Randomized Controlled Cross-Over Pilot Study of the Effectiveness of the Vector NIV Device in Hypercapnic COPD Patients With Expiratory Flow Limitation
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Philips Clinical & Medical Affairs Global



 
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Table of Contents 
 
I. 
Document Control Page(s) ................................................................................ 3 
II. 
Glossary .............................................................................................................. 7 
III. 
Background Information .................................................................................. 11 
IV. 
Study Design Rationale ................................................................................... 14 
V. 
Study Design: ................................................................................................... 16 
VI. 
Selection and Withdrawal of Subjects: ........................................................... 25 
VII. 
Treatment of Subjects: ..................................................................................... 27 
VIII. 
Assessment of Performance ........................................................................... 28 
IX. 
Assessment of Safety ...................................................................................... 28 
X. 
Device Deficiencies .......................................................................................... 31 
XI. 
Statistical Methods ........................................................................................... 31 
XII. 
Direct Access to Source Data / Documents ................................................... 32 
XIII. 
Quality Control and Quality Assurance .......................................................... 33 
XIV. 
Ethics ................................................................................................................. 33 
XV. 
Data Handling and Recordkeeping ................................................................. 34 
XVI. 
Financing and Insurance ................................................................................. 34 
XVII. Registration on ClinicalTrials.gov or other applicable registry .................... 34 
XVIII. Risk and Benefit Analysis ................................................................................ 34 
References ................................................................................................................... 36 
Appendices .............................................................................................................................38 
 

 
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II. Glossary 
 
 
Apnea: The cessation of airflow at the nostrils and mouth for at least 10 seconds.  
Apnea/Hypopnea Index (AHI): The number of apneas and hypopneas per hour of 
sleep 
Auto Adjusting Continuous Positive Airway Pressure Device: A type of CPAP 
machine that monitors changes in breathing and compensates automatically by making 
appropriate therapeutic adjustments in pressure delivery. 
Average Volume Assured Pressure Support (AVAPS): Positive airway pressure 
support that provides a gradual pressure change based on the average of the preceding 
several breaths 
Bi-Level PAP Therapy: Responds to both inspiration and expiration by the patient and 
delivers a set amount of pressure when the patient begins spontaneous inhalation and 
decreasing pressure when exhalation begins 
COPD: Chronic Obstructive Pulmonary Disease 
CPAP Pressure: Pressure needed to maintain an open airway in a sleep apnea patient 
treated with CPAP, expressed in centimeters of water (cm H2O). The positive pressure 
can range from 4 - 25 cm H2O. Different patients require different pressures. The value 
is determined in a CPAP titration study.  
CPAP Therapy: Continuous Positive Airway Pressure: Delivers a constant pressure 
during inspiration and expiration 
Hypersomnolence: Excessive daytime sleepiness 
ODI: 4% Oxygen Desaturation Index 
EFL: Expiratory Flow Limitation: A physiological phenomenon in which an increase in 
driving pressure fails to result in increased expiratory flow. In patients with COPD this 
occurs when the external pressure driving expiration exceeds the recoil pressure 
holding the airways open 
EPAP: Expiratory Positive Airway: Pressure-Physician prescribed pressure for the 
expiratory (breathing out) phase of an individual on Bi-level PAP therapy  
FEV1: Forced Expiratory Volume in one second: The volume of air exhaled in the first 
second of the FVC maneuver and is the most reproducible measurement of airway 
obstruction 

 
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FOT: Forced Oscillation Technique: A method to detect the presence of expiratory flow 
limitation 
FVC: Forced Vital Capacity: Spirometry measurement in which the patient inhales 
maximally and then exhales as rapidly and completely as possible 
IPAP: Inspiratory Positive Airway Pressure: Physician prescribed pressure for the 
inspiratory (breathing in) phase of an individual on Bi-level PAP therapy. 
Noninvasive Positive Pressure Ventilation (NPPV): Mechanical ventilation provided 
noninvasively (by mask or similar interface) rather than through an endotracheal tube or 
tracheostomy. 
Positive End Expiratory Pressure (PEEP): Pressure in the lungs (alveolar pressure) 
above atmospheric pressure (the pressure outside of the body) that exists at the end of 
expiration 
OSA: Obstructive Sleep Apnea: A disorder in which complete or partial obstruction of 
the airway during sleep causes loud snoring, oxyhemoglobin desaturations and frequent 
arousals 
S Mode: Spontaneous Ventilation: Provides ventilation in synchrony with a person’s 
spontaneous breathing efforts; triggering of a breath cycle is only by the patient 
S/T Mode: Spontaneous Timed Ventilation: Provides ventilation in synchrony with a 
person’s spontaneous breathing efforts; triggering of a breath cycle is by the patient or 
the ventilator, should the person fail to trigger the ventilator after a preset time. In 
Spontaneous/Timed mode a "backup" rate is set to ensure that the patient still receives 
a minimum number of breaths per minute if they fail to breathe spontaneously 
Zrs: Total impedance of the respiratory system as measured by the forced oscillation 
technique (FOT) at a forcing frequency of 5 Hz 
Xrs: The reactance (i.e. the imaginary component of the impedance) of the respiratory 
system as measured by the forced oscillation technique (FOT) at a forcing frequency of 
5 Hz. 
ΔXrs: The difference between the mean value of Xrs during expiration (
exp
X
) and the 
mean value of Xrs during inspiration (
insp
X
). A breath is classified as flow-limited if its 
ΔXrs is greater than 2.8 
-1
2
L
s
O
cmH
⋅
⋅
 

 
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Protocol Synopsis 
 
Title: 
Randomized 
Controlled 
Cross-Over 
Pilot 
Study 
of 
the 
Effectiveness of the Vector NIV Device in Hypercapnic COPD 
Patients with Expiratory Flow Limitation 
Study Design: 
This will be a prospective randomized controlled cross-over pilot 
trial to investigate the clinical efficacy and safety of the Vector A-
series NIV device to treat COPD patients with chronic 
hypercapnia. 
Objectives: 
Primary Objective:  To compare treatment effect of providing NIV 
therapy with the Vector NIV Device vs current prescribed NIV in 
patients with hypercapnic COPD and evidence of expiratory flow 
limitation 
 
 
Secondary Objectives:  
• To evaluate treatment effect of Vector on overall quality of 
life 
• To evaluate treatment effect of Vector on sleep quality 
• To evaluate treatment effect of Vector on physical activity 
levels 
• To Evaluate treatment effect of Vector on Ventilator 
collected parameters 
• To Evaluate treatment effect differences on nocturnal 
SpO2 and PaCO2 or TcCO2 

 
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Endpoints: 
 
Primary Endpoint:   
 
Daytime CO2 levels at the end of 4-6 weeks of therapy as 
determined by Arterial Blood Gas (PaCO2) 
 
Secondary Endpoints: 
 
• Average daily device usage  
• Therapy Comfort and Preference 
• Incidence of Unanticipated Serious Adverse Device 
Effects (USADEs) and Serious Adverse Events (SAEs) 
for the Vector vs. the control group.  
 
