The Evaluation of the Astral VAPS AutoEPAP Treatment Algorithm
Phase: PHASE3
Conditions: Upper Airway Obstruction, Respiratory Insufficiency, Respiratory Failure
Sponsor: ResMed

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 1 of 30 
ResMed Confidential 
 
Study Protocol 
 
The Evaluation of the Astral VAPS AutoEPAP Treatment Algorithm 
 
Short Title: Astral VAPS AutoEPAP Clinical Trial 
 
 
Study Number: MA-15-12-15 
 
 
Revision:  4.0 
Date: 06.June.2016 
 
 
Sponsor: 
ResMed Corp 
9001 Spectrum Center Blvd 
San Diego, CA  92123 
(800) 424-0737 
 
 
 
 
 
 
This protocol has been written in accordance with current applicable guidelines (IDE for USA) as well as all 
other relevant additional references, medical and legal. 
The information herein is confidential and the property of ResMed Corp. It is to be used in confidence for 
the conduct of the clinical trial according to written agreement. 
 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 2 of 30 
ResMed Confidential 
 
PROTOCOL SIGNATURE PAGE 
 
 
Protocol: The Evaluation of the Astral VAPS AutoEPAP Treatment Algorithm 
 
Study Number: MA-15-12-15 
 
Version Number: 4.0 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable FDA good clinical practice and ICH GCP guidelines (ICH GCP E6 8.2.2). 
Deviations from the protocol may not proceed without prior approval of the Sponsor and the IRB, unless 
under emergency circumstances where deviations are performed to protect the rights, safety and the well-
being of human subjects. Such deviations shall be documented and reported to the Sponsor and to the IRB 
as soon as possible. 
 
The study may not begin until IRB approval is obtained and regulatory bodies have been notified and all 
additional requirements imposed by the IRB or regulatory body shall be followed. 
 
__________________________________________________________ 
Name of Principal Investigator  
 
 
 
 
__________________________________________________________ 
Signature of Principal Investigator 
 
 
 
Date 
 
 
 
 
 
 
 
 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 3 of 30 
ResMed Confidential 
 
Rev 
Date 
Section 
Change Details 
Rationale 
1.0 
17 Dec 2015 
N/A 
N/A 
Original Release 
2.0 
01.Feb.2016 
6.2.4 
Update power calculation 
definitions and removed 
extraneous reference. 
To be more clear 
with calculations and 
reference only 1 
applicable source. 
6.2.4 
Removed non-inferiority 
calculation. 
Moved to more 
appropriate section. 
12. 
Added explanation for non-
inferiority margin. This was 
previously in section 6.4.2. 
To make protocol 
more clear. 
3.0 
02.Feb.2016 
4.1 
Clarified patient population  
and aim of study 
Clarification 
6.2.2 
Clarified patient population 
for the study 
Clarification 
6.2.4 
Reference non-inferiority 
margin in section 12 and 
rationale for differences in 
events per hour 
Clarification between 
power and non-
inferiority margin 
calculations 
12. 
Further explanation on 
non-inferiority margin and 
clinical justification for the 
margin 
To make statistical 
analysis more clear 
4.0 
06.June.2016 
Various 
iVAPS to VAPS 
To better define the 
objective of 
comparing AutoEPAP 
to manual EPAP; 
these modes will be 
utilized within the 
iVAPS mode on the 
Astral study device 
4.1 
Updated study device with 
current FDA clearance 
status and K number 
Updated language 
referencing previous 
clinical data 
 
To reflect current 
FDA clearance status 
on study device 
Provide clarity to the 
details of this 
research 
4.2 
Update to intended use 
language 
Ensure protocol is 
consistent with 
currently cleared IFU 
language 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 4 of 30 
ResMed Confidential 
5.2 
Update patient description 
to be “respiratory failure” 
Update language of 
patient population to 
be more clinically 
accurate 
6.2.5 
Update to I#6 wording 
Clarify purpose of 
this criteria 
6.2.6 
Removal of “dependent” 
from Exclusion criteria 
Current cleared IFU 
for study device does 
not exclude this type 
of patient 
 
 
7.4 
Update to training process 
Reflect current 
protocol training 
procedures 
 
 
9.1 
Update to appropriate data 
transfer method 
Previous version was 
inaccurate with old 
SD card method 
 
 
9.3 
Summary of Visit 3 added 
Clarification of visit 3 
procedures 
 
 
10. 
Update to study timeline 
and total enrollment 
Change in IEC of 
protocol dictates an 
increase of total 
sample size, and 
consequently, 
increase in study 
timeline 
 
 
14.3.1 
Update to NSR justification 
Provide current FDA 
clearance for study 
device 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 5 of 30 
ResMed Confidential 
Table of Contents 
 
RESPONSIBILITIES AND ADDRESSES ............................................................................................................ 7 
 
ABBREVIATIONS AND DEFINITIONS ............................................................................................................. 8 
 
PROTOCOL SUMMARY .................................................................................................................................... 10 
 
INTRODUCTION ................................................................................................................................................. 12 
4.1. 
BACKGROUND INFORMATION ................................................................................................................. 12 
4.2. 
INTENDED USE ............................................................................................................................................... 14 
 
STUDY OBJECTIVES .......................................................................................................................................... 14 
5.1. 
PRIMARY OBJECTIVE .................................................................................................................................. 14 
5.2. 
SECONDARY OBJECTIVES .......................................................................................................................... 14 
 
STUDY DESIGN .................................................................................................................................................... 15 
6.1. 
ENROLLMENT ................................................................................................................................................ 15 
6.2. 
SELECTION OF SUBJECTS .......................................................................................................................... 15 
6.2.1. 
INFORMED CONSENT .............................................................................................................................. 15 
6.2.2. 
STUDY POPULATION AND RANDOMIZATION.................................................................................. 15 
6.2.3. 
NUMBER OF SUBJECTS ........................................................................................................................... 15 
6.2.4. 
SAMPLE SIZE JUSTIFICATION .............................................................................................................. 15 
6.2.5. 
SUBJECT INCLUSION CRITERIA .......................................................................................................... 16 
6.2.6. 
SUBJECT EXCLUSION CRITERIA ......................................................................................................... 16 
 
STUDY DEVICES ................................................................................................................................................. 17 
7.1. 
ASTRAL DEVICE ............................................................................................................................................ 17 
7.2. 
DEVICE ACCOUNTABILITY ........................................................................................................................ 17 
7.3. 
LABELING ........................................................................................................................................................ 17 
7.4. 
PACKAGING .................................................................................................................................................... 17 
7.5. 
INSTRUCTION FOR USE ............................................................................................................................... 17 
7.6. 
REQUIRED TRAINING .................................................................................................................................. 18 
 
THERAPY .............................................................................................................................................................. 18 
8.1. 
TREATMENT WITH ASTRAL DEVICE ..................................................................................................... 18 
8.2. 
SET UP OF ASTRAL DEVICE ....................................................................................................................... 18 
 
STUDY SCHEDULE ............................................................................................................................................. 18 
9.1. 
VISIT 1 ............................................................................................................................................................... 19 
9.2. 
VISIT 2 ............................................................................................................................................................... 19 
9.2.1. 
VISIT 3 ........................................................................................................................................................... 20 
9.3. 
STUDY COMPLETION ................................................................................................................................... 20 
 
STUDY TIMELINE .......................................................................................................................................... 20 
10.1. 
SUSPENSION OR EARLY TERMINATION OF STUDY ........................................................................... 21 
 
