DirEct Versus VIdeo LaryngosCopE Trial
Phase: NA
Conditions: Acute Respiratory Failure
Sponsor: Vanderbilt University Medical Center

 
1 
 
Clinical Trial Protocol 
 
 
 
Title 
DirEct Versus VIdeo LaryngosCopE Trial (DEVICE) 
Acronym 
DEVICE 
Version 
Version 1.0 
Date 
September 30, 2021 
Protocol Chairs 
Matthew E. Prekker, MD, MPH 
Hennepin County Medical Center and University of Minnesota Medical 
School 
 
Brian E. Driver, MD 
Hennepin County Medical Center and University of Minnesota Medical 
School 
 
Stacy A. Trent, MD, MPH 
Denver Health Medical Center and University of Colorado School of 
Medicine 
 
Matthew W. Semler MD, MSc  
Vanderbilt University Medical Center 
Coordinating Center 
Vanderbilt University Medical Center 
Director: Jonathan D. Casey, MD, MSc 
Network 
Pragmatic Critical Care Research Group (PCCRG) 
Steering Committee Chair: Matthew W. Semler MD, MSc 
Military Principal 
Investigators 
Maj Brit J Long, MD 
US Air Force 59MDW 
 
MAJ. Steven G. Schauer, MD, MS 
US Army Institute of Surgical Research and US Air Force 59MDW 
Civilian Principal 
Investigators 
Adit A. Ginde, MD, MPH 
University of Colorado School of Medicine 
 
Matthew W. Semler MD, MSc  
Vanderbilt University Medical Center 
Sponsor 
Department of Defense 
 
 

 
2 
 
Table of Contents 
 
Table of Contents 
2 
Trial Summary 
4 
1  
Background 
7 
2 
Aims, Hypotheses, and Study Description 
8 
2.1  
Study Aims 
8 
2.2  
Study Hypotheses 
8 
2.3  
Study Description 
9 
3 
Inclusion and Exclusion Criteria 
9 
3.1 
Inclusion Criteria 
9 
3.2 
Exclusion Criteria 
9 
4 
Consent 
9 
4.1  
Information for Patients and Families 
11 
5 
Study Sites, Enrollment, and Randomization 
11 
5.1  
Study Enrollment Locations 
11 
5.2  
Study Enrollment Location 
11 
5.3  
Enrollment and Randomization 
11 
5.3.1  
Pre-Procedural Time-Out to Prevent Enrollment of Ineligible Patients 
12 
5.3.2  
Monitoring and Reporting of Eligibility of Enrolled Patients 
12 
5.3.3  
Handling of Patients Found to Be Prisoners after Enrollment 
12 
6  
Study Procedures 
13 
6.1  
Video Laryngoscope Group 
13 
6.2  
Direct Laryngoscope Group 
13 
7  
Data Collection and Outcome Measures 
13 
7.1  
Data Collection 
13 
7.2 
Recorded Study Outcomes 
16 
7.2.1 
Primary Outcome 
16 
7.2.2 
Secondary Outcome 
16 
7.2.3 
Exploratory Outcomes 
16 
8 
Risks and Benefits 
17 
8.1 Risks of Tracheal Intubation in the ED or ICU 
17 
8.2 Potential Risks of Participation in the DEVICE Trial 
17 
8.3 Potential Benefits of Participation in the DEVICE Trial 
17 
8.4 Minimization of Risk 
18 

 
3 
 
9 
Statistical Considerations 
18 
9.1 
General Considerations 
18 
9.2 
Sample Size Estimation 
18 
9.3 
Analysis Populations 
19 
9.4  
Statistical Analysis 
19 
9.4.1  
Primary Analysis 
19 
9.4.2 
Secondary Analyses 
19 
9.4.4   Handling of Missing Data 
20 
9.4.5    
Interim Analysis 
20 
10 Privacy and Confidentiality 
21 
11 Follow-up and Record Retention 
21 
12 Safety Monitoring and Adverse Events 
21 
12.1 Adverse Event Definitions 
22 
12.2 Monitoring for Adverse Events 
22 
12.3 Recording and Reporting Adverse Events 
23 
12.4 Clinical Outcomes that may be Exempt from Adverse Event Recording and Reporting 
24 
12.5 Unanticipated Problems involving Risks to Subjects or Others 
25 
13 Data and Safety Monitoring Board (DSMB) 
25 
14  
References 
26 
 
 
 
 
 
 

 
4 
 
Trial Summary 
 
Title 
DirEct Versus VIdeo LaryngosCopE Trial (DEVICE) 
Background 
Clinicians perform rapid sequence induction, laryngoscopy, and tracheal 
intubation for more than 5 million critically ill adults as a part of clinical 
care each year in the United States.  Failure to intubate the trachea on the 
first attempt occurs in more than 10% of all tracheal intubation procedures 
performed in the emergency department (ED) and intensive care unit (ICU). 
Improving clinicians rate of intubation on the first attempt could reduce the 
risk of serious procedural complications.  
 
In current clinical practice, two classes of laryngoscopes are commonly 
used to help clinicians view the larynx while intubating the trachea: a video 
laryngoscope (equipped with a camera and a video screen) and a direct 
laryngoscope (not equipped with a camera or video screen).  For every 
laryngoscopy and intubation procedure performed in current clinical 
practice, clinicians use either a video or a direct laryngoscope.  Prior 
research has shown that use of a video laryngoscope improves the 
operator’s view of the larynx compared to a direct laryngoscope. Whether 
use of a video laryngoscope increases the likelihood of successful intubation 
on the first attempt remains uncertain. A better understanding of the 
comparative effectiveness of these two common, standard-of-care 
approaches to laryngoscopy and intubation could improve the care 
clinicians deliver and patient outcomes.  
Study Design 
Multi-center, parallel-group, non-blinded, randomized clinical trial 
Trial Groups 
1.  Video laryngoscope group 
2.  Direct laryngoscope group 
Inclusion Criteria 
1.  Patient is located in a participating unit 
2.  Planned procedure is orotracheal intubation using a laryngoscope 
3.  Planned operator is a clinician expected to routinely perform tracheal  
     intubation in the participating unit 
Exclusion Criteria 
1.  Patient is known to be less than 18 years old 
2.  Patient is known to be pregnant 
3.  Patient is known to be a prisoner 
4.  Immediate need for tracheal intubation precludes safe performance of  
     study procedures 
5.  Operator has determined that use of a video laryngoscope or use of a  
     direct laryngoscope is required or contraindicated for the optimal care of  
     the patient 
Risks 
Participation in this study involves minimal incremental risk because: 

