FiO2 Closed Loop Control Using the ZOLL 731 Series Ventilator
Conditions: Wounds and Injuries, Respiratory Failure
Sponsor: Zoll Medical Corporation

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ZOLL FIO2 CLC Protocol 
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ZOLL Medical 
FiO2 Closed-Loop Control Using the ZOLL 731 Series 
Ventilator
Trial Number – 9703 
Version: 6.1 
9Dec2019 
269 Mill Road 
Chelmsford, MA 01824-4105 
 
 
 
 
 
 
Investigational Plan 
CONFIDENTIAL 
This confidential document is the property of ZOLL Medical Corporation. No unpublished 
information contained herein may be disclosed without the prior written approval of ZOLL 
Medical Corporation. This trial will be conducted in accordance with ISO14155 and in 
accordance with 21 CFR in the United States. Essential documents will be archived by the 
sponsor. Dissemination may only be made with the express written permission of ZOLL 
Medical Corporation. 

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ZOLL FIO2 CLC Protocol 
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TABLE OF CONTENTS  
PAGE 
TABLE OF CONTENTS .............................................................................................................. II 
1. PROTOCOL SUMMARY ....................................................................................................... VI 
2. KEY ROLES AND CONTACT INFORMATION ..................................................................... 10 
3.  INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........... 12 
3.1 Background Information ............................................................................................. 12 
3.1.1 Device Description ....................................................................................... 12 
3.2 Rationale and Report of Prior Investigations ............................................................... 16 
3.2.1 Summary of Investigations of other PCLC of FiO2 Systems......................... 17 
3.2.2 Summary of Investigations of our PCLC of FiO2 System .............................. 19 
3.3 Potential Risks ............................................................................................................ 25 
3.4 Potential Benefits ....................................................................................................... 26 
4. STUDY OBJECTIVES ........................................................................................................... 27 
4.1 Primary Objective ....................................................................................................... 27 
4.1.1a Primary effectiveness variable: .................................................................. 27 
4.1.1b Secondary effectiveness variable: .............................................................. 27 
4.1.2a Primary effectiveness hypothesis ............................................................... 27 
4.1.2b Secondary effectiveness hypothesis .......................................................... 27 
4.1.3 Primary safety variable ................................................................................. 27 
4.1.4 Primary safety hypothesis ............................................................................ 27 
4.2 Secondary Objectives ................................................................................................. 28 
4.3 Study Design .............................................................................................................. 28 
5. STUDY ENROLLMENT AND WITHDRAWAL ....................................................................... 32 
5.1 Study population ......................................................................................................... 32 
5.2 Sample size ................................................................................................................ 32 
5.3 Subject Inclusion Criteria ............................................................................................ 32 
5.4 Subject Exclusion Criteria ........................................................................................... 32 
5.5 Strategies for Recruitment and Retention ................................................................... 33 
5.6 Treatment Assignment Procedures ............................................................................ 34 
5.6.1 Randomization Procedures .......................................................................... 34 
5.6.2 Subject Withdrawal ...................................................................................... 34 
5.6.3 Premature Termination or Suspension of Study ........................................... 34 
6 STUDY INTERVENTION ....................................................................................................... 36 
6.1 Acquisition .................................................................................................................. 36 
6.2 Formulation, Packaging, and Labeling ........................................................................ 36 
6.3 Product Storage and Stability ..................................................................................... 36 
6.4 Accountability Procedures for the Study Product ........................................................ 37 
7  STUDY SCHEDULE ............................................................................................................. 38 
7.1 Screening ................................................................................................................... 38 
7.1.1   Visit 1: Screening/Enrollment .................................................................... 38 

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7.1.2 
Visit 2: Time 0 + 12 hours .......................................................................... 38 
7.1.3  Visit 3: Time 24 hours after the intervention .............................................. 38 
8. STUDY PROCEDURES /EVALUATIONS ............................................................................. 39 
8.1 
Study Procedures/Evaluations .............................................................................. 39 
8.2 
Clinical Laboratory Evaluations ............................................................................. 39 
9. ASSESSMENT OF SAFETY ................................................................................................. 40 
9.1 Specification of Safety Parameters ............................................................................. 40 
9.1.1 Primary Safety variable: ............................................................................... 40 
9.1.2 Secondary safety variables: ......................................................................... 40 
9.2 Unanticipated Problems ............................................................................................. 40 
9.3 Adverse Events .......................................................................................................... 40 
9.4 Serious Adverse Events ............................................................................................. 41 
9.5 Frequency for Event Assessment and Follow-Up ....................................................... 41 
9.6 Characteristics of an Adverse Event ........................................................................... 41 
9.6.1 Relationship to Study Intervention ................................................................ 41 
9.6.2 Expectedness of SAEs ................................................................................. 42 
9.6.3 Severity of Event .......................................................................................... 42 
9.6.4 Reporting Procedures .................................................................................. 42 
10. STUDY OVERSIGHT .......................................................................................................... 43 
10.1 Data Safety Monitoring Board ................................................................................... 43 
10.2 Training .................................................................................................................... 43 
11. CLINICAL SITE MONITORING ........................................................................................... 44 
12. STATISTICAL CONSIDERATIONS..................................................................................... 45 
12.1 Sample size .............................................................................................................. 45 
12.1.1 Primary Efficacy objective: ......................................................................... 45 
12.1.2 Primary Safety objective: ........................................................................... 45 
12.2 Statistical Analysis .................................................................................................... 46 
13. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..................... 48 
14. ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................... 49 
14.1 Ethical Standard ....................................................................................................... 49 
14.2 Institutional Review Board ........................................................................................ 49 
14.3 Informed Consent Process ....................................................................................... 49 
14.4 Exclusion of Women, Minorities, and Children (Special Populations)........................ 49 
14.5 Subject Confidentiality .............................................................................................. 49 
15. DATA HANDLING AND RECORD KEEPING ...................................................................... 51 
15.1 Data Management Responsibilities .......................................................................... 51 
15.2 Data Capture Methods ............................................................................................. 51 
15.3 Types of Data ........................................................................................................... 51 
15.4 Study Records Retention .......................................................................................... 51 
15.5 Protocol Deviations ................................................................................................... 52 
APPENDIX A: DEFINITIONS OF ADVERSE EVENTS ............................................................. 53 
APPENDIX B: DESCRIPTION OF FIO2 PCLC ALARMS .......................................................... 55 
APPENDIX C: REFERENCES, RATIONALE – REPORT OF PRIOR INVESTIGATION ........... 56 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ARDS 
Acute Respiratory Distress Syndrome 
CLC 
Closed-Loop control 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DMP 
Data Management Plan 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
FiO2 
Fraction of Inspired Oxygen 
GCP 
Good Clinical Practice 
GUI 
Genitourinary Medicine 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MC 
Manual Control 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MRI 
Magnetic Resonance Imaging 
N 
Number (of subjects) 
O2 
Oxygen 
PaO2 
Partial Pressure Arterial Oxygen 
PCLC 
Physiologic Closed-Loop Control 
PEEP 
Positive End-Expiratory Pressure 

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ZOLL FIO2 CLC Protocol 
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PHI 
Protected Health Information 
PI 
Principal Investigator 
PID 
Proportional Integral Derivative controller 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SaO2 
Oxygen Saturation 
SOP 
Standard Operating Procedure 
SpO2 
Saturation of Peripheral Oxygen 
UAP 
Unanticipated Problem 
 
 

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ZOLL FIO2 CLC Protocol 
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1. PROTOCOL SUMMARY 
Title: 
FiO2 Closed-Loop Control Using the ZOLL 731 Series Ventilator.  
Précis: 
A randomized, multicentere trial involving critically-ill patients 
comparing conventional, manual control of inspired oxygen (FiO2) 
within a target range, with a computer-controlled, closed-loop FiO2 
delivery using an FDA-cleared continuous ventilator.   
Objectives: 
 
The objective of this study is to demonstrate that physiologic closed-
loop control (PCLC) is at least as safe and effective as manual control 
in keeping hemoglobin oxygen saturation (SpO2) within the target 
range of 92 to 96%.  
The primary efficacy outcome is the relative duration as defined 
by  the total duration of minutes with SpO2 within the target range of 
92 to 96% divided by 720 minutes (the planned duration of the 
study).  Similarly the relative duration for the primary safety outcome 
is defined as the total duration of time that the SpO2 level at or above 
88% divided by 720 minutes. 
Hypothesis: 
We plan to conduct a 2-state statistical test: non-inferiority followed 
by a superiority test. Demonstration of non-inferiority for both the 
effectiveness and safety endpoints is required for study success. 
 
