Mode Of Ventilation During Critical Illness Pilot Trial
Phase: NA
Conditions: Respiratory Failure
Sponsor: Vanderbilt University Medical Center

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
 
Clinical Trial Protocol 
 
Version 1.2 
 
 
Principal Investigator 
 
Kevin Seitz, MD, MSc 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Department of Medicine 
Vanderbilt University School of Medicine 
 
Co-Investigators 
 
Jonathan Casey, MD, MSc 
Matthew Semler, MD, MSc 
Todd Rice, MD, MSc 
Edward Qian, MD 
Bradley Lloyd, RT-ACCS 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Department of Medicine 
Vanderbilt University School of Medicine 
 
Wesley Self, MD, MPH 
Department of Emergency Medicine 
Vanderbilt University School of Medicine 
 
 
 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
2 
 
Table of Contents 
1.0 Trial Summary 
4 
2.0 Background 
6 
3.0 Aims and Hypotheses 
7 
3.1  Study Aims: 
7 
3.2  Hypotheses: 
7 
4.0 Study Description 
7 
4.1  Rationale for Cluster-Level Allocation 
8 
5.0 Inclusion and Exclusion Criteria 
9 
5.1  Inclusion Criteria: 
9 
5.2  Exclusion Criteria: 
9 
6.0 Enrollment / Randomization 
9 
6.1 Study Site: 
9 
6.2  Study Population: 
9 
6.3  Enrollment: 
9 
6.4  Consent: 
9 
6.5 Randomization: 
11 
7.0 Study Procedures 
11 
7.1 Study Interventions: 
11 
7.2 Study Co-interventions: 
13 
7.3 Monitoring Ventilator Mode: 
14 
7.4 Blinding: 
14 
7.5  Data Collection: 
14 
7.6  Outcome Measures: 
15 
8.0 Risks and Benefits 
16 
9.0 Safety Monitoring and Adverse Events 
16 
9.1  Adverse Event Definitions: 
17 
9.2 Monitoring for Adverse Events: 
18 
9.3 Recording and Reporting Adverse Events: 
18 
9.4 Clinical Outcomes that may be Exempt from Adverse Event Recording and Reporting: 
19 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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9.5 Unanticipated Problems involving Risks to Subjects or Others: 
19 
10.0 Statistical Considerations 
20 
11.0 Privacy / Confidentiality Issues 
22 
12.0 Follow-up and Record Retention 
22 
13.0 Data Safety and Monitoring Board (DSMB) 
23 
14.0 References 
23 
Appendix 1: Ventilator Guidelines 
28 
Appendix 2. Ventilator Guidelines Table 
30 
Appendix 3: Spontaneous Breathing Trials and Ventilator Discontinuation Guidelines 
31 
 
 
 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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1.0 Trial Summary 
 
Title 
Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Background 
Landmark trials in critical care have demonstrated that, among critically ill 
adults receiving invasive mechanical ventilation, the use of low tidal volumes 
and low airway pressures prevents lung injury and improves patient outcomes. 
Limited evidence, however, informs the best method of mechanical ventilation 
to achieve these targets.  To provide mechanical ventilation, clinicians must 
choose between modes of ventilation that directly control tidal volumes 
(“volume control”), modes that directly control the inspiratory airway pressure 
(“pressure control”), and modes that are hybrids (“adaptive pressure control”).  
Whether the choice of the mode used to target low tidal volumes and low 
inspiratory plateau pressures affects clinical outcomes for critically ill adults 
receiving mechanical ventilation is unknown. All three modes of mechanical 
ventilation are commonly used in clinical practice.  A large, multicenter 
randomized trial comparing available modes of mechanical ventilation is 
needed to understand the effect of each mode on clinical outcomes.  We will 
conduct a pilot trial evaluating the feasibility of comparing modes for 
mechanically ventilated ICU patients. 
Study Design 
Prospective, unblinded, cluster-randomized, multiple-crossover pilot trial 
Trial Groups 
1. Volume Control group 
2. Pressure Control group 
3. Adaptive Pressure Control group 
Inclusion Criteria 
1. Age ≥ 18 years 
2. Receiving mechanical ventilation through an endotracheal tube or 
tracheostomy 
3. Admitted to the study ICU 
Exclusion Criteria 
1. Patient is pregnant 
2. Patient is a prisoner 
3. Patient was receiving invasive mechanical ventilation at place of residence 
prior to hospital admission 
4. Patient is receiving extracorporeal membrane oxygenation at the time of 
admission to the study ICU 
Randomization 
In this cluster-randomized cluster-crossover trial, the entire study ICU will be 
assigned to a mode of ventilation (volume control, pressure control, or adaptive 
pressure control) and will switch between modes every month in an order 
determined by computer-generated randomization using permuted blocks of 3.   
Primary Outcome 
Ventilator-free days to day 28 after enrollment 
Exploratory 
Outcomes 
Feasibility Outcomes 
• Exposure to assigned study mode in first 3 days: Proportion of time in 
the assigned mode while receiving invasive mechanical ventilation in 
the study ICU between enrollment and 72 hours after enrollment  

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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• Adherence to study mode in first 3 days: Proportion of time in the 
assigned mode while receiving invasive mechanical ventilation in the 
study ICU with a mandatory mode between enrollment and 72 hours 
after enrollment (excluding time spent in spontaneous modes) 
• Time from enrollment to initiation of assigned mode of mechanical 
ventilation 
• Receipt of a “Mode Modification Sheet” completed by treating 
clinicians 
Exploratory Efficacy and Safety Outcomes 
• Median exhaled tidal volume (mL/kg predicted body weight) on each 
study day 
• Exhaled tidal volumes above target range: Proportion of recorded 
breaths with exhaled tidal volume values above the target range 
(>8mL/kg predicted body weight) on each study day 
• Hypoxemia during mechanical ventilation: Episodes of hypoxemia 
during mechanical ventilation: SpO2 < 85% for more than 5 minutes 
• Severe acidemia during mechanical ventilation: Episodes of severe 
acidemia during mechanical ventilation: pH < 7.1 on blood gas 
• Number of blood gas laboratory tests per day while receiving 
mechanical ventilation 
• Pneumomediastinum or pneumothorax during course of mechanical 
ventilation  
• SOFA score daily on the first 7 study days 
• Delirium and coma-free days to day 28 
Exploratory Clinical Outcomes:  
• ICU-free days to study day 28 
• Hospital-free days to study day 28 
• 
In-hospital mortality to study day 28 
Analysis 
The primary analysis of the primary outcome (ventilator-free days) will be 
conducted in an intention-to-treat fashion using a proportional odds model with 
independent covariates of group assignment (volume control, pressure control, 
or adaptive pressure control) and time since beginning enrollment (in days). 
Sample Size 
The trial will be conducted for a total of 9 months as this is the duration needed 
to evaluate the feasibility of the cluster-randomized multiple-crossover design. 
Based on data from a prior trial in the same ICU, we expect to enroll 675 
patients, of whom 69 will be enrolled during washout periods and 606 patients 
will be included in the primary analysis. 
Duration 
9 months 
 
  

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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2.0 Background 
 
Approximately 2-3 million critically ill adults receive invasive mechanical ventilation in the ICU each 
year.1–3 Mechanical ventilation provides support for ventilation and gas exchange while patients recover 
from the underlying causes of their respiratory failure. Mechanical ventilation itself, however, may 
injure the lungs, diaphragm, and other organs,4,5 and in-hospital mortality for mechanically ventilated 
ICU patients remains 25-35%.6  
 