 
5 
 
• All patients eligible for the study are already undergoing tracheal 
intubation with a video laryngoscope or a direct laryngoscope as part 
of their clinical care 
• Use of a video laryngoscope and use of a direct laryngoscope are the 
most common approaches to tracheal intubation of critically ill 
adults in clinical care 
• No benefits or risks are currently known to differ between the two 
approaches 
• If clinicians determine either approach to be required or 
contraindicated for the optimal care of an individual patient, the 
patient is excluded from the study 
Benefits 
The benefits of the DEVICE trial are largely the indirect benefits to future 
patients that will result by a better understanding of whether use of video 
laryngoscope or use of a direct laryngoscope is found to prevent 
complications.   
Consent 
The trial will be conducted with waiver of informed consent because: 
• Participation in the study involves minimal incremental risk 
• Obtaining informed consent prior to emergency tracheal intubation 
of critically ill adults is impracticable 
Randomization 
Using opaque envelopes available in participating units, participants will be 
randomized 1:1 to either use of a video laryngoscope or use of a direct 
laryngoscope on the first laryngoscopy attempt.  Randomization will be 
completed in permuted blocks of variable size and stratified by site. 
Primary Outcome 
Successful intubation on the first attempt, defined as the placement of an 
endotracheal tube in the trachea with a single insertion of a laryngoscope 
blade into the mouth and EITHER a single insertion of an endotracheal tube 
into the mouth OR a single insertion of a bougie into the mouth followed by 
a single insertion of an endotracheal tube over the bougie into the mouth. 
Secondary Outcome 
Incidence of severe complications, defined as the occurrence of one or more 
of the following between induction and 2 minutes after intubation: [1] 
severe hypoxemia (SpO2 <80%), [2] severe hypotension (systolic blood 
pressure <65 mm Hg or new or increased vasopressor administration), [3] 
cardiac arrest not resulting in death within 1 hour of induction, or [4] 
cardiac arrest resulting in death within 1 hour of induction. 
Exploratory 
Outcomes 
Procedural: 
● Duration from laryngoscopy to tracheal intubation – defined as the 
interval (in seconds) between insertion of the laryngoscope into the 
mouth on the first laryngoscopy attempt and final placement of an 
endotracheal tube or tracheostomy tube in the trachea. 
● Number of laryngoscopy attempts 

 
6 
 
● Number of attempts to cannulate the trachea with a bougie 
● Number of attempts to cannulate the trachea with an endotracheal 
tube 
● Reason for failure to intubate on the first attempt 
● Operator-reported aspiration into the airway 
Safety: 
● Esophageal intubation  
● Injury to the teeth 
Clinical: 
● ICU-free days in the first 28 days 
● Ventilator free days in the first 28 days 
● 28-day, all-cause in-hospital mortality 
Analysis 
The primary analysis will be an intention-to-treat comparison of patients 
randomized to the video laryngoscope group versus patients randomized to 
the direct laryngoscope group with regard to the primary outcome of 
successful intubation on the first attempt. The difference in proportion and 
the associated 95% confidence interval will be presented.  Between group 
differences will be examined using a Chi-square test. 
Sample Size 
2,000 patients 
Expected Duration 
18 months 
 
 
 
 
 
 
 

 
7 
 
1  
Background 
Clinicians frequently perform tracheal intubation of critically ill patients in the emergency department 
(ED) or intensive care unit (ICU).  In 10-20% of emergency tracheal intubations, clinicians are unable 
intubate the trachea on the first attempt, which increases the risk of peri-intubation complications.1–4  
Successful laryngoscopy and tracheal intubation requires using a laryngoscope to [1] visualize the 
larynx and vocal cords and [2] create a pathway through which an endotracheal tube can be advanced 
through the oropharynx and larynx and into the trachea.   
In current clinical practice, two classes of laryngoscopes are commonly 
used by clinicians to view the larynx while intubating the trachea: a video 
laryngoscope (equipped with a camera and a video screen) and a direct 
laryngoscope (not equipped with a camera or video screen).  Clinicians use 
either a video laryngoscope or a direct laryngoscope as standard of care for 
every laryngoscopy and intubation procedure performed in current clinical 
practice. 
Direct Laryngoscope.  The Macintosh direct laryngoscope (Fig. 1) consists 
of a battery-containing handle and a blade with a light source. The operator 
achieves a direct line of sight –from the operator’s eye through the mouth to 
the larynx and trachea – by using the laryngoscope blade to displace 
the tongue and elevate the epiglottis.5,6 
Video Laryngoscope.  Video laryngoscopes consist of a fiberoptic 
camera and light source near the tip of the laryngoscope blade, 
which transmits images to a video screen (Fig. 2). The position of 
the camera near the tip of the laryngoscope blade facilitates 
visualization of the larynx and trachea.  
Use of a video laryngoscope and use of a direct laryngoscope are 
both common, standard-of-care approaches the clinicians use to 
perform tracheal intubation in the ED and ICU in current 
clinical care. 
Currently, it is unknown whether use of a video laryngoscope or use of a direct laryngoscope has any 
effect on successful intubation on the first attempt or any other outcome.  Some prior research has raised 
the hypothesis that using a video laryngoscope would increase clinicians’ rate of successful intubation 
on the first attempt by facilitating the view of the larynx.7  Some prior research has raised the hypothesis 
that using a direct laryngoscope would increase clinicians’ rate of successful intubation on the first 
attempt by facilitating a clear pathway for placement of the tube through the mouth into the trachea. 
To date, 8 small single-center randomized trials8–15 and one 371-patient multicenter randomized clinical 
trial16 have been conducted under waiver of or alteration of informed consent to compare use of a video 
vs a direct laryngoscope in the setting of emergency tracheal intubation in the ED or ICU.  Two of these 
trials provide the most direct preliminary data for this proposal.  The “Facilitating EndotracheaL 
intubation by Laryngoscopy technique and apneic Oxygenation Within the ICU (FELLOW)” 
randomized clinical trial, conducted under waiver of informed consent, compared these two standard-of-

 
8 
 
care approaches during 150 emergency tracheal intubations at Vanderbilt University Medical Center, 
finding no difference in the rate of successful intubation on the first attempt between use of a video and 
use of a direct laryngoscope.11 The “McGrath Mac Videolaryngoscope Versus Macintosh Laryngoscope 
for Orotracheal Intubation in the Critical Care Unit (MACMAN)” randomized clinical trial among 371 
critically ill adults found no difference between use of a video vs direct laryngoscope in the rate of 
successful intubation on the first attempt. However, a hypothesis-forming post-hoc exploratory analysis 
of  peri-intubation complications suggested that use of a video laryngoscope may be associated with a 
higher rate of complications than direct laryngoscope (9.5% vs 2.8%, respectively, p=0.01).16  These 
trials were underpowered to rule out small but clinically significant differences in first pass success, and 
were limited to intubations performed by inexperienced trainees in one practice setting (intensive care 
units), but they demonstrated hypothesis-generating findings requiring validation in larger trials that 
reflect the full spectrum of settings, operator specialties, and operator experience levels in which 
emergency tracheal intubation is routinely performed.   
Because of the imperative to optimize emergency tracheal intubation in clinical care, the common use of 
both video and direct laryngoscopes in current clinical practice, and the lack of definitive data from 
randomized trials to definitively inform whether use of a video laryngoscope or a direct laryngoscope 
effects the rate of successful intubation on the first attempt, examining whether one approach increases 
the odds of successful intubation on the first attempt represents an urgent research priority.  To address 
this knowledge gap, we propose to conduct a large, multicenter, randomized clinical trial comparing use 
of a video laryngoscope versus use of a direct laryngoscope with regard to successful intubation on the 
first attempt among critically ill adults undergoing tracheal intubation in the ED or ICU. 
 