Primary effectiveness for non-inferiority: The use of PCLC to 
maintain oxygen saturation (SpO2) within the target range of 92 to 
96%, as measured by the relative duration, is not inferior to the 
manual control (MC). 
 
Secondary effectiveness for non-inferiority: The use of PCLC to 
maintain orxygen saturation (SpO2) within the targe range of 92 to 
96% when FiO2 > 21% and SpO2 ≥ 92% when FiO2 = 21%, as measured by 
the relative duration, is not inferior to the manual control (MC) group. 
 
Primary effectiveness for superiority: The relative duration of time 
with SpO2 within the target range of 92 to 96% is greater in the  PCLC 
compared with manual control (MC) group. 
 
 
Secondary effectiveness for superiority: The relative duration of time 
with SpO2 within the target range of 92 to 96% when FiO2 > 21% and 

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ZOLL FIO2 CLC Protocol 
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SpO2 ≥ 92% when FiO2 = 21%, as measured by the relative duration, is 
greater in the PCLC compared with manual control (MC) group.    
       
Primary safety: The use of PCLC to maintain the SpO2 level at or 
above 88%, as measured by relative duration of time, is not inferior to 
the manual control (MC). 
 
Population: 
The study population will consist of 210 critically-ill patients, male and 
female, between the ages of 18 - 65 who have been exposed to 
trauma and require mechanical ventilation and supplemental oxygen.   
 
 

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ZOLL FIO2 CLC Protocol 
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Number of Sites:  
 
 
4 Sites 
1. The University of Cincinnati Level 1 Trauma Center (Cincinnati, 
Ohio) 
2. The Los Angeles County Medical Center Level 1 Trauma Center 
(Los Angeles, California) 
3. University of Texas Health Science Center at Houston Level 1 
Trauma Center (Houston, Texas) 
4. Regions Hospital Level 1 Trauma Center (St. Paul, Minnesota) 
Description of  
Intervention: 
The trial will use 
 
for automatic adjustment of FiO2 to maintain the SpO2 
within a target range, based on continuous use of pulse oximetry.  
Intubated subjects will be randomized to either manual control of 
FiO2 or closed-loop control of FiO2, during a 12-hour period. The PCLC 
is designed to respond to acute hypoxemia (SpO2 <88%) within 
seconds while preventing hypoxemia and minimizing exposure to 
excessive inspired oxygen levels. 
Study Duration: 
15 months 
Subject Participation 
Duration: 
12 hours of study and 24 hours for follow-up. 
Estimated Time to 
Complete Enrollment: 
12 months 

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ZOLL FIO2 CLC Protocol 
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Schematic of Study Design: 
 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Time 0 
 
 
 
Time 1 
 
 
Time 2 
 
 
 
 
Time 3 
 
 
 
Time 4 
 
 
 
Total N:  Obtain informed consent from legally authorized representative (Informed 
Consent form). Screen potential subjects by inclusion and exclusion criteria; obtain 
history, document status. 
Perform baseline assessments. 
Collect demographic, anatomic injury severity score (ISS), physiologic APACHE II 
markers of disease severity, and admitting diagnoses  Peform initial arterial blood 
gases prior to start of the study.  
  
Follow up 
Final Assessments 
Randomize 
Arm 2 
105 subjects 
Arm 1 
105 subjects 
Start on either manual control or closed-loop control ventilation for 12 hours. 
  
End treatment period 

10 
 
2. KEY ROLES AND CONTACT INFORMATION 
 
Trial Sponsor: 
Primary Contact: 
Address: 
 
Phone Numbers: 
Email: 
ZOLL Medical Corporation 
Elizabeth McMeniman, Associate Director of Regulatory Affairs  
269 Mill Road 
Chelmsford, MA 01824 
office 978-421-9291; fax 978-421-0010 
emcmeniman@zoll.com  
Principal 
Investigator:   
Michael Goodman, MD 
Co-Investigators: 
Kenji Inaba, MD (LA); Meghan Lewis, MD (LA); Laura Moore, MD 
(Houston); Bruce Bennett, MD (St. Paul). 
 
Institutions: 
University of Cincinnati 
University Hospital Medical Center 
Cincinnati, OH 45229 
Phone: (513) 558-6524 
Email: michael.goodman@uc.edu 
 
 
Los Angeles County and University of Southern California (LAC-USC) 
Medical Center 
1200 N. State Street 
Los Angeles, CA 90033 
Principal Investigators: Kenji Inaba, MD, FRCSC, FACS; Meghan 
Lewis, MD 
Phone: (323) 409-7762 
Email: meghan.lewis@med.usc.edu  
Fax: (323) 441-9909 
 
 
University of Texas Health Science Center at Houston 
7000 Fannin 

11 
 
Houston, TX 77030-5401 
Principal Investigator: Laura Moore, MD 
Phone: (713) 500-5493 
Email: Laura.J.Moore@uth.tmc.edu 
 
 
Regions Hospital 
640 Jackson Street 
St. Paul, MN 55101 
Principal Investigator: Bruce Bennett, MD 
Phone: (651) 254-6979 
Email: bruce.a.bennett@healthpartners.com 
 
Medical Monitor 
Greg Mears, MD 
Phone: (303) 801-1892 
Email: gmears@zoll.com 
Other Key 
Personnel: 
Statistician - Eileen King, PhD 

12 
 
3.  INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
3.1 Background Information 
The specific aim of this IDE clinical study is to test a ventilator closed-loop algorithm which will 
continuously adjust the level of inspired oxygen concentration (FiO2) using physiologic closed-
loop control (PCLC) to maintain a target level of hemoglobin oxygen saturation (SpO2) based on 
readings from a pulse oximeter in critically ill patients in the Surgical ICU. Results from the study 
will be applicable to patients in the prehospital environment as well as during transport or 
during mass casualty events.  
3.1.1 Device Description 
The 731 Series ventilator used in the study is identical to the FDA-cleared device (K071526, 
K091238, K103318, K111473) except that the software has been revised to include FiO2 
physiologic closed-loop control algorithm. The ventilator has been cleared for use in the 
hospital and in the prehospital environment as well as during transport. In addition, the military 
has approved the device for use in all military ground and air transport vehicles.   
This study will use a 
 for automatic 
adjustment of FiO2 to maintain the SpO2 at a target value (94% ±1%), see figure 1 and 2. It is 
also designed to respond to acute hypoxemia (SpO2 <88%) within seconds and minimize 
exposure to excessive inspired oxygen. The proposed system is intended for prehospital and 
military use in far forward areas where O2 supplies are limited. By reducing unnecessarily high 
FiO2 the system will reduce exposure of the lungs to O2 and save O2 resources. Additionally, 
preventing hyperoxemia may mitigate the untoward effects of overwhelming oxidative stress.  
The system to be studied uses pulse oximetry for continuous monitoring of oxygenation.
 
 
 
 
 
 
 
 
 
 
 
                                               
 
* 
 

14 
 
 
 
 
 

15 
 
Accessories:  
For the purpose of the study, each device shall be packaged with the standard 731 Series 
accessories which include: AC/DC power supply (p/n 024-0012-00), 6’ AC power cord (US, p/n 
708-0042-00), pulse oximeter connection cable (p/n 708-0037-00), test lung (p/n 820-0132-00) 
and high-pressure oxygen hose (p/n 825-0002-00). Single-patient use consumables: ventilator 
circuit (p/n 820-0106-00) and pulse oximeter sensor (p/n LNCS Adxt), shall be provided in bulk 
packs for use by the investigational team at no cost. All the these accessories have been 
reviewed and cleared with 731 Series Ventilator 510(k) submission.  
In addition, a modified version of the user manual with specific labeling related to CLC shall be 
supplied with each device. A separate package shall contain the laptop, its power supply and the 
USB data connection cable. 
Intended Use: 
The intended use aligns with the intended use of the cleared 731 ventilators except that the 
patient population for PCLC use is in keeping with the study population.  
The Model 731 ventilator is indicated for use in the management of infant through adult 
patients weighing ≥5 kg with acute or chronic respiratory failure or during resuscitation by 
providing continuous positive-pressure ventilation. The FiO2 physiologic closed-loop control 
functionality is intended only for use with patients 18 to 65 years of age who require mechanical 
ventilation as a result of trauma or acute surgical illness who would benefit from automatic 
control of their oxygenation. It is appropriate for use outside the hospital, during transport and 
in austere environments where they may be exposed to rain, dust, rough handling and extremes 
in temperature and humidity. In addition, the device is cleared for use in an MRI environment 
when specifically marked with the “MRI conditional” labeling. It is also not intended for use in 
explosive environments. With an appropriate third-party filter in place, they may be operated in 
environments where chemical and/or biological toxins are present (see External Filter Use in the 
Operation Manual). The Model 731 ventilators is intended for use by skilled care providers with 
knowledge of mechanical ventilation, emergency medical services (EMS) personnel with a basic 
knowledge of mechanical ventilation and by first responders under the direction of skilled 
medical care providers. The device has a full range of ventilation modes (AC, SIMV, CPAP with PS 
and NPPV-PPV).  
For the purposes of the proposed investigation, the device will be labeled for investigational use 
and under the control of the investigational team.  
 
