Multi-Center Randomized Placebo-controlled Trial of Nocturnal Oxygen Therapy in Chronic Obstructive Pulmonary Disease. The International Nocturnal Oxygen (INOX) Trial
Phase: NA
Conditions: Chronic Obstructive Pulmonary Disease, Nocturnal Desaturation
Sponsor: Laval University

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 1 20
 
 
MULTI-CENTER RANDOMIZED PLACEBO-CONTROLLED TRIAL OF NOCTURNAL 
OXYGEN THERAPY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE 
THE INTERNATIONAL NOCTURNAL OXYGEN (INOX) TRIAL 
 1. THE NEED FOR A TRIAL                                                                                                                    
1.1 WHAT IS THE PROBLEM TO BE ADDRESSED? 
Chronic obstructive pulmonary disease (COPD) represents a major health issue in Canada. Among 
Canadians aged  55, the prevalence rate of the disease is about 6% [1-3].  About 750 000 Canadians 
suffer from the disease [2].  COPD represents the fourth leading cause of mortality in men aged  65 and 
the seventh in women aged  65 [4].   Continuous oxygen therapy (CONT-O2) is one of the few 
components of the management of COPD that improves survival.  It is only indicated in patients with 
severe daytime hypoxemia (defined as an arterial oxygen pressure [PaO2] measured in stable state  55 
mmHg or in the range of 56-59 mmHg when clinical evidence of pulmonary hypertension or 
polycythemia are noted) [5;6].  CONT-O2 is usually provided by a stationary oxygen concentrator, with 
or without an additional ambulatory module.  CONT-O2 should be used for at least 15 hours a day [7]. 
Several studies have demonstrated oxygen desaturation during sleep in patients with COPD [8- 
16].   The earliest studies that described this phenomenon included patients with marked daytime 
hypoxemia qualifying for CONT-O2.  Conventional CONT-O2, given 15-18 hours/day, compulsorily 
includes sleep time and therefore corrects sleep-related hypoxemia.  However, sleep-related oxygen 
desaturation often occurs in patients not qualifying for CONT-O2.  Sleep-related oxygen desaturation is 
considered by many physicians as an indication for providing nocturnal oxygen therapy (N-O2) in patients 
who would not otherwise quality for CONT-O2.  This perceived indication stems from the suggestion 
that the natural progression of COPD to its end stages of severe hypoxemia, right heart failure, and 
death  may be  dependent  upon  the  severity of  desaturation  occurring  during  sleep  [17-19].    This 
attractive hypothesis is supported by the fact that hypoxemic episodes during sleep are accompanied by 
increases in pulmonary arterial pressure [20-22] and often by important cardiac arrhythmias [23;24]. 
Supplemental nocturnal oxygen alleviates both the acute increases in pulmonary arterial pressure [20- 
22] and the cardiac arrhythmias [23;24].  It has been suggested that, over the long run, N-O2 may halt 
the  progression  of  long-standing  cor  pulmonale  [5;22]  and  may  prolong  survival  [6].    Practice 
guidelines regarding the indications for N-O2 in COPD not qualifying for conventional CONT-O2 are 
presently imprecise.  Because of this, a number of these patients are currently treated with N-O2 [25]. 
For instance, a recent practice review and appraisal at the Quebec City area’s respiratory home care 
program indicated that, as of September 1st  2006, 74 of the 364 patients (20.3%) registered to the 
program with a primary diagnosis of COPD were receiving home oxygen for nocturnal utilization only 
(Appendix 1).  However, the clinical benefits of N-O2 have yet to be confirmed.  The International 
Nocturnal Oxygen (INOX) trial is intended to address this issue. 
1.2 WHAT ARE THE PRINCIPAL RESEARCH QUESTIONS TO BE ADDRESSED? 
1.2.1 Primary question 
In patients with COPD not qualifying for CONT-O2 who exhibit significant nocturnal arterial oxygen 
desaturation, does N-O2 provided for a period of 3 years decrease mortality or the requirement for 
CONT-O2? 
1.2.2 Secondary questions 
  In the same population, does N-O2 improve disease-specific quality of life? 
  What is the incremental cost-effectiveness ratio of nocturnal oxygen therapy over a 3-year period? 
1.2.3 Hypotheses 
In patients with COPD not qualifying for CONT-O2 who exhibit significant nocturnal arterial oxygen 
desaturation, N-O2 provided for a period of 3 years (1) is effective in decreasing mortality and the 
requirement for CONT-O2, (2) improves disease-specific quality of life, and (3) is cost effective. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 2 20
 
 
1.3 WHY IS A TRIAL NEEDED NOW? EVIDENCE FROM THE MEDICAL LITERATURE 
1.3.1 Continuous oxygen therapy in COPD 
a) CONT-O2: Clinical aspects 
In the early 1980s, two randomized controlled trials of CONT-O2 in patients with COPD were 
published: the United Kingdom Medical Research Council (MRC) Study [5] and the National Heart, 
Lung, and Blood Institute (NHLBI)’s Nocturnal Oxygen Therapy Trial [6].  Both clearly demonstrated 
increased survival from low-flow domiciliary oxygen use in severely hypoxemic (daytime resting PaO2 
 55 mmHg) patients with COPD.  The MRC study randomly assigned patients to receive 15 hours of 
oxygen therapy (including hours of sleep) per day vs. no oxygen therapy at all.  At 5-year follow-up, the 
oxygen therapy group had improved survival: 19 of 42 oxygen therapy patients (42%) had died, 
compared to 30 of the 45 control patients (66%).   The NHLBI trial randomly assigned patients to 
receive oxygen for either 12 hours a day (nocturnal group) or 24 hours a day (continuous group).  The 
CONT-O2 group actually received oxygen for an average of 19 hours a day.   All patients received 
oxygen therapy during sleep.  At 24 months, the overall mortality in the CONT-O2 group was 22.4%, 
whereas it was 40.8% in the N-O2 group (p = 0.01).  Survival of patients in the NHLBI trial who were 
submitted to N-O2 was greater than survival of patients in the MRC trial who were allocated to the 
control group.   This only provides indirect evidence that N-O2 is beneficial, at least in severely 
hypoxemic patients (i.e., those qualifying for CONT-O2).  A more recent randomized trial indicated that 
CONT-O2 does not improve survival in patients with moderate hypoxemia (PaO2: 56-65 mmHg) [26]. 
b) CONT-O2: Economic aspects 
COPD represents a significant burden on health care systems, the main cost drivers being inpatient 
care, medications and oxygen therapy [27-33].  This was confirmed by the recent Confronting COPD 
Survey [34].  In this survey, more than 200 000 households were screened by random-digit dialing in 8 
countries, including Canada.   In the Canadian cohort of the Confronting COPD Survey (3265 
individuals; mean age: 63 years; 44% female), the annual direct cost of the disease was estimated at 
$1997 per patient [35].  The economic burden of COPD was particularly high in terms of inpatient care: 
although  only  14%  of  patients  reported  being  hospitalized  in  the  last  12  months,  hospital  stays 
accounted for over half (53%) of the total direct costs per patient.  Outpatient treatment for COPD 
accounted for over 30% of total direct costs, and the majority of these costs was for home oxygen 
therapy.  Overall, oxygen therapy accounted for 17% of the entire annual direct costs of COPD care. 
1.3.2 Nocturnal oxygen therapy in COPD 
a) N-O2: Clinical aspects 
Three randomized trials directly addressed the issue of the effectiveness of N-O2 in patients not 
qualifying  for  CONT-O2  who  exhibit  nocturnal  oxygen  desaturations  [36-38]  (see  section  1.4 
Reference to a systematic review).  Two looked at the effect of N-O2 on survival [36,37]. 
     The American (Fletcher’s) study [36] 
This randomized, double-blind, three-year trial compared N-O2 at 3 liters/minute delivered by 
concentrator to room air delivered by a defective concentrator (“sham concentrator”).  The primary 
outcome of this trial consisted of pulmonary hemodynamic parameters.  Survival and requirement for 
CONT-O2 were secondary outcomes.  Thirty-eight patients were randomized.  The hemodynamic data 
were limited to 9 sham- and 7 oxygen-treated patients.  The nocturnal desaturator group who received 
supplemental oxygen during sleep over 36 months showed a significant downward trend in pulmonary 
artery pressure (-3.7 mmHg) compared with those in the control group (+ 3.9 mmHg; p = 0.02).  There 
was no significant difference in mortality between the oxygen- and sham-treated patients. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 3 20
 
 
     The French (Chaouat’s) study [37] 
This open trial looked at the effectiveness of N-O2 in patients with COPD with mild-to-moderate 
daytime hypoxemia (PaO2 56-69 mmHg) exhibiting sleep-related oxygen desaturation.  Sleep-related 
oxygen desaturation was defined as spending  30% of the recording time with transcutaneous arterial 
oxygen saturation  90%.  This definition of “nocturnal desaturation” represents the one that is the most 
currently accepted in Canada.   The endpoints included survival, requirement for CONT-O2 and 
pulmonary hemodynamic effects after 2 years of follow-up.  Seventy-six patients were randomized; 41 
were allocated to N-O2 and 35 to no N-O2.  Twenty-two patients (12 in the N-O2 group and 10 in the 
control group, p = 0.98) required CONT-O2 during the follow-up period (35  14 months).  Sixteen 
patients died (9 in the N-O2 group, and 7 in the control group, p = 0.84).  The changes in the mean 
pulmonary artery pressure in the N-O2 group and the control group were not different.  The authors 
concluded that N-O2 had no effect on survival, did not allow delay in the requirement for CONT-O2 
and did not modify the evolution of pulmonary hemodynamics. 
Table 1 is a summary of the American and the French studies.  We computed the relative risks 
and associated 95% confidence intervals from the data reported in the respective articles.  Both trials 
were negative.   However, both were underpowered as demonstrated by the width of the confidence 
intervals surrounding the relative risks. 
  Table 1.  Summary of randomized trials of nocturnal oxygen therapy in COPD  
 
 
 