For patients on mechanical ventilation, tidal volume and inspiratory airway pressures are directly 
related. Increasing tidal volumes increases airway pressures and vice versa. The ventilator can be set by 
clinicians to deliver breaths in one of two ways: either by controlling the volume (“volume control”) or 
the pressure (“pressure control”) administered during the inspiratory phase of the breath. By controlling 
one factor, each mode provides indirect control over the other, as a dependent variable that varies 
proportionally based on the patient’s lung physiology.7 Modern ventilators also offer hybrid modes such 
as adaptive pressure control, allowing clinicians to set a target volume for which the ventilator titrates 
and delivers the pressure controlled breath that is expected to be adequate based on the results of 
previous breaths (e.g. Pressure Regulated Volume Control). The mode of mechanical ventilation must be 
set for each of 2-3 million ICU patients who receive invasive mechanical ventilation.  Yet, whether 
choice of mode affects outcomes remains uncertain. 8–10 
 
Landmark clinical trials in critically ill patients have demonstrated that using smaller tidal volumes and 
plateau pressures (Low Tidal Volume Ventilation) reduces lung injury and improves patient outcomes, 
both for patients with ARDS11 and for patients without ARDS.12 Each of the commonly used modes of 
mechanical ventilation (volume control, pressure control, adaptive pressure control) can achieve these 
low tidal volume and low plateau pressure targets – but minimal data exist to guide the choice of which 
ventilator mode should be used to achieve these targets. Current guidelines recommend delivering low 
tidal volumes and low plateau pressures to all patients on mechanical ventilation and make no 
recommendations regarding the mode of mechanical ventilation used to achieve these targets. 13–18  
Volume control, pressure control, and adaptive pressure control can each be used to accomplish 
adequate gas exchange in critically ill patients, but they differ in how they control tidal volumes and 
inspiratory pressures and synchronize with patient efforts to breathe.19,20  
 
Only two clinical trials have directly compared volume control and pressure control as the modes of 
mechanical ventilation for critically ill adults.  The trials were small and lacked adequate power to 
evaluate for clinically significant difference in patient-important outcomes.21,22 Further, they were 
performed more than 20 years ago, prior to many modern practices of critical care including low tidal 
volume ventilation.  Evidence comparing adaptive modes to volume or pressure control are similarly 
limited to small trials with mixed results.23,24 Reviews and meta-analyses of small and heterogenous 
studies of physiology have also not demonstrated clear superiority of volume control, pressure control, 
or adaptive pressure control.8,9,20  
 
All three modes are in common use in large, international cohorts of ARDS and non-ARDS patients, 
with a slight increase in the use of pressure modes over time.12,25,26 Pressure control modes are the most 
common modes in international cohorts.12,26–28 While ventilator settings for critically ill patients in the 
United States are not as well described, the most recent data on patients in the US receiving 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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contemporary critical care, from a large multi-center cohort of moderate-severe ARDS patients, 
demonstrated that on the first day of mechanical ventilation with ARDS, volume control was used in 
approximately half of patients, with most of the remainder receiving pressure regulated modes in either 
pressure control or adaptive pressure control.29 Among all patients receiving mechanical ventilation in 
the Vanderbilt Medical ICU in 2021, 35% of breaths were in volume control, 31% were in pressure 
control, and 35% were in adaptive pressure control.  
 
Because millions of critically ill adults receive invasive mechanical ventilation each year, a mode of 
ventilation must be selected for every patient, three modes are used commonly in current practice, and 
no high-quality data inform the effect of mode of ventilation on patient outcomes, a large, randomized 
trial is needed to inform the optimal choice of ventilator mode for mechanically ventilated ICU patients. 
Before such a trial can be conducted, however, data are needed to demonstrate the feasibility of 
maintaining adherence to ventilator modes in a pragmatic trial.30–32 
 
3.0 Aims and Hypotheses 
 
3.1  
Study Aims: 
 
• Feasibility Aim:  To assess the feasibility of a cluster-randomized, multiple-crossover trial 
comparing volume control, pressure control, and adaptive pressure control modes.   
 
• Clinical Aim: To evaluate the effect of the same ventilator mode intervention on days alive and 
free of invasive mechanical ventilation in the same population of mechanically ventilated 
critically ill patients. 
 
3.2  
Hypotheses:  
 
• Feasibility Hypothesis:  Comparing volume control, pressure control, and adaptive pressure 
control ventilation among mechanically ventilated ICU patients will be feasible. 
 
• Clinical Hypothesis: Use of an adaptive pressure control mode for mechanically ventilated ICU 
patients will result in more days alive and free of invasive mechanical ventilation than use of 
either a volume control or pressure control mode. 
 
 
4.0 Study Description 
 
To address the aims outlined above, we propose the Mode Of Ventilation During Critical IllnEss 
(MODE) Pilot Trial. This trial will be a prospective, single-center, unblinded, cluster-randomized, 
multiple-crossover trial conducted in the medical ICU at Vanderbilt University Medical Center. During 
the 9 months of enrollment in the MODE trial, the entire medical ICU will be assigned to a single 
ventilator mode with the assigned mode alternating between volume control, pressure control, and 
adaptive pressure control modes every month in a randomly generated sequence. All patients who 
receive invasive mechanical ventilation and meet inclusion criteria without meeting exclusion criteria 
will be enrolled at the initiation of mechanical ventilation. The trial will control only the ventilator mode 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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during controlled mechanical ventilation.  All other aspects of clinical care for patients will remain at the 
discretion of treating clinicians. 
 
4.1  
Rationale for Cluster-Level Allocation: 
 
Group assignment in the MODE trial occurs at the level of the ICU (cluster) for multiple reasons. 
In routine clinical care in the study ICU, 2 to 4 respiratory therapists set the ventilator mode and adjust 
settings to maintain gas exchange and patient comfort for all mechanically ventilated adults, with input 
from nurses and physicians. The management of mechanical ventilation (selection of fraction of inspired 
oxygen, titration of positive end-expiratory pressure, screening for and performance of spontaneous 
breathing trials) is governed by unit-wide protocols implemented by the 2 to 4 respiratory therapists for 
all patients in the unit. Assigning the entire unit to a single ventilator mode both emulates the way 
mechanical ventilation is managed during clinical care and limits contamination that might result from a 
respiratory therapist managing multiple patients assigned to different modes of mechanical ventilation. 
 
Additionally, mechanical ventilation can damage lungs even after brief periods of ventilation, 
and the initial settings have a unique significance.  For example, during the minutes-to-hours of 
temporary mechanical ventilation for surgical procedures, harmful ventilator settings can affect organ 
function and clinical outcomes.34 In critically ill patients, the initial hours of invasive mechanical 
ventilation are also the period with the highest risk of worsening lung injury, dyssynchrony, increased 
work of breathing, and hemodynamic compromise. Prior research has demonstrated that [1] the very 
first ventilator settings at the time the patient is being initiated on invasive mechanical ventilation in the 
ICU are associated with differences in mortality35,36 and [2] the association between ventilator settings 
and mortality is larger for earlier settings compared to later settings.33  The ventilator protocol used to 
set the ventilator mode in the study ICU begins immediately at the time of initiation of mechanical 
ventilation. Enrollment immediately after initiation of invasive mechanical ventilation minimizes pre-
study exposure to other modes and ventilator settings, and it facilitates on-study separation between 
groups.  
 
Recognizing the importance of initial ventilator settings, three recent clinical trials have 
examined other ventilator settings (i.e. end-expiratory pressure, tidal volume, and SpO2 target) by 
attempting to enroll patients soon after the initiation of mechanical ventilation in the ICU. 12,37,38 In these 
patient-level, parallel-group trials, however, the logistical challenges of performing screening, 
enrollment, randomization, and study group assignment resulted in a significant gap between initiation 
of invasive mechanical ventilation and delivery of the respective trial interventions while also leading to 
the exclusion of 60-67% of eligible patients – raising concern for systematic exclusion of important 
patient groups (e.g. patients with higher acuity of illness). In MODE, group assignment at the cluster 
level allows enrollment immediately on initiation of invasive mechanical ventilation in the ICU. This 
approach emulates the manner in which ventilator settings are managed in practice, precludes systematic 
exclusion of important patient groups, decreases pre-study exposure to harmful ventilator settings, and 
facilitates early separation in the receipt of ventilator modes between groups. 
 