 
 
 
 

16 
 
3.2 Rationale and Report of Prior Investigations 
For mechanically ventilated patients, maintenance of adequate oxygenation is a primary goal 
because hypoxemia can lead to cellular hypoxia, organ dysfunction, and/or death.1, 2 At the 
same time, hyperoxemia should be avoided because of the potentially toxic effects of 
supplemental oxygen3-5 and reported detrimental clinical impact of hyperoxemia.6-8 With the 
current standard of care, clinicians manually adjust ventilator settings in order to maintain 
normoxemia; however, normoxia is not always achieved with manual adjustment.9 Automated 
or physiologic closed-loop control (PCLC) of ventilation has potential advantages. With PCLC, 
physiological feedback is used to control the state or output of a dynamic system. Potential 
benefits of CLC are: 1) quicker continuous intervention compared to intermittent caregiver 
intervention, 2) consistent treatment based on physiology and proven algorithms, and 3) 
continued, appropriate treatment in the absence of a skilled caregiver. Medical applications of 
PCLC include anesthesia delivery, fluid delivery, and mechanical ventilation.10-15 Use of PCLC of 
FiO2 is most prevalent in the neonatal population where avoidance of hyperoxemia and 
hypoxemia are especially critical.16, 17   
 
Automated or PCLC of ventilation may be especially valuable for remote operations and 
enroute care (ERC) because PCLC allows for optimal care regardless of location or care team. 
With military and civilian prehospital operations, patients are not always managed by 
physicians or care providers with advanced training. As a result, optimal care or even the 
standard of care may not be possible in prehospital and/or military environments. Even with 
highly trained personnel, ERC of critically injured patients is challenging. During transport 
healthcare providers are faced with space restriction, poor patient access, and vehicle 
motion/turbulence, which make the delivery of high quality patient care difficult. Healthcare 
providers also may risk their own safety during transport because, in order to properly access 
patients, they are often unrestrained.18 Especially in the military setting, clinicians must balance 
the needs of multiple high acuity patients simultaneously during transport and thus may not 
have the capacity to continuously monitor and treat all patients.   
 
While maintenance of adequate oxygenation and prevention of hypoxemia are the primary 
goals for patients requiring ventilation, oxygen consumption is an additional concern with 
military operations. During Critical Care Air Transport (CCAT) by the US Air Force Critical Care 
Air Transport Teams (CCATT), oxygen supplies account for nearly one-third of the mission 
weight. Mission planning commonly involves calculation of required oxygen needs and doubling 
of that value as a margin of safety. Uniform automated control of FiO2 could result in a 
reduction in the amount of O2 used to support patients during ERC by preventing inadvertent 
hyperoxia.  
 

17 
 
Our PCLC of FiO2 system was developed to automatically monitor and manage life support 
ensuring adequate steady-state oxygenation, immediate response to acute desaturation 
events, and controlled use of oxygen for mechanically ventilated patients regardless of the 
treatment location or care team. This review provides a summary of prior investigations related 
to the use of automated control of the FiO2 in mechanically ventilated patients and provides 
justification for the proposed study.     
 
3.2.1 Summary of Investigations of other PCLC of FiO2 Systems 
 
Preclinical FiO2 Physiologic Closed-Loop Control Systems 
The first system of PCLC of FiO2, which used SaO2 as the physiological input, was described in 
1975 by Mitamura et al.19 Although the system was rudimentary, it was effective at maintaining 
SaO2 in animals when changes in SaO2 were minimal. In a series of three investigations, Tehrani 
and colleagues studied a microprocessor controlled system using proportional-integral-
derivative control (PID) to automatically adjust FIO2 using pulse oximetry.20-23 In this series of 
lung model and animal experiments the authors found that the controller was capable of 
restoring oxygen saturation to physiologic levels within 20-25 seconds.20, 21 The authors 
concluded that the system was capable of correcting hypoxemia within seconds while 
preventing hyperoxia, eliminating artifacts, and minimizing oxygen exposure. While they cited 
the need for patient trials, none were accomplished. Raemer et al., also used a PID controller to 
adjust FiO2 based on SpO2 input in a series of animal experiments.24 This system also used an 
artifact rejection algorithm and adjusted the FiO2 gain based on the error signal (difference 
between actual and desired SpO2) and minute ventilation. The response time to reach a stable 
SpO2 after a change in FiO2 was 50-70 seconds. Yu and colleagues also used computer 
simulation to demonstrate the performance of a FiO2 control system and an animal experiment 
validated the model.25 
 
Clinical FiO2 Closed Loop and Open Loop Control Systems in Adults 
Recently, an automatic control of FiO2 system (Evita XL ventilator and Masimo SpO2) was tested 
on 20 ICU patients and compared to 30 historical control patients treated by standard of care 
(manual FiO2 adjustment by nursing staff).26 The system was operated as an open-loop control 
system with a research nurse at the patient’s bedside at all times. Two algorithms with different 
SpO2/FiO2 slopes were tested using a cross-over design. Both algorithms targeted SpO2 of 92to 
96% and acted to increase FiO2 to 100% when SpO2 fell below 85%.  For the patients treated 
with the open loop FiO2 control system, SpO2 was in target range >95% of the time. The steeper 
SpO2/FiO2 slope was slightly better at maintaining SpO2 in target range for the patients that 
were more hypoxemic (PaO2/FiO2<188). Compared to historical controls, patients treated with 
the open-loop FiO2 control spent less time in hypoxemic and hyperoxemic states. 

18 
 
 
Another more complex system of PCLC ventilation, which includes PCLC of FiO2 and PEEP as 
well as adaptive support ventilation (i.e. control of mandatory rate, inspiratory time, tidal 
volume, and inspiratory pressure), has been studied extensively. The safety of this PCLC system 
has been demonstrated in adult patients with normal lungs, ARDS, COPD, post cardiac surgery 
12, 27-30 as well as during weaning from ventilator support of adult13 and pediatric patients.31 A 
lung model also showed good performance of the PCLC system in 4 clinical scenarios (normal 
lungs, brain injury, ARDS, COPD 32 This system has an ability to set target SpO2. Lower setting of 
SpO2 (90 to 92%) resulted in less oxygen use in ICU patients but had no impact on biochemical, 
physiological, or clinical outcomes. While there is ongoing research and use of FiO2 PCLC in 
adults in Europe, the majority of FiO2 control has focused on use in neonates where both 
hypoxia and hyperoxia create significant pathology for these patients.  
 
PCLC systems have also been developed for devices that administer long-term oxygen 
therapy.33, 34 These systems (AccuO2 and O2 Flow Regulator) autonomously titrate the volume 
of oxygen delivered to a patient in response to changes SpO2. In one study, 28 COPD patients 
were treated in a randomized cross-over design with a standard continuous-flow O2 delivery 
system, the CR-50 O2 conserving device, or the AccuO2 CLC system.33 All three systems 
maintained SpO2 near target range but the AccuO2 systems did so with less variability. 
Moreover, the AccuO2 system conserved more oxygen. In another study with a randomized 
crossover design, patients with chronic lung disease were treated during exercise using the 
PCLC O2 Flow Regulator or manual oxygen flow titration by a respiratory therapist.34 Overall, 
SpO2 was higher and less time was spent below SpO2 target when the O2 Flow Regulator PCLC 
system was used.   
 