Exploratory Endpoints:  
• Changes in quality of life scores ((CAT) SGRQ, dyspnea 
ratings mMRC),  
• Ventilator collected parameter differences after 6 weeks 
of use (Respiratory Rate (RR), Minute Ventilation (MV) 
• Sleep Quality differences as measured by PSG and 
actigraphy 
• Changes in activity levels (mean and max activity counts) 
  
 
Study 
Population: 
 
Approximately 30 COPD patients with chronic hypercapnia and 
evidence of expiratory flow limitation will be included. 
Phase: 
Pilot study  
 
Sites/Facilities  
Enrolling 
Participants: 
 
 
Description of 
Study 
Intervention:  
Temple University Hospital 
 
 
 
 
NIV with Auto Adjusting EPAP  
 
  
 
Study Duration: 
Approximately 12 months 
 
Participant 
Duration: 
Approximately 15 weeks   

 
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III. Background Information 
 
Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and 
mortality worldwide.   
Treatment options for COPD patients consist of medications, such as bronchodilators 
and anti-inflammatory drugs, pulmonary rehabilitation, long-term oxygen therapy 
(LTOT), and lung transplantation.  Studies have shown that bronchodilators and anti-
inflammatory drugs show minor or no benefit on long term outcomes but rather are used 
mainly for symptomatic relief.1 Pulmonary rehabilitation has been demonstrated to 
improve functional status and symptoms but there is sparse evidence on long term 
outcomes of this therapy. 2   Lung transplantation is only appropriate for a small number 
of patients; therefore, there is no demonstration of improved long-term survival rate.3, 4 
Of these available therapies, few have been shown to significantly improve long-term 
patient outcomes.  For the severe COPD patient, LTOT is the only treatment that 
demonstrated prolonged survival in controlled studies. 5, 6   But, despite the effectiveness 
of LTOT, COPD is still characterized by a high morbidity and mortality rate.   
Noninvasive positive pressure ventilation (NPPV) is one therapy that may prove 
beneficial to stable COPD patients.  NPPV, also known as NIV, is the use of positive 
pressure ventilation administered via a nasal or full-face mask (that covers both the 
nose and mouth).  This type of ventilation has become a well-established and 
increasingly used therapeutic option for patients with hypercapnic respiratory failure 
(HRF) due to COPD.7  
NPPV, used nocturnally, may improve nighttime hypoventilation that is common with 
COPD patients.  An improvement in nocturnal hypoventilation would reset the 
respiratory center sensitivity for CO2.8 9 This would result in an improvement in daytime 
gas exchange and sleep quality.  It is also known that hyperinflation in patients with 
COPD increases their work of breathing, thus fatiguing the respiratory muscles.10 It has 
been suggested that by applying nocturnal NPPV it would allow the respiratory muscles 
to rest, resulting in muscle function recovery, increased respiratory muscle strength, 
reduced the tendency for fatigue and improvement in pulmonary function and gas 
exchange.11 Adverse effects of NPPV are usually minor and manageable.  The masks 
may cause some discomfort and air pressure and flow have adverse effects.  All 
adverse effects encountered, including mask discomfort, nasal or mouth congestion or 
dryness, eye irritation, gastric insufflation, and nasal bridge ulceration will be recorded 
on data sheets that are part of the case report form. 
COPD is a disease that results in varying degrees of dyspnea, or shortness of breath.  
Spirometry is a method of diagnosing COPD with the diagnosis confirmed by presence 

 
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of a post bronchodilator FEV1 <80% of the predicted value in combination with an FEV1 
/ FVC <70%.   
The presence of airflow obstruction has been identified as one of the main causes of 
dyspnea in patients with chronic obstructive pulmonary disease 1.  Expiratory Flow 
Limitation (EFL) occurs when the driving pressure outside the airways exceeds the 
recoil pressure holding the airway open.  As airflow obstruction worsens, EFL appears 
at much lower flows for a given lung volume and it becomes present at rest or at least 
develops early during exercise 2. 
Previously detection of EFL consisted of either invasive esophageal balloon or relatively 
complex plethysmographic techniques.  An alternative approach, and one that will be 
used in this study, involves the Forced Oscillation Technique (FOT), which is now 
incorporated into the vector device.  
In 2003, Dellacà et al. proposed a new method to detect EFL during quiet breathing 
non-invasively using the FOT. It was based on the observation that COPD patients with 
EFL developed large negative swings in the respiratory system input reactance 
measured at 5Hz during expiration. They used this observation to define a sensitive and 
specific method of determining the presence of EFL. Normally the reactance reflects the 
elastic and inertial properties of the respiratory system but when flow limitation is 
present, the oscillatory signal cannot pass through the choke points and reach the 
alveoli. This produces a marked reduction in the apparent compliance and, 
consequently, a fall in Xrs.  
Although this Xrs reduction is present at all the frequencies, the greatest difference is 
seen at the lowest frequency. Since the quiet breathing signal can interfere with the 
estimation of Zrs at frequencies below 5 Hz, this frequency was used for the forcing 
signal. The difference between the mean value of Xrs during inspiration (
insp
X
) and 
exp
X
  is called
rs
X
∆
. A breath is classified as flow-limited if it’s Xexp, min is greater than 
2.8 
-1
2
L
s
O
cmH
⋅
⋅
. 
This technology has been evaluated in numerous clinical studies for both the detection, 
reduction and abolishment of expiratory flow limitation in patients with COPD.  In 1956, 
Dubios et al, demonstrated the FOT method to be applicable to the measurement of 
airway resistance in patients, evaluation of therapeutic procedures designed to relieve 
airway obstruction, separation of airway resistance from tissue resistance, and study of 
the multiple factors that may affect airway resistance.1 And in additional work in 2006, 
 
 
 