SAFETY ............................................................................................................................................................. 21 
11.1. 
DEFINITION OF ADVERSE EVENTS ......................................................................................................... 21 
11.1.1. 
ADVERSE EVENT (AE) .............................................................................................................................. 21 
11.1.2. 
UNANTICIPATED ADVERSE DEVICE EFFECT .................................................................................. 21 
11.1.3. 
SERIOUS ADVERSE EFFECT (EVENT OR REACTION) (SAE) ........................................................ 21 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 6 of 30 
ResMed Confidential 
 
STATISTICAL ANALYSIS ............................................................................................................................. 22 
12.1. 
WITHDRAWAL OF SUBJECTS .................................................................................................................... 22 
 
DATA MANAGEMENT AND STORAGE ..................................................................................................... 23 
13.1. 
DATA COLLECTION ...................................................................................................................................... 23 
13.2. 
STUDY DOCUMENTATION .......................................................................................................................... 23 
13.3. 
QUERY GENERATION .................................................................................................................................. 23 
13.4. 
DATA STORAGE ............................................................................................................................................. 23 
13.5. 
INSPECTION OF RECORDS ......................................................................................................................... 23 
13.6. 
STUDY FILES AND RECORD RETENTION .............................................................................................. 24 
13.7. 
REGULATORY DOCUMENTATION ........................................................................................................... 24 
13.8. 
DISTRIBUTION OF RESULTS ...................................................................................................................... 24 
 
ETHICAL CONSIDERATIONS ..................................................................................................................... 24 
14.1. 
INSTITUTIONAL REVIEW BOARD (IRB)) ................................................................................................ 24 
14.2. 
PROTOCOL DEVIATIONS ............................................................................................................................ 24 
14.3. 
RISK ANALYSIS .............................................................................................................................................. 25 
14.3.1. 
NON-SIGNIFICANT RISK DETERMINATION ..................................................................................... 25 
14.3.2. 
SUBJECT DATA CONFIDENTIALITY ................................................................................................... 26 
 
QUALITY .......................................................................................................................................................... 26 
15.1. 
SITE SELECTION ............................................................................................................................................ 26 
15.2. 
PSG DATA ......................................................................................................................................................... 26 
15.3. 
TRAINING ......................................................................................................................................................... 27 
15.4. 
SITE MONITORING ....................................................................................................................................... 27 
 
RESPONSIBILITIES ........................................................................................................................................ 27 
16.1. 
CLINICAL INVESTIGATOR RESPONSIBILITIES ................................................................................... 27 
16.2. 
SPONSOR RESPONSIBILITIES .................................................................................................................... 28 
 
REFERENCES .................................................................................................................................................. 29 
 
APPENDIX A – ASTRAL CLINICAL GUIDE .............................................................................................. 30 
 
APPENDIX B – INFORMED CONSENT FORM ......................................................................................... 30 
 
APPENDIX C - CRFS ....................................................................................................................................... 30 
 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 7 of 30 
ResMed Confidential 
 RESPONSIBILITIES AND ADDRESSES 
 
Principal Investigator: 
Lisa Wolfe, MD 
 
 
 
 
Northwestern University 
 
 
 
 
Chicago, IL, USA 
Study Coordination: 
ResMed Corp Medical Affairs 
 
 
 
 
San Diego, CA, USA 
Statistician:  
 
Leslee Willes 
Willes Consulting Group 
San Diego, CA, USA 
Core Lab(s):  
 
PSG Core Lab  
University of California, San Diego 
 
 
 
 
PI: Atul Malhotra, MD 
 
 
 
 
San Diego, CA, USA 
 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 8 of 30 
ResMed Confidential 
 ABBREVIATIONS AND DEFINITIONS 
 
ITEM 
DEFINITION 
AASM 2007 
American Academy of Sleep Medicine 2007 guidelines 
ABGs 
Arterial blood gases 
AHI 
Apnea Hypopnea Index 
COPD 
Chronic Obstructive Pulmonary Disease 
CPAP 
Continuous positive airway pressure 
CRF 
Case report form 
DSBM 
Data & Safety Monitoring Board 
EEG 
Electroencephalography 
EFL 
Expiratory flow limitation 
EPAP 
Expiratory positive airway pressure 
EPR 
Expiratory Pressure Relief (ResMed comfort setting) 
HREC 
Human Research Ethics Committee 
iBR 
Intelligent Back-Up Rate 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
iVAPS 
Intelligent Volume Assured Pressure Support 
Astral 
The name given to the clinical trial device 
LSLV 
Last subject, last visit 
NIPPV 
Non-invasive positive pressure ventilation 
NMD 
Neuromuscular Disease 
NSR 
Non-Significant Risk 
ODI 
Oxygen desaturation index  (≥ 3% desaturation) 
OHS 
Obesity Hypoventilation Syndrome 
OSA 
Obstructive Sleep Apnea 
PAP 
Positive airway pressure 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 9 of 30 
ResMed Confidential 
PS 
Pressure Support 
PSG 
Polysomnography 
PtCO2 
Transcutaneous carbon dioxide 
SIV 
Site initiation visit 
Standard ST mode 
Commercially available ST modes utilizing a fixed EPAP 
UAO 
Upper airway obstruction 
VAPS 
Volume Assured Pressure Support 
 
 
 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 10 of 30 
ResMed Confidential 
 PROTOCOL SUMMARY 
 
Objectives 
The objective of this study is to evaluate AutoEPAP versus manual EPAP in iVAPS mode 
on the Astral device.  
Study Design 
This will be a prospective, multi-center, single-blind, randomized, cross-over design. 
The study will occur in a lab/hospital setting. Eligible subjects that represent patients 
with respiratory failure will complete two PSG study nights.  
Number of 
Subjects 
Up to 40 subjects overall will be randomized to obtain endpoint data on at least 36 
evaluable subjects. This accounts for the expected dropout rate (10%). 
Selection 
criteria 
 
Inclusion criteria for the study are: 
1. Participant has ability to provide written informed consent 
2. Participants aged ≥18 years old 
3. Participant has documented respiratory failure (e.g. sleep hypoventilation with 
historical PtCO2 increase ≥ 10mmHg) and/or daytime hypercapnia (>45 mmHg) 
4. Participant is currently using non-invasive positive pressure ventilation in ST or VAPS 
mode for ≥ 3 months 
5. Participants with a previously documented AHI ≥ 5/hr 
6. Participants with a recently (≤ 12 months ago) reviewed EPAP setting 
Exclusion criteria for the study are: 
1. Participants are not compliant on NIPPV (e.g. < 4 hr/night) 
2. Participants who are pregnant 
3. Participants on oxygen therapy ≥5 L/min 
4. Participants with an invasive interface (e.g. tracheostomy) 
5. Participants who have had an acute exacerbation within the last 3 months that 
resulted in a hospitalisation 
6. Participants who are acutely ill, medically complicated or who are medically unstable 
7. Participants in whom NIPPV therapy is otherwise medically contraindicated 
8. Participants who have had surgery of the upper airway, nose, sinus, or middle ear 
within the previous 90 days 
9. Participants with untreated, non-OSA sleep disorders, including but not limited to; 
insomnia, periodic limb movement syndrome, or restless legs syndrome. 
10. Participants who have the following pre-existing conditions: severe bullous lung 
disease, recurrent pneumothorax or pneumomediastinum, cerebrospinal fluid leak, 
recent cranial surgery or trauma. 
11. Participant does not comprehend English 
12. Participant is unable or unwilling to provide written informed consent 
13. Participant is physically and/or mentally unable to comply with the protocol 
14. Participant is not suitable to participate in the trial for any other reason in the 
opinion of the investigator 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 11 of 30 
ResMed Confidential 
Primary 
Endpoints 
The primary outcome is the Oxygen Desaturation Index (ODI4%) as a measure of upper 
airway obstruction. The primary aim of this protocol is to compare ODI values following 
the use of the AutoEPAP algorithm in comparison to manual EPAP in VAPS mode. 
Secondary 
Endpoints 
The secondary objectives will be used to determine if the AutoEPAP algorithm remains 
effective in treating respiratory failure patients. 
1. To assess the apnea hypopnea index (AHI) as measured by the Astral device. 
2. To assess sleep-breathing parameters (e.g. nadir SpO2 and PtCO2) with 
AutoEPAP algorithm compared to manual EPAP on an Astral device. 
3. To assess sleep parameters (e.g. sleep efficacy and arousal index) with AutoEPAP 
algorithm compared to manual EPAP on an Astral device. 
Scheduled 
Visits 
Visit 1 
• 
Informed Consent 
• 
IEC requirements 
• 
Baseline Characteristics 
• 
Medical History 
 