FiO2 Closed Loop Control Systems in Neonates 
Automated control of FiO2 has been studied most extensively in preterm infants. Control of 
oxygenation is particularly important for preterm infants because hypoxemia is associated with 
increased mortality whereas hyperoxemia can result in severe complications such as 
retinopathy, bronchopulmonary dysplasia, brain injury, and childhood cancer.35-37 PCLC of FiO2 
was validated using simulation in 1985.38 Beddis and Dugdale were amongst the first to study 
PCLC of FiO2 in neonatal patients.39-41 Using an indwelling umbilical PO2 electrode the authors 
were able to demonstrate that the desired range of PaO2 was achieved more frequently during 
closed-loop control compared with manual control (Beddis et al 88% PCLC vs. 72% manual; 
Dugdale et al 75% vs. 45%). Since those first studies, there have been numerous studies of PCLC 
systems of FiO2 with SpO2 as the physiological sensor.16, 17, 42-52 The table below summarizes the 
literature. In all these randomized crossover studies, PCLC of FiO2 was compared to either 
“optimal manual control,” in which an investigator or research nurse was constantly present at 
the patient’s side and fully dedicated to manual FiO2 control, or “routine manual control” in 

19 
 
which the nurse on duty (responsible for 2 or 3 patients) was told to adjust FiO2 as needed to 
maintain SpO2 in the desired range. In all studies, the percent of time in target range was higher 
with PCLC compared with routine manual care and was similar or higher with PCLC compared 
with optimal manual care. Hyperoxia was also avoided with use of PCLC. The incidence of 
extreme hypoxia was comparable or lower with PCLC. 
 
With a different study design, Wilinska and colleagues used the Avea ventilator FiO2 PCLC 
system with Masimo pulse oximeter technology to treat preterm infants.53 In this crossover 
study, the target SpO2 range was alternated between 87-93% and 90-93% every 12 hours over 3 
days. In this study with prolonged use of PCLC, manual FiO2 adjustments were infrequent (<2 
per day). Although the purpose of this study was to compare saturation with two different SpO2 
target ranges, it demonstrated the feasibility of prolonged use of PCLC of FiO2. 
 
Together, these clinical studies demonstrate that PCLC of FiO2 has been safely used to treat 
extremely vulnerable and fragile preterm infants.   
3.2.2 Summary of Investigations of our PCLC of FiO2 System 
 
Computer Simulation 
Our PCLC of FiO2 algorithm has been validated using computer simulation 
 
 
 
 
 
 
 
 
Preliminary Preclinical Trial 
The initial preclinical trial of our PCLC of FiO2 system, which was conducted in 2003-2004, is 
unpublished but described in the attached DARPA report (Darpa Final Report V2.pdf). 
 
    
 
 
 
 
 
 
 

21 
 
 
 
 
 
 
 
.  
 
In summary, this preliminary preclinical study demonstrated the feasibility of our PCLC FiO2 
algorithm as target SpO2 was consistently achieved. 
 
 
 
Recent Preclinical Investigation in Animals with Lung Injury  
In our most recent study we tested our PCLC system in a porcine model of combined 
hemorrhagic shock and acute lung injury.56 We hypothesized that the PCLC would reliably 
maintain safe levels of oxygen saturation in both injured and uninjured animals. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
.  
 

 
 
 
 
 
 
 
 
 
 
 
 
The study examined the ability of the PCLC system to maintain oxygenation in a porcine model 
of hemorrhagic shock and acute lung injury. We found that the PCLC system responded to 
changes in SpO2 with appropriate increases and decreases in FIO2 and maintained the target 
SpO2 range comparably in both injured and uninjured animals.  
 
Enroute Care, In Situ Data Collection 
In an effort to understand the mechanical ventilation challenges faced during en route care and 
to demonstrate use of our ventilator and integrated pulse oximeter in this setting, we collected 
data from a series of ventilated warfighter patients during en route care.59 Twenty-two patients 
were monitored as they were evacuated by USAF CCAT teams from Balad Air Base, Iraq to 
Landstuhl Regional Medical Center (LRMC), Germany during the time period of June to 
September 2006. Patients were managed following the standard of care and monitored both 
with the pulse oximeter from the critical care monitor and a pulse oximeter integrated into the 
Impact 754 ventilator. The preexisting RS-232 data port on the Impact 754 ventilator was used 
to download ventilator settings, and monitored values (i.e. HR and SpO2) every 5 seconds to a 
separate laptop computer.  
 
All 22 subjects survived transport from Iraq to Germany and the data set included 117 hours of 
continuous recording. For five patients, there were no recorded ventilatory changes in flight. 
Three desaturation events, <90%, were recorded lasting 35, 115, and 280 seconds. No 
interventions were recorded during the desaturation events with spontaneous resolution in all 
patients. The FiO2 ranged from 24 - 100% with an average of 49%. FiO2 was the most common 
ventilatory change made by CCAT teams en route averaging 0.27 changes per hour.  SpO2 
ranged from 85 - 100% with a mean of 98%.  
 
Desaturation was defined as a recorded SpO2 of less than 90%. The following three episodes 
were seen: 85% nadir for 35 seconds, 86% nadir for 115 seconds and an 89% nadir for 280 
seconds. No interventions in mechanical ventilation were seen during these desaturation 
episodes with spontaneous resolution to a SpO2 of ≥90% in all patients. 

23 
 
 
Overall the study was the first effort to collect data from patients on life support during enroute 
care. It may be that the human factors in the context of this difficult mission are the most 
important finding. Despite the care provider to patient ratio of no more than 2 patients/team 
(critical care physician, critical care nurse and respiratory therapist), 3 of 22 patients had 
desaturation events (14%) that were unwitnessed and untreated. This finding should not reflect 
negatively on the efforts or skill of the CCAT team but rather on the exceedingly difficult 
challenge of caring for these patients during en route care. It is this context that led us to 
propose that autonomous controller(s) could be beneficial when care providers are not 
available to monitor or manage the patient or when other mission needs (other patients or the 
safety of the care provider is in jeopardy).  
 
Initial Clinical Trial 
We subsequently applied for and received an IDE 
 to study FiO2 PCLC in multi-trauma 
patients who required mechanical ventilation. The results from the first subset of patients were 
published60
 
 
 
The PCLC system used for this study was similar to the system used for the initial preclinical 
study described
 
 
  
 
A total of 95 mechanically ventilated trauma patients were enrolled in this randomized 
crossover study. In random order, patients were treated for 4 hours with the ventilator FiO2 
adjusted by a respiratory therapist according to standard practice and 4 hours with FiO2 
adjusted automatically by the PCLC system. During the control period, clinicians aimed to 
maintain SpO2 of >94% and reduce FiO2 to nontoxic levels (FiO2 <0.50). During the automated 
control period, the PCLC system adjusted FiO2 to a target SpO2 of 94 ±2%. The study was 
conducted with a safety monitor at the bedside.   
 
The primary safety endpoint, total duration of desaturation (SpO2 <88%), was significantly 
longer with manual control compared with automated control (1.25 ±2.64 minutes vs. 0.55 
±1.37 minutes, p=0.0018). SpO2 was maintained in the target SpO2 range of 92 to 96% more 
often during the automated control period compared with the manual control period 
(p<0.001). Oxygen use was significantly lower during the automated control period (1.91 ±1.51 
L/min) compared with manual control period (3.04 ±1.37 L/min, p<0.001). 

25 
 
3.3 Potential Risks 
The risks associated with this trial are minimal.   
Subject risks: 
All subjects will require intubation and mechanical ventilation. The ventilator used in the study 
performs identically to the FDA-cleared device (K071526, K091238, K103318, K111473). There 
are many risks associated with intubation and mechanical ventilation, quite apart from the 
investigational portion of this protocol. These are addressed in the Instructions for Use and 
User Manual for the 731 Series ventilator. The investigational portion of the protocol is the 
algorithm which automatically adjusts the FiO2. During the study, SpO2 will be monitored by 
two pulse oximeters, one used as the input for the FiO2 control and the second as a redundant 
safety monitor.   
Patients enrolled in the trial will have been subject to traumatic injuries or acute surgical illness 
requiring surgical intervention. The multitrauma found in the civilian setting is quite analogous 
to the trauma that can result from combat: penetrating and blunt as well as severe 
hemorrhage. These injuries along with acute surgical illness may include crush injuries, sepsis, 
and blood loss. are anticipated. In the feasibility study, we observed very few safety adverse 
events related to patient condition.  
During the study, SpO2 will be monitored by two pulse oximeters: one used for the output of 
the FiO2 controller and the second as a redundant safety monitor. All subjects will continue to 
be monitored using standard intensive care protocol. Adverse events will be verified based on 
observation, bedside notes and the subject's medical record. 
Appendix A provides the definitions for possible adverse events, including definitions for the 
seriousness, relatedness and device/procedure relatedness. 
Increased oxygen desaturation due to progressive lung dysfunction and missed diagnosis or 
delayed treatment of a condition that causes desaturation (pulmonary embolism, 
pneumothorax, pneumonia) as a result of PCLC titrating are rare and given the use of the 
controller, the subjects oxygenation is maintained. 
 