 
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limitation, will maintain equal levels of gas exchange (PaCO2) will provide patients with 
improved therapy comfort and adherence when compared to standard NIV. 
Primary Endpoint 
1. Daytime CO2 levels at the end of 4-6 weeks of therapy as determined by Arterial 
Blood Gas (PaCO2) 
 
Secondary Endpoints: 
1. Average 30-day Ventilator Usage hours 
2. Patient Comfort and Therapy Preference based questionnaire responses 
Exploratory Endpoints: 
1. Other Ventilator Parameters 
a. Respiratory Rate 
b. Minute Ventilation 
c. % flow limited breaths 
d. Patient ventilation synchrony 
2. Total therapy Titration Time 
3. Screening session parameters 
a. % flow limited breaths 
b. Delta Xrs final screening value  
4. Quality of Life Questionnaire 
5. Activity (measured via the Actiwatch) 
6. Reported Adverse Events 
7. Sleep Quality 
a. Total Sleep Time 
b. Sleep Efficiency  
c. Sleep Stage distribution 
d. Arousal and awakening indices 
e. Nocturnal TcO2 variability 

 
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f. Nocturnal TcO2 averages 
g. Nocturnal SpO2 Saturation 
V. Study Design: 
This will be a prospective, randomized, pilot study with cross-over design.  
Patients who meet inclusion criteria will be randomized in a 1:1 ratio to receive either 
standard of care (SOC) NIV (control) or Vector (Active) for the first 4 to 6-week 
treatment period, followed by the other treatment during the second 4 to 6 weeks (see 
Figure 1). There will be two different patient cohort groups, patients that are current 
users of NIV and patients that are Naïve to NIV. 
 
 

 
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(Figure 1) 
 
A. Schedule of Events: 
Screening Procedures: 
Study Participation Screening (Prior to Visit 1) 
Participants will be contacted by designated study staff from Temple University Lung 
Center Research Team. Participants may be pre-screened through medical records 
over the phone to determine eligibility.  A screening script will include a general review 
of key inclusion and exclusion criteria. Participants that are interested will be scheduled 
for the screening visit at the clinical office. 
Upon screening, study participants will be divided into 2 different cohorts – current NIV 
users and participants that are Naïve to NIV therapy.  

 
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COVID-19 Screening Procedure (All visits) 
Due to the COVID-19 pandemic, participants may be screened for COVID-19 symptoms 
over the phone prior to each scheduled study visit. During each study visit, participants 
may be asked to complete a self-declaration form, which asks about COVID-19 
exposure, current symptoms, and confirms that participants have been briefed on safety 
measures. The form will be used for safety purposes and is not intended for data 
collection. Site COVID-19 safety procedures and documentation will also be followed. 
Study products and materials will either be single use or will be cleaned and disinfected 
per the multi-patient use guidelines in the Instructions for Use.  
 
Study Visit 1 (screening)   
Once the participants arrive, the study will be explained in full detail.  If the participant 
agrees, he/she will be consented into the study and the participant will be given a copy 
of the informed consent.  
Once consent is obtained, and eligibility is confirmed, the following study related 
procedures will be conducted: 
• 
Demographics:  sex, age, ethnicity, and race will be collected 
• 
Anthropometeric Measurements: height, weight, neck circumference will be 
collected. 
• 
Current Medications:  all current medications will be collected. 
• 
Medical History Assessment: information will be collected regarding historical 
spirometry data, PaCO2 level at the time of NIV initiation, COPD history questionnaire, 
smoking history and other relevant medical history including the diagnosis of Sleep 
disordered breathing. 
• 
Physical examination with vital signs to include HR, BP, RR, and SPO2 
maintained at least 88%, and chest auscultation. 
• 
Administration of CAT and STOP-BANG questionnaires.  
• 
Urine pregnancy test for women of childbearing potential 
• 
Mask Fitting:  Participants may have up to two mask fittings in order to determine 
the best possible provided mask while using the Vector NIV device. 
 
 

 
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EFL Screening/Determination and EPAP Titration 
 • 
For the EFL Screening/Determination and EPAP Titration procedure, the 
following device settings will be applied: 
• Pressure Support 
 
            6 cmH2O  
• Max Pressure 
 
 
 26 cmH2O 
• EPAP Min / EPAP Max 
 
4 / 20 cmH2O 
• EPAP setting                                      Auto  
 
• 
EFL Determination: The participant will be asked to lie supine or semi-
recumbently while breathing into the Vector NIV device using the selected mask initially 
for 5 minutes.  This device has a screening test that has the capability of detecting and 
estimating the severity of EFL.  If it is determined that the participant does not have EFL 
after 5 minutes by the device screening indicator, the participant will not continue in the 
study. After the screening is complete, participants will be asked a couple of questions 
about their experience. 
• 
EPAP Titration: If it is determined by the Vector NIV device that the participant 
has EFL, the Vector NIV device will be changed from screening mode to therapy mode 
to delivery BiPAP therapy.  The participants will then breathe on the Vector NIV device 
in the supine position for an additional 20 minutes approximately. During the additional 
20 minutes of breathing, the device will automatically increase the EPAP (and 
concurrently and proportionally the IPAP) until the EFL is abolished (falls below the 
predetermined EFL threshold).  After the titration is complete, participants will be asked 
a few questions about their experience 
• 
While the automatic EPAP Titration is being performed all participants’ SpO2 will 
be monitored via finger pulse oximetry. Oxygen will be provided to patients at the 
clinician’s discretion.  
• 
Patient must stay awake during the EPAP Titration. If the patient falls asleep, 
they will be awoken by study staff. 
• 
The Final EPAP that is determined to abolish the participants EFL will be 
recorded. If the determined EPAP pressure is 6cmH2O or higher, the participant may 
continue to study visit 2. If the determined EPAP is below 6cmH2O then the participant 
will not be scheduled for study visit 2.  
• 
Participants that are determined to have EFL and a titrated EPAP > 6cmH2O will 
be eligible to continue in the study.   

 
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• 
Current NIV users who also have a clinical diagnosis of OSA must have a 
calculated final titrated EFL EPAP that is higher than their EPAP settings of their current 
NIV device in order to continue in the study and to be scheduled for study visit 2.  
 