2 
Aims, Hypotheses, and Study Description 
 
2.1  
Study Aims 
 
● Primary:  
○ To compare the effect of use of a video laryngoscope versus a direct laryngoscope on 
successful intubation on the first attempt among critically ill adults undergoing 
tracheal intubation in the acute care setting. 
 
● Secondary:  
○ To compare the effect of use of a video laryngoscope versus a direct laryngoscope on 
severe complications among critically ill adults undergoing tracheal intubation in the 
acute care setting. 
 
2.2  
Study Hypotheses 
 
● Primary:  
○ Among critically ill adults undergoing tracheal intubation, use of a video 
laryngoscope will increase the proportion of patients who experience successful 
intubation on the first attempt, compared with use of a direct laryngoscope. 
 
 
 

 
9 
 
● Secondary  
○ Among critically ill adults undergoing tracheal intubation, use of a video 
laryngoscope will decrease the proportion of patient who experience a severe 
complication, compared with use of a direct laryngoscope. 
 
2.3  
Study Description 
 
To address these aims, we propose a multi-center, non-blinded, parallel-group, randomized clinical trial 
evaluating the effect of use of a video laryngoscope versus a direct laryngoscope on successful 
intubation on the first attempt among critically ill adults undergoing tracheal intubation. Patients located 
in participating EDs and ICUs who are determined by treating clinicians to require tracheal intubation 
and who meet eligibility criteria will be enrolled and randomly assigned to either use of a video 
laryngoscope or use of a direct laryngoscope.  All other decisions regarding the intubation procedure 
will be at the discretion of the treating clinicians.   
 
3 
Inclusion and Exclusion Criteria 
 
3.1 
Inclusion Criteria 
 
1. 
Patient is located in a participating unit. 
2. 
Planned procedure is orotracheal intubation using a laryngoscope. 
3. 
Planned operator is a clinician expected to routinely perform tracheal intubation in the 
participating unit. 
 
3.2 
Exclusion Criteria 
 
1. 
Patient is known to be less than 18 years old. 
2. 
Patient is known to be pregnant. 
3. 
Patient is known to be a prisoner. 
4. 
Immediate need for tracheal intubation precludes safe performance of study procedures. 
5. 
Operator has determined that use of a video laryngoscope or use of a direct laryngoscope is 
required or contraindicated for the optimal care of the patient.   
 
4 
Consent 
 
Use of a video laryngoscope and use of a direct laryngoscope are both common approaches to 
emergency tracheal intubation during emergency tracheal intubation in the ED and ICU.  Both represent 
standard-of-care treatment in current clinical practice.  Results from prior clinical trials are conflicting 
and do not demonstrate superiority of one approach over the other.  Consequently, some guidelines do 
not strongly recommend for or against the use of a video laryngoscope or a direct laryngoscope on the 
first attempt at tracheal intubation of critically ill adults.17 As a result, significant variation exists in the 
use of a video laryngoscope vs use of a direct laryngoscope in current clinical practice.2  This trial will 
only enroll patients who are undergoing emergency tracheal intubation as part of their clinical care for 
whom the treating clinicians feel that either a video laryngoscope or a direct laryngoscope would be 
consistent with the optimal care of the patient. We will request a waiver of informed consent because the 
study involves minimal incremental risk and obtaining informed consent would be impracticable. 

 
10 
 
 
Participation in this study involves minimal incremental risk because: 
• Both approaches to tracheal intubation being compared are commonly used in routine clinical 
care; 
• Both are interventions to which patients would be exposed even if not participating in the study 
(all patients undergoing laryngoscopy and tracheal intubation receive either a video laryngoscope 
or a direct laryngoscope); 
• No established differences in risk and benefit are known to exist between the two approaches 
based on the currently available data; and 
• Patients are only eligible to participate if their treating clinicians have determined that both 
approaches are acceptable for the optimal care of the patient. 
 
Obtaining informed consent would be impracticable because: 
• The expected medical condition of patients requiring emergency tracheal intubation in the 
ED or ICU is critical. Based on prior trials in the same patient population and setting, 
approximately 70% of patients eligible for the DEVICE trial will be experiencing 
encephalopathy (altered mental status) due to their illness.  The anticipated median Glasgow 
coma scale score will be 11 (equivalent to moderate brain injury).  Among the minority of 
patients whose level of consciousness is not impaired, 45-55% will be experiencing acute 
delirium.  Thus, most patients eligible for DEVICE will not have the capacity to provide 
informed consent. Further, family members or legally authorized representatives (LAR) are 
frequently unavailable when critically ill patients undergo intubation in the ED or ICU.   
• The time available for patients or LARs to consider participation will be insufficient.  Even 
in instances in which a patient retains capacity, or an LAR is immediately available, a 
meaningful informed consent is precluded by the rapid clinical events leading up to emergency 
tracheal intubation.  No published literature has quantified the time from the decision to perform 
emergency tracheal intubation (the inclusion criteria for DEVICE) until the initiation of the 
intubation procedure (the trial intervention). In a convenience sample of 25 consecutive 
intubations in the VUMC ED or ICU, approximately 50% of intubations occurred within 5 
minutes after treating clinicians verbalized the decision to intubate (or placed a written order for 
an induction medication).  Obtaining informed consent for research requires study personnel to 
assess decisional capacity, identify an LAR when appropriate, review the informed consent 
document in a quiet setting, and provide sufficient time for the patient or LAR to process the 
information, assess the risks and benefits of participation, and ask question.  Meaningful 
informed consent cannot be executed in the 5 minutes between the decision to perform 
emergency tracheal intubation and the initiation of the procedure.  Emergency tracheal intubation 
of critically ill adults is a time-sensitive procedure for which every minute of delay increases the 
likelihood of hypoxemia, hypotension, and peri-procedural cardiac arrest.  Delaying emergency 
tracheal intubation for a critically ill adult to attempt a meaningful informed consent process 
would be unsafe, impracticable, and unethical. 
 
Because the study involves minimal incremental risk, the study would not adversely affect the welfare or 
privacy rights of the participant, and obtaining informed consent would be impracticable, we will 
request a waiver of informed consent. Numerous previous randomized trials comparing two standards of 

 
11 
 
care for emergency intubation have also been completed under a waiver of informed consent, including 
multiple small trials comparing the identical interventions studied in DEVICE.8–16,18–25 
 
4.1  
Information for Patients and Families 
 
Information regarding the study will be made available to each patient and family following intubation 
using a patient and family information sheet.  The sheet will inform the patient of his or her enrollment 
in the DEVICE study, describe the study, and provide contact information for the research team for any 
questions or concerns. 
 
 
5 
Study Sites, Enrollment, and Randomization 
 
5.1  
Study Enrollment Locations 
 
1. Participating emergency departments 
2. Participating intensive care units 
 
5.2  
Study Enrollment Location 
• Participating emergency departments 
• Participating intensive care units 
 
5.3  
Enrollment and Randomization 
All patients requiring emergency tracheal intubation in a participating ED or ICU will be screened for 
eligibility for the DEVICE trial using the eligibility criteria in Section 3.  Patients who do not meet 
inclusion criteria will be considered ‘ineligible.’ Patients who meet inclusion criteria but also meet at 
least one exclusion criterion will be considered ‘excluded.’  For patients who meet inclusion criteria but 
are not enrolled, the reason for exclusion will be recorded.   
 