 
 
 
 
Progressive lung dysfunction in this patient population may be difficult to diagnosis within the 
12-hour study period. Increased neutrophilia, defencins, and other inflammatory responses 
may lead to increased lung permeability. The current protocol is clear on how to proceed. If 
there is a sustained increase in FiO2 without an increase in O2 saturation, then the subject will 
be evaluated by the clinical team and other diagnostic measures will be employed: chest x-ray, 
ultrasound, CT scan to assist in understanding the sustained desaturation.   

26 
 
Progressive lung dysfunction may occur in the presence of pneumothorax, pneumonia, 
pulmonary embolism or other condition(s) directly related to the subject’s traumatic injuries. 
We anticipate that if progressive lung dysfunction does occur, FiO2 will be maximized to ensure 
oxygen saturations above the 92% level. In addition, subjects will be evaluated by the clinical 
team at the institution to determine any additional diagnostic or therapeutic measures, such as 
CT scan, PEEP, anticoagulant therapy, etc.  
In cases where the FiO2 cannot be titrated from 1.0, the subject will continue in the manual 
control but the data will not be used because an FiO2 of 1.0 will not inform the study. 
Delay of treatment of a condition that causes desaturation is unlikely to occur in this patient 
population. Subjects will be cared for in a 2:1 ratio with an ICU nurse and a respiratory 
therapist. Symptoms of sustained hypoxia will be noted immediately and strategies employed 
to treat the hypoxemia will be employed, even in the absence of a specific diagnosis. Pulmonary 
embolism, pneumonias or pneumothorax will be readily diagnosed with diagnostic radiological 
tests. 
Ventilator risks: 
There are known risks associated with all ventilatory strategies. These are well known and 
characterized in the 731 Operation Manual. The PCLC adapted Operation Manual also includes 
specific information on the operation and management of the device during PCLC operation. 
There are no unanticipated ventilator-centric risks associated with this protocol. 
3.4 Potential Benefits 
One potential benefit to participants is the constant equilibration of oxygen saturation to 
remain within the physiologic target range of 92 to 96%, preventing exposure to excessive 
inspired O2 levels while at the same time preventing transient hypoxemia. 
Another potential benefit will be the ability to prevent hyperoxemia, by keeping the SpO2 
within the target range. 

27 
 
4. STUDY OBJECTIVES 
The specific objective of this IDE clinical study is to test a physiologic closed-loop algorithm 
which will continuously adjust the level of inspired oxygen concentration (FiO2) of a mechanical 
ventilator using physiologic closed-loop control (PCLC) to maintain a target level of hemoglobin 
oxygen saturation (SpO2) based on readings from a pulse oximeter in critically ill patients in the 
Surgical ICU. Results from the study will be applicable to patients in the hospital and in the 
prehospital environment as well as during transport. The 731 Series ventilator used in the study 
is identical to the FDA-cleared device (K071526, K091238, K103318, K111473) except that the 
software has been revised to support include FiO2 control algorithm. In addition, the military 
has approved the device for use in all military ground and air transport vehicles.  
4.1 Primary Objective 
The primary effectiveness objective is to demonstrate that use of PCLC is not inferior to the 
manual control in keeping hemoglobin oxygen saturation (SpO2) within the target range of 92 
to 96% while the primary safety objective is to demonstrate that the use of PCLC is not inferior 
to the manual control in maintaining the oxygen saturation (SpO2) at or above 88% level. 
4.1.1a Primary effectiveness variable: 
To assess the  relative duration of time with SpO2 between 92 and 96% (inclusive) during the 
study period. 
4.1.1b Secondary effectiveness variable: 
To assess the relative duration of time with SpO2 between 92 and 96% (inclusive) when 
FiO2>21% and SpO2 ≥ 92% when FiO2 = 21%. 
4.1.2a Primary effectiveness hypothesis 
The use of PCLC to maintain hemoglobin oxygen saturation (SpO2) within the target range of 92 
to 96%, as measured by the relative duration, is not inferior to the manual control (MC). 
4.1.2b Secondary effectiveness hypothesis 
The use of PCLC to maintain hemoglobin oxygen saturation (SpO2) within the target range of 92 
to 96% when FiO2 > 21% and SpO2 ≥92% when FiO2 = 21%, as measured by the relative duration, 
is not inferior to the manual control (MC). 
 
4.1.3 Primary safety variable 
To assess the  relative duration of time with SpO2 <88% during the study period. 
4.1.4 Primary safety hypothesis 
The use of PCLC to maintain hemoglobin oxygen saturation (SpO2) level at or above 88%, as 
measured by the relative  duration, is not inferior to the manual control (MC). 

28 
 
4.2 Secondary Objectives 
Four additional safety related question will be addressed: 
1. The rate of serious adverse events related to the PCLC is not different than those attributed 
to the MC group 
2. The rate of serious adverse events not related to the PCLC is not different than those 
attributed to the MC group 
3. The number of missed diagnosis attributed to the PCLC is not different than those 
attributed to the MC group 
4. The rate of device related adverse events related to the PCLC is not different than those 
attributed to the MC group.  
4.3 Study Design 
• The trial will employ a two group parallel design in which subjects will be randomized to one 
of the two ventilatory strategies for a 12 hour period. Twelve hours was selected because it 
captures most scenarios where mechanical ventilation could be required in the preshospital 
and transport environments in both military and civilian use. The two ventilatory strategies 
are: 1) manual adjustment of the ventilator FiO2 by the treatment team based on physician 
order or according to current protocol (manual control period) or 2) automatic adjustment 
by the system algorithm (closed-loop period). Manual adjustment will use the same SpO2 
target (94%) as the closed loop system. During closed-loop control, the FiO2 can be over-
ridden by the clinician at any time. 
 
• This is a multicenter trial with four sites (The University of Cincinnati Level 1 Trauma Center, 
The Los Angeles County Medical Center Level 1 Trauma Center, The University of Texas 
Health Science Center at Houston Level 1 Trauma Center, and Regions Hospital Level 1 
Trauma Center). All patients age 18 to 65 inclusive admitted to the Trauma/Acute Care 
service and requiring invasive mechanical ventilation will be screened for the study. This age 
range is intended to represent the group of warfighters and support personnel to be 
treated with this system. These patients will be unable to provide consent due to the 
severity of their injuries. Their legal representative will be approached as soon as possible. 
Once consent has been obtained the patient will be randomly assigned to one of the two 
study arms and enrolled in the study; subjects are not considered to be enrolled in the 
study until they have been successfully randomized to receive either CLC or manual control 
of the study ventilator.   
 
• Baseline characteristics including demographic information, anatomic Injury Severity Score 
(ISS), physical exam findings, and physiologic (APACHE II) markers of disease severity, and 
admitting diagnoses will be assessed for all subjects. An arterial blood gas obtained prior to 
study enrollment will be recorded to define the degree of lung injury. Ventilator settings 
and vital signs immediately prior to the start of the clinical study will also be recorded. 

29 
 
Subjects will be studied for a total of 12 hours and will be monitored for an additional 24 
hours 
 
• During the entire study period, oxyhemoglobin saturation (SpO2) will be continuously 
recorded. In addition, patient vital signs and ventilator settings (mode, respiratory rate, tidal 
volume, FiO2, airway pressures, PEEP) will be monitored continuously and recorded. Any 
blood gases (including pH, PaCO2, and PaO2) performed for routine care will also be 
recorded. Following the first hour of each study period, a single blood gas will be drawn to 
verify the relationship of SpO2 and SaO2 and to assure adequate PaCO2 and pH. The total 
amount of blood drawn will be ~1 teaspoon (5 ml). During each study period the number of 
manipulations of FiO2 by clinicians and by the system algorithm will be recorded 
automatically. The Case Report Form will also capture the times of any clinically significant 
events (hypotension, defibrillation, adjustment of FiO2 by ≥10%) and these times will be 
merged to the measurement times. This data acquisition plan (collection of data from the 
monitor, ventilator, and CRF elements) will provide the ability to interpret the results in 
detail and monitor the safety of the trial. 
 
As noted previously, the primary efficacy variable will be control of SpO2 within the target 
range, 92 to 96%. The table below compares the protocol for both the manual and PCLC 
periods. 
 
Variable 
Manual Control 
Closed-Loop Control 
FiO2 
Set as directed by clinician  
Set as directed by clinician 
SpO2 Target 
92 to 96% following the Manual 
Protocol, Figure 3 
92 to 96%, using the PCLC 
system 
SpO2 Desaturation 
Upper Limit 
88% 
88% 
If Desaturation Occurs 
Follow manual control protocol 
(figure 3) 
Permit closed-loop algorithm 
to manage unless otherwise 
directed by clinician. 
 