NIV SOC Titration (NIV Naïve Cohort only) 
Participants who are NIV naïve and determined to have EFL with a titrated EPAP 
>6cmH2O will then undergo standard SOC titration (Appendix A) in order complete a 2 
week NIV acclimation period.  Initiation of SOC titration will take place under the 
supervision of the study investigator, research coordinator and / or healthcare 
professional (Respiratory Therapist, Sleep Technician, etc.).  
After successful completion of the device titration, participants will be given one-on-one 
operational instructions on the Vector device by clinical study staff. The Vector therapy 
will not be enabled. The device will be set up with the optimal pressures determined 
from the SOC titration. In addition to the application of the settings determined by the 
SOC titration, the Automated Airway Management (AAM) feature will be enabled with 
the minimum set EPAP to 4 cmH2O and a maximum of 20 cmH2O.  This feature will 
adjust the EPAP to maintain upper airway patency.  
The purpose of the 2 week NIV acclimation period is to determine if the patients that are 
naïve to NIV will adhere to therapy and also if they potentially have underlying OSA that 
require 90% EPAP pressures higher than the determined EFL titrated EPAP at the 
screening visit. After receiving training on the device, participants will also be given a 
user manual, mask, and tubing and be asked to use the device at home for 2 weeks. 
Study Visit 2 (Randomization and Titration)  
Upon successful completion of the screening procedures, participants in the NIV current 
user cohort will be asked to return to the research center within the next 7 days (+2 
days). Study participants in the NIV naïve Cohort will be asked to return to the research 
center in 14 days (+ 2 days). Participants in the NIV naïve cohort will have the data from 
their device downloaded and reviewed.  
Participants in the NIV naïve cohort will be excluded from continuing in the study if the 
average nightly device use is < 4 hours per night OR the average nightly 90% EPAP 
pressures are greater than the titrated EFL EPAP pressure determined during the 
screening visit. 90% EPAP values will be accessed through the CareOrchestrator 
patient management platform. 
During study visit 2, qualified participants will be randomized to one of the two therapy 
orders. In addition to being randomized, participants will be set up with the activity 

 
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monitor, fill out baseline study questionnaires, receive one-on-one training and 
instructions on how to use the Vector device.   
Randomization:  
Participants will be randomly assigned to either 1) Vector NIV followed by SOC NIV or 
2) SOC NIV followed by Vector NIV. Randomization will be generated via a 
randomization website. For the SOC NIV therapy, participants will be required to use a 
Vector Device in place of their current NIV device. The Vector therapy will not be 
enabled, and the device will be set according to their current SOC NIV prescription. 
 
Cohort 1 (NIV Current Users): Participants in Cohort 1, regardless of randomized 
therapy order, will be required to undergo the Vector device titration at study visit 2.  
(Appendix A) For the participants randomized to SOC NIV first, the settings determined 
from the Vector device during the randomization visit will then be applied when they 
cross over to Vector NIV at visit 3.  
Cohort 2 (NIV Naïve): Participants in Cohort 2, regardless of randomized therapy order, 
will be required to undergo the Vector device titration at study visit 2.  (Appendix A) 
Participants in cohort 2 who were randomized to SOC NIV first will have previously 
been titrated to SOC NIV therapy at visit 1. 
Initiation of the Vector NIV titration will take place under the supervision of the study 
investigator, research coordinator and / or healthcare professional (Respiratory 
Therapist, Sleep Technician, etc.). Appendix A outlines the protocol and device settings 
that will be used for the Vector device titration. For the participants in Cohort 2 that are 
initially randomized to SOC arm, clinical study staff will follow currently established NIV 
standard of care titration protocols.  After successful completion of the of the Vector NIV 
titration, participants will be given one-on-one operational instructions on the device by 
clinical study staff. They will also be given a user manual, mask, and tubing and be 
asked to use the device at home for 4 to 6 weeks. For the participants in Cohort 2 that 
are randomized to SOC arm, they will continue to use the Vector device as they did 
during the 2-week home acclimation period with the previously determined SOC NIV 
settings.  
Phone Follow-ups: 
Participants will be sent home with the Vector device with their randomized therapy.  
During the initial week, the participant will be contacted daily to determine if there are 
any problems with the device and to encourage compliance. Participants will be asked 
to use the Vector device at night for the following 6 weeks. Participants will then be 
contacted weekly from week 2 to the last week of their take home period (maximum of 6 
weeks). During the second take home period, all participants will be called daily during 
the first week only. 

 
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Study Visit 3 (Overnight Sleep Study) (within 4 to 6 weeks of visit 2) 
Participants will be asked to come to the sleep lab at a scheduled date and time. The 
sleep testing will begin near the subject’s usual bedtime and ends at approximately 6 
A.M. 
Prior to the sleep study with the therapy device, the trained technologists will verify 
mask size, fit, and adjustment.  The sleep test will involve using the device the 
participant has been receiving therapy from in the initial 4 to 6 weeks. Details of the 
PSG set up can be found in the standard procedures section of the protocol. 
Morning ABG, Therapy Comfort and HRQL assessments:  Following the completion of 
the sleep study (morning after), all participants will return to the research center where 
their activity monitors will be downloaded, fill out study-related questionnaires as well as 
have their ABGs collected. Details on ABG collection and study questionnaires can be 
found in the standard procedure section of the protocol. Participants in Cohort 1 that 
were randomized to their current NIV device for the initial 6 weeks will now be asked to 
use the Vector device for the next 6 weeks. The Vector device will be set up with the  
Device settings determined during the titration procedure at study visit 2.  
Study Visit 4 (Overnight Sleep Study - within 4 to 6 weeks of visit 3) 
Participants will be asked to report to the sleep lab for the second overnight sleep study 
at a scheduled date and time. The sleep testing will begin near the subject’s usual 
bedtime and end at approximately 6 A.M. 
Prior to the sleep study with the therapy device, the trained technologists will verify 
mask size, fit, and adjustment that was determined at study visit 1. Details of the PSG 
set up can be found in the standard procedures section of the protocol.   
Morning ABG, Therapy Comfort and QOL assessments:  Following the completion of 
the sleep study (morning after), all participants will have to return to the research center 
where their activity monitors will be downloaded, fill out study related questionnaires as 
well as have their ABGs collected. Details on ABG collection and study questionnaires 
can be found in the standard procedures section of the protocol. 
In the event that participants are unable to come into the research clinic for visit 3 or 4, 
remote administration of questionnaires via telephone or direct mail may be conducted. 
Participants may be asked to return their device SD cards via direct mail using a 
provided postage-paid envelope.  
 
