanced airway 
management (placement of an endotracheal tube or supraglottic airway) following medication 
administration. 
Regardless of treatment arm, we anticipate that enrolled subjects will benefit from increased monitoring 
of primary and secondary outcomes, specifically, a focus on adequate pain control and pain management 
complications including respiratory compromise, hypotension, decreased sensorium, and need for 
advanced airway control. 
Institutional Review Board: A central IRB at the University of Pittsburgh will be utilized for the 
regulatory needs of studies. All current LITES Network sites have IRBs which have experience and 
engagement with central IRB procedures. 
Training and Participating Site Coordination: As the clinical coordinating center for the trial, the 
University of Pittsburgh (LITES) at the University of Pittsburgh will be collaboratively responsible for all 
research coordinator training, provider training. Research coordinators, providers and associated staff will 
be trained during the months prior to the trial start date regarding the scientific basis for the study, 
specific inclusion and exclusion criteria, study procedures and SOPs. Training verification and retraining 
will occur if new staff is hired at individual participating sites.  
X. 
Safety Monitoring 
Adverse Event and Non-compliance definitions   
a. Adverse event means any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related. 
b. Adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset of all 
suspected adverse reactions where there is reason to conclude that the drug caused the event. 

15 
 
c. Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than “adverse reaction” 
d. Reasonable possibility.  For the purpose of  safety reporting, “reasonable possibility” means there 
is evidence to suggest a causal relationship between the drug and the adverse event. 
e. Unexpected adverse event/reaction refers to an event/reaction that is not consistent with the risk 
information described in the package insert and general investigational plan. 
f. Life-threatening, suspected adverse reaction.  A suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site principal investigator) or 
Sponsor, its occurrence places the patient or research subject at immediate risk of death.  It does 
not include a suspected adverse reaction that had it occurred in a more severe form, might have 
caused death. 
g. Serious, suspected adverse reaction. A suspected adverse reaction is considered “serious” if, in 
the view of the Investigator (i.e., the study site principal investigator) or Sponsor, it results in any 
of the following outcomes: death, a life-threatening adverse reaction, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
h. Reportable non-compliance refers to a failure on the part of the investigator or study team 
member to follow the terms of the IRB approved protocol or abide by applicable laws or 
regulations, that adversely affect the rights and welfare of subjects or significantly compromises 
the quality of the research data.  Incidents of non-compliance on the part of the subject are not 
considered reportable. 
i. 
Unanticipated Problem Involving Risk to Subjects or Others (UPIRTSO) refers to any accident, 
experience, or outcome that meets the following criteria: unexpected in terms of nature, severity 
or frequency; related, or possibly related, to a subject’s participation in research; and places 
subjects or others at greater risk of harm (including physical, economic, or social) than was 
previously known or recognized. 
Assessing and Reporting Adverse Events (AEs) and Non-compliance: Adverse events will be 
reviewed by the study sites and assessed for relationship to the study intervention.  Investigators and 
study team will determine if any related adverse events occur during the period from enrollment through 
study participation termination. If reportable adverse events occur, they will be recorded on the adverse 
event case report form in the electronic data capture system, which will be submitted to the Coordinating 
Center. All reported adverse events will be classified by: a) Severity (fatal or life-threatening, serious, or 
non-serious); and b) Expected vs. Unexpected.  An event will be determined to be unexpected if it is not 
consistent with the risks identified in the package insert or with the information provided in the general 
investigational plan.  Please refer to the table below for timelines for reporting. 
This study population is expected to have a relative low number of serious adverse events but will include 
death from trauma related injuries.  Expected adverse events that are related or possibly related to the 
intervention will be documented and reviewed for changes in nature, severity, or frequency across the 
study population.   
 