At enrollment, patients will be randomized in a 1:1 ratio to undergo intubation using a video 
laryngoscope or a direct laryngoscope using randomly permuted blocks of variable size. The 
randomization will be stratified by study site (each participating ED and ICU will comprise a different 
stratum). The study group assignments will be placed in opaque randomization envelopes, which will be 
located within participating units. Study group assignment will remain concealed to study personnel and 
treating clinicians until after the decision has been made to enroll the patient in the study.  
 
To facilitate rapid enrollment during this time-sensitive procedure, sequentially numbered 
randomization envelopes will be located adjacent to the equipment required for emergency tracheal 
intubation (i.e., airway equipment cart, ICU work room).  When the need for emergency tracheal 
intubation is recognized, envelopes will be obtained by the treating clinician performing the intubation 
(referred to as the “operator”) or by a delegate while the operator sets up the equipment required for 
intubation.  Inclusion and exclusion criteria will be posted with randomization envelopes and printed on 
the outside of enrollment envelopes.  As the operator sets up the equipment for emergency tracheal 
intubation, a verbal “pre-procedural time-out” (described below) will be performed. Based on the 
experience from our 8 prior randomized clinical trials using the same process to perform randomization 
and group assignment during emergency tracheal intubation, all enrollment procedures can be completed 

 
12 
 
in less than one minute. For a small number of particularly urgent intubations (e.g., an intubation for 
cardiac arrest), the urgency of the procedure or the limited availability of clinical personnel will preclude 
obtaining and opening the randomization envelope. These cases will be excluded using the exclusion 
criterion that states “Immediate need for tracheal intubation precludes safe performance of study 
procedures” (see Section 3). 
 
As with all trials conducted to date by our investigators, we will evaluate for the possibility of selection 
bias via the systematic exclusion of particular groups of patients.  A prospective list of excluded patients 
will be maintained by site PIs.  Data captured on excluded patients will be limited to date of exclusion 
and reason for exclusion. Data captured on excluded patients will be limited to date of exclusion and 
reason for exclusion. The number and reasons for excluded will be reported at the time of trial 
publication via a consort diagram. No patient-level information on excluded patients will be entered into 
the study database.  The coordinating center will not receive any patient-level data on excluded 
participants. 
 
5.3.1  Pre-Procedural Time-Out to Prevent Enrollment of Ineligible Patients 
 
The enrollment materials for the trial will include instructions for a pre-procedural timeout in which 
treating clinicians or a delegate recite aloud the inclusion and exclusion criteria and confirm eligibility 
prior to enrollment. This process requires less than 10 seconds and can be completed while the 
equipment and medications needed for tracheal intubation are being obtained. This approach has been 
successfully used to confirm eligibility prior to enrollment in multiple prior trials [NCT03928925, 
NCT03787732]. 
 
5.3.2  Monitoring and Reporting of Eligibility of Enrolled Patients 
 
For all enrolled patients, study personnel will independently verify eligibility criteria at the time of study 
record creation. In the instance that a patient is enrolled who did not meet eligibility criteria, this will 
represent a protocol violation. Site investigators will report such a protocol violation to the trial primary 
investigators and coordinating center within 24 hours of becoming aware of the occurrence of a 
protocol violation. The primary investigators and coordinating center will report the details of such a 
protocol violation to the IRB within 7 days of becoming aware of the occurrence of a protocol violation. 
 
5.3.3  Handling of Patients Found to Be Prisoners after Enrollment 
 
Prisoners typically present with obvious physical signs such as prison uniforms, handcuffs, and the 
presence of law enforcement.  Training of treating clinicians and the enrollment procedures listed above 
(posting of inclusion and exclusion criteria alongside enrollment envelopes and a “pre-enrollment time-
out” with verbal recitation of eligibility criteria) have proven to be effective in preventing the enrollment 
of prisoners in recent trials. 
 
If a patient who presents to the ED or ICU is not known to be a prisoner at the time of enrollment and 
following enrollment is discovered to be a prisoner or becomes a prisoner between enrollment and the 
end of study follow up, all study procedures will stop immediately, the patient will be withdrawn from 
the study, and the patient’s study record will be expunged of all study data except the anonymous study 
ID and randomized group assignment. Because both study interventions are one-time, standard-of-care 

 
13 
 
interventions which the patient was likely to receive in clinical care even if not participating in research, 
no further follow-up will occur. 
 
6  
Study Procedures 
 
For enrolled patients, study group assignment determines only the choice of laryngoscope.  Operators 
may opt to use the non-assigned laryngoscope type on the first laryngoscopy attempt if it is felt to be 
required for the safe care of the patient.  The occurrence of such “crossover” event will be recorded 
along with the indication.  All other aspects of the intubation procedure in both study groups will be at 
the discretion of the operator.  For all patients in the trial, best practices in tracheal intubation will be 
encouraged according to clinical protocols in the study settings. 
 
6.1  
Video Laryngoscope Group 
 
 
  
  
  
 
 
For patients assigned to the video laryngoscope group, the operator will use a video laryngoscope on the 
first laryngoscopy attempt. A video laryngoscope will be defined as a laryngoscope with a camera and a 
video screen. Trial protocol will not dictate the brand of video laryngoscope.   
 
6.2  
Direct Laryngoscope Group 
 
For patients assigned to the direct laryngoscope group, the operator will use a direct laryngoscope on the 
first laryngoscopy attempt. A direct laryngoscope will be defined as a laryngoscope without a camera 
and a video screen. Trial protocol will not dictate the brand of direct laryngoscope or the blade shape. E 
 
7  
Data Collection and Outcome Measures 
 
7.1  
Data Collection 
 
Data collected for the purposes of this study will come from three sources: [1] variables documented in 
the electronic health record as part of clinical care, [2] variables recorded by clinical staff’s bedside 
observation during the intubation procedure, and [3] variables reported by the operator immediately 
following the intubation procedure. Data from the electronic medical record will be collected by trained 
study personnel (key study personnel) using a standardized electronic case report form.  It is infeasible 
to have research staff present during each emergency tracheal intubation.  Therefore, clinical staff not 
participating in the tracheal intubation procedure will collect data elements relevant to outcomes of 
emergency tracheal intubation using a standardized electronic case report form. These variables are 
readily available by bedside observation and do not require interaction with the patient but are not 
uniformly documented in the electronic health record (e.g., lowest oxygen saturation and lowest blood 
pressure from induction to two minutes after tracheal intubation).  Immediately following the intubation 
procedure, the operators will record data elements known only to them (e.g., glottic view obtained 
during the procedure and visualization of gastric aspiration in the oropharynx).  Operators and clinical 
staff observing the procedure at the bedside will not be considered key study personnel. Training will be 
provided to clinicians who may serve as operators or bedside observers.  The activities of these 
clinicians will be limited to the reporting of data routinely reported as part of clinical care.   
 