 

 
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A. Standard Procedures 
Arterial Blood Gas / Room Air SpO2 assessment 
Arterial blood gases and SpO2 should be collected with the participant breathing room 
air for at least 15 minutes prior.  The participant should rest in the seated position for 10 
minutes prior to drawing the sample.   
Quality of Life Questionnaires (QOL) 
Health related quality of life (QOL) measurement is an important tool for measuring 
health status changes in participants receiving an intervention.  The COPD Assessment 
Test (CAT)12, St. George Respiratory Questionnaire13 and Modified Medical Research 
Council Dyspnea Questionnaire (MMRC)14 will be used in this study.  Participants will 
be asked to complete these questionnaires at Visits 2-4.   
PSG’s 
During all lab nights, participants will be set-up with a standard PSG montage that will 
include the following sensors: 
• Two RIP belts secured around the chest and abdomen to measure movements 
associated with breathing effort 
• A small sensor which attaches to the chest belt to measure body position 
• Lead II ECG electrode derivation 
• EEG electrodes attached to the scalp and face to measure sleep stages 
(including at least C4, C3, A1, A2, O1, O2, GND EEG, Left Outer Canthus (LOC) 
and Right Outer Canthus (ROC) EOG and submental EMG) 
• A flexible finger sensor placed on the finger to measure oxygen saturation 
(average signaling time of 3 seconds) 
• A microphone attached to the skin at the base of the neck to measure snoring 
sounds 
• Surface electrodes attached to the skin bilaterally over the anterior tibialis 
muscle, to measure leg movements 
• Transcutaneous CO2 monitoring 
 
Scoring 
All sleep studies will be scored by the qualified site personnel.  All sleep variables will 
be classified and scored using the 2007 AASM criteria15 additionally, all sleep variables 
will be scored using a modified Hypopnea rule as defined below. 
• 
Apneas will be scored according to AASM Scoring Manual rules VIII.3.A, B. 
• 
Hypopneas will be scored according to the AASM Scoring Manual rule VIII.4.A for 
desaturations with a nadir below 90%. 

 
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For hypopneas yielding desaturations with a nadir of 90% or greater, a modified rule 
VIII.4.A will be used that requires an arousal (rule V.1.A) to accompany the event for 
scoring as a hypopnea. 
NOTE: If the participant slept less than 3 hours on any lab night, they, may be asked to 
repeat the overnight sleep test. If the patient is unwilling to repeat the sleep test, 
furthermore, a replacement participant will then be enrolled.  
Actigraphy Measurements & Sleep Diary 
Actigraphy is a method of measuring activity and sleep which is achieved by wearing a 
small watch-like device for an extended period of time.  Most units contain an 
accelerometer and continually record the movement it undergoes.  These data are later 
read to a computer for analysis.  These data will provide an objective record of physical 
activity and sleep / wake patterns throughout the 6 weeks of home use.   
The wrist-worn actigraph device will provide a continuous measure of both how much 
the participant has slept during the night and how active they are during the day.  There 
is an event button that the participant will be asked to press when the participant is in 
bed, near asleep and also upon awaking.  
Participants may be asked to keep a sleep diary during the last two weeks of each arm 
of the study in order to supplement the actiwatch data. The study team will call the 
participant to remind them to start using the diary. 
VI. Selection and Withdrawal of Subjects: 
Inclusion Criteria 
1. Age > 40 years of age; < 80 years of age 
2. Ability to provide consent 
3. COPD patients with hypercapnia (as defined as > 52mmHg) who are either 
current NIV users or naïve to NIV 
4. On average, use NIV more than 4 hours per night (Current NIV users). 
5. Must present with EFL via screening of the Vector device at 3 cmH2O  
6. Have an EPAP to abolish EFL greater or equal to 6cmH2O 
Exclusion Criteria:  
1. Any major non-COPD uncontrolled disease or condition, such as congestive 
heart failure, malignancy, liver or renal insufficiency (that requires current 
evaluation for liver or renal transplantation or dialysis), amyotrophic lateral 
sclerosis, or severe stroke, or other condition as deemed appropriate by 
investigator as determined by review of medical history and / or participant 
reported medical history 
2. Suffering from a COPD exacerbation (Defined as hospital admission, ER/urgent   
care visit, MD visit with medication change or other intervention deemed to be    

 
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clinically significant by the investigator at the time of data collection or in the 14 
days prior to data collection 
3. Self-reported Pregnancy or positive pregnancy test for women of childbearing 
   potential. 
4. Employee or family member that is affiliated with Philips  
5. Currently employed by a manufacturer of respiratory products or family member 
employed by a manufacturer of respiratory products 
6. Any history of giant bulla (size >1/3 hemi-thorax) 
7. History of pneumothorax < 6 months 
8. Participants currently using a PAP or NIV device at home with a documented 
EPAP setting on their current device that is greater than the calculated EPAP 
determined during the therapy session of the screening visit (Current NIV 
Users). 
9. Life expectancy ≤12 months as determined by clinical investigator 
10. Low BP: Systolic <90 
11. Recent cranial surgery (i.e, less than 1 year) 
12. Impaired swallowing as reported by participant or diagnostic exam 
13. Recent upper airway or GI surgery within the past 6 months 
14. Unable to be fitted with mask 
15. Excessive secretions as reported by clinical investigator/physician assessment, 
inability to maintain a patent airway or adequately clear secretions, or at risk for 
aspiration of gastric contents 
16. Diagnosed with acute sinusitis or otitis media 
17. Epistaxis, causing pulmonary aspiration of blood 
18. Existing respiratory failure 
19. Participants who are naïve to NIV (Cohort 2) that use the device fewer than 3 
out of 7 nights during the second week of the 2-week acclimation period 
20. Participants who are naïve to NIV (Cohort 2) that average less than 4 hours of 
device use during the second week of the 2-week acclimation period 
21. Participants who are naïve to NIV (Cohort 2) with an average nightly 90% 
EPAP pressure during the second week of the 2-week acclimation period that is 
higher than the titrated EFL EPAP pressure determined at the screening visit. 
 