 
 
 
 
 
 
 
 
 
 
 

30 
 
 
 
When the subject is in the manual control period, FiO2 will be adjusted manually following the 
protocol in Figure 3. If SpO2 falls below 88%, the ventilator will trigger the Low SpO2 alarm 
(medium priority) and the treatment team will respond and take corrective actions. This is the 
current standard of care. In order for this to take place, the alarm must trigger, a caregiver must 
respond, determine the cause, and take corrective action. 
 
Figure 3 
The closed-loop control system includes both audible and visual alarms to alert the clinician of 
an unreliable signal from the pulse oximeter, malposition of the pulse oximeter sensor, and 
subject SpO2 less than 88%. Details of these alarms are documented in Appendix B which is 
taken from the Operation Manual. All alarms and low SpO2 conditions will be recorded 
automatically on the laptop computer data logger. 
If the subject requires a procedure in the ICU that the standard of care requires an increase in 
FiO2 to 1.0 (e.g. bronchoscopy) the data collection will automatically continue but such data will 

31 
 
not be considered in the statistical analysis because such procedures are not part of the trial 
protocol. The Case Report Form will capture such events and note the times that such 
procedures began and were completed. Data inclusion in the statistical analysis will resume 
once FiO2 control returns to the trial protocol. If the subject requires transfer to the operating 
room, radiology for treatment or some other non-ICU location, data collection will not be 
included in the statistical analysis until the subject returns to the ICU. These incidents outside of 
the ICU will also be captured on the Case Report Form. The goal of the study will be to have a 
minimum of 12 hours of data collection for each subject in either arm of the study 

32 
 
5. STUDY ENROLLMENT AND WITHDRAWAL 
5.1 Study population 
All patients between the ages of 18 and 65 inclusive, admitted to the Trauma/Acute Care 
service and requiring invasive mechanical ventilation will be screened for the study. This age 
range is intended to represent the group of warfighters and support personnel to be treated 
with this system. 
5.2 Sample size 
The target sample size is 105 subjects per study arm for a total of 210 subjects. The detail of the 
sample size estimation is given in section 12. 
5.3 Subject Inclusion Criteria 
All subjects must meet all of the inclusion criteria and none of the exclusion criteria in order to 
be eligible to participate: 
• The subject's legally authorized representative will provide signed and dated informed 
consent. 
• Age 18 - 65, inclusive. 
• Admission to a surgical or neurosurgical intensive care unit following traumatic injury or 
acute surgical illness 
• Requirement for endotracheal intubation 
• Requirement for mechanical ventilation 
• Patient is currently receiving inspired oxygen concentration (FiO2) ≥40% 
5.4 Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
• Age under 18 or over 65  
• Isolated or severe head injury (Glasgow Coma Scale = 6 or less) with expected 
survival less than 24 hours 
• Brain death 
• Anticipated survival less than 48 hours 

33 
 
• Pregnant female 
• Patient in whom a pulse oximeter cannot detect a reliable signal due to hypotension, 
hypothermia, or other injury 
• Known carbon monoxide poisoning 
• Uncontrolled diabetic 
• Patient who is unable to maintain SpO2 level of 88% at an FiO2 of 100% due to their 
medical condition. 
(NOTE: Being in the trial would impose no additional risk to a patient who presents 
with this condition however, data from a patient presenting with this 
pathophysiology would not provide insight into the performance of the controller as 
it would simply maintain that patient on an FiO2 of 100%.) 
• Patient with chronic hypercarbia. 
• Patient where a physician believes that FiO2 PCLC could be detrimental to the 
management of the patient. 
• Prisoner 
• SpO2 to SaO2 difference >4% 
• Patient with core temperature <35° C 
5.5 Strategies for Recruitment and Retention 
There will be no compensation to subjects for study participation.   
We anticipate subject participation not to exceed 24 hours of data collection (to produce 12 
hours of evaluable data) for the entire study; however subjects will be monitored for adverse 
events for 24 hours following the end of the intervention. Subjects will be terminated from the 
study after the 24 hour period ends. 
We have chosen the four Level 1 trauma units to maximize recruitment of a study population 
that meets all of the inclusion criteria. Each trauma unit admits approximately 85 trauma 
patients/year that would be eligible for this study and we plan to recruit equal numbers of 
subjects from each trauma unit. If this is not feasible, no more than 60% of the total subjects 
will come from a single study site.  

34 
 
5.6 Treatment Assignment Procedures 
5.6.1 Randomization Procedures  
Once informed consent has been obtained from the patient’s family or legal representative, the 
patient will be enrolled in the study and randomly assigned to one of the two ventilatory 
strategies. Subjects will be randomized using a stratified, blocked randomization scheme with 
random block sizes of 4 and 6, generated by the study statistician. Study participants will be 
allocated with equal probability to each study group with stratification by center. The 
randomization procedure will generate a study number for each participant that links the 
corresponding group allocation in accordance with block size and strata. An independent 
statistician which is not part of the research team will validate and generate the final 
randomization assignment. As each subject is entered into the study, study personnel in 
Cincinnati will consult this randomization scheme to determine which study arms will the 
subject need to be assigned to.  
5.6.2 Subject Withdrawal 
Subject’s authorized legal representative may voluntarily withdraw consent from the study or 
the investigator may terminate a subject's participation. 
An investigator may terminate a study subject’s participation in the study if: 
• Any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the subject. 
• The subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
Subject discontinuation due to an AE, or other medical condition, will be followed up by the 
clinical study site staff to insure appropriate care and to record any events that are related or 
unrelated to safety or effectiveness outcomes of this study and this will be reported to the 
DSMB. 
5.6.3 Premature Termination or Suspension of Study   
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
See the list below. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the principle 
investigator, funding agency, the Investigational Device Exemption (IDE) sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the principal investigator will 
promptly inform each of the IRBs and will provide the reason(s) for the termination or 
suspension. Circumstances that may warrant termination include, but are not limited to: 

35 
 
• Determination of unexpected, significant, or unacceptable risk to subjects resulting from 
the PCLC system or study design. 
• Insufficient adherence to protocol requirements by the study team. 
• Data that is not sufficiently complete and/or evaluable.  

36 
 
6 STUDY INTERVENTION 
Study Product Description 
The device used in the in study is a 731 Series ventilator whose software has been modified to 
include FiO2 PCLC. In all other ways the device is identical to devices that are used routinely by 
civilian and military care providers. The 731 has an integrated pulse oximeter that provides the 
signal used by the PCLC algorithm to adjust the FiO2 as required. In addition to the standard 
ventilator and pulse oximetry alarms, the modified code also has additional alarms that are 
related to PCLC, these are described in Appendix B. The data signal also includes all alarm and 
device condition information (power status, battery status, barometric pressure, ambient 
temperature, etc.).  
6.1 Acquisition 
Study product will be loaned to the study team by the sponsor and will include: 
• Ventilator with modified software bearing appropriate investigation labeling 
• Single-patient use breathing circuits 
• Single-patient use pulse oximeter sensors 
• AC/DC power supply 
• Data acquisition computer with shielded USB interface cable 
• Operating manual that covers both normal and PCLC operation and alarm features. 
At the conclusion of the study or in the event the study is terminated prematurely, the 
ventilator and all durable accessories will be returned to the sponsor.  
6.2 Formulation, Packaging, and Labeling 
The ventilator will be labeled for investigational use only and will be under the control of the 
study team at each location. Consumables are not modified and are supplied in their standard 
packaging.  
6.3 Product Storage and Stability 
Product will be under the control of the study team at each location who will be responsible for 
configuring the system for use in the study. While the study will take place in an ICU setting the 
device is cleared for an extreme range of operating and storage environments and as such, no 
special storage requirements are necessary. Processing the device between patients will follow 
the procedures defined in the standard labeling which calls for single-use consumables to be 
discarded while the device is cleaned following the hospital’s device cleaning procedures.  

37 
 
6.4 Accountability Procedures for the Study Product 
Each study location will provided with 2 systems, as described above. The systems will be under 
the control of the local study team. Consumables will be provided as needed. At the conclusion 
of the study or in the event the study is terminated prematurely, the ventilator and all durable 
accessories will be returned to the sponsor.  

38 
 
7  STUDY SCHEDULE 
7.1 Screening 
7.1.1   Visit 1: Screening/Enrollment  
 
• Obtain and document consent from family member or legal representative on screening 
consent form. 
• Review medical history to determine eligibility based on inclusion/exclusion criteria. 
• Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• Perform medical examinations needed to determine eligibility. 
 