Trials 
 
 
Outcomes 
Risk with 
therapy 
Risk without 
therapy 
Relative risk 
(95% CI) 
Fletcher  [36]   mortality 
5/19 
6/19 
0.8 (0.3 – 2.2) 
 
  progression to CONT-O2 
6/19
1/19
6.0 (1.1 – 36.4)
 
  composite outcome* 
11/19
7/19
1.6 (0.8 – 3.3)
Chaouat [37]   mortality 
9/41
7/35
1.1 (0.5 – 2.6)
 
  progression to CONT-O2 
12/41
10/35
1.0 (0.5 – 2.1)
 
  composite outcome* 
19/41
14/35
1.2 (0.7 – 2.0)
* composite outcome: mortality or requirement for CONT-O2 
    The German (Orth’s) study [38] 
In a pilot randomized, placebo-controlled cross-over trial, Orth et al. [38] investigated the influence of 
N-O2 on quality of life in 19 daytime normoxemic COPD patients with nocturnal oxygen desaturation 
that was defined according to the French criteria.  Each treatment period lasted 6 weeks.  Mortality was 
not an outcome in this trial.  Significant differences were observed only in the sleep dimension of the 
Nottingham Health Profile.  All the other dimensions of the Nottingham Health Profile, SF-36 and St- 
George’s Respiratory Questionnaire showed no difference between N-O2 and placebo.   The authors 
concluded that N-O2 was not able to improve quality of life within 6 weeks after initiation of therapy. 
b) N-O2: Economic aspects 
We could not locate any economic evaluation specifically investigating the cost-effectiveness of N-O2. 
However, given i) the total Canadian population with COPD - 750 000 individuals [2], ii) the annual 
direct cost of COPD in Canada - $1997 per patient [34], iii) the proportion of this budget dedicated to 
home oxygen therapy - 17% [34], and iv) the proportion of patients with COPD receiving home oxygen 
for nocturnal utilization only - 20% (Appendix 1), we estimate that the annual direct cost of nocturnal 
oxygen therapy in Canada amounts to $51 million. 
1.3.3 Preliminary work done by the applicants to support the clinical trial 
a) Survey and needs assessment of Canadian respirologists 
We recently conducted a mail survey of all the respirologists registered in the 2006 Canadian Medical 
Directory in order to characterize their perception and clinical practice regarding the indications and 
prescription of nocturnal oxygen therapy in COPD ([39]; Appendix 2).  Another important objective 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 4 20
 
 
was to determine what would be considered as an important treatment effect of N-O2 in a placebo- 
controlled randomized trial.  We found that Canadian respirologists are highly interested by the issue of 
nocturnal oxygen desaturation in COPD.  The response rate to the survey was 60%, with 99% of the 
respondents indicating that the problem of nocturnal oxygen desaturation is clinically relevant.   The 
survey identified wide variations in clinical practices among physicians in several areas of the 
management of nocturnal oxygen desaturation (including its definition, its diagnostic modalities and the 
perceived indications of N-O2).  The results of the survey emphasized the needs for further research. 
b) Results of a five-site pilot feasibility study 
We successfully completed a pilot study looking at the prevalence of nocturnal desaturation in a cohort 
of patients with COPD and moderate hypoxemia (PaO2: 56 to 69 mmHg).  Its results are summarized 
in Appendix 3.  From this pilot study of 128 patients conducted in 5 clinical sites that will participate in 
the INOX trial, we determined that 40% (95% CI: 31 – 49) of the patients with moderate-to-severe 
COPD not qualifying for CONT-O2 are nocturnal oxygen desaturators. 
c) Accuracy of home oxygen oximetry to exclude obstructive sleep apnea in COPD 
Whether  home  nocturnal  oximetry is  sufficient  to  distinguish  between  sleep  apnea and  nocturnal 
oxygen desaturation alone (i.e., without sleep apnea) is debated.  We studied, in a blind comparison of 
home nocturnal oximetry and laboratory polysomnography, consecutive patients with COPD and 
nocturnal oxygen desaturation (Appendix 4).  We found that, in patients with significant nocturnal 
oxygen desaturation, home nocturnal oximetry has high negative predictive value (but poor positive 
predictive value) for the diagnosis of OSA.   These results impact on the diagnostic strategies we 
propose (see section 2.5.4 Nocturnal desaturation: operational definition and patient selection). 
d) Utility scores in patients with oxygen-dependent COPD 
The clinical importance of CONT-O2 for patients with severe COPD is unknown.  We addressed this 
important question in a cross-sectional study of 102 patients with oxygen-dependent COPD (Appendix 
5) to determine whether a prescription of CONT-O2 approaches the value (i.e., utility) of death for 
patients with severe COPD. We administered the SF-36 to 102 patients with oxygen-dependent COPD 
in order to derive utility scores (SF-6D scores) [40].  We found that the prescription of CONT-O2 is a 
critical step in the life of patients with severe COPD.  The results of this study bear on the choice and 
appropriateness of the primary outcome of the INOX trial (see section 2.8.1 Primary outcome). 
1.4 REFERENCE TO A SYSTEMATIC REVIEW 
1.4.1  Published and updated meta-analysis 
A meta-analysis of domiciliary oxygen in COPD was published in 2005 in the Cochrane Library [41]. 
Its objective was to determine the effect of domiciliary oxygen therapy on survival in patients with 
COPD.  The studies of CONT-O2 were considered separately from those of N-O2.  The authors only 
identified the two randomized trials (Fletcher’s and Chaouat’s) on which we commented on in the 
previous section.   There was no difference in mortality between the treated and the control groups. 
Considering mortality as the only outcome, the pooled odds ratio was 0.97 (95% CI: 0.41 – 2.31).  The 
authors concluded that N-O2 has no effect on survival, without commenting on the lack of precision of 
the treatment effect. 
To complement this meta-analysis, we searched in January 2009 the Cochrane Airways Group 
Specialised Register of Trials in COPD which is derived from systematic searches of bibliographic 
databases including the Cochrane Central Register of Controlled Trials (Central), Medline, Embase and 
CINHAL.  Also, we hand-searched the 2005 to 2008 American Thoracic Society, American College of 
Chest Physicians and European Respiratory Society meeting abstracts.   We did not uncover any 
additional completed or ongoing trial considering mortality or disease progression as outcomes 
(Appendix 6).  In addition, we conducted a meta-analysis of the composite outcome (i.e., mortality or 
requirement for CONT-O2) from the data presented in Table 1.  There was no difference between the 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 5 20
 
 
treated and the control groups (pooled odds ratio: 1.57 [95% CI: 0.75 – 3.26]). 
1.4.2 The need for a trial: conclusion 
From this review of the literature and our preliminary work, we conclude that: 
  nocturnal oxygen desaturation may be a determinant in the natural progression of COPD to its end 
stages severe hypoxemia, right heart failure, and death; 
  Most Canadian respirologists have already prescribed nocturnal oxygen to patients with COPD and 
isolated nocturnal oxygen desaturation. Current evidence from two randomized controlled trials and 
their meta-analysis does not support this prescription; 
  the current utilization of N-O2 in Canada is associated with annual cost that we estimated at $51 M; 
  the cost-effectiveness of N-O2 remains unexplored. 
These conclusions are consistent with those of two recent workshops of the NHLBI on the needs and 
opportunities of clinical research in COPD [42;43].  The latest workshop specifically targeted oxygen 
therapy in COPD [43].  Both identified N-O2 as a research priority in order to inform clinical decision 
making with regard to home oxygen therapy. 
1.5 HOW WILL THE RESULTS OF THIS TRIAL BE USED? 
The results of this study will be used to inform clinical decision-making.  The INOX trial will provide a 
definitive answer to questions regarding an intervention that has gained wide popularity among patients 
and prescribing physicians over the last few years without any evidence of its effectiveness.  For 
instance, from our recent survey of Canadian respirologists, 87% of the respondents indicated that they 
have already prescribed nocturnal oxygen to patients with COPD and isolated nocturnal oxygen 
desaturation ([39]; Appendix 2).  This contrasts with the opinion of the Canadian Thoracic Society that 
“there is currently no evidence to support the use of nocturnal oxygen to improve survival, sleep quality 
or quality of life in patients with isolated nocturnal desaturation” [7].  Undoubtedly, those who allocate 
financial resources (including governments and insurance companies) will be interested in this study. 
1.6 DESCRIPTION OF RISKS TO THE SAFETY OF PARTICIPANTS INVOLVED IN THE TRIAL 
Low-flow oxygen is safe [44].  Its benefits in appropriately selected individuals clearly outweigh the 
small risks.  Elevations in PaCO2 occur in some COPD patients receiving low-flow oxygen.  The effect 
is generally small in magnitude and is not progressive in response to oxygen therapy alone. Nonmedical 
hazards such as fire have been described in current smokers but are unusual [45].  Current smokers will 
be excluded from the INOX trial.   This risk does not exist in patients using “sham-concentrators”. 
Minor problems such as skin rash or nasal irritation are usually easily handled with topical treatments. 
 2. THE PROPOSED TRIAL                                                                                                                       
2.1 WHAT IS THE PROPOSED TRIAL DESIGN? 
A 3-year, multi-center, randomized, double-blind, placebo-controlled trial of N-O2.  The primary end- 
point is a composite outcome made up of (1) all-cause mortality or (2) requirement for CONT-O2. 
2.2 WHAT ARE THE PLANNED TRIAL INTERVENTIONS? 
Patients will be randomly assigned to three years of treatment with either (1) home N-O2, or (2) sham 
therapy with ambient air. 
2.2.1 Experimental intervention group: nocturnal oxygen therapy 
N-O2 will be delivered overnight from an electrically-powered oxygen concentrator (NewLife Intensity 
Oxygen Concentrator, AirSep Corporation, Buffalo, NY, USA).  The concentrator provides a constant 
source of oxygen from ambient air using a molecular sieve that removes nitrogen and water from air to 
deliver 95% oxygen at flow rates of up to 4 liters/minute.  Patients will be instructed to receive N-O2 
throughout the night, from the time they go to bed up to the time they get up.  The flow of oxygen will 
be that allowing the nocturnal saturation to be > 90% for  90% of the recording time.  This will be 
assessed by the mean of pulse oximetry during a full-night recording (test night).  Oxygen will be 
provided via nasal catheters.   Titration procedure (Appendix 7): We anticipate that, in about two third 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 6 20
 