 

 
14 
 
The following variables will be recorded: 
 
Baseline:  
● age 
● sex 
● race and ethnicity 
● height 
● weight 
● body mass index 
● Acute Physiology and Chronic Health Evaluation (APACHE II) score  
● active medical problems at the time of enrollment 
● comorbidities  
● indication for intubation 
● vasopressor receipt in the hour prior to enrollment 
● highest FiO2 in the hour prior to enrollment 
● lowest SpO2/FIO2 ratio (or PaO2/FIO2 ratio) in the hour prior to enrollment 
● Glasgow Coma Scale score 
● oxygen delivery device at enrollment 
● assessment of the likelihood of a difficult intubation 
● presence of difficult airway characteristics 
○ limited mouth opening 
○ limited anatomic neck mobility 
○ cervical immobilization due to trauma 
○ increased neck circumference 
○ facial trauma 
○ obesity 
○ body fluids anticipated to obscure laryngeal view 
● operator’s level of training and specialty 
● operator’s prior intubation experience  
 
Peri-procedural:  
 
Enrollment to induction 
● SpO2 and FiO2 at enrollment 
● oxygen saturation from enrollment to induction 
● approach to preoxygenation 
● duration of preoxygenation 
 
Induction to first laryngoscopy attempt 
● time of sedative administration (induction) 
● sedative agent and dose 
● neuromuscular blocking agent and dose 
● administration of an intravenous fluid bolus prior to induction 
● administration of a vasopressor prior to induction 
● SpO2 at induction 
● systolic blood pressure at induction 
● approach to oxygen administration and ventilation between induction and laryngoscopy 
 
 

 
15 
 
First laryngoscopy attempt to successful intubation 
● time of start of first laryngoscopy attempt 
● laryngoscope model, blade size, blade shape on first attempt 
● use of video screen (if applicable) on first laryngoscopy attempt 
● best Cormack-Lehane grade of glottic view on the first laryngoscopy attempt 
● presences of body fluids obstructing laryngeal view 
● presence of upper airway obstruction or edema 
● receipt of chest compressions at time of first laryngoscopy attempt 
● number of intubation attempts 
○ number of times laryngoscope entered mouth 
○ number of times bougie entered mouth (if applicable) 
○ number of times endotracheal tube entered mouth 
● reason for failure of first intubation attempt (if applicable) 
● device(s) used on subsequent intubation attempts (if applicable) 
● necessity of an additional operator  
● esophageal intubation 
● injury to the teeth 
● operator-reported aspiration between induction and intubation 
● time of successful tracheal intubation 
● endotracheal tube size 
● lowest SpO2 from induction until 2 minutes after intubation 
● lowest systolic blood pressure from induction until 2 minutes after intubation 
● new or increased vasopressor use from induction until 2 minutes after intubation 
● cardiac arrest from induction until 2 minutes after intubation not resulting in death within 
1 hour of induction 
● cardiac arrest from induction until 2 minutes after intubation resulting in death within 1 
hour of induction 
 
In-hospital: 
 
24 hours after enrollment 
● new pneumothorax detected in the first 24 hours after induction 
● vasopressor receipt at 24 hours after induction 
● SpO2 at 24 hours after induction 
● FiO2 at 24 hours after induction  
● PEEP at 24 hours after induction 
● systolic blood pressure at 24 hours after induction 
28 days after enrollment 
● 28-day in-hospital mortality 
● ventilator-free days 
● ICU-free days 
 
 
 
 
 
 

 
16 
 
7.2 
Recorded Study Outcomes 
 
7.2.1 Primary Outcome 
 
The primary outcome is successful intubation on the first attempt. Successful intubation on the first 
attempt is defined as placement of an endotracheal tube in the trachea with a single insertion of a 
laryngoscope blade into the mouth and EITHER a single insertion of an endotracheal tube into the 
mouth OR a single insertion of a bougie into the mouth followed by a single insertion of an endotracheal 
tube over the bougie into the mouth.  
 
The primary outcome will be collected by an observer trained in recording the number of insertions of 
the laryngoscope blade into the mouth and the number of insertions of a bougie and endotracheal tube 
into the mouth. If data on the primary outcome from the independent observer are missing, the 
operator’s self-report of successful intubation on the first attempt will be used. 
 
7.2.2 Secondary Outcome 
 
The secondary outcome is severe complications occurring between induction and 2 minutes after 
successful intubation, defined as one or more of the following:  
1. severe hypoxemia (lowest oxygen saturation measured by pulse oximetry < 80%); 
2. severe hypotension (systolic blood pressure < 65 mm Hg or new or increased vasopressor 
administration); 
3. cardiac arrest not resulting in death; or  
4. cardiac arrest resulting in death.   
 
Cardiac arrest will be considered to have resulted in death if a patient who experienced cardiac arrest 
between induction and 2 minutes after intubation died within the 1 hour following intubation. 
 
7.2.3 Exploratory Outcomes  
 
Exploratory procedural outcomes: 
● Duration of laryngoscopy and tracheal intubation – defined as the interval (in seconds) between 
the first insertion of a laryngoscope blade into the mouth and the final placement of an 
endotracheal tube or tracheostomy tube in the trachea. 
● Number of laryngoscopy attempts 
● Number of attempts to cannulate the trachea with a bougie or an endotracheal tube 
● Successful intubation on the first attempt without a severe complication 
● Reason for failure to intubate on the first attempt 
o Inadequate view of the larynx 
o Inability to intubate the trachea with an endotracheal tube 
o Inability to cannulate the trachea with a bougie 
o Attempt aborted due to change in patient condition (e.g., worsening hypoxemia, 
hypotension, bradycardia, vomiting, bleeding) 
o Technical failure of the laryngoscope (e.g., battery, light source, camera, screen) 
o Other 
● Operator-reported aspiration 

 
17 
 
Exploratory safety outcomes: 
● Esophageal intubation 
● Injury to the teeth 
 
Exploratory clinical outcomes: 
● ICU-free days in the first 28 days 
● Ventilator free days in the first 28 days 
● 28-day all-cause in-hospital mortality 
 
 
8 
Risks and Benefits  
 
8.1 Risks of Tracheal Intubation in the ED or ICU 
Patients who are severely ill enough to require emergency tracheal intubation in the ED or ICU as part 
of their clinical care are at high risk of complications.  Many patients are undergoing intubation for 
hypoxemia or hemodynamic instability.  Severe hypoxemia or cardiovascular instability occurs during 
nearly half of intubations in the ED and ICU, and cardiac arrest occurs in approximately 1-in-25 cases.  
In 10-20% of emergency tracheal intubations, clinicians are unable intubate the trachea on the first 
attempt, which increases the risk of these severe peri-intubation complications.1–4   
 
Other complications during intubation may include aspiration (approximately 2.8% of cases), 
esophageal intubation (1.3%) injury to oral or dental structures (0.2%), and pneumothorax (0.1%).  The 
long-term consequences of complications occurring during emergency tracheal intubation are unclear.  
Neurologic recovery from traumatic brain injury may be worse after hypoxemia due to secondary 
ischemic insult. 
 