 
 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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5.0 Inclusion and Exclusion Criteria 
 
5.1  
Inclusion Criteria: 
 
1. Age ≥ 18 years 
2. Receiving mechanical ventilation through an endotracheal tube or tracheostomy 
3. Admitted to the study ICU. 
 
5.2  
Exclusion Criteria:  
 
1. Patient is pregnant 
2. Patient is a prisoner 
3. Patient receiving invasive mechanical ventilation at place of residence prior to hospital 
admission 
4. Patient receiving extracorporeal membrane oxygenation at the time of admission to the study 
ICU.  
 
6.0 Enrollment / Randomization 
 
6.1 
Study Site:   
 
• Medical Intensive Care Unit at Vanderbilt University Medical Center 
 
6.2  
Study Population:   
 
All adults located in the study ICU for whom the treating clinicians have decided invasive mechanical 
ventilation is required will be enrolled unless meeting exclusion criteria.  Patients will be included 
regardless of age, gender, race, or other clinical factors.  
 
6.3  
Enrollment:   
 
All adult patients who do not meet exclusion criteria will be enrolled immediately upon receipt of 
invasive mechanical ventilation in the study ICU.   
 
6.4  
Consent:  
 
Volume control, pressure control, and adaptive pressure control are all common approaches to 
controlled mechanical ventilation for critically ill adults.  All represent standard-of-care treatments in 
current clinical practice.  Results from prior clinical trials do not demonstrate superiority of one 
approach over the other.  Current clinical guidelines do not recommend any specific mode of mechanical 
ventilation.14,16–18 As a result, significant variation exists in the use of volume control, pressure control, 
and adaptive pressure control for patients in routine clinical care with ARDS29 and those without 
ARDS.26 In the study ICU, all three modes are currently in use in routine care. Of all patients on 
mechanical ventilation in the study ICU in 2021, 35% of mandatory breaths were in volume control 
mode, 31% were in pressure control mode, and 35% were in adaptive pressure control. This trial will 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
10 
 
only enroll patients who would already receive continuous mandatory ventilation with one of these three 
modes as part of their routine clinical care. When the primary medical team feels that the patient needs 
care with a specific ventilator mode different from what is assigned by the study, the team can alter the 
ventilator mode for the patient and use the mode that they believe is the correct mode for the patient. 
Only patients for whom the primary team feels that the ventilator mode assigned by the study is 
acceptable will continue with that assigned ventilator mode. We will request a waiver of informed 
consent because the study involves minimal risk and obtaining informed consent would be 
impracticable. 
 
Participation in this study involves minimal risk because: 
• The three interventions being compared are commonly used in routine clinical care in the 
study ICU; 
• All are interventions to which the patient could be exposed even if not participating in the 
study (all patients receiving the initiation of mechanical ventilation receive one of these 
modes of continuous mandatory ventilation); 
• No established differences in risk and benefits are known to exist between the studied 
approaches to mechanical ventilation based on the currently available data; and 
• The trial only determines the mode of ventilation when treating clinicians feel all three 
modes would be consistent with optimal care for the individual patient – otherwise 
treating clinicians select the mode of ventilation via a Mode Modification Sheet. 
 
The MODE trial is designed as a cluster-randomized multiple-crossover trial to ensure that the mode 
selected at the time of initiation of mechanical ventilation is consistent with trial group assignment, 
preventing contamination between groups and capturing the period of mechanical ventilation in which 
ventilator settings have the strongest association with outcomes. 
 
Obtaining informed consent before initiation of mechanical ventilation in the study ICU would be 
impracticable because: 
• The expected medical condition of patients at the time of initiation invasive mechanical 
ventilation in the ICU is critical. All patients will be critically ill and receiving continuous 
intravenous sedation at the time of enrollment.  Thus, all patients eligible for MODE will not 
have the capacity to provide informed consent. Further, data from prior trials in the same patient 
population and setting demonstrate that prior to intubation and initiation of mechanical 
ventilation, approximately 70% of patients eligible for the MODE 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.  Further, family members or legally authorized representatives (LAR) are frequently 
unavailable when critically ill patients undergo intubation in the ED or ICU.   
• The intervention is delivered by unit-level protocols. Mechanical ventilator settings and 
titrations are performed by respiratory therapists using unit-level protocols.  In this cluster-
randomized trial, the entire unit will be assigned to the same mode of mechanical ventilation for 
each 1-month block.  Obtaining informed consent from every eligible patient in the ICU prior to 
emergency tracheal intubation and initiation of mechanical ventilation would be impracticable. 
 
  

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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Because the study involves minimal 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 care for 
interventions such as emergency intubation and methods of respiratory support during critical illness 
have been completed with waiver of informed consent.39–47  
 
6.5 
Randomization: 
 
During each one-month block of the study, the ICU will be assigned to either volume control, pressure 
control, or adaptive pressure control. The order of the study group assignments will be generated by 
computerized randomization using permuted blocks of 3 to minimize the impact of seasonal variation. 
The last 3 days of each block will be a washout period during which the ICU will continue to use the 
assigned mode, but new patients will not be included in the primary analysis. The 3-day washout period 
will limit the number of patients who experience a ‘crossover’ from one assigned mode to another while 
receiving a mandatory mode of mechanical ventilation.  
 
  
7.0 Study Procedures 
 
7.1 
Study Interventions: 
 
Ventilator Mode:  
 
Volume Control Group: Patients assigned to the volume control group will receive volume control as 
the initial mode of ventilation and whenever they are receiving continuous mandatory invasive 
mechanical ventilation. 
 
Pressure Control Group: Patients assigned to the pressure control group will receive pressure control 
as the initial mode of ventilation and whenever they are receiving continuous mandatory invasive 
mechanical ventilation. 
 
Adaptive Pressure Control Group: Patients assigned to the adaptive pressure control group will 
receive adaptive pressure control as the initial mode of ventilation and whenever they are receiving 
continuous mandatory invasive mechanical ventilation. 
 
Characteristics of each of the three modes of ventilation are presented in Table 1. 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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Ventilator Settings and Titration:  
In the study ICU and the United States generally, respiratory therapists have primary responsibility for 
determining the initial settings for invasive mechanical ventilation and titrating these settings for clinical 
goals (e.g., SaO2, pCO2, target tidal volume, target plateau pressure, etc.). To set and titrate mechanical 
ventilator settings, respiratory therapists use clinical protocols jointly developed by respiratory therapy 
and physician leaders. For patients enrolled in the MODE trial, respiratory therapists will use preexisting 
clinical protocols for volume control, pressure control, and adaptive pressure control in use in the study 
unit (Appendix 1-3). 
 
Initiation of Mechanical Ventilation:  All mechanically ventilated patients being initiated on invasive 
mechanical ventilation in an ICU initially receive a “mandatory” mode of ventilation (e.g., volume 
control, pressure control, or adaptive pressure control) immediately following intubation.  Mandatory 
modes are necessary for patients being initiated on invasive mechanical ventilation in an ICU, because 
patients nearly uniformly received sedation or neuromuscular blockade for placement of the 
endotracheal tube and do not have the spontaneous respiratory effort required to allow a “spontaneous” 
mode of ventilation. When respiratory therapists select the initial ventilator settings for a patient being 
initiated on invasive mechanical ventilation in the ICU, they will select the assigned mode of ventilation 
(volume control, pressure control, or adaptive pressure control). As prior studies have demonstrated that 
ventilator settings early in patients’ course of invasive mechanical ventilation may affect clinical 
outcomes,33 ensuring the first set of ventilator settings includes the mode of ventilation assigned by the 
study will prevent contamination with non-assignment ventilator modes and ensure delivery of the study 
intervention during a key period of patients’ critical illness. 
 