 
of the cases, the needed oxygen flow will be 2 liters/minute.  This statistic comes from a chart review of 
the patients with COPD receiving nocturnal oxygen therapy at the Quebec City Respiratory Home Care 
Program (Appendix 1).  This flow will be given during a first test night.  If this flow of oxygen is not 
enough to keep the saturation > 90% for  90% of the recording time, then an additional test night will 
be needed, with the oxygen flow rate increased by 1 liter/minute per night, up to 4 liters/minute. A third 
night of testing will be scheduled exceptionally to patients who are prescribed 4 liters/minute. This 
ultimate  test  is  to  assess  what  is  the  percentage  of  these  patients  who  are  receiving  an  optimal 
treatment.  This process will be the responsibility of study personnel whose only other involvement in 
the trial will be the installation of the home oxygen concentrators.  Following each test night, the result 
of the oximetry will be transmitted to the coordinating center by e-mail for assessment by a trained 
technician  with  no  other  involvement  in  the  trial.    Feedbacks  will  be  provided  within  48  hours 
according to the decision tree provided in Appendix 7. 
2.2.2 Control group: sham therapy with ambient air (sham concentrator) 
The patients allocated to the control group will receive ambient air delivered overnight through an 
electrically-powered oxygen concentrator rendered ineffective by bypassing the sieve beds.   The 
ineffective concentrators will have the same external appearance as the effective ones, allowing the trial 
to be double-blinded.  We have received approval by Health Canada in order to proceed with the 
modifications on the oxygen concentrators.  Titration procedure (Appendix 7): The patients in the 
control group will also be submitted to air flow adjustment.   The results of the oximetry performed 
during those nights will also be sent to the coordinating center but will be disregarded.  To preserve 
blinding, patients in the control group will be submitted to additional test oximetries, with the airflow 
rate increased by 1 liter/minute, up to 4 liters/minute. 
2.3 WHAT ARE THE PROPOSED ARRANGEMENTS FOR ALLOCATING PARTICIPANTS TO TRIAL GROUPS? 
Patients will be randomized after informed consent is obtained. The randomization process will consist 
of a computer-generated random listing of the two treatment allocations blocked by variable blocks of 
four and six in alternance and stratified by site.  Randomization will be through central allocation and 
coordinated by the Laboratoire de télématique biomédicale (LTB) of the Respiratory Health Network of 
the Fonds de la recherche en santé du Québec (FRSQ).  A letter of agreement is included in Appendix 
8.  Physicians and research staff will be unaware of the treatment allocation prior to or following 
randomization.  At the time of randomization, each patient will be provided with a site-specific study 
number according to the randomization schedule.   The results of the randomization will only be 
communicated by the LTB to the individual responsible for the preparation, delivery and installation of 
the home concentrators and oxygen flow titration. 
2.4 WHAT ARE THE PROPOSED METHODS FOR PROTECTING AGAINST OTHER SOURCES OF BIAS? 
2.4.1 Double-blinding 
The primary outcome of our trial is a composite outcome made up of all-cause mortality or requirement 
for CONT-O2 (section 2.8.1 Primary outcome).  The requirement for CONT-O2 is determined at least 
in part by the actions of clinicians.   Although it follows strict criteria and guidelines defined in this 
protocol, there is conceivably potential for more aggressive surveillance (monitoring) of arterial blood 
gases in those in the control group, leading to an increased likelihood of prescription of CONT-O2 in 
this group.  In this regard, a real placebo arm seems most appropriate in order to minimize biases. 
Therefore, this study will be double blinded. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
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2.4.2 Avoiding the threat of co-interventions 
In randomized trials in COPD, few interventions really altered disease progression and reduced 
mortality.  CONT-O2 in patients with severe hypoxemia is one of them [5;6].  Smoking cessation also 
reduced mortality in patients with mild COPD [46].  Smokers will be excluded from this trial.  Lung 
volume reduction surgery reduced mortality in highly selected patients with severe emphysema [47]. 
Finally, the evidence that inhaled corticosteroids reduce mortality in patients with COPD is still 
controversial [48;49].  Therefore, co-intervention is unlikely to distort the results of the trial.  However, 
because of the extended follow-up period (3 years), new therapies may emerge or ongoing trials may 
demonstrate positive effects of currently available treatment modalities on mortality.  We will monitor 
and record co-interventions that might arise throughout the trial period.  Because clinical practice often 
varies across centers and new therapies are often introduced in different ways throughout centers, the 
randomization will be stratified by centers. 
2.5 WHAT ARE THE PLANNED INCLUSION/EXCLUSION CRITERIA? 
2.5.1 Clinical settings 
This multi-center randomized trial was initiated by the Respiratory Health Network of the Fonds de la 
recherche en santé du Québec (FRSQ).  It has also received the support of the Canadian Respiratory 
Clinical Research Consortium (Appendix 9) and will be conducted throughout Canada by a group of 
respirologists  knowledgeable  in  the  area  of  COPD  and  clinical  research.     This  network  has 
demonstrated its ability to conduct large trials by successfully completing an important trial of a self- 
management program in patients with severe COPD [50], a trial comparing 3 drug regimen in COPD 
[51;52], and another trial of home-based respiratory rehabilitation in COPD [53;54].  These 3 studies, 
all published in high-impact journals, involved respectively 191, 449 and 252 patients in 7, 27 and 10 
Canadian centers, respectively.  The list of co-investigators are provided in Appendix 10. 
2.5.2 Inclusion criteria 
 Patients with a diagnosis of COPD supported by a history of past smoking and obstructive disease: 
FEV1 < 70% predicted, FEV1/FVC < 70% and a total lung capacity by body plethysmography > 
80% predicted; 
 Stable COPD at study entry, as demonstrated by (1) no acute exacerbation and (2) no change in 
medications for at least 6 weeks before enrollment in the trial; 
    Non-smoking patients for at least 6 months before enrollment in the trial; 
    Mild-to-moderate daytime hypoxemia with a resting SpO2 (room air)  95% [86]; 
 Patients  fulfilling  the  current  definition  of  nocturnal  oxygen  desaturation,  i.e.,    30%  of  the 
recording time with transcutaneous arterial oxygen saturation  90% on at least one of two 
consecutive recordings; 
    Ability to give informed consent. 
2.5.3 Exclusion criteria 
  Patients with severe hypoxemia fulfilling the usual criteria for CONT-O2 at study entry: PaO2  55 
mmHg; OR PaO2  59 mmHg with clinical evidence of at least one of the following: (1) peripheral 
edema (cor pulmonale); (2) hematocrit  55%; (3) right ventricular hypertrophy (P pulmonale on 
ECG: 3 mm in leads II, III, aVf; 
 Patients with proven sleep apnea (defined by an apnea/hypopnea index of  15 events/hour [55]) or 
suspected sleep apnea on oximetry tracings; 
    Patients currently using N-O2; 
 Patients with known left heart or congenital heart diseases, interstitial lung diseases, bronchiectasis 
as the main cause of obstructive disease, lung carcinoma, severe obesity (body mass index  40 
kg/m2), or any other disease that could influence survival. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
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2.5.4 Nocturnal desaturation: operational definition and patient selection 
a) Definition of “nocturnal desaturation” using home oximetry 
Significant “nocturnal desaturation” will be defined on the home oximetry as  30% of the recording 
time (time in bed) with a transcutaneous arterial oxygen saturation < 90% [37;56].  This definition is 
currently accepted in Europe and Canada [39;56].  Continuous nocturnal saturation (SaO2) monitoring 
will be obtained with the PalmSAT 2500™ oximeter only (Nonin Medical Inc., Plymouth, MN, USA). 
Data will be digitally recorded and downloaded to a computer with dedicated software for data 
interpretation which will also be based on visual inspection of the printed report.  Only recordings of at 
least 4-hour duration will be accepted. 
To be enrolled in the trial, all patients will undergo two oximetric studies [57] separated from 
each other by  2 weeks.  Each oximetry recording will be classified as follows: 
  Nocturnal desaturation (i.e.,  30% of the recording time with a transcutaneous arterial oxygen 
saturation < 90%) without suspicion of associated sleep apnea (i.e., steady tracing with non-periodic 
variation in saturation throughout sleep – typical example in Appendix 11A); 
  Nocturnal desaturation (i.e.,  30% of the recording time with an arterial oxygen saturation < 90%) 
with suspicion of associated sleep apnea (i.e., cyclical changes in saturation in addition to the 
desaturations – typical example in Appendix 11B); 
     No nocturnal desaturation (i.e., < 30% of the recording time with a saturation < 90%). 
A  flow  diagram  detailing  the  diagnostic  procedures  following  the  screening  home  oximetries  is 
provided in Appendix 12.  Patients with at least one abnormal recording demonstrating nocturnal 
desaturation with no suspicion of associated sleep apnea on both oximetries will be directly eligible, 
without further testing.  This procedure is based on our finding that the recording time with an oxygen 