Visit 2 (Night 1) and 3 (Night 2) 
• 
Mask fitting 
• 
Overnight PSG, including oximetry and PtCO2 
 
 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 12 of 30 
ResMed Confidential 
 INTRODUCTION 
4.1. Background Information 
Patients with chronic respiratory insufficiency or failure such as those associated with Chronic 
Obstructive Pulmonary Disease (COPD) [1], Obesity Hypoventilation Syndrome (OHS) [2], 
Obstructive Sleep Apnea (OSA) [3] or Neuromuscular Disease (NMD) [4, 5] are increasingly managed 
with domiciliary non-invasive positive pressure ventilation (NIPPV) [1, 6-8]. 
Optimal settings of non-invasive ventilation are usually titrated manually and require time and 
expertise [9]. One such setting is expiratory positive airway pressure (EPAP) which is used to manage 
the lower airway and, if needed, prevent upper airway obstruction (UAO). In order to optimally 
adjust a fixed EPAP setting in a NIPPV device, a sleep study is usually required where respiratory 
flow waveforms may be monitored and recorded [10]. The waiting time for NIPPV titration sleep 
studies can be lengthy and/or be poorly performed due to resource limitations, and once they are, 
respiratory flow waveforms are often not recorded. In the instances where respiratory flow 
waveforms are recorded and analyzed, optimization of fixed EPAP settings are only based on the 
patient’s condition for that single night. As a result, single night titrations may not capture significant 
alterations in factors which may affect the level of EPAP required, such as posture [11] and sleep 
state (e.g. supine in REM) [12]. 
Additionally, patient requirements may change over time due to progression of their chronic illness, 
weight fluctuations and prescribed medications, and, in some patients, changes in tissue edema 
location and severity with posture changes [13]. As such, the EPAP pressures, which are all under 
clinician control, are set during a titration study and must be high enough to deal with the worst 
conditions which may occur during the night. Clinicians must also regularly monitor patients, and 
possible perform re-titrations to make sure the manually set EPAP is optimal. 
For all these reasons, an automatic adjustable EPAP (i.e. “AutoEPAP”) with clinician controlled 
minimum and maximum EPAP levels, may offer advantages over a fixed EPAP for managing UAO.  
While an AutoEPAP algorithm could be used in the context of conventional fixed pressure support 
bilevel therapy (e.g. Spontaneous/Time (ST) mode), it would be useful to be used with a therapy 
mode which aims to automate all other aspects of ventilation as much as possible. Similar 
automated techniques have been successfully developed and established in current practice for 
OSA and periodic breathing [14, 15].  
The Astral ventilator includes the Intelligent Volume Assured Pressure Support (iVAPS) (ResMed, 
Sydney, Australia, K152068) mode - a pressure support servoventilator which automatically adjusts 
pressure support to achieve a target alveolar ventilation (minute ventilation minus the anatomical 
deadspace) for patients who require mechanical continuous or intermittent ventilation. The amount 
of anatomical deadspace is calculated from an algorithm based on patient height. iVAPS also has a 
variable respiratory backup rate (i.e. Intelligent breathing rate; iBR), in which the set backup rate is 
delivered during periods of hypoventilation or central apnea only. When the user is breathing 
spontaneously and is triggering the device, the iBR algorithm will decrease the backup rate down to 
2/3 of the ‘target breath rate’. When necessary, iBR will rapidly increase the backup breath rate to 
the set ‘target breath rate’ to achieve target alveolar ventilation. The ‘Target breath rate’ is set 
according to the user’s spontaneous breath rate during quiet wakefulness or in accordance with 
clinical needs (i.e. optimal PaO2 and PaCO2). The ‘Target breath rate’ can be measured and set by 
the ventilator itself, or manually adjusted by the clinician. Clinical trials evaluating a VAPS mode 
have been performed and have demonstrated VAPS is equivalent in treating respiratory 
insufficiency or failure as per manually titrated  pressure support ventilation [16, 17, 19, 20, 21, 22, 
23]. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 13 of 30 
ResMed Confidential 
Patients with respiratory failure may also have upper airway obstruction. These patients therefore 
may benefit from NIPPV therapy which incorporates the management of volume assurance 
pressure support (i.e. VAPS) and UAO (i.e. AutoEPAP).  
One such algorithm which has been developed is the iVAPS AutoEPAP algorithm (ResMed, Sydney, 
Australia). The iVAPS AutoEPAP algorithm has been previously trialed in patients with respiratory 
insufficiency or failure such as Obesity Hypoventilation Syndrome (OHS), Chronic Obstructive 
Pulmonary Disease (COPD) or neuromuscular disease (NMD) [24]. The patients completed two sleep 
studies (PSG) with iVAPS: one a manually titrated EPAP, and a second sleep study to observe and 
record the EPAP pressure generated from the AutoEPAP algorithm. Results showed that the 
algorithm was able to automatically titrate the EPAP level to effectively treat UAO in conjunction 
with respiratory insufficiency or failure compared to iVAPS mode with a fixed EPAP pressure. 
Treatment of UAO was shown to be comparable between the manually titrated EPAP with iVAPS, 
versus iVAPS AutoEPAP (mean AHI 1.7 (2.8) hr-1 and 1.3 (2.3) hr -1, respectively; p = 0.52) [24]. 
The aim of this study is to now compare the AutoEPAP algorithm with  manual EPAP in iVAPS mode 
on an Astral ventilator. It is proposed that the automatic settings of  AutoEPAP will be as effective 
at managing respiratory failure and UAO as manual EPAP on the Astral device. Specifically 
demonstrating that the AutoEPAP function is as effective at treating UAO as manual EPAP. 
Astral is a homecare and hospital ventilator and not compatible with PSG systems for the 
measurement of respiratory flow estimate for the scoring of AHI. While total flow might be 
measured at the outlet of the Astral ventilator, this flow would include uncompensated components 
of flow from the mask vent and unintentional mask leak that will vary both within the breath due 
to varying pressure and over a longer time course due to changing mask leak. Based on the offset 
and variation of these components, accurate measurement of apneas and hypopneas would not be 
possible. 
Since it is not technically feasible to calculate AHI, a surrogate for AHI is the ODI4% based on pulse 
oximetry that can be accurately obtained with PSG systems whilst a patient is using the Astral 
ventilator. 
Clinically, ODI4% correlates exceptionally well with the AASM 2007 scoring rules for AHI (r = 0.98) 
[25]. See figure 1.  
 