8.2 Potential Risks of Participation in the DEVICE Trial 
Participation in this study involves minimal incremental risk because: 
• Both approaches to tracheal intubation being compared are commonly used in routine clinical 
care; 
• Both are interventions to which patients would be exposed even if not participating in the study 
(all patients undergoing emergency tracheal intubation receive either a video or a direct 
laryngoscopy); 
• No established differences in risk and benefit are known to exist between the two approaches 
based on the currently available data; and 
• Patients are only eligible to participate if their treating clinicians have determined that both 
approaches are acceptable for the optimal care of the patient. 
Although no risks are currently known to differ between intubation with a video laryngoscope and 
intubation with a direct laryngoscope (both standard-of-care approaches in currently clinical care), it is 
possible that the results of the DEVICE trial will ultimately demonstrate a difference between the two 
approaches in the risk of hypoxemia, hypotension, cardiac arrest, aspiration, or another outcome. 
 
8.3 Potential Benefits of Participation in the DEVICE Trial 
The primary benefits of the DEVICE trial will be the indirect benefits to society that would result if one 
type of laryngoscope is found to prevent complications.  Because millions of critically ill adults undergo 

 
18 
 
emergency tracheal intubation each year, if one of the two approaches were found to prevent serious 
complications, the findings would immediately improve the care provided to millions of severely ill 
patients. Compared to the minimal risks of participation in the study, the pursuit of these benefits is 
reasonable.   
 
8.4 Minimization of Risk 
Federal regulations 45 CFR 46.111(a)(1) require that risks to patients are minimized by using 
procedures which are consistent with sound research design. This trial meets this human subjects 
protection requirement by incorporating numerous design elements to minimize risk to patients.  
 
Both video laryngoscopy and direct laryngoscopy have been used in clinical practice for years with an 
established safety profile in the same populations included in the DEVICE trial.  To further mitigate 
risk, we will exclude patients for whom treating clinicians determine that a specific laryngoscope is 
required or contraindicated for the optimal care of the patient.  
 
The trial protocol includes monitoring of adverse events, robust assessment of clinical outcomes, and an 
interim analysis by an independent DSMB, empowered to stop the trial or modify the trial protocol at 
any time. 
 
Finally, to limit the risks associated with the collection of protected health information (PHI), the 
minimum amount of PHI necessary for study conduct will be collected. The data will be coded and 
stored in a secure online database (REDCap) only accessible by the investigators. REDCap tools will be 
used to ensure that the PHI that is collected is only visible to investigators at the healthcare system 
where the patient is enrolled. To protect participant privacy, REDCap tools will be used to ensure that 
only deidentified data can be exported for use during analysis. 
 
 
9 
Statistical Considerations 
 
9.1 
General Considerations 
We will present summary tabulations by treatment group. For categorical variables, the number and 
proportion of patients within each category (with a category for missing data as needed) of the parameter 
will be presented. For continuous variables, the number of patients, mean or median as appropriate, and 
standard deviation or interquartile range as appropriate, will be presented.  
 
We will analyze a single pre-specified primary outcome and a single pre-specified secondary outcome 
using a chi-square test. Consistent with recommendations of the Food and Drug Administration26 and 
the European Medicines Agency,27 each will be tested using a two-sided P value with a significance 
level of 0.05. For all other analyses except safety analyses, emphasis will be placed on the estimate of 
effect size with 95% confidence intervals, as recommended by the International Committee of Medical 
Journal Editors,28 and no corrections for multiple comparisons will be performed. 
9.2 
Sample Size Estimation 

 
19 
 
The minimum clinically important difference in successful intubation on the first attempt that would be 
required to justify routine use of a video laryngoscope rather than a direct laryngoscope in clinical care 
is uncertain. The current trial will be designed to detect a 5% absolute difference between groups in the 
incidence of successful intubation on the first attempt. An absolute difference of 5% in successful 
intubation on the first attempt is similar to or smaller than the difference considered to be clinically 
meaningful in the design of prior airway management trials.8,11,24 Assuming an incidence of successful 
intubation on the first laryngoscopy attempt of 80% in the direct laryngoscope group based on data from 
a recently completed trial in the same ED and ICU settings, detecting a 5% absolute increase in the 
incidence of successful intubation on the first attempt with 90% power at a two-sided alpha level of 0.05 
would require enrollment of 1,920 patients (960 per group), anticipating 16 enrolling sites (clusters) and 
an intra-cluster correlation of 0.05. Anticipating missing data for up to 4% of patients, we will plan to 
enroll a total of 2,000 patients (1,000 per group).   
9.3 
Analysis Populations 
The primary analysis will occur in an intent-to-treat (ITT) fashion among all patients randomized, 
excluding only those patients whose data was withdrawn from the study (e.g., a patient who became a 
prisoner during the follow up period).   
9.4  
Statistical Analysis 
Before enrollment is complete, a complete final statistical analysis plan will be made publicly available. 
Analyses conducted in accordance with the statistical analysis plan will be identified as a priori. Any 
additional analyses requested by the investigators or reviewers after completion of enrollment will be 
identified as post hoc. 
9.4.1  Primary Analysis 
Main analysis of the primary outcome. The primary analysis will be an intention-to-treat comparison of 
patients randomized to the video laryngoscope group versus patients randomized to the direct 
laryngoscope group with regard to the primary outcome of successful intubation on the first attempt. The 
difference in proportion and the associated 95% confidence interval will be presented.  Between group 
differences will be examined using a Chi-square test. 
9.4.2 Secondary Analyses 
We will perform: 
1. Intention-to-treat comparisons of secondary, exploratory, and safety outcomes; and 
2. Intention-to-treat comparison of the primary outcome between groups using a generalized linear 
mixed effects model including a random effect for site and fixed effects for group assignment 
and pre-specified baseline variables, including: age; sex; body mass index; and location at 
enrollment (ED or ICU). 
 
 
 
 

 
20 
 
9.4.3 Effect Modification (Subgroup Analyses) 
 
To evaluate whether pre-specified baseline variables modify the effect of study group assignment on the 
primary outcome, we will perform logistic regression modelling with the primary outcome as the 
dependent variable and independent variables of the study group, the proposed effect modifier, and the 
interaction between the two. Any interaction term with a p-value less than 0.1 will be considered to 
identify an effect modifier. To account for non-linear relationships, continuous variables will be 
analyzed using restricted cubic splines with between 3 and 5 knots. Forest plots will be used to 
graphically display the adjusted analyses, and locally weighted regression or partial effects plots will be 
used to portray the association between continuous covariates and the outcome. A full list of 
prespecified subgroup analyses will be outlined in the detailed Statistical Analysis Plan and will include: 
 
● Operator Experience 
o Total number of previous intubations performed by operator 
o Number of previous intubations performed by operator with a direct laryngoscope 
● Operator’s planned video laryngoscope (hyperangulated blade vs. non-hyperangulated blade) 
● Location (ED vs ICU) 
● Presence of difficult airway characteristics 
● Indication for tracheal intubation of trauma (Yes vs No) 
● Chest compressions being delivered during the first laryngoscopy attempt (Yes vs No) 
 
9.4.4   Handling of Missing Data  
We anticipate that no data on the primary outcome will be missing. When data are missing for the 
secondary or exploratory outcomes, we will perform complete-case analysis, excluding cases where the 
data for the analyzed outcome are missing. There will be no imputation of missing data for these 
outcomes. In adjusted analyses, missing data for covariates will be imputed using multiple imputations. 
9.4.5    Interim Analysis 
 
The DSMB will conduct a single interim analysis for efficacy at the anticipated halfway point of the 
trial, after enrollment of 1,000 patients. The stopping boundary for efficacy will be met if the P value for 
the difference in the primary outcome (successful intubation on the first attempt) between groups using a 
Chi-square test is 0.001 or less. Using this conservative Haybittle–Peto boundary (P ≤ 0.001) will allow 
the final analysis to be performed using an unchanged level of significance. 
 