saturation < 90% on two consecutive oximetries is highly correlated, indicating consistency in the 
pattern of desaturation captured on repeated recordings (Appendix 3).     In order to certify uniformity 
in the diagnosis of nocturnal desaturation and in the detection of sleep apnea [58], all the oximetries 
will be reviewed at the coordinating center by a sleep specialist (Dr. F. Sériès) before randomization. 
b) Polysomnography: do we need it in all patients? 
COPD and obstructive sleep apnea are common conditions.   The combination of COPD and sleep 
apnea is referred to as the “overlap syndrome” [59].  A recent population-based study indicated that 
both conditions are not linked by common pathophysiological mechanisms, and that their association is 
only by chance [60].  The routine utilization of sleep studies in patients with COPD to distinguish 
between sleep apnea and nocturnal oxygen desaturation alone (i.e. without sleep apnea) is controversial. 
On one hand, the access to diagnostic facilities for patients with suspected sleep apnea in Canada is 
unfortunately very limited [61], and the requirement of a polysomnography for all patients in the frame 
of this study would be unrealistic.  On the other hand, 42% of the Canadian respirologists think that all 
COPD patients with significant nocturnal desaturation should have a polysomnography to rule out sleep 
apnea [39].   In a blind comparison of home nocturnal oximetry and laboratory polysomnography in 
consecutive patients with COPD and nocturnal oxygen desaturation, we found that, in patients with 
significant nocturnal oxygen desaturation, home nocturnal oximetry has high negative predictive value 
for the diagnosis of OSA (Appendix 4).  However, home nocturnal oximetry has a poor positive 
predictive value for the diagnosis of OSA.  It is on the basis of this study that we constructed the 
algorithm for the patients’ screening and selection.     In patients with an oximetry tracing suggestive of 
sleep apnea, patients will be excluded, unless sleep apnea is ruled out on the basis of a formal sleep 
study performed off-protocol.  In such cases, the investigator will have to submit to the coordinating 
center the results of either a Type-1 or Type-2 sleep apnea evaluation study (i.e., complete laboratory or 
full ambulatory polysomnography, Appendix 13) confirming the absence of sleep apnea before the 
patient is randomized [62].  The sleep studies will all be reviewed by a sleep specialist (Dr. F. Sériès). 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
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Sleep apnea will be defined as an apnea/hypopnea index  15 [55]. 
2.6 WHAT IS THE PROPOSED DURATION OF TREATMENT PERIOD? 
In the British MRC trial [5], 500 days elapsed before any effect of CONT-O2 appeared, when compared 
to no oxygen therapy at all.  Therefore, we believe that a 2-year study would be too short since it seems 
unlikely that the benefit of N-O2 would appear in such a short period of time.  The trial we propose 
would follow the patients for a period of 3 years, thus increasing the probability of clinical events in 
both groups.  At 3-year follow-up, all patients will be offered to remain in the trial for an additional 
year.  Those who accept will sign a new consent form applying to the extended period. 
2.7 WHAT IS THE PROPOSED FREQUENCY AND DURATION OF FOLLOW-UP? 
Each patient will be followed-up for a period of 3 years, with regular visits (every 4 months) at his/her 
respective study site.  The schedule of follow-up procedures is provided in Section 2.9.1.  During the 
extended follow-up period, the same procedures as in Year 3 apply.   Details regarding the outcome 
measurement are provided in section 2.8 and 2.13 (Compliance issues). 
2.8 WHAT ARE THE PROPOSED PRIMARY AND SECONDARY OUTCOME MEASURES? 
2.8.1 Primary outcome 
a)  Composite outcome: all-cause mortality or requirement for CONT-O2 
All-cause mortality or requirement for CONT-O2 will define the composite and primary outcome.  All- 
cause mortality is preferred over disease-specific mortality because of difficulties in classifying causes 
of death [63] and the lack of validity of death certificates in patients with COPD [64]. 
Although we realize the difficulties related to composite outcomes in clinical trials, the 
requirement of CONT-O2 must represent an endpoint of this trial for clinical and methodological reasons. 
The primary reason is that the condition of participants may deteriorate to the point that CONT-O2 is 
required.  This situation is particularly problematic because CONT-O2 compulsorily includes sleep time 
(and therefore N-O2).  If mortality was the only outcome, and if CONT-O2 was prescribed because of 
disease progression to a patient allocated to N-O2, N-O2 would then become CONT-O2 (which is of 
proven effectiveness in improving survival in COPD). Similarly, if CONT-O2 was prescribed in a patient 
allocated to the control group, it would then represent an important contamination.  Both situations would 
represent important threats to the validity of our trial. 
In addition, we understand that the choice of a composite outcome requires that its components 
(1) are of similar importance, (2) occur with similar frequency [65].  We provide herein data to support 
our view that our composite outcome is appropriate: (1) Importance: In a cross-sectional study, we 
derived utility scores (SF-6D scores) [40] in 102 patients with oxygen-dependent COPD (Appendix 5). 
The mean utility score was 0.60 (SD: 0.11).  For comparison, this utility score is worse than that attached 
to a large myocardial infaction, stroke leaving permanent moderate deficit, or dissecting or ruptured 
aortic aneurysm, three conditions considered in the cardiovascular literature as appropriate in composite 
outcomes that include mortality [66].  (2) Frequency: Typical patients with COPD not qualifying for 
CONT-O2 who desaturate during sleep have, on average, an FEV1 35-40% predicted [15].  These 
patients have a 3-year mortality of 20% [37].  The rate of prescription of CONT-O2 in patients with 
significant nocturnal oxygen desaturation is similar to this mortality rate.  In the French trial [37], 29% 
were prescribed CONT-O2 during the study period; 40% reached one or the other of the endpoints. 
b) Criteria for CONT-O2 and initiation of CONT-O2 
The widely accepted criteria for CONT-O2 derived from the NHLBI’s Nocturnal Oxygen Therapy Trial 
[6] will be used (see section 2.5.3 Exclusion criteria).  These criteria are always met in either of the two 
following clinical circumstances: 
     In stable patients (> 45 days from an acute exacerbation of COPD; Appendix 14A): 
    Patients may become severely hypoxemic over time, following a slow decline in lung function that 
characterizes the natural course of the disease.  In such circumstances, the requirement for CONT-O2 is 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
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captured through periodic surveillance.  At each protocol-based follow-up visit, patients will be submitted 
to pulse oximetry at rest using a PalmSAT 2500™ oximeter (Nonin Medical, Inc. Plymouth, MN, USA) 
that estimates arterial saturation in oxygen with a precision of ± 2%.   The criteria for CONT-O2 
requirement defined in section 2.8.1.b correspond to a saturation  90%.  If pulse oximetry at rest gives a 
saturation  92%, then direct arterial blood gas measurement is not required.  Otherwise, arterial blood 
gas must be sampled for direct PaO2 measurement.  Patients whose PaO2 falls below 56 mmHg during 
the follow-up period may be given conventional CONT-O2.  The trial end-point will then be reached. 
Vital status will also be determined at 3 years for all the participants. 
     In unstable patients ( 45 days following an acute exacerbation of COPD; Appendix 14B): 
Patients may become severely but temporarily hypoxemic during an acute exacerbation of COPD 
necessitating hospitalization.  In such circumstances, oxygen therapy may be prescribed for a short period 
of time, especially if the oxygen therapy allows the patient to be safely discharged from the hospital 
sooner [67].  Any decision regarding the maintenance of oxygen therapy (i.e., the requirement of CONT- 
O2 following short-term oxygen therapy) must be made after a period of clinical stability of at least 30 
days [67]. Reevaluation must occur within 12 weeks after the end of the treatment of the exacerbation. 
The primary endpoint will be considered to be reached only when CONT-O2 criteria are met.  Vital 
status will be determined at 3 years for all the participants. 
Details regarding the prescription procedures in such circumstance are provided in section 2.9.2. 
2.8.2 Secondary outcomes 
The secondary outcomes are described in section 2.10. 
2.9 HOW WILL THE OUTCOME MEASURES BE MEASURED AT FOLLOW-UP? 
2.9.1 Baseline evaluation and protocol-based follow-up visits (Table 2 and 2.1) 
The usual socio-demographic and clinical characteristics will be obtained at baseline.  Spirometry will 
be performed according to the American Thoracic Society requirements [68], lung volumes 
measurement by plethysmography [69], and carbon monoxide diffusion capacity measurement by the 
single-breath method [70].  All arterial blood gases will be measured while breathing at room air.  In 
case of death, the date at which the primary outcome is reached will be obtained directly from chart 
review, contact with the treating physician or on the basis of interviews with surviving relatives during 
the protocol-based home visits or telephone interviews. 
Table 2. Schedule of follow-up procedures 
FLOW CHART 
0 
4 m 
8 m 
1 yr 
16 m 
20 m 
2 yrs 
28 m 
32 m 
3 yrs 
Core questionnaire + spiro 
√ 
  