 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 14 of 30 
ResMed Confidential 
Figure 1. Correlation of ODI and AHI 
 
Secondary aims include assessing the other potential physiological (i.e. sleep and sleep-breathing 
variables and gas exchange) that the algorithm may have on the patient. 
4.2. Intended Use 
The Astral device provides continuous or intermittent ventilatory support for patients who require 
mechanical continuous or intermittent ventilation (ResMed, Sydney, Australia, K152068). 
Intelligent Volume Assured Pressure Support (iVAPS) is a mode of therapy for patients who require 
mechanical ventilation. The Astral device with the AutoEPAP algorithm and manual EPAP in iVAPS 
mode will be used in this protocol. 
 STUDY OBJECTIVES 
5.1. Primary Objective  
The primary outcome is the Oxygen Desaturation Index (ODI4%). The primary aim of this protocol 
is to compare ODI values following the use of the  AutoEPAP algorithm in comparison to  manual 
EPAP on the Astral ventilator. 
5.2. Secondary Objectives 
The secondary objectives will be used to determine if the AutoEPAP algorithm remains effective in 
treating respiratory failure. 
1. To assess the apnea hypopnea index (AHI) as measured by the Astral device. 
2. To assess sleep-breathing parameters (e.g. nadir SpO2 and PtCO2) with AutoEPAP algorithm 
compared to manual EPAP on an Astral device. 
3. To assess sleep parameters (e.g. sleep efficacy and arousal index) with AutoEPAP 
algorithm compared to manual EPAP on an Astral device. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 15 of 30 
ResMed Confidential 
 STUDY DESIGN 
This will be a prospective, multi-center, single-blind, randomized, cross-over design. The study will occur 
in a lab/hospital setting. This study will be conducted at several centers in the United States. 
6.1. Enrollment 
Subjects will be recruited from pulmonary clinics at each site. 
6.2. Selection of Subjects 
6.2.1. 
Informed Consent 
The consent form is written in accordance with applicable data privacy acts and FDA 
Regulations and approved by the responsible Institutional Review board (IRB). 
The investigator or responsible staff will explain the nature, purpose and risks associated 
with the study. The patient will be given sufficient time to consider the study’s implications 
before deciding whether to participate. Information materials created by the investigators 
and Sponsor must be approved by the responsible IRB prior to use.  
A signed, IRB-approved consent form must be obtained from the patient prior to the 
performance of any protocol-related testing or treatment procedures. The consent 
process must be performed by a designated clinical study team member authorized by the 
IRB to consent patients and listed on the Delegation of Authority Log as having privileges 
to consent patients. A signed copy of the consent form must be maintained in the study 
files and a copy provided to the patient. The patient’s permanent medical records should 
indicate study participation. 
6.2.2. 
Study Population and Randomization 
Enrolled subjects will be representative of patients with respiratory failure who fulfill the 
inclusion criteria and none of the exclusion criteria for this study and who sign the consent 
form(s) are considered as potential candidates for randomization into the study. 
After verification of the subject's eligibility for the study, the study coordinator will assign 
the subject to 1 of 2 arms of the study, using the computer-generated randomization 
schedule provided by the Sponsor. 
This is a single-blind study. This means that the subjects will be blinded to the 
randomization group that they are assigned to; the site Investigator and site study staff 
will know which randomization group the subject has been assigned to. The scorer(s) of 
the PSG will be blinded to which therapy is being used for objective determination of the 
primary and secondary endpoints.  
6.2.3. 
Number of Subjects 
Up to a total of 40 subjects will be enrolled across all centers. 
6.2.4. 
Sample Size Justification  
This study is powered for demonstrating ODI4% non-inferiority between the AutoEPAP 
algorithm and  manual EPAP algorithm on the Astral device. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 16 of 30 
ResMed Confidential 
This protocol has been powered with the following inputs based on a previous study [26]. 
Expected mean difference in ODI: 0 
Expected standard deviation in ODI: 1.55 
Power = 80% 
Alpha = 0.05 
 
Power to detect a difference of 1 per hour using a paired two-tailed t-test: 
n = (Zα + Zβ)2 × (SD/difference)2 = 22.84 = 23 
Therefore, based on a crossover non-inferiority hypothesis test (one in which the outcome 
is dependent) we can be 95% sure that a sample size of 23 is sufficient to detect inferiority 
of  AutoEPAP compared to  with manual EPAP with respect to difference of ODI. 
 
The update to this protocol (v3.0 to v4.0) was completed to be consistent with the recent 
FDA clearance of Astral with iVAPS. The increase in enrollment goal will provide additional 
power (95%) to detect a difference between AutoEPAP and manual EPAP. 
 
We pre-specify a non-inferiority margin for ODI4% of 2 per hour (refer to Section 12). 
Basing the sample size on being able to detect the smallest difference in ODI (1 per hour) 
will provide greater power, through a larger sample size, in testing the non-inferiority 
margin (2 per hour).  
6.2.5. 
Subject Inclusion Criteria 
1. Participant has ability to provide written informed consent 
2. Participants aged ≥18 years old 
3. Participant has documented respiratory failure (e.g. sleep hypoventilation with 
historical PtCO2 increase ≥ 10mmHg) and/or daytime hypercapnia (>45 mmHg) 
4. Participant is currently using non-invasive positive pressure ventilation in ST or VAPS 
mode for ≥ 3 months 
5. Participants with a previously documented AHI ≥ 5/hr 
6. Participants with a recently (≤ 12 months ago) reviewed EPAP setting 
6.2.6. 
Subject Exclusion Criteria 
1. Participants are not compliant on NIPPV (e.g. < 4 hr/night) 
2. Participants who are pregnant 
3. Participants on oxygen therapy ≥5 L/min 
4. Participants with an invasive interface (e.g. tracheostomy) 
5. Participants who have had an acute exacerbation within the last 3 months that 
resulted in a hospitalisation 
6. Participants who are acutely ill, medically complicated or who are medically unstable 
7. Participants in whom NIPPV therapy is otherwise medically contraindicated 
8. Participants who have had surgery of the upper airway, nose, sinus, or middle ear 
within the previous 90 days 
9. Participants with untreated, non-OSA sleep disorders, including but not limited to; 
insomnia, periodic limb movement syndrome, or restless legs syndrome. 
10. Participants who have the following pre-existing conditions: severe bullous lung 
disease, recurrent pneumothorax or pneumomediastinum, cerebrospinal fluid leak, 
recent cranial surgery or trauma. 
11. Participant does not comprehend English 
12. Participant is unable or unwilling to provide written informed consent 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 17 of 30 
ResMed Confidential 
13. Participant is physically and/or mentally unable to comply with the protocol 
14. Participant is not suitable to participate in the trial for any other reason in the opinion 
of the investigator 
 STUDY DEVICES 
ResMed (ResMed, Sydney, Australia, K152068) is a developer, manufacturer and distributor of medical 
device equipment, including the Astral device which is designed for treating patients with respiratory 
disorders. ResMed is also the manufacturer responsible for the iVAPS and  AutoEPAP algorithms. 
7.1. Astral device 
The ResMed “Astral” device is a mixed mode ventilator and for this protocol will provide mechanical 
ventilation. The Astral device will have iVAPS with manual EPAP and AutoEPAP algorithms, and the 
clinician will have the ability to manually change between the two modes.  
The Astral device will deliver positive airflow to the patient via approved tubing and a vented mask. 
The device will therefore only come into direct contact with the surface of the skin, primarily the 
hands, during movement, setup, or adjustment of the device.  
For the purpose of this clinical trial, user and clinical guides (Appendix A) will be provided with the 
devices to the clinicians and participants which will include iVAPS AutoEPAP specifications.  
The iVAPS AutoEPAP algorithm is currently not approved by the FDA, and is therefore considered 
an Unapproved Medical Device.  
7.2. Device Accountability 
An accurate and current accounting of the dispensing of ResMed devices (Astral) will be maintained 
on an on-going basis by a qualified member of the study site using the Sponsor-provided “Device 
Disposition Log”. The serial number unique to each Astral device will be documented on this Log. 
Devices will be made available to the investigator by ResMed. If a replacement device is dispensed, 
it will be documented per device accountability procedure. All non-disposable ResMed devices must 
be returned to ResMed at the end of the study. 
7.3. Labeling 
The label contains the information as required by relevant regulatory requirements: 
a) Sponsor name and address 
b) Serial number to identify the individual device 
c) Instruction For Use 
7.4. Packaging 
The Astral device is FDA 510(k) cleared (K152068) and will be used with the standard packaging. 
“Investigational Use Only” stickers will be placed on all study devices prior to sending to study 
sites. 
7.5. Instruction for Use 
The devices will be used as specified in the relevant Instructions for Use provided by ResMed Corp. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 18 of 30 
ResMed Confidential 
•
Provide consent 
•
Meet eligibility criteria 
•
Collect baseline data 
Visit 1 
For the purpose of this clinical trial, the Astral device is intended to treat stable patients with 
respiratory failure and who weigh at least 30 kg..  
7.6. Required Training 
Subjects will be instructed on usage of the devices by the local Investigators or designee. ResMed 
will provide the investigators' training.  
All staff involved in the clinical trial will be experienced in the operation and set-up of NIPPV devices 
and PSG. The site will be provided with User and Clinical Guides to assist with device setup and 
operation.  
 