Maintenance of Mechanical Ventilation: 
Study protocol will determine the ventilator mode from enrollment until the first of: (1) extubation from 
mechanical ventilation, (2) transfer out of the study ICU, (3) completion of a ventilator Mode 
Modification Sheet by treating clinicians, or (4) end of the one-month study block. If a patient is 
enrolled, extubated, and re-intubated during the same study block, the study protocol will again 
determine the ventilator mode until they meet one of the aforementioned criteria. Study protocol does 
not determine the ventilator mode during time-periods in which the patient is not receiving invasive 
Table 1. Characteristics of the modes of mechanical ventilation. 
Group Assignment 
Volume Control 
Pressure Control 
Adaptive Pressure 
Control 
Ventilator Mode 
Designation 
Volume Control 
Pressure Control 
Pressure Regulated 
Volume Control 
Control Variable 
Volume 
Pressure 
Pressure 
Breath Sequence 
Continuous  
mandatory ventilation 
Continuous 
mandatory ventilation 
Continuous  
mandatory ventilation 
Targeting Scheme 
Set-point 
(clinician sets target 
volume) 
Set-point 
(clinician sets target 
pressure) 
Adaptive 
(clinician sets target 
volume and ventilator 
titrates pressure to 
achieve target volume) 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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mechanical ventilation, is not receiving a continuous mandatory mode of ventilation (e.g., when patients 
who are no longer deeply sedated are weaned to pressure support ventilation), is not physically located 
in the study ICU (e.g., during transport), or is undergoing an invasive procedure (e.g., bronchoscopy). 
 
Modification of Ventilator Mode: At any time, any member of the clinical team (respiratory therapist, 
nurse, nurse practitioner, or physician) may use any mode of mechanical ventilation if determined to be 
needed for the optimal treatment of any specific patient.  If modifying the mode of ventilation is 
necessary, the date, time, and reason for modification of the mode will be prospectively recorded. 
 
Details of each mode modification will be collected and monitored on a Mode Modification Sheet. In 
our prior cluster-crossover trial using the same approach to modification of therapy assignment, treating 
clinicians exercised the ability to modify the assigned therapy for approximately 5% of patients.39 
 
Anticipated examples of conditions for which treating clinicians may elect to override the assigned 
mode include:   
- 
Refractory hypoxemia 
- 
Peak pressures persistently high (>40 cm H20) 
- 
Asynchrony or dyssynchrony not amenable to changes within the assigned mode of ventilation  
- 
Excessive work of breathing  
- 
Barotrauma (pneumothorax or pneumomediastinum) 
- 
Inability to limit tidal volumes delivered 
- 
Intrinsic PEEP 
- 
Other 
 
7.2 
Study Co-interventions: 
 
Ventilator Adjustment:  For all patients regardless of group assignment, existing clinical ventilator 
protocols will be used to target a tidal volume of 6 mL/kg PBW and a plateau pressure <30 cm H20, 
while maintaining a respiratory rate less than 35 and pH of at least greater than 7.15, with a target of 7.3 
to 7.45. (Appendix 1-3) Respiratory therapists will titrate volume or pressure settings according to the 
patient’s ventilator mode to achieve these parameters and manage asynchrony and patient discomfort if 
it occurs. 
 
Liberation from Mechanical Ventilation: Each day of mechanical ventilation, all patients in the study 
ICU are assessed for safety of a spontaneous awakening trial (SAT) and spontaneous breathing trial 
(SBT)48 using the SAT and SBT safety criteria from the Awakening and Breathing Controlled (ABC) 
trial.49 These criteria relate to the non-respiratory clinical status of the patient and the PEEP and FiO2 
settings which will be managed similarly across groups. As such, the SAT and SBT procedures will be 
handled in the same way for each patient, regardless of study group assignment. Definitions of SAT and 
SBT failure and the ventilator settings and duration of the SBT will be those used in the ABC trial and 
used in routine clinical care in the study ICU.  For patients who have passed an SAT and SBT, the 
decision to discontinue invasive mechanical ventilation will be made by the treating clinicians. 
 
Fraction of Inspired Oxygen (FiO2) and Positive End-Expiratory Pressure (PEEP): Institutional 
protocols in the study ICU will ensure that mechanically ventilated patients in MODE on each study 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
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mode receive FiO2 and PEEP titration according to the ARDSNet Lower PEEP/higher FiO2 table 
(except for patients with severe ARDS, for whom the higher PEEP/lower FiO2 table is applied)50,51 
 
Sedation and Analgesics: Institutional protocols in the study ICU will ensure that mechanically 
ventilated patients in MODE on each study mode receive similar management of pain, agitation, and 
delirium52 targeting Critical Care Pain Observation Tool (CPOT)53, Richmond Agitation-Sedation Scale 
(RASS)54,55, and Confusion Assessment Method for the ICU (CAM-ICU) scores.56,57  
 
7.3 
Monitoring Ventilator Mode: 
 
For all mechanically ventilated patients in the study ICU, ventilators display settings such as mode and 
measurements such as observed tidal volume on a digital display at the patient’s bedside in real time. 
For critical measurements such as respiratory rate, minute ventilation, and peak pressures, audible 
alarms from the ventilator alert clinicians to potentially dangerous situations. These settings and 
measurements are sampled and uploaded automatically into the EMR frequently and are stored in the 
data warehouse. This will allow for much more accurate assessment of the ventilator modes that patients 
receive over the course of the day compared to prior trials which documented ventilator mode once or 
twice daily.58,59 
 
Feedback on Ventilator Mode Adherence:  During the study, study personnel will monitor compliance 
with the assigned ventilator mode.  Study personnel will remotely monitor ventilator modes up to four 
times daily from 4AM through 10PM Monday through Friday and during a convenience sample of 
weekend hours to provide feedback to treating clinicians and explore reasons why patients are not 
receiving the assigned mode of mechanical ventilation,  
 
Study personnel will attend respiratory therapy group meetings, nursing unit board meetings, and ICU 
physician leadership meetings to educate staff about the study, solicit safety concerns and adverse 
events, and identify and address barriers to ventilator mode assignment compliance. This approach to 
daily monitoring and intermittent feedback to clinical personnel successfully achieved 80% compliance 
with the assigned intervention in a prior cluster-crossover trial of ventilator settings in the same ICU.39 
 
7.4 
Blinding:   
 
Similar to prior ventilator mode studies among critically ill adults, patients and clinicians will not be 
blinded to study group assignment.21,58,59  Observer bias will be minimized by use of objective endpoints 
collected and automated data extraction from the EHR (see Data Collection below). 
 
7.5  
Data Collection:   
 
The MODE trial will primarily use structured data collected in routine clinical care, exported daily from 
the institution’s EHR into an Enterprise Data Warehouse, along with data from the patient registration, 
billing, and laboratory clinical information systems.  We have previously validated the quality of this 
method of data collection against the reference standard of two-physician manual chart review,60 and the 
planned approach to electronic dataset generation for the MODE trial has already been successfully 
employed for the conduct of four prior pragmatic trials.39,61–63  

Principal Investigator: Kevin Seitz            
  
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Electronically extracted data elements will include:  
Enrollment (Day 0): date and time of clinical events (hospital admission, ICU admission, intubation); 
source of admission to study ICU; age; sex; race; ethnicity; height, weight;64 SOFA score;65 Glasgow 
Coma Scale score;66 Elixhauser Comorbidity Index;67 history of present illness; vital signs (temperature, 
heart rate, systolic blood pressure, diastolic blood pressure, SpO2); mechanical ventilator settings (mode, 
set and exhaled tidal volumes, set and actual respiratory rate, minute ventilation, set and total positive 
end-expiratory pressure, peak pressure, plateau pressure, inspiratory time, flow pattern, FiO2); serum 
laboratory values (white blood cell count, hemoglobin, platelet count, sodium, potassium, bicarbonate, 
creatinine, bilirubin, alanine aminotransferase, aspartate aminotransferase, lactate, arterial and venous 
pH, PaCO2,PaO2, SaO2).   
 