16 
 
Organization 
Unexpected, fatal or 
life-threatening 
suspected adverse 
reactions 
Unexpected, 
serious, suspected 
adverse reactions 
Expected 
adverse 
reactions 
Reportable 
non-
compliance 
UPIRTSO 
IRB 
24 hours 
10 working days 
No reporting 
10 working 
days 
10 
working 
days 
Dept. of 
Defense 
30 calendar days 
30 calendar days 
No reporting 
30 calendar 
days** 
30 
calendar 
days* 
DSMB 
24 hours 
7 calendar days 
At next 
meeting 
(every 6 
months) 
At next 
meeting (every 
6 months) 
14 days* 
 
*reported based on IRB determination that event is UPIRTSO 
**reported based on IRB determination that non-compliance is serious or continuing 
 
Data Safety Monitoring Board (DSMB): A Data and Safety Monitoring Board (DSMB) will be 
created to review this study and provide recommendations regarding study continuation to the Sponsor.  
After initial approval and at periodic intervals (to be determined by the committee) during the course of 
the study, the DSMB responsibilities are to: 
a. Review the research protocol, informed consent documents and plans for data and safety 
monitoring; 
b. Evaluate the progress of the study, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention, participant risk versus benefit, adverse 
events, unanticipated problems, performance of the trial sites, and other factors that can affect 
study outcome; 
c. Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants or 
the ethics of the study; 
d. Review clinical center performance, make recommendations and assist in the resolution of 
problems reported by the study site Investigators; 
e. Protect the safety of the study participants; 
f. Report on the safety and progress of the study; 
g. Make recommendations concerning continuation, termination or other modifications of the 
study based on the observed beneficial or adverse effects of the treatment under study; 
h. Monitor the confidentiality of the study data and the results of monitoring;  

17 
 
i. Assist by commenting on any problems with study conduct, enrollment, sample size and/or data 
collection. 
j. The DSMB will include experts in emergency medicine, surgery (trauma/critical medicine), 
bioethics and biostatistics.  Members will consist of persons independent of the investigators who 
have no financial, scientific, or other conflict of interest with the study.  Written documentation 
attesting to absence of conflict of interest will be required.   
k. The University of Pittsburgh Office of Clinical Research, Health Sciences will provide the 
logistical management and support of the DSMB.  A safety officer (chairperson) will be 
identified at the first meeting.  This person will be the contact person for serious adverse event 
reporting.  Procedures for this will be discussed at the first meeting. 
l. The first meeting will take place before initiation of the study to discuss the protocol, approve 
the commencement of the study, and to establish guidelines to monitor the study. The follow-up 
meeting frequency of the DSMB will be determined during the first meeting.  An emergency 
meeting of the DSMB will be called at any time by the Chairperson should questions of patient 
safety arise.  
XI. 
Quality Control, Assurance and Confidentiality 
 
Protocol Compliance: The participating study site Investigators will not deviate from the protocol for 
any reason without prior written approval from the IRB except in the event of the safety of the research 
subject. In that event, the study site Investigator will notify the reviewing IRB immediately, if possible, 
and request approval of the protocol deviation, or, if prospective IRB approval is not possible, the study 
site Investigator will notify the reviewing IRB promptly following the respective protocol deviation. The 
study site Investigator will inform the reviewing IRB of all protocol deviations and unanticipated events 
involving risks to the research subjects and others, and will obtain prospective IRB approval for all 
proposed protocol changes. Persistent or serious noncompliance may result in termination of the study 
site’s participation in the research study. 
 
Protocol Deviations: Due to the relative focused inclusion criteria and the short intervention period, 
we expect few protocol deviations as compared to other large multicenter trials. If monitoring reports 
demonstrate evidence of continuing protocol deviations, we will analyze them to determine if they are site 
specific or common across the study. We will note if specific inclusion or exclusion criteria are being 
misinterpreted, if a certain time point in testing is being omitted, or if a common set of data elements are 
missing. If the deviations are site specific, retraining will be done at the site. If the problems are study 
wide, we will discuss them with the other investigators, the DoD and the IRB to see if the protocol needs 
to be amended or recruitment put on hold. 
 
Privacy and Confidentiality: The study site Investigator’s and members of their research team will 
make reasonable effort to ensure the research subjects’ confidentiality. Subject name and other 
identifiable information will be kept in a secure, locked, limited access area. 
 
Investigator Responsibilities:  The study site Investigators will agree to implement the IRB approved 
protocol and conduct the study in accordance the ICH GCP Guidelines (E6, Section 5) as well as all 
applicable national, state and local laws. The study will be performed in accordance with ethical 
principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical 
Practice, and applicable regulatory requirements. 

18 
 
 
 
 
Time Table: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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