It is expected that the trial site will use their usual equipment for conducting overnight pressure 
determination PSGs for the purpose of the investigational sleep studies. Therefore, it is not 
anticipated that any additional training on using the study equipment is required for the trial site.  
 
Prior to the commencement of the study, the Sponsor will educate the investigators and site 
coordinators on the protocol, including data collection and data management. The Sponsor will 
educate the investigators and site coordinators on any protocol amendments and updates. 
 THERAPY 
8.1. Treatment with Astral device  
During this study, the Astral device will be used in a clinic setting during monitored PSG testing. 
AutoEPAP and manual EPAP will be used in iVAPS mode for this study. 
8.2. Set up of Astral device 
For initiation of therapy, for subjects in either arm of the study, the Astral device will be set with 
clinically appropriate settings, as determined by the treating physician and investigator.  These 
settings include: target volume and minimum and maximum pressure support (PS). For subjects 
randomized to the manual EPAP group on Visit 2, the EPAP settings will be based on the subject’s 
previous titrated settings.  For subjects randomized to the AutoEPAP group on Visit 2, the minimum 
and maximum AutoEPAP settings will be set to default, or as clinically appropriate. Additional details 
and instructions will be included in the study Manual of Procedures. 
 
 
 
 
 
 STUDY SCHEDULE 
A summary of the procedure is summarized in Figure 2.  
Figure 2. Summary of trial procedure  
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 19 of 30 
ResMed Confidential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1. Visit 1 
Participants will be recruited from existing hospital patient databases. Participants will be pre-
screened and those meeting the required criteria will be contacted by the investigators via follow 
up phone call or during an office visit, and asked if they wish to take part in the study. 
Participants wishing to participate will attend the sleep clinic/hospital where written informed 
consent will be obtained (Appendix B). All participants will be checked for study eligibility using the 
Inclusion/Exclusion criteria of this protocol. Participants who do not meet the eligibility criteria will 
not be included in the study. Participants meeting the eligibility criteria will have baseline 
information collected, including participant demographics, medical history, and information about 
the participants’ current therapy.  If available, the following information will also be collected into 
the subject chart: diagnostic sleep study report, their most recent spirometry report, and at the 
physicians’ discretion, a capillary blood gas test. 
9.2. Visit 2 
Participants will attend an office visit where they will be randomized (1:1) to receive iVAPS with 
AutoEPAP or iVAPS with manual EPAP first. Participants will be randomized according to a 
computer-generated randomized list. 
Participants will undergo an overnight PSG at the site per their randomized group assignment. Full 
PSG set-up, data acquisition, monitoring and reporting will be performed using the AASM 2007 
criteria. Therapy will be delivered using the clinical trial device, Astral. At least 4 hours of recording 
will be required.  

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 20 of 30 
ResMed Confidential 
Participants’ trial devices will be setup according to the therapy settings detailed in the Therapy 
section of this protocol.  The set-up of  manual EPAP or AutoEPAP settings shall occur before lights 
out. Study staff will also set up the subject to test PtCO2. This may be done with a device clipped to 
the outside of the subject’s ear, and does not introduce risk to the subject. 
Ensure a new USB flash drive is labelled and inserted into the Astral device prior to the 
commencement of the study. The device’s ID number is to be recorded in the CRF before the end 
of the visit. Ensure there is an SD card in the machine, and the SD card is labelled with the participant 
ID number, therapy type, Night 1. 
Visit 1 and 2 may be conducted on the same day. 
9.2.1. Visit 3 
Participants will undergo an overnight PSG at the site per their randomized group assignment. Full 
PSG set-up, data acquisition, monitoring and reporting will be performed using the AASM 2007 
criteria. Therapy will be delivered using the clinical trial device, Astral. At least 4 hours of recording 
will be required.  
Participants’ trial devices will be setup according to the therapy settings detailed in the Therapy 
section of this protocol.  The set-up of  manual EPAP or AutoEPAP settings shall occur before lights 
out. Study staff will also set up the subject to test PtCO2. This may be done with a device clipped to 
the outside of the subject’s ear, and does not introduce risk to the subject. 
Ensure a new USB flash drive is labelled and inserted into the Astral device prior to the 
commencement of the study. The device’s ID number is to be recorded in the CRF before the end 
of the visit. Ensure there is an SD card in the machine, and the SD card is labelled with the 
participant ID number, therapy type, Night 2. 
The completion of Visit 3 marks the completion of study participation. Participants will return to 
their usual NIPPV therapy and have the option of keeping the mask and chinstrap that was used 
during the study. 
9.3. Study Completion 
PSG scoring will be centralized to ensure scoring consistency across sites. De-identified scored PSGs, 
Astral devices and flash cards will be returned to the Sponsor following study completion. 
Data analysis will be performed by an independent statistician. 
A final study report will be prepared by ResMed’s Medical Affairs department. 
 
 
 
  STUDY TIMELINE 
The investigators estimate it will take up to 16 weeks to recruit a total of 40 participants from all US sites. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 21 of 30 
ResMed Confidential 
Each participant is to attend 2-3 visits to the site (Visit 1 and 2 may be combined). Visits 2 and 3 will be 
overnight visits at the site’s sleep unit. Ideally, sleep studies will occur on 2 consecutive nights. However, 
it is permitted that Night 2 can occur within 1 week from Night 1. 
Therefore, the duration of the study is expected to take approximately 5 months to complete. This time 
frame also accounts for data monitoring, analysis and the development of the clinical study report.  
10.1. Suspension or Early Termination of Study 
The study or a site may be suspended or terminated early by the Sponsor, IRB or regulatory body, 
including but not limited to issues with safety, disease management, and unethical conduct. Should 
this occur, all participants currently participating in the trial will be notified, will be withdrawn safely 
from the study, and will resume their usual NIPPV therapy. 
 SAFETY 
The investigator is responsible for monitoring the safety of subjects enrolled into the study at the study 
site. The investigator or qualified designee will enter the required initial and follow-up information 
regarding adverse events on the appropriate eCRF within the EDC system. Investigators are responsible 
for following all serious adverse events (SAEs) until resolution, stabilization, or the event is otherwise 
explained, and to report serious adverse events as well as serious injury or death that were related to 
(caused by or contributed to) the Astral study device in accordance with their local IRB requirements. 
Investigators should follow usual clinical practice at their institutions for reporting serious events to the 
regulatory authorities. 
11.1. Definition of Adverse Events 
11.1.1. Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a medical product and which not necessarily have to have a causal 
relationship with this treatment. 
11.1.2. Unanticipated Adverse Device Effect 
Unanticipated adverse device effect is any serious adverse effect on health or safety, any 
life-threatening problem or death caused by, or associated with a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence 
in the application; or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects. 
11.1.3. Serious Adverse Effect (event or reaction) (SAE) 
Any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
(voluntary hospitalizations for elective surgeries are not considered as serious 
adverse events) 
• 
results in persistent (symptomatic or moderate) or significant disability /incapacity 
• 
an important medical event; or 
• 
is a congenital anomaly/birth defect 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 22 of 30 
ResMed Confidential 
 