Daily On-Study (Days 0-28): Vital signs, ventilator settings, screening for and performance of 
spontaneous awakening trials and spontaneous breathing trials, and serum laboratory values (as above); 
Mean daily dose of sedative infusions (propofol, dexmedetomidine, morphine, fentanyl, and 
midazolam); CAM status; RASS score; Daily completion of each element from ICU Liberation Bundle 
(A-F); Beginning and end time of Spontaneous Breathing Trials; vasopressor and inotrope infusions 
(norepinephrine, epinephrine, vasopressin, phenylephrine, dobutamine, angiotensin-2, dopamine); 
“Mode Modification Sheet” (use, time, reason); Characteristics of treating clinicians (respiratory 
therapist, attending, pulmonary fellow, registered nurse) providing direct care; Use of therapies for 
refractory hypoxemia (prone positioning, ECMO, neuromuscular blockade, inhaled pulmonary dilators); 
SOFA score; ARDS criteria by the Berlin Definition;68 Stage II or greater AKI by KDIGO criteria;69 
cardiac arrest, pneumothorax or pneumomediastinum.   
 
Termination (Days 0-28):  Vital status at 28 days; time of liberation from invasive mechanical 
ventilation; receipt and duration of vasopressors; receipt and duration of renal replacement therapy; 
tracheostomy; duration of ICU and hospital admission.   
 
7.6 
 Outcome Measures: 
 
Primary Outcome:   
The primary outcome is ventilator-free days (VFDs) to day 28 after enrollment.   
 
VFDs will be defined as the number of calendar days alive and free of invasive mechanical ventilation 
from the final receipt of invasive mechanical ventilation through 28 days after enrollment.  Outcome 
ascertainment will cease at the time of hospital discharge or 28 days after enrollment, whichever occurs 
first.  Receipt of invasive mechanical ventilation will be considered to end when patients undergo the 
final tracheal extubation or disconnection of the ventilator from a tracheostomy tube between enrollment 
(day 1) and day 28 after enrollment.  Patients who die prior to discharge on or before day 28 will receive 
zero VFDs. Patients whose final receipt of invasive mechanical ventilation occurs on the day of 
enrollment and survive to day 28 will receive 27 VFDs. Patients who continue to receive invasive 
mechanical ventilation at day 28 will receive zero VFDs.  Patients who are discharged from the hospital 
prior to day 28 and are receiving invasive mechanical ventilation at the time of discharge will receive 
zero VFDs.  Patients who are removed from invasive mechanical ventilation and are discharged from the 
hospital without invasive mechanical ventilation prior to 28 days will be assumed to remain alive and 

Principal Investigator: Kevin Seitz            
  
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free of invasive mechanical ventilation between hospital discharge and day 28.  For patients who are 
removed from invasive mechanical ventilation, return to invasive mechanical ventilation, and are 
subsequently removed again from invasive mechanical ventilation prior to day 28, VFDs will be counted 
from the final receipt of invasive mechanical ventilation prior to day 28.   
 
Feasibility Outcomes 
- 
Exposure to assigned study mode in first 3 days: proportion of time in the assigned mode while 
receiving invasive mechanical ventilation in the study ICU between enrollment and 72 hours 
after enrollment.  
- 
Adherence to study mode in first 3 days: proportion of time in the assigned mode while receiving 
invasive mechanical ventilation in the study ICU with a mandatory mode between enrollment 
and 72 hours after enrollment (excluding time spent in spontaneous modes). 
- 
Time from enrollment to initiation of assigned mode of mechanical ventilation 
- 
Receipt of a “Mode Modification Sheet” completed by treating clinicians 
 
Exploratory Efficacy and Safety Outcomes 
- 
Median exhaled tidal volume (mL/kg predicted body weight (PBW)) on each study day 
- 
Exhaled tidal volumes above target range: proportion of recorded breaths with exhaled tidal 
volume values above the target range (> 8mL/kg PBW) on each study day 
- 
Hypoxemia during mechanical ventilation: episodes of hypoxemia during mechanical 
ventilation: SpO2 < 85% for more than 5 minutes 
- 
Severe acidemia during mechanical ventilation: Episodes of severe acidemia during mechanical 
ventilation: pH < 7.1 on blood gas 
- 
Number of blood gas laboratory tests per day while receiving mechanical ventilation 
- 
Pneumomediastinum or pneumothorax during course of mechanical ventilation  
- 
SOFA score daily on the first 7 study days 
- 
Delirium and coma-free days to day 28 
 
Exploratory Clinical Outcomes:  
- 
ICU-free days to study day 28 
- 
Hospital-free days to study day 28 
- 
In-hospital mortality to study day 28 
 
8.0 Risks and Benefits 
 
Although no risks are currently known to differ between mechanical ventilation with volume control, 
pressure control, and adaptive pressure control (all standard-of-care approaches in currently clinical 
care), it is possible that the results of the MODE trial will ultimately demonstrate a difference between 
the approaches in the risk of ventilator-free days, hypoxemia, delirium and coma free days, or another 
outcome. The benefits of this research will include understanding the effect of choice of ventilator mode 
on outcomes for the 2-3 million adults per year who receive invasive ventilation. 
 
9.0 Safety Monitoring and Adverse Events 
 

Principal Investigator: Kevin Seitz            
  
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Assuring patient safety is an essential component of this protocol. Mechanical ventilation with volume 
control, pressure control, and adaptive pressure control are all standard-of-care interventions that have 
been use in clinical practice for decades with an established safety profile. This protocol further ensures 
safety of its participants through: 
a. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse 
events from pressure control, volume control, or adaptive pressure control settings; 
b. Permitting treating clinicians to change the ventilator mode at any time for any patient in 
whom they feel a ventilator mode different from the assigned mode is required for the 
safe treatment of the patient; 
c. Systematic collection of outcomes relevant to the safety of ventilator mode selection; 
d. Structured monitoring, assessment, recording, and reporting of adverse events. 
 
9.1  
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.  Adverse events 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 

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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. 
 
9.2 
Monitoring for Adverse Events: 
 
For patients whose mode of mechanical ventilation is controlled by the trial, investigators will evaluate 
for the occurrence of adverse events daily as part of the assessment of ventilator modes.  Investigators 
will assess any adverse events that occur for whether the adverse event meets the criteria for recording 
and reporting outlined below. 
 
9.3 
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 investigator 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 investigator will record a 
preliminary 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 investigator will report the adverse 
event to the principal investigator within 24 hours of the investigator becoming aware of the adverse 
event.  For any other adverse event requiring recording and reporting, the investigator will report the 
adverse event to the principal investigator within 72 hours of the investigator becoming aware of the 
adverse event.  The principal investigator will make the final determination regarding each characteristic 
for the adverse event, including seriousness, expectedness, and 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: 
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 DSMB and IRB within 7 
days after notification of the event. 

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Serious but non-fatal and non-life-
threatening, unexpected, and definitely 
related, probably or possibly related, or of 
uncertain relationship. 
Report to DSMB and IRB within 7 
days of notification of the event. 
All other adverse events meeting criteria for 
recording and reporting. 
Report to DSMB and IRB as part of 
continuing review. 
The investigator 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). 
 
9.4 
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 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, hypercarbia, acute hypoxemic respiratory failure, 
pneumothorax; 
o Cardiac – hypotension, cardiac arrest or shock with or without receipt of vasopressors; 
o Delirium or coma; 
• 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, a pneumothorax that the investigator considers Definitely Related 
to ventilator mode would be both recorded as a study-specific clinical outcome and recorded and 
reported as a Serious and Definitely Related adverse event. 
 
9.5 
Unanticipated Problems involving Risks to Subjects or Others: 
 
Investigators must also report to the principal investigator Unanticipated Problems Involving Risks to 
Subjects or Others (“Unanticipated Problems”), regardless of severity, associated with study procedures 

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within 24 hours of the 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.  
Upon becoming aware of any event that may represent an Unanticipated Problem, the investigator will 
assess whether the event represents an Unanticipated Problem by applying the criteria described above.  
If the investigator determines that the event represents an Unanticipated Problem, the investigator will 
record the Unanticipated Problem in the Unanticipated Problem electronic case report form in the trial 
database.  The investigators will obtain information about the Unanticipated Problem and report the 
Unanticipated Problem to the DSMB and the IRB within 15 days of becoming aware of the 
Unanticipated Problem. 
 