7.1.2 Visit 2: Time 0 + 12 hours  
• Administer the intervention that will be either manual control of FiO2 or automated 
closed-loop-control of FiO2 depending on the randomization assignment. Following 
administration of the intervention 
• Assess physiological status 
• Record adverse events as observed by investigator. 
• Record results of physical examinations. 
• Record any clinician changes in ventilator settings. 
• Record any blood gas results from routine care 
• Assess vital signs 
7.1.3  Visit 3: Time 24 hours after the intervention 
• Assess physiological status 
• Record adverse events as observed by investigator. 
• Record results of physical examinations. 
• Assess vital signs 

39 
 
8. STUDY PROCEDURES /EVALUATIONS 
8.1 
Study Procedures/Evaluations 
1. 
Medical history from medical records. 
2. 
Physical examination (list the vital signs [including height and weight] 
and organ systems to be assessed. Address details in the MOP.); if 
appropriate, discuss what constitutes a targeted physical examination 
and at what visits it may occur.   
8.2 
Clinical Laboratory Evaluations 
1. 
Baseline blood gas analyses, as ordered by the clinical team. 
2. 
Arterial blood gases 
3. 
Continuous transcutaneous oxygen saturation 

40 
 
9. ASSESSMENT OF SAFETY 
This study involves a previously cleared continuous ventilator with an investigational 
component – the physiologic closed-loop controller. Reporting of certain events is mandatory 
because of the study population or study design characteristics; the study is conducted at 
multiple sites, and will require centralized safety oversight. 
9.1 Specification of Safety Parameters 
9.1.1 Primary Safety variable: 
 
To assess the relative duration of time with SpO2 <88% during the study period. 
9.1.2 Secondary safety variables: 
• Evaluation of missed diagnoses  
• Rate of serious device-related AEs 
• Rate of serious AEs not related to the device 
• Rate of device-related AEs 
9.2 Unanticipated Problems 
We consider unanticipated problems involving risks to subjects or others to include, in general, 
any incident, experience, or outcome that meets 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 informed consent document; and (b) the characteristics of the 
subject population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
9.3 Adverse Events 
An adverse event is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. 

41 
 
9.4 Serious Adverse Events 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred) 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect   
• An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
9.5 Frequency for Event Assessment and Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout the study.  
The PI will record all reportable events with start dates occurring any time after the patient is 
randomized until 24 hours after the subject is removed from the study ventilator. At each study 
visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 
9.6 Characteristics of an Adverse Event 
9.6.1 Relationship to Study Intervention 
To assess relationship of an event to study intervention, the following guidelines are used: 
1. 
Related (Unlikely, Possibly, Related) 
i. The event is known to occur with the study intervention. 
ii. There is a temporal relationship between the intervention and event 
onset. 
iii. The event abates when the intervention is discontinued. 
iv. The event reappears upon a re-challenge with the intervention. 
2. Not Related 

42 
 
i. There is no temporal relationship between the intervention and event 
onset. 
ii. An alternate etiology has been established. 
9.6.2 Expectedness of SAEs 
The Study PI will be responsible for determining whether an SAE is expected or unexpected. An 
adverse event will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the intervention. All serious 
adverse events will be subsequently reported to the DSMB. 
9.6.3 Severity of Event 
The following scale will be used to grade adverse events: 
1. Mild: no intervention required; no impact on activities of daily living (ADL) 
2. Moderate: minimal, local, or noninvasive intervention indicated; moderate impact on 
ADL 
3. Severe: significant symptoms requiring invasive intervention; subject seeks medical 
attention, needs major assistance with ADL 
9.6.4 Reporting Procedures 
 
SAE’s require expedited reporting when meeting the following criteria: 
• The incident is serious 
• Unexpected given the subject’s condition and use of mechanical ventilation 
• Suspected adverse reaction to closed-loop control of FiO2. This would include a 
determination by the PI that the event is not related to consequences of the underlying 
disease or condition under study or events common in the study population.   
 
These events are required to be reported to the FDA within 7 calendar days of the sponsor’s 
initial receipt of the information if characterized as fatal or life-threatening. Non-fatal or non-
life threatening events must be reported no later than 15 calendar days after the sponsor 
determines that the serious suspected adverse reaction (SSAR) or other information qualifies 
for reporting.  
 
All SAEs are to be reported to the IRB and the DSMB as per policy. 
The Data Safety Monitoring Board (DSMB) will be required to review all SAEs periodically 
regardless of causality.   
 

43 
 
10. STUDY OVERSIGHT 
10.1 Data Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) composed of members with 
expertise in clinical medicine, mechanical ventilation, anesthesia, and biostatistics will provide 
oversight of safety events. The DSMB will meet after approximately 25%, 50%, and 75% of the 
study is enrolled, but not less than once per year. If safety concerns arise, more frequent 
meetings may be held. The DSMB will operate under the rules of the approved charter.   
• The DSMB will contact Zoll to assure there is prompt identification of any adverse 
event(s) that could affect either human subject protection and/or clinical study data 
quality. This monitoring will include both on-site and off-site file review of the 
communal data depository which will have all of the IDE data, forms etc. 
• Adverse events are defined in Appendix  of the Protocol.   
• Adverse events and safety data will also be reviewed by the study medical monitor who 
will have authority to terminate the study at any time due to safety concerns. 
• ZOLL is responsible for stopping the trial if there is a risk to either human subject 
protection and/or clinical study data quality and reporting the decision to the FDA. 
10.2 Training  
The procedures for the physiologic closed-loop ventilation on the 731 Series ventilators are 
familiar to the University of Cincinnati Medical Center (UC). The staff has been trained and is 
experienced with the 731 Series ventilator as the device is currently used at UC for care and 
transport of patients. Training for the other clinical sites will be performed by staff from UC, 
based on their expertise, training and a Modified Operation Manual. Training will detail: study 
design, contraindications of use, using the closed-loop system, new alarms associated with the 
closed-loop functionality, interpreting the closed loop symbols on the user interface, 
documentation requirements (case report form) and adverse event reporting. 
 

44 
 
11. CLINICAL SITE MONITORING 
Clinical trial monitoring will be conducted to ensure that the rights and well-being of human 
subjects are protected, to verify that the reported clinical trial data are accurate, complete, and 
verifiable from source documents, and to verify that the conduct of the trial is in compliance 
with the currently approved protocol/amendment(s), with Good Clinical Practices (GCP), and 
with the applicable regulatory requirement(s). Both on-site and remote monitoring will be 
conducted.  
 
 

45 
 
12. STATISTICAL CONSIDERATIONS 
12.1 Sample size  
 12.1.1 Primary Efficacy objective:  
The primary efficacy endpoint is the relative duration of time where SpO2 remains between 92 
and 96% (inclusive). This will be obtained from continuously monitoring the subjects SpO2 level 
throughout the study period such that at least 12 hours of monitoring data are available for 
each subject. The difference in the average amount of time will be the basis for the efficacy 
outcome comparison between the two ventilatory strategies. 
To assess power for this objective the sample size calculation is based on preliminary data 
estimating  the relative duration of time that SpO2 remains between 92 and 96% (inclusive). To 
determine the noninferiority margin, the guidelines provided by FDA were followed 
(http://www.fda.gov/downloads /drugs/guidancecomplianceregulatoryinformation 
/guidances/ucm202140.pdf). From our preliminary data, the relative duration of time  in which 
the SpO2 remained between 92 and 96% in a four hour time interval for the MC group was 0.30 
with 95% CI (0.23, 0.38).  Following  the guideline mentioned above we used half of the lower 
confidence bound to be the margin of non-inferiority (i.e. 0.12, which is equivalent to 7.2 
minutes per hour)  From our preliminary data, the SD for the MC and PCLC group  was 0.33 and 
0.23 respectively.  Assuming a noninferiority margin of 0.12, a sample size of 91 subjects per 
group will achieve 80% power with a 2.5% one-sided significant level when the true difference 
between the group means is assumed to be zero. Allowing a 15% attrition rate for potential 
withdrawal of subjects the required sample size is 105 per group. 
12.1.2 Primary Safety objective: 
The primary safety endpoint is the relative duration of time with SpO2 <88%  over the study 
period. This will be observed by continuously monitoring each subject’s SpO2 level throughout 
the study period such that at least 12 hours of monitoring data are available for each subject. 
From our preliminary data the observed relative time where SpO2 <88%  was 0.004 and 0.002 
for the MC and PCLC group respectively. The proposed sample size of 105 per group will allow 
us to conclude non-inferiority with a  margin of 0.004 (which is equivalent to 15 seconds/hr) 
with 95% power with a 2.5% one-sided significant level. 
Therefore for this study we are proposing to enroll a total of 210 subjects to test the 
noninferiority hypothesis for both our primary safety and effectiveness outcomes. For all 
sample size estimates, PASS version 12 (PASS, NCSS LLC., Utah, US) was used.  
If noninferiority is demonstrated, the proposed sample size also has 80% power to test for the 
superiority of the LLC group versus MC group both in terms of the primary effectiveness and 
safety outcomes if the true difference between ventillatory strategies is at least 0.14 (which is 
equivalent to 8.2 minute per hour) for the primary efficacy endpoint and is at least 0.003 (which 
is equivalent to 10 second per hour) for the primary safety endpoint.  