All known details of the SAE will be sent to the Principal Investigator and Sponsor within 
24 hours. Together the PI and Sponsor will determine whether the SAE may be device 
related and whether it is safe for the trial to continue.  The PI and Sponsor will determine 
if the SAE requires reporting to the IRB, and will follow the SAE to completion. 
 
 STATISTICAL ANALYSIS 
Data recorded during ‘Ramp’ time (i.e. the time taken for the pressures to increase to the prescribed 
settings when the device is first turned on) will be excluded. Data will be checked for normality. If the 
data is normally distributed, descriptive data will be presented as mean and standard deviation (SD), 
and marginal differences. Comparisons between the two modes will be done using paired T-test. 
If the data is not normally distributed, descriptive data will be presented as median and interquartile 
range (IQR). Comparative analysis between  AutoEPAP and  manual EPAP will be performed using the 
Mann-Whitney U test.  
A p < 0.05 will be considered significantly different between  AutoEPAP and manual EPAP if: 1. there is 
no significant difference between AutoEPAP and manual EPAP or 2.  AutoEPAP is significantly better 
than manual EPAP, than the null hypothesis will be rejected and the AutoEPAP algorithm will be 
considered as ‘passed’.  
We pre-specify a non-inferiority margin for ODI4% of 2 per hour and specify a statistical test for non-
inferiority as: 
Non-inferiority margin for ODI: d=2 
H0: μA – μB ≤ -d (new algorithm is inferior) 
H1: μA – μB > -d (new algorithm is non-inferior) 
 
To show non-inferiority the lower bound of the 95th confidence interval of the difference between the 
groups must not cross the margin boundary (ODI4% of 2 per hour). 
Which will be tested with a single-sided t-test with an alpha of 0.05 and a power of 80%. This pre-
specified non-inferiority margin for ODI4% of 2 per hour is considered clinically unimportant, is the 
same margin as used in a previous study [26], and 2 per hour represents approximately 7% of severe 
UAO (30 per hour). 
We also pre-specify that we will reject subjects where the ODI4% cannot be controlled during the 
control arm phase ( manual EPAP). This is defined as an ODI ≥ 10 per hour. This process will be 
documented in the study Manual of Procedures and training provided for all participating sites. 
12.1. 
Withdrawal of Subjects 
Due to factors not able to be predicted prior to the commencement of clinical studies, participants may 
at times either “drop-out” or withdraw from the study by their own volition, or be withdrawn from the 
study by the investigator or Sponsor. Data from participants who are excluded, drop-out or withdraw 
from the study prior to study completion will be collected until the point of study discontinuation, unless 
the participant explicitly withdraws his/her data. Where participants formally revoke their consent, 
which includes the revocation of consent for any data collection, all data collected from these 
participants will not be used in any data analyses. 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 23 of 30 
ResMed Confidential 
All efforts will be made to follow-up on the collection of missing data. If collection of missing data is not 
possible, all enrolled participants’ remaining collected data will still be included in the final data set for 
analysis on the condition that the participant has completed all required study-related procedures. 
Enrolment is considered as taking place at the point of randomization. 
 DATA MANAGEMENT AND STORAGE 
13.1. 
Data Collection 
All raw data from the study will be non-identified format and documented on: 
• 
CRF’s (Appendix C) 
• 
Sleep study reports (which details sleep and respiratory variables and therapy settings) 
• 
Flash drives from the devices.   
13.2. 
Study Documentation 
Throughout the conduct of the study, all required data will be entered into the eCRF for each 
subject. The investigator should ensure the accuracy, completeness, and timeliness of the data 
reported to the Sponsor in the eCRFs and in all required reports and will be asked to sign and date 
the appropriate eCRF page(s) to verify the data collected. Data entered into the eCRF must be 
consistent with source documents. Any change or correction to an eCRF will be captured in the EDC 
system audit trail.  
The clinical site will provide study data to the Sponsor by recording data in the EDC System (21 CFR 
Part 11 compliant).  
In cases of subject-reported data, the eCRF will be the source record. 
 