10.0 Statistical Considerations 
 
Sample size justification.   
The purpose of this trial is to assess feasibility of a cluster-randomized, cluster-crossover design. To 
assess whether compliance can be maintained after cross-over events, we will need to observe two cross-
over events to each mode while maintaining an equal number of treatment blocks for each mode. Doing 
so will require a total of 9 months. Based on the experience of a prior trial in the same ICU,70 we 
anticipate an average of 75 patients on mechanical ventilation will be enrolled per month. In 9 months, 
we expect to enroll 675 patients, of whom 69 will be enrolled during washout periods and excluded from 
the primary analysis. The resulting 606 patients will be included in the primary analysis.  
 
While the sample size was determined to demonstrate feasibility of the cluster-crossover design, we 
anticipate this pilot will be the largest randomized trial of ventilator modes to date, and as such, we plan 
to compare ventilator free days to day 28 (primary outcome) between groups. In a prior cluster-
randomized cluster-crossover trial in the same ICU,70 mechanically ventilated patients experienced a 
median of 22 VFDs [IQR 0-25 VFDs] and an intra-cluster intra-period correlation of 0.01.  With 606 
(202 in each group) patients in the primary analysis, a standard deviation in the primary outcome of 
VFDs of 11 days, and a two-sided alpha of 0.05, the MODE trial will have 80 percent statistical power 
to detect an absolute difference between groups in the sole primary clinical endpoint of Ventilator Free 
Days of 3 days. 
 
Primary Analysis of the Primary Clinical Outcome 
The sole pre-specified primary outcome of ventilator free days will be compared between the three trial 
groups in an intention-to-treat fashion among all patients enrolled in the trial except those admitted 
during one of the 3-day washout periods. To estimate the conditional effect of a group assignment on an 
individual patient given the values of the covariates for that patient, we will use a proportional odds 
model with independent covariates of group assignment (volume control, pressure control, or adaptive 

Principal Investigator: Kevin Seitz            
  
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pressure control) and time. Time (in days) will be treated as a continuous variable with values ranging 
from 1 (first day of enrollment) to 272 (final day of enrollment) and will be analyzed using restricted 
cubic splines with multiple knots to allow for non-linearity resulting from seasonality or secular trends. 
In addition to assessing for an overall group effect within the model, we will estimate the differences 
between each pair of modes by extracting 95% confidence intervals from the model. 
 
Sensitivity Analyses of the Primary Clinical Outcomes: 
We will repeat the primary clinical outcome analysis with adjustment for pre-specified baseline 
covariates. 
 
We will repeat the analyses of the primary outcome and feasibility outcomes among all patients enrolled 
in the trial including those initiated on invasive mechanical ventilation in the study ICU during one of 
the pre-specified 3-day washout periods. 
 
Analysis of Effect Modification for the Primary Outcomes. 
We will examine whether pre-specified baseline variables modify the effect of study group on the 
primary clinical outcome using formal tests of statistical interaction in a proportional odds model.  
Independent variables will include study group assignment, the potential effect modifier of interest, and 
the interaction between the two (e.g., study group * history of COPD) and time.  Significance will be 
determined by the P value for the interaction term, with values less than 0.10 considered to suggest a 
potential interaction and values less than 0.05 considered to confirm an interaction.  
 
We will examine whether the following baseline variables modify the effect of study group on the 
primary outcome: 
• Age (continuous variable); 
• Duration of invasive mechanical ventilation prior to enrollment (0 minutes; 1 to 360 minutes; 
>360 minutes); 
• Pre-enrollment fraction of inspired oxygen (FiO2)(continuous variable); 
• SOFA score at enrollment (continuous variable); 
• Shock receiving vasopressors (yes, no) 
• Indication for intubation (categories are not mutually exclusive) 
o Hypoxemic respiratory failure (yes, no); 
o Hypercarbic respiratory failure (yes, no); 
o Altered mental status or airway protection (yes, no); 
• Chronic Obstructive Pulmonary Disease (yes, no); 
 
Analysis of the Exploratory, Feasibility, and Clinical Outcomes 
Each of the exploratory outcomes will be compared between groups in an intention-to-treat fashion in 
the primary analysis population. Continuous outcomes will be compared between groups in a similar 
manner as the primary clinical outcome. A logistic model will be used for binary outcomes, a 
multinomial model for categorical outcomes, and a proportional odds model for ordinal and continuous 
outcomes. 
 
Corrections for multiple testing 

Principal Investigator: Kevin Seitz            
  
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We have pre-specified a single primary clinical outcome, which will have a test of statistical 
significance for difference between groups.  Consistent with recommendations of the Food and Drug 
Administration and the European Medicines Association, the clinical outcome will be tested using a 
two-sided p-value with a significance level of 0.05.  For all other 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, and no corrections for multiple comparisons will be performed. 
 
Handling of missing data 
The primary outcome is not anticipated to be missing for any patients. Missing data will not be imputed 
for the primary outcome or any secondary or exploratory outcomes. In adjusted analyses, missing data 
for covariates will be imputed using multiple imputations. 
 
Interim Analysis 
In addition to ongoing monitoring of safety throughout the trial, we will plan for the DSMB to conduct a 
single interim analysis for safety after the ICU has been assigned to each of the three study modes, that 
is, after enrollment of patients for 3 months. At the interim analysis, the DSMB will evaluate the 
incidence of the following outcomes across the study groups (volume control, pressure control, or 
adaptive pressure control): 
- 
Pneumomediastinum or pneumothorax during the course of mechanical ventilation,  
- 
Episodes of hypoxemia while receiving invasive mechanical ventilation: SpO2 < 85% for more 
than 5 minutes, 
- 
In-hospital mortality to study day 28. 
The stopping boundary for safety will be met if the P value for the difference between groups is 0.016 or 
less, which is an a priori threshold determined by adjusting the p-value threshold of 0.05 for multiple 
comparisons by dividing 0.05 by the 3 outcomes. The DSMB will consider whether it is necessary to 
stop the trial or whether randomization to any one study group should be stopped, while the other two 
groups continue enrolling patients. Given the design of the study is to demonstrate feasibility and pilot 
trial procedures rather than demonstrating efficacy, there will be no stopping boundary for efficacy or 
futility.   
 
 
            
11.0 Privacy / Confidentiality Issues 
 
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 and the Mode Modification Sheets will be entered into the secure 
online database REDCap. Only key study personnel will have access to the REDCap database. Hard 
copies of the treating clinician Mode Modification Sheet will be stored in a locked room until after the 
completion of enrollment and data cleaning. 
 
All data will be maintained in the secure online database REDCap until the time of study publication. At 
the time of publication, a de-identified version of the database will be generated. 
 
12.0 Follow-up and Record Retention 

Principal Investigator: Kevin Seitz            
  
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Patients will be followed after enrollment for 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 treating clinician Mode Modification Sheet will be used for manual data entry into the 
REDCap database and stored in a locked room until after the completion of enrollment and data 
cleaning. All data will be maintained in the secure online database REDCap until the time of study 
publication. Once data are verified and the database is locked, all hard copies of Mode Modification 
Sheets will be destroyed. At the time of publication, a de-identified version of the database will be 
generated. 
 
 
13.0 Data Safety and 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 
- 
Protocol 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, safety concerns, or 
inadequate performance. 
 
The DSMB will consist of members with expertise in critical care medicine, pulmonary medicine, 
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 Principal Investigator 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 
with the assistance of the Principal Investigator. The DSMB will have the ability to recommend that the 
trial end, be modified, or continued unchanged. 
 
 
14.0 References 
 
1.  
Wunsch H, Angus DC, Harrison DA, Linde-Zwirble WT, Rowan KM. Comparison of Medical 
Admissions to Intensive Care Units in the United States and United Kingdom. Am J Respir Crit Care 
Med 2011;183(12):1666–73.  
2.  
Wunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn JM. The 
epidemiology of mechanical ventilation use in the United States*: Crit Care Med 2010;38(10):1947–53.  
3.  
Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of 
critical illness in adults. The Lancet 2010;376(9749):1339–46.  
4.  
Slutsky AS, Ranieri VM. Ventilator-Induced Lung Injury. N Engl J Med 2013;369(22):2126–36.  