 
 √ 
  
  
   √ 
  
  
 √ 
Arterial blood gas 
√ 
(√)1 
(√)1 
 √ 
 (√)1 
 (√)1 
     √ 
 (√)1 
 (√)1 
 √ 
Stipends 
√ 
 √ 
  √ 
 √ 
   √ 
 √ 
   √ 
   √ 
   √ 
 √ 
PFT (Plethysmography) 
√ 
  
 
 √ 
  
  
   √ 
  
  
 √ 
Pulse oxymetry 
 
 √ 
  √ 
  
   √ 
 √ 
 
   √ 
   √ 
Quality of life questionnaires         √                                 √                                    √                                       √ 
Health Care qst (fup call or 
visit)2                                                                                       √√        √√        √√        √√        √√        √√         √√         √√        √√ 
Home visits for compliance3                                √          √          √          √          √          √           √           √          √ 
2 nights of nocturnal oxymetry      √ 
Baseline information form             √ 
Consent form(s)                              √ 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
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FLOW CHART 
40 m 
44 m
4 yr
Core questionnaire + spiro 
 
 
√ 
Arterial blood gas 
  (√)1     (√)1 
√ 
Stipends 
 
√    
√ 
√ 
PFT (Plethysmography) 
 
 
√ 
Pulse oxymetry 
√ 
√ 
 
Quality of life questionnaires 
 
 
√ 
Health Care qst (fup call or 
visit)2 
 
√√ 
 
√√ 
√√ 
Home visits for compliance3 
√ 
√ 
√ 
1Depending on the result of the arterial saturation in oxygen measured by pulse oximetry. 
2Health care utilization will be measured through telephone contacts with patients every two months (see section  2.10.3). 
3Home visits will be performed by home care service provider staff and payments will be done from the INOX coordinating 
centre. 
Patients who accept to proceed with a 4th year of follow-up, the same procedures as in Year 3 will apply 
in Year 4 (Month 28 = Month 40, Month 32 = Month 44, and Month 36 = Month 48). 
Table 2.1 Schedule of the extended follow-up at Year 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Depending on the result of the arterial saturation in oxygen measured by pulse oximetry. 
2Health care utilization will be measured through telephone contacts with patients every two months (see section  2.10.3). 
3Home visits will be performed by home care service provider staff and payments will be done from the INOX coordinating 
centre. 
2.9.2 Procedures during acute exacerbations of COPD necessitating oxygen therapy 
a) Definition and treatment 
An exacerbation of COPD will be defined as a new respiratory event of complication prompting patient 
evaluation  and  initiation  of  additional  treatment  regimens  (including  antibiotics  and/or  systemic 
steroids) in an office or emergency department [71].  The evaluation plan and treatment at the onset of 
an exacerbation will be the responsibility of the treating physician.   No restriction on the treatment 
regimen during the exacerbation will be imposed. 
b) Assessment of oxygen requirement during and following an exacerbation (Appendix 14B) 
During an exacerbation prompting medical evaluation, arterial oxygen saturation measurement by pulse 
oximetry is part of the routine assessment.   Patients may then be found to be severely hypoxemic. 
Home oxygen therapy may then be prescribed for a short period of time (usually 4 to 6 weeks).  In such 
circumstances, this prescription of oxygen is not definitive.  The indication of home oxygen must be 
reassessed.  If short-term oxygen therapy is prescribed following an acute exacerbation, the patient is 
reevaluated after a period of clinical stability of at least 30 days (and no more than 90 days).  If the 
patient still meets the criteria for CONT-O2 defined in section 2.5.2, CONT-O2 is then prescribed. 
This prescription is then permanent and the trial endpoint is reached.   Otherwise, oxygen therapy is 
stopped and the patient is not considered oxygen-dependent.  The trial endpoint is not reached. 
2.10 WILL HEALTH SERVICE RESEARCH ISSUES BE ADDRESSED? 
2.10.1 Disease-specific quality of life: St. George’s Respiratory Questionnaire (SGRQ) 
The SGRQ is a disease-specific questionnaire that has been extensively validated in patients with all 
grades of respiratory diseases including advanced COPD [72].  The questionnaire consists of 76 items 
divided into three domains (symptoms, activity, and impact).  Scores range from zero (perfect health) to 
100 (worst possible) for each component. A change in score of 4 units is clinically significant [73;74]. 
2.10.2 Generic quality of life and utility measure: SF-36 
The SF-36 is a generic questionnaire that measures 8 dimensions of health: physical functioning, role 
limitation due to physical problems, role limitation due to emotional problems, social functioning, mental 
health, energy/vitality, bodily pain and general health perceptions [75;76].   In order to use the SF-36 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
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information in a cost/utility analysis, the SF-36 scores will be converted to a single « preference-based » 
utility score indicating the value that would be given to their health state by the general population. 
This will be done by extracting the appropriate SF-36 responses and using them to complete a 6-item 
health state classification, the SF-6D [40].   The SF-6D utility score will be combined to produce 
quality-adjusted life years (QALYs).  The product of the SF-6D score at 3-year follow-up (or the latest 
SF-6D score recorded at the time the primary outcome of the trial is reached) and the duration of life up 
to 3 years will give the QALYs produced for each patient. 
2.10.3 Comorbidity: Charlson Index 
The Charlson index is a validated one page questionnaire developed to assess comorbidities and their 
impact on prognosis in longitudinal studies[87]. 
2.10.4 Health economics: costs and health care utilization 
The estimates of the cost of COPD treatment for the two intervention groups will be based on the 
utilization of the intervention resources during the study period.  The social and health care perspectives 
will be adopted. The resources and the cost estimate sources are the following: 
     professional  time:  the  time  required  for  intervention  activities  will  be  recorded  by  the  study 
professionals. This will include time required for material maintenance, patients’ education, and home 
follow-up visits.   Professional costs for each patient will then be calculated by multiplying the time 
associated with the patient’s treatment by the hourly remuneration of the appropriate professional. 
     intervention materials: cost of durable materials associated with the intervention will be based on 
the market price, the expected economic life, and an appropriate discount rate. 
     health care utilization: health care utilization will be collected by a questionnaire administered by 
telephone every two months (Appendix 15). We have adapted a questionnaire developed by the 
Respiratory Health Network of the FRSQ that was used in a prospective cohort study of patients with 
COPD in Quebec.  Physician visit costs will be estimated by province-specific remuneration plans.  For 
non-physician services, we will obtain costs from professional associations.  Hospital inpatient costs 
will be estimated by province-specific indices of health resource intensity.  For medication, we will use 
the price given on the list of drugs reimbursed through province-specific drug insurance programs. For 
specific analysis on costs related to utilization of health care services we will build a model with the use of 
the data extracted from the RAMQ and the MED-ECHO provincial databases with the consent of the 
subjects from the province of Quebec. 
2.11 WHAT IS THE PROPOSED SAMPLE SIZE? 
2.11.1 Sample size calculation 
Typical patient with COPD not qualifying for CONT-O2 who desaturate during sleep have, on average, 
an FEV1 35-40% predicted [15].  In their randomized trial, the French group reported a 3-year mortality 
of 20% [37].  These figures are consistent with the survival rate of patients with COPD reported in the 
literature [77], including a large North American study (n = 985) [78].  In this study, the mean FEV1 
was 36% of predicted and the average follow-up, 35 months; mortality was 23%.  Mortality rates are 
similar to the rate of prescription of CONT-O2.  In addition, in the French study [37], 29% were 
prescribed  CONT-O2  during  the  study  period;  40%  reached  one  or  the  other  of  the  endpoints. 
Therefore, we anticipate the 3-year event rate (i.e., mortality or requirement for CONT-O2) among 
patients not receiving N-O2 to be around 40%.  In terms of planning, we are targeting a 30% relative 
reduction in this in the experimental group (i.e., an event rate in the control group of 40% and an event 
rate of 28% in the N-O2 group, or an absolute difference in event rates of 12%).  This absolute 
difference is consistent with the minimal clinically important difference elicited by Canadian 
respirologists in our national survey (14%; Appendix 2).  The level of statistical significance is set at p 
= 0.05 (two-sided).   Translating this in terms of our proposed log rank test (section 2.16.1), we 
calculated that 300 patients per group (total sample size: 600) will provide us with a power of 90% 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
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[79].  We will enrol a total of 630 patients to account for potential consent withdrawal.  Sample size 
issues are further discussed in Appendix 16. 
2.11.2 Feasibility: results of a five-site pilot feasibility study 
The results of our pilot study (section 1.3.3b and Appendix 3) also carry information on the number of 
patients we need to screen in order to reach the target sample size of 630 patients.  Given that 40% of 
the patients with moderate-to-severe COPD not qualifying for CONT-O2 exhibit nocturnal oxygen 
desaturation, 1575 will have to be screened in order to identify these 630 eligible individuals.  In our 
survey of Canadian respirologists, we found that, on average, 30% of the respondents’ practice 
(including that of our co-investigators) is dedicated to the care of patients with COPD (Appendix 2). 
This information clearly demonstrates that nocturnal oxygen desaturation in patients with COPD is not 
a rare occurrence and that the investigators have access to a large pool of potentially eligible patients. 
2.12 WHAT IS THE PLANNED RECRUITMENT RATE? 
We anticipate that the recruitment will be completed within  4 years.   Twenty-seven centers with 
specific facilities and expertise have already agreed to participate in the trial (Appendix 10).  A realistic 
objective is to enroll 25 patients in each centre during the recruitment period. 
2.13 ON WHAT EVIDENCE ARE THE COMPLIANCE FIGURES BASED? 
Objective daily duration of oxygen use through the concentrator during each treatment period will be 
measured using the concentrators’ counter clock recording the number of hours of utilization. This 
information will be recorded by a respiratory therapist during regular home visits scheduled every 4 
months. The home visits for all the participating sites will be done by respiratory therapists from the 
home care company, hired by the INOX coordinating centre. Patients who have used their N-O2 or 
sham therapy during at least 70% of the total time in bed over the 3-year trial will be judged to have 
been compliant. Total time in bed will be estimated from the typical daily time in bed self-reported at 
baseline. Patients who are non-compliant will be included in the primary intention-to-treat analysis. 
2.14 WHAT IS THE LIKELY RATE OF LOSS TO FOLLOW-UP? 
In case of withdrawal, we will attempt to ascertain the primary outcome through review of death 
certificates from provincial statistics registries and chart review to determine whether the patient has 
been placed on CONT-O2 therapy.  We anticipate the rate of loss to follow-up or consent withdrawal to 
be less than 5%.  The total sample size will be augmented accordingly to 630. 
2.15 HOW MANY CENTERS WILL BE ENVOLVED? 
Twenty-seven centers agreed to participate in the INOX trial (Appendix 10). 
2.16 WHAT IS THE PROPOSED TYPE OF ANALYSES? 
2.16.1 Statistical analysis 
The primary analysis will follow an intent-to-treat approach. The distribution of time to achievement of 
the primary composite outcome (all-cause mortality or requirement for CONT-O2) will be estimated by 
the Kaplan-Meier method, and the difference between the two study groups will be evaluated with a 
log-rank test. The estimated relative risk of mortality or requirement for CONT-O2 with its 95% 
confidence interval will be computed.  Multivariable analyses with the Cox proportional-hazards model 
will be used to estimate the simultaneous effects of prognostic factors (including gender, age, FEV1, 
and comorbidities) and on the composite outcome.  Differences will be considered to be statistically 
significant at the 0.05 level.  All statistical tests will be two-sided.  The analyses for changes in quality- 
of-life measures will follow a similar approach: they will be based on an intention to treat approach and 
simple initial analyses will be followed by multivariable adjusted analyses.    Although we anticipate 
minimal loss to follow-up, the effect of loss to follow-up will be explored through the use of a variety 
of imputation strategies, including multiple imputation to examine the robustness of our findings, and 
any conclusions that vary substantively will be clearly identified. 

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Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
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2.16.2 Economic issues: cost effectiveness analysis 
An incremental cost effectiveness analysis will be undertaken to assess the efficiency of nocturnal 
oxygen therapy.  The overall costs and effects of the two groups will be used to calculate incremental 
cost effectiveness ratios according to the following equation: R = (CT - CC) / (ET - EC) = C / E, where 
R is the incremental cost effectiveness ratio, CC  and EC  are the means of the control group costs and 
effect, respectively, CT and ET are the means of the treatment group costs and effect, respectively, and 
C and E are the incremental cost and incremental effect, respectively [80].  Protocol-specific costs 
will be disregarded in the control group.  The effect of therapy will be defined in terms of mortality, 
life-years and utility (section 2.10.2).   Univariate and multivariable sensitivity analyses will be 
conducted to test the robustness of the results.  Non parametric analyses (i.e., bootstrapping) will be 
used to derive confidence intervals for the incremental cost effectiveness ratios [81].  Although there is 
no accepted standard for what constitutes good value, benchmarks against which the average 
comparative cost-effectiveness ratios of N-O2 will be measured are available [82]. 
2.17 WHAT IS THE PROPOSED FREQUENCY OF ANALYSES? (INTERIM ANALYSIS) 
One interim analysis for efficacy will be conducted.  All analyses will be run blindly and reported as 
such to the Data Monitoring Committee (DMC).  At the interim analysis, the decision to stop or 
continue the trial will be made according to the DMC’s charter that we developed according to the 
DAMOCLES Study Group’s recommendations ([83]; Appendix 17).  The suggested stopping rules 
(Haybittle-Peto procedure [84;85]) will be subject to approval by the DMC during its first meeting. 
2.18 ARE THERE ANY PLANNED SUBGROUP ANALYSES? 
The following a priori hypothesis will be explored: the effect of N-O2 depends on the severity of 
nocturnal desaturation which may be defined in terms of % of time in bed with a saturation  90% or in 
terms of mean saturation throughout the recording time (see section 2.5.4).  In addition to the traditional 
threshold of 30% of the time with a saturation  90%, the effect of N-O2 will be analyzed according to 
various thresholds of desaturation. 
2.19 HAS ANY PILOT STUDY BEEN CARRIED OUT USING THIS DESIGN? 
We have not conducted any pilot study using this design.  However, the French trial (Chaouat et al. 
[37]) is a clear demonstration that a randomized trial of N-O2 is feasible. 
 3. TRIAL MANAGEMENT                                                                                                                        
3.1 DAY-TO-DAY MANAGEMENT 
The Coordinating Centre (Hôpital Laval, Quebec City) will provide central guidance and support to 
participating centers for protocol adherence. Copies of the data collection forms with information on 
the eligibility criteria will be sent to the Coordinating Centre before randomization (see section 2.3). 
Supporting documentation of the primary outcome will be forwarded no later than six weeks after 
occurrence or at the end of the trial if the primary outcome was not reached.  Data management will be 
centralized at the Coordinating Centre.  The Executive Committee (i.e., the principal investigator [YL], 
Dr. François Maltais and the study coordinator) will develop or modify all policies regarding the daily 
operations of the trial.  It reports all safety concerns to the Steering Committee and the DMC. 
3.2 ROLE OF PRINCIPAL APPLICANT AND CO-APPLICANTS 
The principal applicant sits on the Executive committee (section 3.1).  In addition, the principal 
applicant and the co-applicants are all members of the Steering Committee (section 3.3). 
3.3 STEERING AND DATA MONITORING COMMITTEES 
The Steering Committee is responsible for the design, execution, analysis and publication of results of 
the trial.   Specific terms include (1) ratification of all major policy changes made by the Executive 
Committee; (2) review of all potential safety problems encountered by the Executive Committee; (3) 
review of accrual patterns; (4) review of randomization and data collection procedures as required. (5) 
discussion of any other concerns of any member of the Committee. 