The DSMB will reserve the right to stop the trial at any point, request additional data or interim 
analyses, or request modifications of the study protocol as required to protect patient safety.   
 
At the interim analysis, the DSMB will evaluate the rate of the primary outcome in the direct 
laryngoscope group.  If the rate of the primary outcome in the direct laryngoscope group differs 
substantially from the original estimate of 80.0%, the DSMB may suggest that the investigators perform 
a sample size re-estimation to maintain adequate statistical power to detect the planned relative risk 
difference in the primary outcome between groups. 
 
 

 
21 
 
10 
Privacy and Confidentiality 
 
All patients will be assigned a unique study ID number for use in the coded study database.  Study 
personnel will access patients’ electronic health records at three planned time points: immediately 
following enrollment; when collecting baseline demographics and comorbidities (may occur anytime 
between enrollment and final data collection); and when collecting clinical outcomes (any time after the 
first of discharge or 28 days following intubation).  The electronic health record may be accessed again, 
as needed, between enrollment and study publication to respond to queries from the coordinating center 
focused on ensuring data completeness and quality. The minimal PHI that is collected will be visible 
only to site investigators at the site where the patient was enrolled.  The dataset for analysis will contain 
the unique study ID and no other patient identifiers.  At the time of publication, a fully de-identified 
version of the database will be generated. 
 
At no time during this study, its analysis, or its publication will patient identities be revealed in any 
manner. The minimum necessary data containing patient or provider identities will be collected. Data 
collected from the medical record will be entered into the secure online database REDCap. Hard copies 
of the data collection sheet completed at the time of the airway management event will be stored in a 
locked room until after the completion of enrollment and data cleaning. Following publication of the 
study results, all hard copies of data collection forms will be destroyed and the REDCap database will be 
fully de-identified in accordance with institutional regulations. 
 
 
11 
Follow-up and Record Retention 
 
Patients will be followed after enrollment for up to 28 days or until hospital discharge, whichever occurs 
first. Data collected from the medical record will be entered into the secure online database REDCap. 
Hard copies of the data collection sheet completed at the time of the airway management event will be 
stored in a locked room until after the completion of enrollment and data cleaning.  Once data are 
verified and the database is locked, all hard copies of data collection forms will be destroyed. All data 
will be maintained in the secure online database REDCap until the time of study publication. The 
minimal PHI that is collected will be available only to site investigators at the site where the patient was 
enrolled. At the time of publication, a de-identified version of the database will be generated. 
 
12 Safety Monitoring and Adverse Events 
Assuring patient safety is an essential component of this protocol.  Use of a video laryngoscope and use 
of a direct laryngoscope are both standard-of-care interventions that have been used in clinical practice 
for decades with an established safety profile. However, any trial conducted during a high-risk, time-
sensitive procedure like tracheal intubation of critically ill patients raises unique safety considerations. 
This protocol addresses these considerations through: 
1. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse events 
from intubation using a video laryngoscope or intubation using a direct laryngoscope; 
2. Systematic collection of outcomes relevant to the safety of intubation using a video laryngoscope or 
intubation using a direct laryngoscope; 
3. Structured monitoring, assessment, recording, and reporting of adverse events. 
 

 
22 
 
12.1 Adverse Event Definitions 
Adverse Event – An adverse event will be defined as any untoward or unfavorable medical occurrence 
in a human subject temporally associated with the subject’s participation in the research, whether or not 
considered related to the subject’s participation in the research.  Any adverse event occurring during the 
research will be classified according to the following characteristics: 
 
● Seriousness – An adverse event will be considered “serious” if it: 
o Results in death; 
o Is life-threatening (defined as placing the patient at immediate risk of death); 
o Results in inpatient hospitalization or prolongation of existing hospitalization;  
o Results in a persistent or significant disability or incapacity; 
o Results in a congenital anomaly or birth defect; or  
o Based upon appropriate medical judgment, may jeopardize the patient’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition. 
 
● Unexpectedness – An adverse event will be considered “unexpected” if the nature, severity, or 
frequency is neither consistent with: 
o The known or foreseeable risk of adverse events associated with the procedures involved 
in the research that are described in the protocol-related documents, such as the IRB-
approved research protocol; nor 
o The expected natural progression of any underlying disease, disorder, or condition of the 
subject experiencing the adverse event and the subject’s predisposing risk factor profile 
for the adverse event. 
 
● Relatedness – The strength of the relationship of an adverse event to a study intervention or 
study procedure will be defined as follows:  
o Definitely Related: The adverse event follows (1) a reasonable, temporal sequence from a 
study procedure AND (2) cannot be explained by the known characteristics of the 
patient’s clinical state or other therapies AND (3) evaluation of the patient’s clinical state 
indicates to the investigator that the experience is definitely related to study procedures.  
o Probably or Possibly Related: The adverse event meets some but not all of the above 
criteria for “Definitely Related”. 
o Probably Not Related: The adverse event occurred while the patient was on the study but 
can reasonably be explained by the known characteristics of the patient’s clinical state or 
other therapies.  
o Definitely Not Related: The adverse event is definitely produced by the patient’s clinical 
state or by other modes of therapy administered to the patient.  
o Uncertain Relationship: The adverse event does not fit in any of the above categories. 
 
12.2 Monitoring for Adverse Events 
The time interval during which patients will be monitored for the occurrence of adverse events begins at 
randomization and ends at the first of hospital discharge or 28 days.  Adverse events occurring before 
randomization or after hospital discharge or 28 days will not be collected. The lead investigator at each 
enrolling site will have primary responsibility for overseeing the monitoring, assessment, and reporting 

 
23 
 
of adverse events. Site study personnel will evaluate for the occurrence of adverse events by manual 
review of the electronic health record and by communication with treating clinicians.  Site study 
personnel will evaluate for the occurrence of adverse events by manual review of the electronic health 
record at two time points.  The first will occur as close as feasible to 24 hours after randomization during 
initial data collection.  The second will occur at the first of hospital discharge or 28 days after 
enrollment during final data collection.  Study personnel at each site will also communicate regularly 
with the treating clinicians who perform tracheal intubation in the study environments between 
enrollment and 28 days after enrollment to solicit information about any potential adverse events.  If 
study personnel at a site identify a potential adverse event, the lead investigator at the site will be 
immediately notified.  The lead investigator at the site will assess the seriousness, unexpectedness, and 
relatedness of the potential adverse event.  With assistance as needed from the coordinating center and 
the trial primary investigator, the lead investigator at the site will determine whether the event qualifies 
for recording and reporting. 
 