Withdrawal: 
The term “discontinuation” refers to the participant’s premature withdrawal from the 
study prior to completing all procedures.  Participants may be discontinued from the 
study for any of the following reasons: 
 
• If in the investigator’s judgement, continuation in the study may prove harmful to 
the participant.  Such a decision may be precipitated by adverse events, including 
fever, nausea, rash, changes in vital signs, or the development of a new medical 

 
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condition.  The investigator will be solely responsible for making medical/safety 
decisions regarding the participant’s continued participation in the study. 
• Noncompliance;  
• At the request of the participant. 
• Further admission with AECOPD as the primary diagnosis 
The study team will document whether or not each participant completed the study.  If, 
for any participant, study treatment or assessments were discontinued, the reason will 
be recorded. 
For the naïve NIV patient cohort, participants will be allowed to keep the device until a 
marketed device can be provided to them through normal commercial distribution 
pathways.   
The study goal is to have 30 participants successfully complete the study.  It is 
estimated that 50 patients may need to be enrolled in order to complete 30 
VII. 
Treatment of Subjects: 
A. Intended Use  
The BiPAP A40 EFL Ventilator (Vector ventilator) is intended to provide non-invasive 
ventilatory support to treat patients weighing over 10Kg (22lbs.) with Obstructive Sleep 
Apnea (OSA) or Respiratory Insufficiency. It is intended to be used within the home, 
institutional/hospital, and diagnostic laboratory environments. This device is not 
intended for life support. The BiPAP A40 EFL screening and therapy is intended for 
patients weighing over 30Kg (66lbs.) with obstructive sleep apnea (OSA) or Respiratory 
Insufficiency with primary cause being chronic obstructive pulmonary disease (COPD) 
to screen for the presence, and abolishment of Expiratory Flow Limitation 
B. Contraindications: 
• Inability to maintain a patent airway or adequately clear secretions 
• At risk for aspiration of gastric contents 
• Diagnosed with acute sinusitis or otitis media 
• Epistaxis, causing pulmonary aspiration of blood 
• Hypotension, defined as systolic BP < 90 
• Existing respiratory failure  
 
There will be no restrictions on concomitant medications during the course of the study.  
If medications change during the study, participants will be asked to let their 
pulmonologist know. 

 
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C. Monitoring: 
This clinical study will be monitored by Philips (Sponsor) in compliance with the Code of 
Federal Regulations (CFR) for clinical research; namely, 21 CFR Parts 50, 54, 56 and 
812 and others as applicable. The purpose of such monitoring is to assure that the 
study remains in compliance with the approved protocol, investigator agreement and 
regulatory requirements, to verify the completeness, reliability and accuracy of study 
data and to resolve any issues that arise during the conduction of the study. The 
Sponsor will conduct monitoring visits periodically as specified by the monitoring plan. 
Monitoring will be conduct by trained clinical research professionals.  
It has been determined that this study does not require a Data Safety Monitoring Board 
(DSMB). 
D. Unscheduled Visits 
Unscheduled calls and or visits will be documented in the participant study file upon 
occurrence. Participants may be asked to receive additional phone calls and or visits 
in order to evaluate any device issues should they occur. 
 
VIII. 
Assessment of Performance  
Device performance will be based on the following patient physiological and device 
recorded parameters: 
• Daytime PaCO2 levels after 30-day period, method (Visits 3 and 4) 
• Nocturnal TCO2 levels during sleep study (Visits 3 and 4) 
• Nocturnal SpO2 levels during sleep study (Visits 3 and 4) 
• Ventilator collected parameters over the 30-day use period (RR, MV, usage 
hours) (Visits 3 and 4) 
IX.  Assessment of Safety 
Serious adverse events, occurring during the course of the study will be collected, fully 
documented, and reported to the Western Institutional Review Board, according to their 
guidelines, by the Principal Investigator, Dr. Gerald Criner, MD or sponsor staff. Serious 
adverse events will be reviewed by the Sponsor within 24 hours of the study team being 
aware of the event.  
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related. 
An adverse device effect (ADE) is an AE related to the use of an investigational medical 
device. 

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Serious Adverse Events 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect. Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
Unanticipated Serious Adverse Device Effect 
A USADE is a serious ADE which by its nature, incidence, severity or outcome has not 
been identified in the current version of the risk analysis report. 
Severity of Event 
The following guidelines will be used to describe AE severity: 
•
Mild – Events require minimal or no treatment and do not interfere with the
participant’s daily activities.
•
Moderate – Events result in a low level of inconvenience or concern with the
therapeutic measures. Moderate events may cause some interference with
functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require
systemic drug therapy or other treatment. Severe events are usually potentially
life-threatening or incapacitating. Of note, the term “severe” does not necessarily
equate to “serious”.
Relationship to Study Intervention 
All AEs must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her 
clinical judgement. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect. 
•
Related – The AE is known to occur with the study intervention, there is a
reasonable possibility that the study intervention caused the AE, or there is a
temporal relationship between the study intervention and event. Reasonable

 
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possibility means that there is evidence to suggest a causal relationship between 
the study intervention and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the 
study intervention caused the event, there is no temporal relationship between 
the study intervention and event onset, or an alternate etiology has been 
established. 
 
Adverse Event Assessment and Follow-Up 
Adverse events will be collected on an ongoing basis following signing of informed 
consent. Detailed information regarding the event will be recorded on the appropriate 
form in the electronic case report form (eCRF), where the Investigator will determine the 
severity of the event, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the 
event. Follow-up data to ascertain the existence of residual effects from the event will 
be obtained. Serious adverse events must be reported to the sponsor within 24 hours of 
discovering the occurrence of the SAE. The research staff is required to complete and 
submit the sponsor’s standard SAE form detailing the event. 
Serious Adverse Event and Unanticipated Adverse Device Effect Reporting 
The study investigator will complete an SAE/Unanticipated Adverse Device Effect Form 
and submit to the study sponsor and to the reviewing IRB as soon as possible, but in no 
event later than 5 working days after the investigator first learns of the effect. The study 
sponsor is responsible for conducting an evaluation of an unanticipated adverse device 
effect and shall report the results of such evaluation to local regulatory authorities and to 
all reviewing IRBs and participating investigators within 10 working days after the 
sponsor first receives notice of the effect. Thereafter, the sponsor shall submit such 
additional reports concerning the effect to local regulatory authorities. 
Device Deficiencies 
All device deficiencies, use or user errors, and equipment failures will be documented. 
Use or User errors will be captured as part of the source documentation. Device 
deficiencies and equipment failures will be kept on a separate log. The serial numbers 
and type of deficiency/failure will be captured. Unanticipated device deficiencies that 
lead to SAE’s will be reviewed with the principal investigator (PI) and reported to the 
IRB as required. 
All unexpected adverse events will be collected and reviewed.  As any events will be 
reported electronically or directly from a person the study team will collect the onset, 
duration, intensity and treatment required, outcome and action taken. In addition to 

 
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adverse event reporting, the study staff will report a summary of the protocol findings, 
participant recruitment, drop-outs, and events to the IRB annually.  
All Adverse Events will be followed for 30 days or until resolution, whichever comes first. 
X. Device Deficiencies  
All device deficiencies use or user errors, and equipment failures will be documented.  
Use or User errors will be captured as part of the source documentation.  Device 
deficiencies and equipment failures will be kept on a separate log.  The serial numbers 
and type of deficiency/failure will be captured. Unanticipated device deficiencies that 
lead to SAE’s will be reviewed with the PI and reported to the IRB as required.  
XI. Statistical Methods  
 
Determination of Sample Size 
No power analysis was performed to determine the sample size for this pilot 
study.  The results of this study may be used to power a larger pivotal trial. 
 