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Version Date: 07/21/2023 
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5.  
Vassilakopoulos T, Petrof BJ. Ventilator-induced Diaphragmatic Dysfunction. Am J Respir Crit 
Care Med 2004;169(3):336–41.  
6.  
Esteban A, Frutos-Vivar F, Muriel A, et al. Evolution of Mortality over Time in Patients 
Receiving Mechanical Ventilation. Am J Respir Crit Care Med 2013;188(2):220–30.  
7.  
Chatburn RL, El-Khatib M, Mireles-Cabodevila E. A Taxonomy for Mechanical Ventilation: 10 
Fundamental Maxims. Respir Care 2014;59(11):1747–63.  
8.  
Marini JJ. Point: Is Pressure Assist-Control Preferred Over Volume Assist-Control Mode for 
Lung Protective Ventilation in Patients With ARDS? Yes. Chest 2011;140(2):286–90.  
9.  
MacIntyre N. Counterpoint: Is Pressure Assist-Control Preferred Over Volume Assist-Control 
Mode for Lung Protective Ventilation in Patients With ARDS? No. Chest 2011;140(2):290–2.  
10.  
Branson R. Should Adaptive Pressure Control Modes Be Utilized for Virtually All Patients 
Receiving Mechanical Ventilation? Respir CARE 2007;52(4):11.  
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Acute Respiratory Distress Syndrome Network. Ventilation with Lower Tidal Volumes as 
Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress 
Syndrome. N Engl J Med 2000;342(18):1301–8.  
12.  
Writing Group for the PReVENT Investigators, Simonis FD, Serpa Neto A, et al. Effect of a 
Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients 
Without ARDS: A Randomized Clinical Trial. JAMA 2018;320(18):1872.  
13.  
Chiumello D, Brochard L, Marini JJ, et al. Respiratory support in patients with acute respiratory 
distress syndrome: an expert opinion. Crit Care 2017;21(1):240.  
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Barbas CSV, Ísola AM, Farias AM de C, et al. Brazilian recommendations of mechanical 
ventilation 2013. Part I. Rev Bras Ter Intensiva 2014;26(2):89–121.  
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Del Sorbo L, Goligher EC, McAuley DF, et al. Mechanical Ventilation in Adults with Acute 
Respiratory Distress Syndrome. Summary of the Experimental Evidence for the Clinical Practice 
Guideline. Ann Am Thorac Soc 2017;14(Supplement_4):S261–70.  
16.  
Fan E, Del Sorbo L, Goligher EC, et al. An Official American Thoracic Society/European 
Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: 
Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit 
Care Med 2017;195(9):1253–63.  
17.  
Griffiths MJD, McAuley DF, Perkins GD, et al. Guidelines on the management of acute 
respiratory distress syndrome. BMJ Open Respir Res 2019;6(1):e000420.  
18.  
Papazian L, Aubron C, Brochard L, et al. Formal guidelines: management of acute respiratory 
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Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
25 
 
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Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
26 
 
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Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation 
of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 
2001;29(7):1370–9.  

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
27 
 
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Kacmarek RM, Villar J, Sulemanji D, et al. Open Lung Approach for the Acute Respiratory 
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the Electronic Health Record. J Med Syst 2016;40(7):167.  
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Intensive Care Unit. The SALT Randomized Trial. Am J Respir Crit Care Med 2017;195(10):1362–72.  
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KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter 2012;2(Suppl):8.  
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Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill 
Adults. N Engl J Med 2018;378(9):829–39.  
 
  
 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
28 
 
Appendix 1: Ventilator Guidelines 
 
SUMMARY OF VUMC MICU VENTILATOR PROTOCOL GUIDELINES:  
 
Ventilator Set Up and Adjustment: 
 
1. Calculate Predicted Body Weight (PBW):  
a. In males = 50 - 2.3 (height (inches) - 60) 
b. In females = 45.5 + 2.3 (height (inches) - 60) 
2. Select Mode and initial default settings: 
a. Volume Control. Set Tidal Volume (Vt) to target 6 mL/kg PBW. Set Flow Pattern: 100 or 
[square-wave icon]; Set T pause (s): 0.  
b. Pressure Regulated Volume Control. Set Vt to target 6 mL/kg PBW. 
c. Pressure Control. Set PC above PEEP to 15 cmH2O, set inspiratory time to 0.9 s and confirm 
delivered Vt is appropriate for target 6 mL/kg PBW.  
3. Set initial respiratory rate (RR) to approximate baseline Minute Ventilation (12-16 bpm, not > 35 
bpm). 
4. Set alarms:  
For VC and PRVC: High Peak Pressure alarm at 40 cm H20 
For PC: Low Minute Ventilation alarm at 2 L/min less than the current Minute Ventilation 
5. Adjust Vt and RR to achieve pH and plateau pressure goals below. 
 
Lung Protective Ventilation Goals – Vt ≤ 6 mL/kg PBW, Pplat < 30 cmH20 
 
*For Pressure Control, where Vt cannot be directly adjusted, adjust PC over PEEP in increments of 2 
cmH20 and monitor resulting Vt to achieve the changes outlined below. 
 
If Vt > 6 mL/kg PBW:  
Reduce Vt by 1 mL/kg at intervals ≤ 2 hours until Vt = 6 mL/kg PBW. 
If Pplat > 30 (or PIP > 35):  
Decrease Vt by 1 mL/kg steps to a minimum of 4mL/kg PBW.  
If Pplat < 25 and Vt < 6 mL/kg:  
Increase Vt by 1 mL/kg until either Pplat > 25 or Vt = 6 mL/kg PBW. 
If Pplat <3 0 and breath stacking occurs:  
May increase Vt in 1 mL/kg increments to maximum of 8 mL/kg PBW. 
 
Ventilation Goals - pH: 7.30-7.45 
 
If pH 7.15-7.30:  
Increase RR until pH > 7.30 or PaCO2 < 25 (Max RR = 35). 
If RR = 35 and PaCO2 < 25:  
May give NaHCO3, to be managed by primary team. 
If pH < 7.15:  
Increase RR to 35. 
If pH remains < 7 .15 and NaHCO3 considered or infused:  

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
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29 
 
Vt may be increased until pH >7.15 or Vt = 8 mL/kg PBW (Pplat target may be exceeded). 
 
If pH >7.45:  
Decrease RR rate. 
 
Oxygenation goals - SpO2: 88-95% or PaO2: 55-80 mmHg. 
 
Use incremental FiO2/PEEP combinations below to provide minimum FiO2 and PEEP necessary to 
achieve PaO2 or SpO2 goals. 
 
FiO2 
0.3-0.4 
0.4 
0.5 
0.5 
0.6 
0.7 
0.7 
0.7 
0.8 
0.9 
0.9 
0.9 
1 
PEEP 
5 
8 
8 
10 
10 
10 
12 
14 
14 
14 
16 
18 
18-25 
 
Other Settings 
 
I:E ratio goal: 1:1.0 – 1-3.0. Adjust Ti to achieve goal. 
If FiO2 = 1.0 and PEEP = 24 cmH20, may adjust I:E to 1:1. 
Avoid inverse-ratio ventilation. 
Trigger: 1.6 L/min by default, can be increased or reduced to improve synchrony 
Tinsp rise (s): 0.15 s by default, can be increased or decreased to improve ventilation 
 
Monitoring and Documentation: 
 
Measure & record Pplat with inspiratory pause of at least 0.5 s, SpO2, Total RR, Vt and pH (if available) 
at least every 4 hours AND after each change in PEEP, Vt, or PC above PEEP settings.  
 
Once the patient tolerates FiO2 < 0.5 and PEEP < 8 cmH2O, advance to Part II: Spontaneous Breathing 
Trial Readiness Assessment and Ventilator Discontinuation Guidelines. 
 