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Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
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The draft DMC’s charter is provided in Appendix 17.  The members of the DMC are Dr. James 
Brophy (Cardiology and Clinical epidemiology, McGill University), Dr. Nick Anthonisen (Respiratory 
medicine, University of Manitoba), and Dr. Robin Roberts (Biostatistics, McMaster University). 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
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Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
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Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 18 20
 
 
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1999; 22: 667-689. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 19 20
 
 
63. Jensen HH, Godtfredsen NS, Lange P, et al. Potential misclassification of causes of death from 
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Risk in Health.  http://www.nemc.org/icrhps/resprog/cevr/default.asp . 2006. 12-11-2006. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Research proposal
02OCT2013 
Page 20 20
 
 
83. DAMOCLES Study Group. A proposed charter for clinical trial data monitoring committees: 
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383. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
APPENDIX 1 
 
HOME OXYGEN THERAPY  IN COPD AT THE QUEBEC CITY AREA RESPIRATORY 
HOME CARE PROGRAM: RESULTS OF A PRACTICE REVIEW AND APPRAISAL 
Laurence Beaulieu-Genest, Sylvie Martin MSc, Yves Lacasse MD, MSc. Centre de recherche, 
Centre de Pneumologie, Hôpital Laval, Institut universitaire de cardiologie et de pneumologie de 
l’Université Laval, Québec, Canada. 
Background : Sleep-related oxygen desaturation is considered by many physicians as an indication of 
providing nocturnal oxygen therapy in patients with severe chronic obstructive pulmonary disease 
(COPD) who would not otherwise quality for continuous oxygen therapy (i.e., oxygen therapy provided 
for at least 15-18 hours a day).  Although current evidence from two randomized controlled trials does 
not support its prescription, nocturnal oxygen therapy is covered by the Quebec medical insurance 
program.  The proportion of patients with COPD receiving home oxygen for nocturnal utilization only is 
unknown. 
Objectives:  (1) To determine, among the patients with a primary diagnosis of COPD receiving oxygen 
therapy through a specialized respiratory home care program, the proportion of patients on nocturnal 
oxygen therapy only vs. those on continuous oxygen therapy; (2) to investigate the appropriateness of 
home oxygen prescriptions. 
Methods: This study took place at the Quebec City area’s respiratory home care program.   This 
program is funded by the Quebec universal medical insurance plan and delivers home care (mainly 
home oxygen therapy and related services) to registered patients with any chronic lung disease.  We 
reviewed the chart of all patients with a primary diagnosis of COPD registered to the program as of 
September 1st 2006.  The following information was extracted: (1) clinical characteristics, including 
gender, age, FEV1, FEV1/FVC, and the date of prescription of oxygen therapy; (2) whether the patients 
was receiving at the time of the study nocturnal oxygen therapy alone or continuous oxygen therapy. 
For those on nocturnal oxygen therapy alone, we noted the results of the nocturnal pulse oximetry that 
lead to this prescription, and whether nocturnal oxygen therapy was preceded by a course of continuous 
oxygen therapy.  For those on continuous oxygen therapy, we noted the results of the arterial blood gas 
that lead to this prescription, the clinical circumstances in which oxygen therapy was initiated (e.g., 
following an exacerbation of COPD or following a slow decline in lung function that characterizes the 
natural course of the disease), and whether continuous oxygen therapy was preceded by a course of 
nocturnal oxygen therapy. 
Results: As of September 1st  2006, 364 patients with a primary diagnosis of COPD were receiving 
oxygen therapy through our respiratory home care program.  74 (20%) were receiving home oxygen for 
nocturnal utilization only; the other 290 patients were on continuous oxygen therapy.  Table 1 compares 
the clinical characteristics of the patients on continuous oxygen therapy vs. those on nocturnal oxygen 
therapy. On average, patients on CONT-O2 had more severe disease than those on N-O2. 
Continuous oxygen therapy (n = 290): Information on the initiation of continuous oxygen therapy was 
available in 278 of the 290 patients (96%).  Continuous oxygen therapy was initiated in the course of an 
acute exacerbation of COPD in 189 (68%) of them and was preceded by a course of nocturnal oxygen 
therapy in 19%.  Following the initial prescription, the indication of continuous oxygen therapy was 
ascertained during a follow-up visit in 152 of these 189 patients (80%).  This reevaluation took place 61 
days (median) following the initial prescription.  Upon reevaluation, mean pO2 was 51 mmHg (SD: 5) 
and the mean pCO2 was 50 mmHg (SD: 9 mmHg).  The prescription of continuous oxygen therapy was 
inappropriate (i.e., pO2  60 mmHg) in 5 of the 269 patients (2%) for whom baseline arterial pO2 was 
available. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
Prescription of nocturnal oxygen therapy (n = 74):  Nocturnal oxygen therapy was preceded by a course 
of continuous oxygen therapy in 34 patients (46%).  Information on the initiation of nocturnal oxygen 
therapy was available in 61 patients (82%).   According to the most accepted definition of “significant 
nocturnal oxygen desaturation”, the prescription of nocturnal oxygen therapy was inappropriate in 4 of the 
61 patients (7%) for whom baseline nocturnal oximetry results were available. 
Conclusions: Although the benefits of nocturnal oxygen therapy have yet to be confirmed, 20% of the 
patients with a primary diagnosis of COPD receiving oxygen therapy through our respiratory home care 
program were receiving home oxygen for nocturnal utilization only.  Most prescriptions meet the current 
guidelines of home oxygen therapy.  The most important area for further improvement is the systematic 
reevaluation of patients following the initial prescription of continuous oxygen therapy in the course of an 
acute exacerbation of the disease. 
 
Table 1.   Nocturnal vs. continuous oxygen therapy in COPD at the Quebec City Respiratory Home 
                  Care Program                                                                                                                              
Nocturnal oxygen 
Continuous 
P 
  
therapy  
oxygen therapy  
 
 
Number of patients 
74 
290 
 
 
Age, mean (SD) 
74.3 (9.9) 
74.6 (8.9) 
 
0.8 
 
Gender (male, n, %) 
41.9% 
44.8% 
 
0.4 
 
FEV1 % predicted, mean (SD) 
47.4 (17.7) 
37.6 (15.3) 
 
 0.0001
 
FEV1/FVC, mean (SD) 
59.2 (17.6) 
48.2 (15.3) 
 
0.0001 
 
Time (number of months) since the introduction 
of therapy (as of September 1, 2006), mean (SD) 
22.8 (25.9) 
31.5 (31.3) 
 
0.02 

Multi-center randomized trial ofnocturnal oxygen therapy in chronic obstructive pulmonary disease- The
International Noctumal Oxygen (INOX) trial. 
Lacasse, Yves 
020CT2013 
Appendix to protocol
 
 
L
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal 
APPENDIX2 
 
 
 
 
 
 
ORIGINAL  ARTICLE 
 
 
 
Nocturnal oxygen therapy  in patients with 
chronic obstructive pulmona ry disease: A 
survey of Canadian  respirologists 
 
Yves Lacasse MD MSc,Frédéric Sériès MD,Sylvie Martin MSc, François Maltais MD 
 
 
 
Y Lacasse, F Sériès, S Martin, F  Maltais.  Nocturnal oxygen 
therapy  in   patient   wi th   chronic  obstr uc tive   pul mo nary 
discasc: A  survey of  Canadi.an  rcspirologists.  Can   Hespir   J 
2007;14(6):343-348. 
 
BACKG ROUND:Currcnt evidence de-.cs ncJt dcorlr suppôrr the pro· 
'rision of noctuma1 O'X)•gcn t.hctclpy in p-1-u-ienrs wi rh chronic obstructivt: 
pulmonary  discaso  (COPD)  who  desawrare   during  slcep  but who 
would not orhcrwi<e qualify for long-tcrm oxygen therJpy (LTOT). 
OBJECTl VES:T,,characrerize the perception and cHruca!practicc 
of Canadian respîrologl.sts regarding  the indicatloru and  pro;cription 
of noctumal oxygcn   rherap\' in  COPO, and   to  determine what 
Canadi.:m  respirologists con.sider  an  important rreaunent effect  of 
nocturnal oxygt!'n therapy in a randomi:ed, pl:.J.cebo-controllcù trial. 
METHODS: A mail survey of allrhe rcspirologl>t:s rcgistcrcd  ln the 
2006 Canadian Medical Directory was conducred. 
RESULTS:A  rotai of 543 physidans were surveyed. The responsc rate 
was 60%,  and  99% of the  respondents  indicarcd  thar the  problem of 
noctuml oxygen desa.tura.tion is clinically  relevant.  Eighty·rwo  per 
cent inrerpret  oximetry tracings thcmsdves, and 87% have acce:>.'i w a 
•lecp  bboratory.  Fony-rwo p<r cent  bdreve that  ali COPD patients 
with significant n..x:rutnal de&1turation should have a polysomnogr(l - 
phy ro rule out slccp apnen, and 41% would pr<scnbe noctumal oxygen 
th rapy  to active .smuL:. rs. Assuming a ri.5k of dearh  or progrcssim  to 
LTOT of 40% ovcr a three-yenr pcriod, the respirologisr:s indic  tcd that 
to declare  noctumal  oxygen  chtrapy effec.!:ivc in reducing 1he wtc of 
ftt41jor dinical events in <l dinical  trial, the  minimal ah.,._)lute ri.sk dir 
fcr:ence of death or progrcs.,;; ion to LTOT bc.tween oxygcn and room air 
breathing should be 14%. 
CONCLUSlONS:  Canodian  respirologists  are  intcrcsred   in  the 
issue of noctumal oKygcn dcsaturation in COPD. There is variation 
in dinica l rract"ices among Canadian respirologist,;;  in severdl aspects 
of the  management of this problem. 
 
Key  Words:COI'D; Mail questionnaire; Oxygen the.apy; Survey 
 
ong-rerm oxygm therapy (LTOT) is che on ly component of 
the  management of chronic  obst ructive pulmonary discase 
(COPD)  thar  im proves surviva l in patients  with severe day- 
cime hypoxemia (defincd as an arterial oxygen prcs.;ure (Pa0 ] 
2 
measured in the stable srate of 55 mmHg or lower, or i n the 
range of 56 mmHg to 59 mml-lg when clinicat evidence of pul - 
monary   hypertension  or   polycythemia   are   nC>ted) ( 1,2). 
Severa!srudies (3- 11) have demclnstrnted oxygen Jcsaturation 
durîng sleep in patients with COPD. The carlicsc stud ies thar 
described  this  phenomenon  included  patients  with  marked 
L'oxygénothérapie  nocturne chez les personnes 
attein tes d 'une  maladie pulmonaire obstructive 
chronique  : une enquête auprès des 
pneumologues canadiens 
 
HISTORIQUE : Lt·s données probantes C0uf',mrcs. n'étayent paclaire· 
ment   l'administrll.t.ion  d 'o:xygénothérarie  nocwrne- chez  les  pet$0nnes 
auéintt"s d'une maladie  pulmona ire bh tnx:tlve chronique (MPOC) qui 
déS<lturcnr  pendam  leur  50mmetl ma is qui   ne  .seraient  p,1s  a utrement 
OOmissiblcs à une oxygénothérapie à long terme  (OTIT). 
OBJECTlFS : Car::tctérber la pe.rccrtion et la pratique clinique des pneu- 
mologues  canad1enau  sujet   des   indications     et  de  la  prcsçription 
d'ox)·génochémpi!! nocturne en cas de MP()C  er Jétenniner cc qules 
pncumok.gues c:m.".ldi.t:ns considérct'Jit>nt  comme  un effet important  du 
trairemenr par oxy é-noth  rapit'  nocrurnc dans  le cadre  d 'un  essai  aléa 
toi re contrôlé contre rlaçebo. 
{ÉTHODOLOGI E :Les autems ont mené une enquête postale auprès 
de  tous  les pneumologuinsc::riu dm  le Canadian Medical DirccrO'ry de 
2006. 
RÉSULTATS : Au  torill, 543 méJ ,.'Cins  ont  étsondé. Le tau x de 
r pvll$e émit  de 60  %, er 99% des  réJXIndams ont  indiqué  que  le prob-- 
lème  de désl=louation  noctumc en oxygène érait  pcrtincm d'un poinc de 
vue clinique. Qmme- vingt·dt•ux  pour cent interpréta ient  t"ux·m me5  le 
1!1teé  d'oxymétrie. ct  87 % avaient accès à un  bbornt0irc  du  wmmcil. 
Qunra.mc.-deux pour cent étaient d'avis que toute:r. les pe nnes attcimes 
dt" MPC.X::: présemam une  import.ante dsatutation  nocturne!  devroièm 
::;u ir une  polysonm0graphie pour  &:anet  la possibilité d'a pnée  d u :som 
meil, N 41 % presc:.rira11:nt une ('x ygénothémpie nocturne aux iumeun 
actifs.  En  rostulam un  risque  de dé.c:è.s  ou  d'évolution vers ronT de 
40 %  sur  trois  aru,   lt$  pneumologues ont   indiqué   qlle  pour  déclarer 
l'ox:ygénothéri pie nocturne e:ftÎC.:'lC<! à réduire le taux d'événèmenu clin· 
iques majeurs cl<JOJ!._, cadre d'un  essai cl inique,  L,_  différence minima le de 
riSo.Jue absolu  de  décès  ou  d "évolu tion  vers  l'OTLT emre la respiration 
d'o).')'gène et C("IIC d'air ambiant devnüt $'élever à 14 %. 
CONCLUSIONS : Les pneumologues canadit>ns .s'intéressent à la ques· 
tion  de l'oxygén01hérnpie nocturne:  en cas de  MPCX::. On  rem."lfque une 
varitaion de la pratique c:linique des pneumolow;eca.n."ldicm à l'égard de 
divers alpects de la prise en chrge de ce problème. 
 