12.3 Recording and Reporting Adverse Events 
The following types of adverse events will be recorded and reported: 
● Adverse events that are Serious and Definitely Related, Probably or Possibly Related, or of 
Uncertain Relationship. 
● Adverse events that are Unexpected and Definitely Related, Probably or Possibly Related, or of 
Uncertain Relationship. 
 
Adverse events that do not meet the above criteria will not be recorded or reported.  Adverse events that 
the lead investigator at a site assesses to meet the above criteria for recording and reporting will be 
entered into the adverse event electronic case report form in the trial database.  The lead investigator at 
the site will record an assessment of each characteristic for the adverse event, including seriousness, 
unexpectedness, and relatedness.  For any adverse event that is serious AND unexpected, and definitely 
related, probably or possibly related, or of uncertain relationship, the lead investigator at the site will 
report the adverse event to the coordinating center and the trial primary investigators within 24 hours of 
becoming aware of the adverse event.  For any other adverse event requiring recording and reporting, 
the lead investigator at the site will report the adverse event to the coordinating center and the trial 
primary investigators within 72 hours of becoming aware of the adverse event.  The coordinating center 
and the trial principal investigator will coordinate with the lead investigator at the site to obtain 
information about the adverse event regarding each characteristic for the adverse event, including 
seriousness, expectedness, and relatedness.  The lead investigator at the site will be responsible for 
making final determinations regarding seriousness and unexpectedness.  The coordinating center and 
trial principal investigator will be responsible for making final determinations regarding relatedness. 
 
For adverse events that meet the above criteria for recording and reporting, the coordinating center will 
notify the DSMB, the IRB, and the sponsor in accordance with the following reporting plan: 
 
 
 
 
 

 
24 
 
Characteristics of the Adverse Event 
Reporting Period 
Fatal or life-threatening (and therefore 
serious), unexpected, and definitely related, 
probably or possibility related, or of uncertain 
relationship. 
Report to the DSMB, IRB, and sponsor within 
7 days after notification of the event. 
Serious but non-fatal and non-life-threatening, 
unexpected, and definitely related, probably 
or possibly related, or of uncertain 
relationship. 
Report to DSMB, IRB, and sponsor within 15 
days of notification of the event. 
All other adverse events meeting criteria for 
recording and reporting. 
Report to DSMB in regularly scheduled 
DSMB safety reports. 
The coordinating center will distribute the written summary of the DSMB’s periodic review of reported 
adverse events to the IRB in accordance with NIH guidelines: (http://grants.nih.gov/grants/guide/notice-
files/not99-107.html).  
12.4 Clinical Outcomes that may be Exempt from Adverse Event Recording and Reporting 
In this study of critically ill patients at high risk for death and other adverse outcomes due to their 
underlying critical illness, clinical outcomes, including death and organ dysfunction, will be 
systematically collected and analyzed for all patients. The primary, secondary, safety, and exploratory 
outcomes will be recorded and reported as clinical outcomes and not as adverse events unless treating 
clinicians or site investigators believe the event is Definitely Related or Probably or Possibly Related to 
the study intervention or study procedures.  This approach – considering death and organ dysfunction as 
clinical outcomes rather than adverse events and systemically collecting these clinical outcomes for 
analysis – is common in ICU trials. This approach ensures comprehensive data on death and organ 
dysfunction for all patients, rather than relying on sporadic adverse event reporting to identify these 
important events.  The following events are examples of study-specific clinical outcomes that would not 
be recorded and reported as adverse events unless treating clinicians or site investigators believe the 
event was Definitely Related or Probably or Possibly Related to the study intervention or study 
procedures: 
● Death (all deaths occurring prior to hospital discharge or 28 days will be recorded); 
● Organ dysfunction 
o Pulmonary – hypoxemia, aspiration, acute hypoxemic respiratory failure, pneumothorax 
o Cardiac – hypotension, shock, vasopressor receipt, cardiac arrest; 
● Duration of mechanical ventilation; 
● Duration of ICU admission; 
● Duration of hospitalization 
 
Note: A study-specific clinical outcome may also qualify as an adverse event meeting criteria for 
recording and reporting. For example, an injury to the teeth that the investigator considers Definitely 
Related to randomization to use of a direct laryngoscope would be both recorded as a study-specific 
clinical outcome and recorded and reported as a Serious and Definitely Related adverse event. 
 

 
25 
 
12.5 Unanticipated Problems involving Risks to Subjects or Others 
Investigators must also report Unanticipated Problems Involving Risks to Subjects or Others 
(“Unanticipated Problems”), regardless of severity, associated with study procedures within 24 hours of 
the site investigator becoming aware of the Unanticipated Problem. An Unanticipated Problem is 
defined as 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 IRB-approved research protocol; and (b) 
the characteristics of the subject population being studied; AND 
● Definitely Related or Probably or Possibly Related to participation in the research (as defined 
above in the section on characteristics of adverse events); AND  
● Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
If any study personnel at a site become aware of an event that may represent an Unanticipated problem, 
they will immediately contact the lead investigator for the site.  The lead investigator at the site will 
assess whether the event represents an Unanticipated Problem by applying the criteria described above.  
If the lead investigator at the site determines that the event represents an Unanticipated Problem, the 
lead investigator at the site investigator will record the Unanticipated Problem in the Unanticipated 
Problem electronic case report form in the trial database.  The lead investigator at the site will then 
communicate that an Unanticipated Problem has occurred to the coordinating center and the trial 
principal investigator within 24 hours of the lead investigator at the site becoming aware of the 
Unanticipated Problem.  The coordinating center and principal investigator will coordinate with the lead 
investigator at the site to obtain information about the Unanticipated Problem.  The coordinating center 
will report the Unanticipated Problem to the DSMB, IRB, and sponsor within 15 days of becoming 
aware of the Unanticipated Problem. 
 
13 Data and Safety Monitoring Board (DSMB) 
The principal role of the DSMB is to assure the safety of patients in the trial. They will regularly 
monitor data from this trial, review and assess the performance of its operations, and make 
recommendations to the steering committee and sponsor with respect to:  
● Participant safety and risk/benefit ratio of study procedures and interventions 
● Initial approval of the protocol and subsequent amendments (with specific attention to study 
population, intervention, and study procedures) 
● Adherence to the protocol requirements 
● Completeness, quality, and planned analysis of data  
● Ancillary study burden on participants and main study  
● Possible early termination of the trial because of new external information, early attainment of 
study objectives, safety concerns, or inadequate performance 
 
The DSMB will consist of members with expertise in bioethics, emergency medicine, pulmonary and 
critical care medicine, anesthesia, biostatistics, and clinical trials. Appointment of all members is 
contingent upon the absence of any conflicts of interest. All the members of the DSMB are voting 
members. The coordinating center, principal investigators, and unblinded study biostatistician will be 
responsible for the preparation of all DSMB and adverse event reports. The DSMB will develop a 
charter and review the protocol and patient notification forms during its first meeting. Subsequent 
DSMB meetings will be scheduled in accordance with the DSMB Charter. The DSMB will have the 
ability to recommend that the trial end, be modified, or continued unchanged. 
 

 
26 
 
14  
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Tracking of Protocol Versions: 
 
Version 1.0 – Initial Submission (September 30, 2021)