 
 
 
 
 
 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
30 
 
Appendix 2. Ventilator Guidelines Table  
 
Volume Control 
Pressure Control 
Adaptive Pressure 
Control 
Mode option 
Volume Control 
Pressure Control 
Pressure Regulated 
Volume Control 
(PRVC) 
Tidal Volume 
target (mL/kg 
PBW) 
6  
6  
6  
Tidal Volume range 
(mL/kg PBW) 
4 - 8 
4 - 8 
4 - 8 
Initial breath 
settings 
Tidal volume to 6 
mL/kg PBW 
PC over PEEP to 15 
cm H20, Insp Time to 
0.9 sec 
Tidal volume to 6 
mL/kg PBW 
Achieving target 
Tidal Volume 
Directly adjust tidal 
volume  
Dependent on 
adjustment of PC 
over PEEP  
Adjust tidal volume 
directly 
Plat Pressure target 
(cm H20) 
≤ 30 
≤ 30 
≤ 30 
Achieving target 
Plateau Pressure 
Dependent on 
adjustment of tidal 
volume  
Directly adjust PC 
over PEEP 
Dependent on 
adjustment of  
tidal volume 
Flow 
Set directly 
Dependent ventilator 
and patient factors 
Dependent ventilator 
and patient factors 
Flow Pattern  
Square waveform 
Decelerating, 
dynamic 
Decelerating, 
dynamic 
Arterial pH goal 
7.3 - 7.45 
7.3 - 7.45 
7.3 - 7.45 
Ventilator rate 
(breaths/min) 
≤ 35 
≤ 35 
≤ 35 
Oxygenation goal 
by PaO2 (mmHg) 
55 - 80 
55 - 80 
55 - 80 
Oxygenation goal 
by SpO2 (%) 
88 - 95 
88 - 95 
88 - 95 
Positive end-
expiratory pressure 
Set with FiO2-
PEEP table 
Set with FiO2-PEEP 
table 
Set with FiO2-PEEP 
table 
Inspiratory: 
Expiratory ratio 
1:1 - 1:3 
1:1 - 1:3 
1:1 - 1:3 
Extubation 
evaluation  
MICU  
SBT Readiness and 
Extubation 
Guidelines 
MICU  
SBT Readiness and 
Extubation 
Guidelines 
MICU  
SBT Readiness and 
Extubation 
Guidelines 
 
 
 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
31 
 
Appendix 3: Spontaneous Breathing Trials and Ventilator Discontinuation Guidelines  
 
Part I – Spontaneous Breathing Trial Readiness Assessment 
  
Every morning or at least once daily, patients will undergo screening and trial in a Spontaneous 
Awakening Trial (SAT) performed by bedside nursing. If the patient passes the SAT, then the patient 
should be promptly evaluated in a Spontaneous Breathing Trial (SBT) Readiness Assessment as a safety 
screening: 
 
If all of the following criteria have been present for more than 2 hours, then evaluate the patient for 
progression to Spontaneous Breathing Trial:  
a) 
FiO2 ≤ 0.5 & PEEP ≤ 8 cmH2O 
b) 
Values of both PEEP and FiO2 ≤ values from previous 12 hours. 
c) 
Not receiving neuromuscular blocking agents 
d) 
Patient is exhibiting adequate inspiratory efforts (if not, decrease the ventilator rate to 50% of 
baseline level for up to 5 minutes to detect inspiratory effort). 
e) 
Systolic arterial pressure > 90 mmHg without significant vasopressor support (< 10 mcg/min of 
norepinephrine or < 5 mcg/kg/min dopamine or dobutamine will not be considered a vasopressor). 
 
Part II – Spontaneous Breathing Trial (SBT) 
 
If criteria a-e above are met, then initiate a trial of at least 30 minutes of spontaneous breathing with 
FIO2 ≤ 0.5 using any of the following approaches: 
1. 
Pressure support ≤ 5cmH2O, PEEP ≤ 5cmH2O 
2. 
CPAP ≤ 5 cmH2O  
3. 
T-piece 
4. 
Tracheostomy mask  
 
Monitor for tolerance using the following: 
1. 
SpO2 ≥ 88% and / or PaO2 ≥ 60 mmHg.  FiO2 may be increased to 0.5 if necessary to maintain 
oxygenation in the target range. 
2. 
Mean spontaneous tidal volume ≥ 4 mL/kg PBW (if measured) 
3. 
Total Respiratory Rate ≤ 35 / min (< 5 min at RR > 35 may be tolerated, example post 
suctioning) 
4. 
pH ≥ 7.30 (if measured) 
5. 
No respiratory distress (defined as 2 or more of the following): 
a. 
Heart rate ≥ 120% of the 06:00 rate (≤ 5 min at > 120% may be tolerated) 
b. 
Marked use of accessory muscles 
 
c. 
Abdominal paradoxical breathing 
d. 
Diaphoresis 
e. 
Marked subjective dyspnea. 
 
If any of the goals 1-5 are NOT met, revert to previous ventilator settings with Positive End-expiratory 
Pressure and FiO2 = previous settings and reassess for SBT the next morning. 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
32 
 
The clinical team may decide to change mode of support during spontaneous breathing (PS = 5cmH2O, 
CPAP, tracheostomy mask, or T-piece) at any time.  
 
Part III – Decision to Remove Ventilatory Support 
 
For intubated patients, if tolerance criteria for spontaneous breathing trial (1-5 above) are 
met for at least 30 minutes, continue with unassisted breathing and extubate if clinically indicated under 
the direction of team physicians.  However, the spontaneous breathing trial can continue for up to 120 
minutes if tolerance remains in question (in fragile patients).   
 
If any of criteria 1-5 are NOT met during spontaneous breathing (or 120 minutes has passed without 
clear tolerance), then the ventilator settings that were in use before the attempt to wean will be restored 
(Positive End-expiratory Pressure and FiO2 = previous settings) and the patient will be reassessed for an 
SBT the following day. 
 
 
 
 

Principal Investigator: Kevin Seitz            
  
Version Date: 07/21/2023 
Study Title: Mode Of Ventilation During Critical IllnEss (MODE) Pilot Trial 
Institution: Vanderbilt University Medical Center 
 
 
 
33 
 
Tracking of Protocol Versions: 
 
Version 1.0 – Initial Protocol (IRB approval on 10/18/22) 
 
Version 1.1 – Protocol revisions after initial meeting with DSMB (10/21/22, IRB approval on 12/6/22) 
- Adjusted for multiple testing at the interim analysis by dividing p-value threshold used to stop for 
safety outcomes being formally evaluated, as follows:  
“The stopping boundary for safety will be met if the P value for the difference between groups is 
0.016 or less, which is an a priori threshold determined by adjusting the p-value threshold of 
0.05 for multiple comparisons by dividing 0.05 by the 3 outcomes.”  
 
- Clarified that the DSMB is empowered, in addition to making recommendations regarding 
stopping the trial, to make a recommendation to drop one arm of the three-armed trial if one arm 
appears significantly worse than the remaining two arms. The following has been added: 
“The DSMB will consider whether it is necessary to stop the trial or whether randomization to 
any one study group should be stopped, while the other two groups continue enrolling patients.” 
 
- Clarified what mode of ventilation is recommended for patients who are extubated and 
reintubated during the study block by adding: 
“If a patient is enrolled, extubated, and re-intubated during the same study block, the study 
protocol will again determine the ventilator mode until they meet one of the aforementioned 
criteria.” 
 
Version 1.2 – Minor protocol revisions to align with Statistical Analysis Plan (7/21/23, IRB approval 
pending): 
- Clarified definitions of exploratory outcome variables 
- Clarified definition of primary outcome 
- Modified choices of variables to be analyzed as potential effect modifiers 
- Modified definition of the variable for Acute Respiratory Distress Syndrome  
- Removed the plan for additional statistical approaches to the analysis of the primary outcome