 
General Considerations 
The primary analysis will be performed including all consented participants.  
Descriptive data tables will be provided for all variables of interest.  Continuous 
data will be presented by mean, standard deviation, median, minimum, and 
maximum observation.  Data will be presented in the untransformed and 
transformed format (if applicable) for each continuous variable.  Categorical data 
will be presented as frequencies and percentages.  All formal statistical analyses 
will be performed using either SAS® or SPSS® software.  Significance tests will 
be conducted at a two-sided significance level of p < 0.05. 
 
There are no statistical criteria for terminating the study.  No sensitivity analysis 
will be completed, and any deviations to the original statistical plan will be noted 
in the analysis report. 
 
Participant Disposition 
Participant disposition, including the total number of participants enrolled, 
completed, early terminations and withdrawals, will be presented. A listing will be 
provided with the reasons for discontinuation. 
 
Demographics and Baseline Characteristics  
 Participant demographics (e.g., age and gender) and baseline characteristics 
will be summarized for all participants enrolled and for evaluable participants. 
 

 
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Primary Analysis 
Since this was a crossover study, the endpoints were compared between the two 
therapies as paired samples.  For each continuous endpoint, the paired 
differences will be examined for normality using the Shapiro-Wilk and 
Kolmogorov-Smirnov tests, and if the distribution does not deviate significantly 
from normality, the treatment effect will be examined using a paired t-test; 
otherwise, the endpoint was examined using the non-parametric Wilcoxon 
Signed-Ranks test.  Categorical data will be evaluated using the McNemar Test. 
 
Safety Analysis 
Safety evaluations will be performed by recording clinical adverse events at the 
time originally reported, and they will be followed at regular intervals until 
resolution.  Adverse events will be provided in data listings. 
 
Missing Data 
It is not anticipated that imputation methods will be necessary in this study. 
 
Interim Analysis 
Since this is a pilot study, descriptive statistics may be reviewed as the study is 
ongoing, but formal statistical comparisons will be performed after the study is 
completed. 
XII. 
Direct Access to Source Data / Documents  
Only site clinical study staff and approved Philips staff working with the research will 
know the identity of the participants.  All information recorded by the study team and 
provided for analysis will be given a study ID number. A unique source record will be 
available for each study participant and will include informed consent review process, 
HIPAA completion (as applicable), medical history, and concomitant medications.  
Privacy rules and requirements according to federal and state governing regulations will 
be implemented. All the information collected as part of this study will be kept 
confidential. All information collected for this study will be kept in a secured area or 
stored in a password protected computer if digital. Except when required by law, 
participants will not be identified by name, social security number, address, telephone 
number, or any other direct personal identifier in study records. For records disclosed to 
Philips participants will be assigned a unique code number.   
Results of the study related data, medical history, and information obtained from the 
questionnaire and device data will be reported and received by Philips.  Philips will use 
participant study data for research purposes to support engineering objectives 
described in this protocol.   

 
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In addition, participant records may be reviewed in order to meet federal and state 
regulations.  Reviewers may include representatives from the FDA or similar 
government authorities in other countries where the device is being used, and Philips 
for the purposes of the following side effects, and to gather additional information 
related to the study, and the Institutional Review Board (IRB).  Participant permission for 
review of confidential information is granted by signing the associated informed consent.  
Philips will ensure that it follows all applicable state and federal data protection 
regulations.  
A. Provisions to Protect the Privacy Interests of Participants:   
Participants will only interact with approved members of the research staff and will have 
the option to decline to provide any information that they are uncomfortable revealing. 
All research staff (site and sponsor) will receive training regarding the protection of 
human subject data.  Participant’s medical records will only be accessed after obtaining 
written consent from the participant and will only be reviewed by members of the 
research staff for whom review of this information is necessary for continued 
participation in the study (e.g. Philips research staff and study investigator reviewing the 
medical records). Participant identifiers, other than study ID number must be redacted in 
date before sending to sponsor. 
B. Case Report Forms  
Study related case report forms (CRF’s) and source documentation will be collected and 
maintained by the sponsor, will be kept confidential, and stored in a secure location if on 
paper or on a secure server or protected device.  Only staff delegated by the PI will 
have the ability to enter in, or make changes to, the CRF’s and source documents.  
XIII. 
Quality Control and Quality Assurance  
The PI and study personnel will be trained to the study protocol, study product, TMF 
documents, monitoring plan, CRFs and/or eCRFs, direct data reporting, and all Sponsor 
expectations, as applicable. Once complete, training and delegations will be 
documented for PI and study personnel. 
Data queries will be addressed by delegated study personnel and CRF/ eCRFs will be 
reviewed and signed off by PI prior to study closure. Monitoring will be completed in 
accordance with US CFR, ICH-E6 GCP Section 6, and ISO 14155:2011 as applicable.      
XIV. 
Ethics  
This study will be submitted and reviewed by the Western Institutional Review Board.  
All participants will be consented prior to completing the trial. The Primary Investigator 
will review all adverse events as it relates to the study device. 