day time hypoxemia qualifying for LTOT Conventional LTOT, 
gi""n  15 h/day to 18 h/day, compulsorily includes sleep cime 
and   rherefore  corrects  slecp-relared   hypoxemia.   However, 
slcep-related oxygcn desatumtion  oftcn occurs in patients  not 
qualifying for LTOT Slcep-rclaœd oxygen desaturat ion is con- 
sidercd by many physicians os an ind ication for providing noc- 
tumal  oxygen  therapy  in  patients  who  would  not  otherwise 
qualif·; Îor LTOT  This  perccived  indication  stems from  the 
suggestion that  thnatu ral progression of COPD  to  its  end 
stages of chtonie  pulononary hypertension,  severe h·;poxemia, 
Centre de recherche, Hôpical La.'<ll, lnsti<ut uniwrsitaire de cardiologie et de pneumologte de l'Uni<•ersité Laval , Saince-Foy, Québec 
Corre.<P<mdence: Dr YŒs Lacasse, Centre de l'neumologte, Hôpiwl Lat-al, 2725 Chemm Sainte-Foy, Sainte-PO)·, Québec GJV 405 . 
Telephone 418-656-4747, fax 418-656-4762, e-mail Yved.<>casse@med.ulaval ca 
 
Can Respir J Vol 14 No 6 September 2007 
C>2007 Pulsu.s Group lnc.  Ail richrs  reserved 
343 

Multi-center randomized trial ofnocturnal oxygen therapy in chronic obstructive pulmonary disease- The
International Noctumal Oxygen (INOX) trial. 
Lacasse, Yves 
020CT2013 
Appendix to protocol
 
 
Amount requested in year 1 
$2 039 554 
Appendices to Research proposal 
 
 
 
 
 
lacasse et al 
 
 
righr hearr failure and dearh  is dependent  on  the severity of 
desaruration oc.:urring during sleep (12,13). 
Dcspite the  lack of clear  guidance  by scicntific  societies 
regarding the indications for and use of noctumal oxygcn. ther- 
apy in COPD  patients not qualifying for conventional LTOT, 
a number of patients are curremly  treattd  with nocrurna!oxy- 
gen (\4)- This is occurring even after two small randomized, 
controlled  trials (!5,16) and their meta-analysis {17)  do not 
clearly support  this clinical  pr; cticc. Furrher re;earch  is war- 
ranted in this area. 
Wc report rhe resulrs of a mail survey of Canadian  respirol- 
ogi.sts thar was conductetl  with the primary objective of char- 
acterizing their perception  and clinicat  practice regard ing the 
indications  and prescription  of  nocturnal  oxygen  therapy  in 
patienL• with COPD. Our secondai)· objecti·,e was ro deter- 
mine what Canadian  re:;pirologisrs consider as an  important 
ueatment effcct of nocnJmal  oxygen rherapy in  a  placebo· ( 
rù0m air) controllecl clin ica! trial. The  present stuc! y is ns a n 
important prdiminary step in our planning of a 03tional mul- 
ticen tre,  randomized,  conuollcd  trial  of  oxygen  therapy  in 
patients wirh COPD. in which the primary outcomc is a corn· 
posite of aU-cause mortality or progression to LTOT. 
 
METHODS 
 
it to he dtnic:ally effcctivcr'). The  second  question  direcrly 
clicited a numher needed ro treat {NNT) {"To considcr noc- 
tuma l oxygcn  therapv  effective  in  patients  with COPD, to 
how many patients would you he willing ro adminisrer noctur- 
nal oxygen to prevenr one patient from a ma jor clin ica] event 
{ie, death or progression to LTOT) over a 3-yea.r periodr'). 
ln  the final secuon  of the questionnaire,  the  respondents 
were invited to infonn the authors about their pott·nrial interest 
in participa ting in a fuuJte nmdornizcd trial of noctumal oxygen 
ther:•py in COPD patients. The French version of the question- 
naire was pilot-te>ted on five respirologi.sts and  translated  into 
English after mod ifications and  clarifications were made. Five 
minutes were sufficient to compl ete the qucsdonnaire. 
 
Survey 
The survey was conductcd  in April and May 2006 accord ing to 
the  'total design  method'  dts·cribed  hy Dillmao  {20). Ea ch 
re.pirologist was maHe:d a package  containing  a cover lerter. a 
questionnaire  in his/hcr languag.: {French or  English) and  a 
prcpaid rcpl y envelopt'. Each questionnaire was numbcred and 
coJed  for identification, and  to protec:t confidentiality. This 
fltst shipping was then  foltowed after one week by a reminder 
postcard. Four wçeks larer, those who had not responded to the 
initial question na i re were sent a second package that was idcnr 
Study  population 
A  total of 543 respiro!ogists who wcre registereJ  in the 2006 
Canadian M edical Directory, which lisrs more than 90% of the 
physicians currcntly licensed in the country, were surveyed. 
 
Questionnaire 
The  mail survey was orga nized into four sections. The  first 
section  was designee! to col!ect general information about the 
respondents,  i ncluding sex,  year of graduation, clin ica!ex pe- 
rience  with  the  management of COPD, and  thcir  involve· 
ment  in  the  org.,nization  and/or  delivery  of  home  ox ygen 
thcrapy services in Ù1ci r area. The second section  related  to 
the diagnosis ;md treatment of nocturna l desaruratlon.ln th is 
section,  the questionnaire includcd four short scenarios to 
examine   the   perceivcd    i nd ica tions  for   nocturna l  home 
oximerry in specifie dinîcl circurnsrances. 
The  third  sect ion of  the questionnaire  was to determine 
what Canadinn  t<'Spirologists consider as a minimal important 
treatmenr effect of noctumal oxygen  therapy on  morrality or 
disease progression. Such information  has importa nt implica- 
tion> for sample-size calculation  in randomizcd trials {18). The 
followi ng background information  was provided: 
Although  nocru rna!  oxygen   is  often   prescr ibed   in 
patients wirh COPD,  the  magnitude  of its treatmenc  efiect 
( if any)  rem a ins uoknown. From the  curr  nr  lirerature,  we 
k now tha t, ovcr a three-year period:  the mortaliry of pa ricots 
with moderare-to-severe COPO not qualify ing for LTOT but 
who  desatu race overn ight  is about  20%; and  an addit iona l 
20% will be ptescribed  LTOT became  of disea>e progression. 
Therefore, the threc- year major clinica l event  rare (i ncluding 
progression  to severe  hypoxaemia   nece>5ira ring  LTOT  nr 
dea th)  i n this group of patients is roughh:40%. 
TI1e supp()rtiog  refcrencs {16,19) werc  not citcd  ln  the 
questionnaire. The  minimal  imponant difference  was deter 
mined  using two differen t questions. The  fim  one  addressed 
tical  to the  first one, excert  for the  cover lettcr  mcntioning 
thar theit questionnaire had not yet been received. 
 
Statistics 
Response rate:The response rate was calcu lated as the ratio of 
analyzable responses  over  the  n umber of eligible  physicians 
thar were reached (21): 
 
Response rate .oc 
Number of respondents wntributing_to Lhe anal)-sfs 
Numbt>r of qut>. st fonn.aires sent- (Nonehgiblc -t Nc•nteach.lble) 
 
Physicians who ret urne-cl their questionnaire indicaring th3t 
they do not see patients presemi ng with COPD  in their prnc· 
tice were designared 'noneligible'. Physicianwhose first pack- 
agc::   was  rcturned   to  us  werc  designatcd  'non reachablt"'. 
Newfoundland  and  Labrador, Nova  Scotia,   Pr ince  Edward 
Island  and  New  Bruns wick were ana l yzed as  Ù>e   'Atlantic 
provinces',  a nd Alberta, Saskatchewan and  Manitoba  as the 
'Prai ries'. The other  provinces (Ontario, Quebec  and  British 
Columbia)  were analyzed scpamtdy. A  respon;e rate of 60% 
was predicted a priori (21). 
A n al ysis: Dcscrirtive sraristics (proportions and  means ± SDs 
when appropriate)  were usetl to characterize the  respondents 
and to report the rcsul ts of tht! survey. For each respondenr, the 
absolute risk difference corresponding  to the  minimal  lmpor· 
tant  difference  in  ma jor event  rate  betw"cn  trca ted  paricn rs 
and   umreared   patients   was  calcu latcd  by  subtractiog  the 
J cxpccted evem  ra re in the t.teared group (tlicited by the ques- 
tionnaire)  from  the  esrimated  event   rate  in  the  unucated 
group {which was assumee! tn be 40%). From this absolure risk 
difference,  the corresponding NNT was compur ed {computed 
NNT1/absolure  risk difference).  Finally,  the  concordance 
between the computed NNT and th<, dicited N NT usi ng the 
imradass correlation coelticient was ex:mlined {22). 
the issue of bencfit of  nocnJrnal oxygen in terrns of absolute 
risk reduction {"To what proportion would you like to see noc- 
 
Rcsponden rs 
RESULTS 
tu rnal oxygen therapy decrease this event rate before declaring 
 
344 
Fivc hundred forty·thrce re>1Jlrologists were sem the que,tion- 
naire, and 332 replied. Of  th se  respondcnts,  280 comrleted 
 
Can Respir J Vol 14 No 6 September 2007 

020CT2013 
Appendix to protocol
Multi-center  randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease - The
International  Noctumal  Oxygen (INOX) trial. 
Lacasse, Yves 
Amount requested in year 1 - $2 039 554 
Appendices to Research proposal
 
 
 
 
 
 
 