The site PI or designee and the clinical monitor will review completed eCRFs for accuracy, 
discrepancies, and missing information. The information entered into the eCRF will be accessible to 
the appropriate ResMed Medical Affairs personnel. 
13.3. 
Query Generation 
Any data queries will be sent to site for reconciliation via the eCRF system and final close-out will 
be from the study monitor. 
13.4. 
Data Storage 
All electronic systems used by the site and Sponsor will have adequate security to protect patient 
privacy and data integrity. All paper documentation will be locked in a secured cupboard. All trial 
data and documentation will be retained for a minimum of 15 years before it is destroyed. Access 
to data maintained in the EDC System is strictly limited to authorized personnel. 
13.5. 
Inspection of Records 
Periodically the Sponsor or representative will review the Investigator study file and the study 
data to verify compliance with applicable regulations and the protocol, and to verify accuracy of 
the data. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 24 of 30 
ResMed Confidential 
13.6. 
Study Files and Record Retention 
The investigator must maintain adequate and accurate records as specified in Essential Documents 
for the Conduct of a Clinical Trial (E6, Section 8 of the ICH Guideline for GCP) to enable the conduct 
of the study to be fully documented and the study data to subsequently be verified. These 
documents should be classified into two separate categories: (1) investigator’s study file and (2) 
subject clinical source documents. 
Essential documents must be retained until at least 2 years after notification by the Sponsor that 
the investigations have been discontinued OR 2 years after the last approval of a marketing 
application. The investigator must notify the Sponsor prior to destroying any clinical study records. 
13.7. 
Regulatory Documentation 
Documents that must be provided to the Sponsor prior to study initiation are: 
• 
Signed, dated current (within 2 years) curriculum vitae of Investigator and Sub-
Investigator(s) 
• 
Financial disclosure for physicians and nurses 
• 
Signed (original), dated Investigator Agreement 
• 
Assurance that the IRB complies with requirements set forth in Title 21 Part 56 of the Code 
of Federal Regulations. The required documentation consists of name and address of the 
IRB, a current list of members including title, gender, occupation and any institutional 
affiliation of each member. A general assurance number from the Department of Health and 
Human Services may be substituted for this list. 
• 
Written notification (copy) to the Investigator from the IRB approving the protocol 
• 
IRB approved informed consent (copy) and any other adjunctive materials to be used in the 
study as required. 
13.8. 
Distribution of Results 
Data analyses will be completed by an independent statistician and the clinical study report will be 
completed by the Sponsor.  
Any published and presented data will be non-identifiable.  
 ETHICAL CONSIDERATIONS 
14.1. 
Institutional Review Board (IRB) 
The investigator must have written and dated approval from the IRB for the protocol, consent 
form, subject recruitment materials/process (advertisements), and any other written information 
to be provided to subjects. The investigator should also provide the IRB with a copy of the product 
labeling information and any updates. The investigator will provide the IRB with reports, updates, 
and other information (e.g., safety updates and protocol amendments) as required by regulations. 
14.2. 
Protocol Deviations 
An investigator is required to conduct this study in accordance with the signed Investigator's 
Agreement, this Investigational Plan, applicable laws and FDA regulations, and any conditions of 
approval imposed by the reviewing IRB and FDA. According to FDA regulation 21 CFR § 
812.150(a)(4), an investigator shall notify the sponsor and the reviewing IRB of any deviation from 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 25 of 30 
ResMed Confidential 
the investigational plan to protect the life or physical well-being of a subject in an emergency. Such 
notice shall be given as soon as possible, but no later than five working days after the emergency 
occurred. Except in such an emergency, prior approval by the sponsor is required for a change in or 
deviations from a plan and, if these changes or deviations could affect the scientific soundness of 
the plan or the rights, safety or welfare of human subjects, FDA and IRB approval may also be 
required in accordance with 21 CFR § 812.35(a). 
14.3. 
Risk Analysis 
14.3.1. Non-Significant Risk Determination 
The Astral device with the iVAPS algorithm has been cleared (K152068) by the FDA to provide 
therapy to patients who require mechanical continuous or intermittent ventilation. The device is 
intended for home and hospital use. The purpose of this study is to evaluate the effect of a new 
algorithm that auto titrates EPAP to treat patients with UAO and respiratory failure.  
Clinical personnel will observe the subject on the fitting and use of all Astral devices. They will 
monitor the subject’s clinical parameters and will intervene, if required. 
As per FDA good practice guidelines (21 CFR 10.115), this study protocol as well as the Astral device 
was assessed for risk to participants. As this study does not meet the definition of significant risk as 
defined by 21 CFR 812.3(m), the investigative team has determined that this protocol and the Astral 
device is non-significant risk.    All subjects will maintain all other therapy regimens per standard 
clinical care; this protocol does not dictate any other adjustments to the participants’ care regimen 
and there are no protocol-required assessments or procedures that pose significant risk to the 
participants. As required by the FDA, the IRB(s) will review this study protocol and make the final 
determination of NSR designation. 
Subjects should be encouraged to discuss any issues they are having with therapy during the study. 
The investigator should assess for changes in the health or well-being of the subject in response to 
general, non-directed questioning (e.g., “How are you feeling while using the therapy?”).  Side 
effects should be documented on the site’s source documents. Any transient side effects, at a 
minimum, should be documented in the clinic record.  
Furthermore, if during the evaluation the subject believes the mask or therapy is intolerable, the 
study staff will be instructed to discontinue use of the protocol device on the patient and ensure 
the patient returns to using their current mask and therapy. Potential expected adverse events are 
believed to be mild and similar to other commercially available mask systems. 
Participants will be asked to use the study device only during the two study visits that are fully 
attended PSG nights in a sleep lab.  The attending technicians have experience setting up the eligible 
patient population in this study.  All subjects return to their current NIPPV therapy after completing 
the study visits. 
As the trial involves a minimally tested algorithm for the treatment of respiratory failure, there is a 
small chance that treatment will be ineffective and will result in a maximum of one night with 
suboptimal therapy. This may result in a temporary increase in the participant’s CO2 levels causing 
dyspnea, tachypnea, flushing, and/or sweating. This is being mitigated in two ways: 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 26 of 30 
ResMed Confidential 
1. Trained study staff are able to stop the study and resume normal treatment at any time if 
they feel the patient requires more effective treatment.  
2. Participants' oxygen and carbon dioxide levels will be monitored overnight using oximetry 
and transcutaneous CO2 monitoring equipment (as per routine practice), to ensure further 
medical treatment is not required for hypoxia or hypercapnia. 
Potential expected adverse events are believed to be mild and similar to other commercially available 
NIPPV systems. The anticipated adverse effects during this trial are minimal and limited to those 
recognized with standard use of NIPPV treatment. These include: 
• 
drying of the nose, mouth, or throat 
• 
nosebleed 
• 
bloating 
• 
ear or sinus discomfort 
• 
eye irritation 
• 
skin rashes on the face from the mask 
Eligible patients will already be established on NIPPV treatment (ST or VAPS mode). It is expected 
that any anticipated adverse events linked to AutoEPAP in iVAPS mode will be similar to ST or VAPS 
modes. 
14.3.2. Subject Data Confidentiality 
All information and data collected for this study protocol concerning subjects or their participation 
in this investigation will be considered confidential. Only authorized Sponsor personnel or a Sponsor 
representative will have access to these confidential files. All data will be handled in accordance with 
applicable local laws. Authorized FDA personnel or Regulatory Authorities have the right to inspect 
and copy all records pertinent to this investigation. All data used in the analysis and reporting of this 
investigation will be without identifiable reference to specific subject name. 
 QUALITY 
Quality Control is defined as the operational techniques and activities, such as monitoring, undertaken 
within the quality assurance system to verify that the requirements for quality of the study related 
activities have been fulfilled. 
Quality Control should be applied to each stage of data handling to ensure that all data are reliable and 
have been processed correctly. 
15.1. 
Site Selection 
The sites should have previously participated in clinical studies and must have adequate experience, 
time, staff, and facilities to perform all required duties. Sites must permit clinical trial related 
monitoring, audits, IRB review, and regulatory inspections, providing direct access to source 
data/documents, as appropriate 
15.2. 
PSG Data 
This study will utilize a sleep core lab to ensure consistency in scoring across all participants and all 
sites.  The sleep core lab member responsible for scoring the participant PSGs will be blinded to the 
subject’s randomization group as well as to the therapy settings of the participant. It is the 
responsibility of the site investigator to collect and send this data to the sleep core lab. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 27 of 30 
ResMed Confidential 
15.3. 
Training 
The clinical monitor will conduct an initiation visit at each site to review relevant documentation 
such as the clinical protocol, study manual, Astral Instructions for Use, GCP, applicable regulations, 
and investigator’s obligations with site study personnel. In addition, training on the Data 
Management System will be conducted. If new study staff members are employed at the site after 
the initiation meeting, experienced site personnel must train new employees as noted above and 
document the training (contact the clinical monitor for instructions on how to document the 
training). 
15.4. 
Site Monitoring 
The study will be initiated by the study monitor, or designee, during an on-site visit after all required 
documents have been processed. Qualified clinical monitors will perform on-site monitoring visits 
as frequently as is deemed necessary. 
During the site visits, the monitor will compare the data entered into the eCRF with the source 
documents. In addition, the monitor will verify that standards of Good Clinical Practice (GCP) are 
being followed. Findings from the review of eCRFs, source documents and study conduct will be 
discussed with the investigator. The Sponsor expects that, during monitoring visits, the study 
coordinator and investigator will be available, the source documentation will be available and a 
suitable environment will be provided for review of study related documents 
  RESPONSIBILITIES 
16.1. 
Clinical Investigator Responsibilities 
With the approval of their institution‘s IRB/EC, qualified investigators will conduct the CAT-HF 
clinical investigation in accordance with the Declaration of Helsinki: “Recommendations Guiding 
Medical Doctors in Biomedical Research Involving Human Subjects”. Each site principal investigator 
and their co-investigators are responsible for the following: 
• 
Completion of all required agreements  
• 
Screening and evaluation of subjects 
• 
Strict adherence to the Clinical Protocol, Study Manual of Procedures and all Federal 
Regulations 
• 
Supervising investigational device use and return 
• 
Obtaining informed consent prior to study related procedures and the collection of data 
during study and follow-up examinations in a timely manner 
• 
Timely reporting of all SAEs and UADEs 
• 
Providing death notes, when applicable 
It is acceptable for the site principal investigator to delegate one or more of the above functions to 
an associate or co-investigator, however, the site principal investigator remains responsible for 
proper conduct of the clinical investigation and signing an investigator agreement. The investigation 
is non-transferable to other centers attended by the investigator unless prior approval is obtained 
from the appropriate IRB/EC and the Sponsor. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 28 of 30 
ResMed Confidential 
16.2. 
Sponsor Responsibilities 
The Sponsor will provide each site with a study Manual of Procedures and study materials. The 
Sponsor will train study personnel on the clinical study protocol and procedures. Clinical monitors 
will conduct site visits in order to ensure the site procedures are being carried out in accordance 
with the clinical study protocol and GCP. Clinical monitors will ensure that the study is progressing 
as expected, study data are accurate and up to date, data recording is complete, and protocol 
deviations are recorded and reviewed with the PI. Throughout the study period, the clinical monitor 
will be available to address any issues that may arise. This availability includes access by phone, fax, 
and/or e-mail. An additional site visit or conference call may be scheduled at the end of the study 
period to formally close the clinical study. 
 