46 
 
12.2 Statistical Analysis  
For the primary outcomes, the intent-to-treat (ITT) population will be used for all efficacy and 
safety analyses. All subjects that were randomized and started the assigned ventilation strategy 
protocol will be included in the ITT. All summary tables for quantitative parameters will display 
mean, standard deviation, median, interquartile range, and range (minimum and maximum), as 
well as number of missing data (if relevant). All summary tables for qualitative parameters will 
display counts, percentages and number of missing data if relevant. Baseline characteristics will 
be described using the ITT population. Demographics, medical history and other baseline 
variables will be summarized as appropriate to the type of data. The primary effectiveness 
outcome will be defined as the proportion of time during the 12 hour monitoring period that 
the subject’s SpO2 levels were within the target range relative to the actual total monitoring 
time (which is targeted to be 12 hours for all subjects). By using the proportion of time instead 
of the actual time, we are able to normalize the outcome based on the total amount of 
monitoring time available. We will assess normality of the response variables within each of the 
two groups by visual inspection of the histograms and box plots and by performing the test for 
normality of data using the Shapiro Wilk test.  If the assumption of normality for the primary 
effectiveness outcome does not seem tenable, we will use the arcsine square root 
transformation which is recommended to normalize skewed percentage data.  A one-sided 
lower 97.5% confidence interval will be calculated for the difference between the two  
monitoring strategy groups  (PCLC minus MC) in terms of the effectiveness outcome (duration 
where SpO2 remains between 92 and 96% relative to the total monitoring time) and the lower 
limit will be compared to the noninferiority margin of 0.12. Similar analyses will be conducted 
for the secondary effectiveness outcome with the only difference being the way the duration is 
calculated for the secondary effectiveness outcome.  For this analysis, the target duration will 
be calculated as amount of time that SpO2 remains between 92 and 96% when FiO2 > 21% and 
SpO2 ≥ 92% when FiO2 = 21%. The safety outcome (duration where SpO2 remains above 88% 
relative to the total monitoring time) will be assessed using a one-sided lower 97.5% confidence 
interval and the lower limit will be compared to the non-inferiority margin of 0.004. If non-
inferiority is established for an endpoint, we will proceed in conducting a superiority test and 
will compare the lower confidence limit to 0.   
For the analysis of secondary safety outcome, data point estimates will be reported with 95% 
confidence intervals followed by a Fisher’s Exact Test at the 5% level of confidence. Specifically 
the percentage of subjects reporting at least one adverse event (i.e serious, any device related, 
etc.) will be calculated for each group  and compared using Fisher’s Exact Test. The relative risk 
of each adverse event with the corresponding two-sided 95% confidence interval will be 
presented.  
Missing data: The primary analysis is an intent to treat analysis. In order to minimize the 
possibility of missing data,  the total duration of monitoring will be extended for each subject as 
needed in order to collect at least 12 hours of evaluable data.  As a sensitivity analysis, the 
primary outcome measure also will be calculated as the relative time the subject was on target 
compared to the total amount of time they were on manual or closed-loop control. Therefore 
each subject should have the outcome measurement. The amount of missing data is expected 

47 
 
to be low based on past experience with subject retention. However there is a very low 
probability that some subjects may die before completing 12 hours of monitoring on the 
device. In this case, the relative duration will be derived by using the total duration of time the 
subject was on target relative to the monitoring time until they died. If a subject does not have 
12 hours of monitoring data on the device due to a reason other than death, we will conduct 
sensitivity analysis by assuming different scenarios. In a worst case scenario, the primary 
outcome will be computed as the total time in the target range divided by 720 minutes. In a 
best case scenario, the primary outcome will be computed as the total time in the target range 
divided by the total amount of time the subject was observed (i.e. <720 minutes). In the event 
of missing data on the primary safety and efficacy outcomes (except where the subject died), 
the reason for the missing values will be explored, and the pattern of missing values (e.g. 
missing at random, missing completely at random) will be evaluated. In addition, analyses 
excluding those subjects without 12 hours of monitoring will also be conducted as sensitivity 
analyses. 
 

48 
 
13. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate medical and research records for this study, in compliance 
with regulatory and institutional requirements for the protection of confidentiality of subjects.  
Study staff will permit authorized representatives of regulatory agencies to examine (and when 
required by applicable law, to copy) research records for the purposes of quality assurance 
reviews, audits, and evaluation of the study safety, progress and data validity. Subjects’ medical 
records will be made available to study monitors and auditors.  
 

49 
 
14. ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
ZOLL will ensure that this study is conducted in full conformity with the principles set forth in 
The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, and codified in 45 CFR Part 46.  
14.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any subject is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented in the study.   
14.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in 
the study and continues throughout study participation. Extensive discussion of risks and 
possible benefits of study participation will be provided to subjects and their families, if 
applicable. A consent form describing in detail the study procedures and risks will be given to 
the legally authorized representative. Consent forms will be IRB-approved, and patient’s family 
or legal representative is required to read and review the document or have the document read 
to him or her. The investigator or designee will explain the research study to the legal 
representative and answer any questions that may arise. The legal representative will sign the 
informed consent document prior to any study-related assessments or procedures. The family 
or legal representative may withdraw consent at any time throughout the course of the study.  
A copy of the signed informed consent document will be given to the family or legal 
representative for their records. The rights and welfare of the subjects will be protected by 
emphasizing to the family or legal representative that the quality of their clinical care will not 
be adversely affected if they decline to participate in this study. 
The consent process will be documented in the clinical or research record.   
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
Individuals aged 18 to 65, of any gender or racial/ethnic group are eligible to participate in the 
study. 
14.5 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover any study information 
relating to subjects. 

50 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
ZOLL may inspect all study documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) for the 
study subjects. The clinical study site will permit access to such records. 

51 
 
15. DATA HANDLING AND RECORD KEEPING 
15.1 Data Management Responsibilities 
Complete documentation of the data management tasks and processes will be maintained as 
part of the Data Management Plan (DMP). The DMP will provide information such as key 
personnel and outline processes for CRF and database development, data cleaning and data 
reconciliation.   
 
15.2 Data Capture Methods 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the local investigator. All source documents and laboratory reports will be 
reviewed by the study team and data entry staff, who will ensure that they are accurate and 
complete.   
 
Subject data will be collected during the subject participation period and will be recorded onto 
case report forms (CRFs) as applicable. Data that are reported and available in an electronic 
format can be maintained in that manner and does not have to be reported onto a CRF, 
although it can be integrated into our database, described below.   
 
This project will use Medidata Rave® as its Electronic Data Capture (EDC) software, which is a 
robust EDC platform for capturing, managing and reporting clinical research data. This system 
includes a robust query management system based on the Data Quality Plan, which will identify 
data quality checks to be programmed into the database design. Frequent monitoring of the 
database throughout the study will allow for corrective action to be taken quickly if problems 
are identified with the data collection process.     
15.3 Types of Data 
Patient data collected will be: vital signs (blood pressure, heart rate), all laboratory studies 
including hematology and chemistry blood panels, arterial blood gases, end-tidal CO2 
measurements, transcutaneous oxygen saturation, airway pressure, compliance, resistance. 
Ventilator data will include ventilator settings, ventilator output, FiO2, rate, tidal volume, etc.  
15.4 Study Records Retention 
Study records will be maintained for at least three years. Study documents will be retained for a 
minimum of 2 years or until at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without 
the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 

52 
 
15.5 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Procedures requirements. The noncompliance may be on the part of the 
subject, the investigator, or study staff. As a result of deviations, corrective actions will be 
developed and implemented promptly. 
All deviations from the protocol must be addressed in study subject source documents and 
promptly reported to ZOLL and the local IRB, according to their requirements.  

54 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
. 
 

55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

56 
 
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