 
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All data will be kept confidential and in a secure location if on paper or on a secure 
server or device. Only approved study personnel will have access to study related 
documents. All electronic data shall be stored in a coded data set.  All paper documents 
shall be kept in a secure area.  Study data and source will be made available for study 
related monitoring or audits by the IRB/IEC, sponsor, or regulatory inspection(s).   
Results of the study related data, and information obtained from the engineering study, 
will be collected, received and reported by Philips.  Philips will use participant study data 
for research purposes to support scientific and marketing objectives described in this 
protocol.   
XV. 
Data Handling and Recordkeeping  
Hard copies of the study will be kept on site for at least 2 years after study completion.  
The sponsor will maintain study records indefinitely. Records will be stored at Iron 
Mountain, a secure information management services company.  
XVI. 
Financing and Insurance  
If the participant is injured during the course of the trial and as a direct result of this trial, 
they should contact the Principal Investigator, Gerald Criner, MD. The participant will be 
directed to seek clinically appropriate medical care for that injury. However, we cannot 
guarantee that the medical care and treatment will be provided without charge or that it 
will be paid for by the participant’s insurance company, and the costs incurred may 
ultimately be the participant’s responsibility.  
XVII. Registration on ClinicalTrials.gov or other applicable registry  
This trial will be registered on Clinical Trials.gov. It is the intent that these data may be 
used for to support regulatory clearance and/or consideration for a submission to peer 
review publication. 
XVIII. Risk and Benefit Analysis  
A. Potential Risks and Discomforts 
 
Adverse effects of NPPV are usually minor and manageable.  The masks may cause 
some discomfort and air pressure and flow have adverse effects.  All adverse effects 
encountered, including mask discomfort, nasal or mouth congestion or dryness, eye 
irritation, gastric insufflation, and nasal bridge ulceration will be recorded on data sheets 
that are part of the case report form.   
The risks of using the Vector NIV Device are minimal.  Use with the NPPV devices may 
cause a decrease in the inability to adequately clear secretions, an increased risk for 
aspiration of gastric contents, increase in symptoms of sinusitis or otitis media, and 
decrease in blood pressure.  These are minimal risks of using the device and should 
they occur during the course of the study, they be recorded.  Other more serious 
adverse effects, such as pneumothorax or aspiration pneumonia, are distinctly unusual 

 
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in the outpatient setting, but will be recorded if they occur.  Significant adverse events 
will be reported to the Institutional Review Board. Patients currently on NIV may find 
Vector to be less comfortable than their previous NIV, but this is not a real medical risk. 
 
Arterial blood gas determinations are part and parcel of routine pulmonary function 
testing and are performed by trained respiratory therapists on a daily basis.  The blood 
gas draws as part of this study is consistent with usual care in initiating NIV. The 
research technician will employ the usual precautions while performing such a 
procedure by employing adequate aseptic technique.  The arterial blood gas sampling 
test can cause pain, tenderness or swelling at the puncture site and possibly bleeding, 
local infection, lightheadedness or fainting. 
Standard PSG (sleep study) risks might include: complaints of skin irritation from the 
adhesives or tapes used to secure the electrodes and any necessary skin preparation.   
Participants may also find some of the chemical adhesive smells offensive. The 
participant may sleep poorly. 
The patient may sleep poorly during the nocturnal sleep study and thus may be sleepy 
the next day. If the patient is too sleepy to drive home, other forms of transportation will 
be utilized. 
COVID-19 is a risk with any in-person activity, but proper mitigation strategies, including 
COVID-19 screening, disinfection, and other site safety procedures, will be implemented 
to minimize patient risk. 
Thus, we believe that although there may be discomforts associated with the use of this 
device and study related procedures, the risks are minimal. 
B. Potential Benefits 
Although participation in this trial will not result in any direct benefit to the subject, they 
will be contributing to generalizable data that will help improve device design and 
function 
C. Compensation for Research-Related Activities 
Participants will only be compensated for the activities that they complete. Participants’ 
payment will be in the form of a Gift card/Clinicard according to the following schedule. 
 
 
 

 
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For taking part in this research, participants may be paid up to a total of $750.00 or 
$800.00 as per the schedule below: 
Visit Number 
Amount 
Visit 1 
$50.00 ($100 for Naïve only)  
Visit 2 
$100.00 
Visit 3 
$300.00 
Visit 4 
$300.00 
TOTAL 
$750.00 ($800 for Naïve only)  
 
D. Publication  
It is the intent that these data will be used/considered for a submission to peer review 
publication, white paper or scientific abstract 
 
References 
 
1. Rennard SI, Serby CW, Ghafouri M, et al. Extended therapy with ipratropium is 
associated with improved lung function in patients with COPD. Chest 1996; 110: 62-70 
2. Reis AL, Kaplan RM, Limberg TM, et al. Effects of pulmonary rehabilitation on 
physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary 
disease. Ann Intern Med 1995; 122: 823-832 
3. Lung transplantation: report of the ATS workshop on lung transplantation: American 
Thoracic Society, Medical Section of the American Lung Association. Am Rev Respir 
Dis 1993; 147: 772-776 
4. Benditt JO, Albert RK. Lung reduction surgery: great expectation and a cautionary 
note. Chest 1995; 107: 297-298 
5. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung 
disease: a clinical trial: Nocturnal Oxygen Therapy Trial Group. Ann Intern Med 1980; 
93: 391-398 
6. Long term domiciliary oxygen therapy in chronic hypoxic core pulmonale complicating 
chronic bronchitis and emphysema: report of the Medical Research Council working 
party. Lancet 1981; 1: 681-686 

 
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7. Windisch W., et al, Outcome of Patients with Stable COPD Receiving Controlled 
Noninvasive Positive Pressure Ventilation Aimed at a Maximal Reduction of PaCO2. 
Chest 2005; 128: 657-662  
8. Douglas NJ, Calverley PMA, Legget RJE, et al. Transient hypoxemia during sleep in 
chronic bronchitis and emphysema. Lancet 1979; 1: 1-4 
9. Roussos C. Function and fatigue of respiratory muscles. Chest 1985; 88: 124S-132S 
10. Hill N, Leger P, Criner G. Clinical indications for noninvasive positive pressure 
ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and 
nocturnal hypoventilation – a consensus conference report. Chest 1999; 116: 521-534 
11. Braun NM, Marino WD. Effect of daily intermittent rest of respiratory muscles in 
patients with severe chronic airflow limitation (CAL). Chest 1984; 85: 59S-60S 
12. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development 
and first validation of the COPD Assessment Test. Eur Respir J. 2009 Sep;34(3):648-
54.  
13. Jones PW, Quirk FH, Baveystock CM. The St. George's Respiratory Questionnaire. 
Resp Med 1991;85 (suppl B):2531. 
14. Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest. 
1988;93(3):580-586. 
15. American Academy of Sleep Medicine - The ASSM Manual for the Scoring of Sleep 
and Associated Events, 2007; 1-59.