 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 29 of 30 
ResMed Confidential 
 REFERENCES 
1. Budweiser, S., et al., Predictors of survival in COPD patients with chronic hypercapnis respiratory 
failure receiving noninvasive home ventilation. Chest, 2007. 131(6): p. 1622-1624. 
2. Masa, J.F., et al., The obesity hypoventilation syndrome can be treated with noninvasive mechanical 
ventilation. Chest, 2001. 119: p. 1102-1107. 
3. Remmers, J.E., et al., Pathogenesis of upper airway occlusion during sleep. Journal of Applied 
Physiology, 1978. 44(6): p. 931-938. 
4. Ward, S., et al., Randomised controlled trial of non-invasive ventilation (NIV) for nocturnal 
hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia. Thorax, 
2005. 60(12): p. 1019-1024. 
5. Laghi, F. and M.J. Tobin, Disorders of the respiratory muscles. Am J Respir Crit Care Med, 2003. 168(1): 
p. 10-48. 
6. Bott, J., et al., Randomised controlled trial of nasal ventilation in acute ventilatory failure due to 
chronic obstructive airways disease. Lancet, 1993. 342: p. 503. 
7. Oscroft, N.S., et al., A prospective, randomised, single-blind, crossover study comparing standard bi-
level with volume assured non-invasive positive pressure ventilation in chronic obstructive pulmonary 
disease patients with chronic ventilatory failure. Thorax, 2008. 63(suppl VII): p. S78. 
8. Sullivan, C.E., et al., Reversal of obstructive sleep apnea by continuous positive airway pressure 
applied through the nares. Lancet, 1981. 1: p. 862-865. 
9. Miljeteig, H. and V. Hoffstein, Determinants of continuous positive airway pressure level for 
treatment of obstructive sleep apnea. Am Rev Respir Dis, 1993. 147: p. 1526-1530. 
10. Stradling, J.R., et al., Relative accuracy of algorithm-based prescription of nasal-CPAP in OSA. Respir 
Med, 2004. 98: p. 152-154. 
11. Steier, J., et al., Neural Respiratory Drive in Obesity. Thorax, 2009. 64: p. 719-725. 
12. Steier, J., et al., Sleep-disordered breathing in unilateral diaphragm paralysis or severe weakness. Eur 
Respir J, 2008. 32(2): p. 289-297. 
13. Chiu, K.L., et al., Fluid Shift by Lower Body Positive Pressure Increases Pharyngeal Resistance in 
Healthy Subjects. American Journal of Respiratory and Critical Care Medicine, 2006. 174(12): p. 1378-
1383. 
14. Teschler, H., et al., Automated continuous positive airway pressure titration for obstructive sleep 
apnea syndrome. Am J Respir Crit Care Med, 1996. 154: p. 734-740. 
15. Teschler, H., et al., Adaptive pressure support servo-ventilation: a novel treatment  for Cheyne-Stokes 
respiration in heart failure. Am J Respir Crit Care Med, 2001. 164: p. 614-619. 
16. Battisti, A., et al., Automatic adjustment of noninvasive pressure support with a bilevel home 
ventilator in patients with acute respiratory failure: a feasibility study. Int Care Med, 2007. 
doi:10.1007/s00134-007-0550-1. 
17. Hussein, K., Non invasive spontaneous dual ventilation in critically ill patients with chronic 
obstructive pulmonary disease. Egypt J Chest Dis Tuberc, 2015. 
http://dx.doi.org/10.1016/j.ejcdt.2015.08.016. 
18. Oscroft N.S., et al., A Randomised Crossover Trial Comparing Volume Assured and Pressure Preset 
Noninvasive Ventilation in Stable Hypercapnic COPD. Journal of Chronic Obstructive Pulmonary 
Disease, 2010. 7: p. 398-403. 
19. Jaye, J., Chatwin, M., Dayer, M., Morrell, M.J. and Simonds, A.K., Autotitrating versus standard 
noninvasive ventilation: a randomised crossover trial. Eur Respir J, 2009. 33: p. 566-573. 
20. Battisti, A., Tassaux, D., Bassin, D., Jolliet, P., Automatic adjustment of noninvasive pressure support 
with a bilevel home ventilator in patients with acute respiratory failure: a feasability study. 
Intensive Care Med, 2007. doi: 10.1007/s00134-007-0550-1. 
21. Oscroft, N.S., Chadwik, R., Davies, M.G., Quinnell, T.G., Smith, I.E., Volume assured versus pressure 
preset non-invasive ventilation for compensated ventilatory failure in COPD. Respiratory Medicine, 
2014. 108: p. 1508-1515. 
22. Kelly, J.L., Jaye, J., Pickersgill, R.E., Chatwin, M., Morrell, M.J., Simonds, A.K., Randomized trial of 
‘intelligent’ autotitrating ventilation versus standard pressure support non-invasive ventilation: 
Impact on adherence and physiological outcomes. Respirology, 2014. 19: p. 596-603. 

Astral VAPS AutoEPAP Clinical Trial (MA-15-12-15) 
 
Version 4.0, 06.June.2016 
Page 30 of 30 
ResMed Confidential 
23. Ekkernkamp, E., Storre, J., H., Windisch, W., Dreher, M.,  Impact of Intelligent Volume-Assured 
Pressure Support on Sleep Quality in Stable Hypercapnic Chronic Obstructive Pulmonary Disease 
Patients: A Randomized, Crossover Study. Respiration, 2014. doi: 10.1159/000364946. 
24. Bassin D, et al. D630-105 AutoVPAP with AutoEEP for Upper Airway Obstruction Clinical Trial Report. 
ResMed Ltd. 2014. Data unpublished. 
25. Tsai, W.H., Flemons, W.W., Whitelaw, W.A., Remmers, J.E.. A comparison of apnea-hypopnea 
indices derived from different definitions of hypopnea. American Journal of Respiratory and Critical 
Care Medicine, 1999. 159: p. 43-8. 
26. Ketheeswaran, S., et al., D280-019 The Evaluation of the Sleep-Breathing treatment algorithm: 
AutoEPAP iVAPS. ResMed Ltd., 2015. Data unpublished. 
 APPENDIX A – ASTRAL CLINICAL GUIDE 
 APPENDIX B – INFORMED CONSENT FORM 
 APPENDIX C - CRFs