Nocturnaloxygen in COPD 
 
TABLE 1 
Perceived indications of nocturnal home oximetry i n 
specifie clinical circumstances (n=276) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure  1) Definittan of 'significan< noe<umal oxygen  desaturarion' 
(ll 5 resporulenr.s; four owliers do not appear 011 the graph) expressed 
in terniS of perunrage of the rewrding  lime spent below a git<en rhresh· 
old saturation. Sa01Arrerial oxygen saU<rarion 
 
the questionnaire and 52 indicated thar they are not involved 
 
 
Clinicalscenarlo 
Scenario #1 
Mt W is a 63-year-o!d patnt with severe chronic 
obstructive pulmonary disease  (COPO). He has been 
stable during the pre'lious year. His resting oxygen 
saturation is 93%, 
Scenario #2 
M(s X is a patient with physical signs of right l'leart 
failure who otherwise does not quarify for long-term 
oxygen therapy 
Scenario  #3 
Mrs Y was hospitalîzed two months aga for an acute 
exacerbation of COPO tha! was complicated by 
severe hypoxemia. She then left the hospital with a 
new prescription of home oxygen. Upon re-evaluation, 
her resting Pa02 (at room air) is now 65 mmHg. 
Scenario #4 
Mr Z is a 74 year.-old patient with severe COPD 
(FEV1, 36% pred•cted) who snores and complains 
or mild daytime sleepiness. 
Number (%) of 
respondents who 
would request a 
noctumaloximatry 
 
48 (17.4) 
 
 
 
 
269 (97.5) 
 
 
 
138 (50.0) 
 
 
 
 
269 (97.5) 
in  the care  of patients  wirh COPD.  Twenty-three  packages 
were retumed  by the  post office a<  undeliverable. Therefore, 
the  response rate among potentia lly eligible respondenrs was .. 
(332-52)/(543-[52+23]), or 60%. 
Ali  the  regions  of  the  country   wcre  represented,  with 
response rares ranging from 80% in rhe Atlantic  provinces ro 
49% in the Prairies. Twenry-three per cent of the respondents 
were female.  On  average,  the  rcspondents  were in  clinicat 
prncrice for 23±9 years. A significant proportion of the respon- 
dcnrs' clinical  pr-.lctice  ws dedicated  to  the  care of patients 
wi rh COPD  (mean 30±17%). One  hundred fiftrcspirologists 
(54%)  indicated  that  they  are involved  in the organization 
and/or delivcry of home oxygen rhempy in their arca. 
 
Diagnosis and !rearment of nocrurnal  desaturation 
Only four respondents (1%)  indicatcd thar the problem of 
nocturnal  oxygcn desaturati<'n in pat ients with COPD should 
not be considered.These rcspondents were insrructed not ro go 
furrher in the questionna ire and to retum  it as is. 
Among the other  276 resJX>ndenrs, 87% indicated rha t they 
have already prescri bed noctumal ox)·gen; 97% have access to 
pulse oximerers, and 82%  interpret  oximctry  t:racings them- 
selves. ln addition,  87%  of the  respondenrs have  access to a 
sleep laborarory  in  their insti tution.  For 42% of  the  rcspon· 
dents, a full sleep srudy was dcemed  ncces.<ary  in ali cases to 
rule Oll t sleer  apnea. Fifty-scven per cent of the respondents 
indicated thar one abnormal rccording is Sllfficimt to prescribe 
n octumal  oxygcn; two abnonnal  rewrdings  arc neœssary for 
35% ,,(the respondcnrs. Forey-one percent of the respondcn ts 
would prescribe home oxygen (either LTOT or noctumal oxy- 
gen only) co acti,,e smokers. 
The question  related  to the definition  of 'significant  noc- 
turnal   oxygen   desaturation' genera ted   a   wide  range   of 
responses. The  vast majority  (95%)  indicated  thar  the  time 
spent below a given threshold  is an important factor def in ing 
noctumal oxygen desaturation. However, bot h the  time and 
 
Gan Respir J Vol14 No 6 September  2007 
FEV1 Forced ex.piratory volume in 1 s; Pa02 Arl&n8J oxygen ptessure 
 
 
the   threshold   varied   considerably  among  respondents 
(Figure 1 ). Approximately one-third of the respondents ( 34%) 
also considered the avewgc saturation  over the entire  record- 
ing rime to be important. The average saturation  (88±2%)  was 
quite sinülar  among  respondents  (n=90). Fin ally, the lowesc 
snwra tion (79±5%)  rcached duri ng the night was aL>o impor- 
tant  for 25% of the  rcspondems  (n =62). Sixry-rhree  respon- 
denrs  idemificd  othr facto" defining  'significant  nocrumal 
dcsatumtion', the most frequent  bei ng pol ycythemi"· cor pul- 
monole, symptoms of lefr heart fa il ure at nighr, ventr icular car- 
diac arrhythmias and unstable ischemie hcart disease. 
The clinical scenarios and the associared rcsponses are pre- 
senter! in :rable 1. Clearly, the respondents would not screen for 
noctumal  oxygen desaturation in patients wi th stahlc  COPD 
(scenario  #l). Physical signs of  right  heart  failure  w irhour 
severe dayt ime hypoxemia would prom pt most responden ts ro 
look for noctumal  oxygen dc:saturation (scen;uio #2).The find- 
ing of an adequate Pa01at the time of re-evalua tion, following 
an acure exacerbation  complicmed  by severe hypoxemia, was 
seen as an  indication  of looking for noctumal  desaruration  in 
on·half of  the  respondcnts  (scenano  •J ). Finally, the  vast 
m;jority of respondcnts wou Id look for slep apnca even in eid- 
er!y patients  with severe COPD  (scenar io #4). 
 
Determination of the  m inin1al cli nicall y important  difference 
The absülute risk clifferenœ considered as m i ni mal to declare 
noctumal   oxygen  rhetnpy effective  in  rcducing  the  ra re oi 
major clinical  events compared  with room air breathing  was 
14±6%.  The  mean  compured  NNT  was 9. '\1.-'hen  directly 
elicited  by the questionnai re, the mean NNT  was 13±12. Nn 
concordance  was found between the computed  NNT and  the 
NNT directly el ici red hy the quest ionnaire (i ntraclass correla- 
tion coefficient of 0.0; Figure 2). 
 
345 

020CT2013 
Appendix to protocol
Multi-center  randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease - The
International  Noctumal  Oxygen (INOX) trial. 
Lacasse, Yves 
 
 
4)
15
.. 
Amount requested in year 1 
$2 039 554 
Appendices to Research proposal 
 
 
 
 
 
Lacasse et al 
 
 
 
50 
45 
40 
z
1- z 35 
"C    30 
:; 25 
20 
0 
(.) 
10 
5 
0 
0    5   10  15  20  25  30  35  40  45  50 
Elicited NNT 
Figure 2) Uu:k  of concordance  bertvw>  the COmf)uted number nedeà 
w treat (NNT) and  che elicired  NI'IT 
 
 
lnterest in participating  in a future  randomizcd trial 
One  hundred  cight  respondcnts  (39%)  from  ali  regions of 
Canada  indicatcd  thar they would be interested  in participar- 
ing  in  a  mndomized  trial  of  noctumal   oxygen  therapy  in 
patients with COPD. 
 
DISCUSSION 
The response rare wc obtained (60%)  was typical of physicians' 
reply ro mailed survey,, which  usually "''erages  50% to 55% 
(21). We atremptcd  10 investigate the potential for nonre- 
spondent  bias by makmg a priori predictions  on the response 
rate, and  by examining  the  representation   in  the survey of 
physiciam  from ali  the  regions  in  the  country. The ovemll 
response mte  met our a  priori  prediction. Also, ali  pans  of 
Canada  were rerrcsented  in the survey. 
Why should respirologisrs be inreresred in nocturnal  oxy- 
gen desaturarion!COPD clearly represents a significant  bur- 
den of health care systems wherevcr it has been assessd  (23). 
Home oxygcn th rapy comes in second place (on!y after hospi- 
talizarions) among  the  most expensive  healrh  carc  resourccs 
for COPD (24). ln the Canadian  cohort of the Confronting 
COPD s urvey (24)  (3265 individuals; mean age of 63 years; 
44% female), oucpatient  treatment  for COPD  accounted  for 
over 30% of tOtal direct cosr.s, the majority of which  was for 
home oxygcn therapy.Overall, home oxygen rherapy accounted 
for  almost  20% of the entite  annual  direct  costs for COPD 
(24).  Informai surveys among respiratory home care progmms i 
n Qucbec  indicare  thar 15%  ro 20% of  those who  receivc 
home oxygen therapy thmugh thesc rrograms have becn pre- 
scribed  oxygcn for noctumal   use only. Given   th.c  resourccs 
allocaced to noct:umal oxygen rherapy, its prescription should 
therefore  be just ifiable by dcmonstr.ning 8n improvement  in 
clinicat outcomes other than the mere correction of nocturnal 
oxygen desaruration. 
1-Iowever, the current evidence thar noctumal  oxygen ther· 
apy prolo•.gs survival cornes only from the indirect comparison 
of the  resulrs of the  British Medical Research Council  Study 
(1)  with those of the Noctumal  Oxygen Therapy  Trial of the 
 
346 
TABLE 2 
Key elements of the upcoming Canadian Nocturnal 
Oxygen (CANOX) trial 
Study population 
Patients with chronic obstrucHve pu,monary disease fulfi!Ung the definition of 
nOdumal oxygen desaturation, ie, 30% or more of the recording time wfth 
transctrtaneous arterial oxygen saturation lowet than 90% on two consecutive 
tecordtngs. Patients with sleep apnea were excluded. 
Intervention 
Nocturnaloxygen therapy delivered overnight to allow the oxygen 
saturation to be h gher than 90%; placebo (room air ) delivered by a 
defective concentmtor (sham coneentrator). 
Outcome 
Composite of either aU-cause mortality or requirement for longrlerm oxygen 
therapy. 
Design 
Three-year multicentre, placebo-controlled, randomized trial. 
 
 
National   Heart,   Lung,  and  Blood Institut<  (2),  and   thesc 
resultapply on ly to severely hypoxemic pati nts wit·h COPD, 
ie, rhose with a diurnal  Pa02 of 55 mmi-Ig or lower. To date, 
only two randomized trials directly addrcssed the issue of noc- 
tumal oxygen therapy in patients wirh COPD  with significant 
nocrurnal oxygen desaturation  who wou ld not othcrwise qual- 
ify for LTOT  (15,16). The  recent  mew-analysis by Cranston 
er al ( t7) concluded  tha t nocturnal  oxygcn  has no effect on 
survival (pooled OR 0.97;95% Cl 0.41 to 2.31). 1-Iowever, the 
au thors did not comment on the lack of precision in the effect 
estirnatc. 
Among  the  recent  COPD  trearment  guidelines  (25-28). 
only the Canadian document (28} addressed the issue of noc- 
tumal oxygen therapy, al beit in vague terms. Two recent work- 
shops  of  the   National   Heatt.  Lung. and   Blood   l nsritutc 
identified  nocturnal  oxygen therapy as a research pr iority in 
COPD  (25,29).  This situation  stimulared  our  planning  of a 
randomized trial of nocturna l oxygcn therapy in pntien"with 
COPD,  the Canadian Nocturna l Oxygen (CANOX) tria l, in 
which the ultim ate ohjcctive wou ld be to examine thè effect of 
nücturnal oxygen  on mona lity and disease progression re\1uir· 
ing LTOT (Table 2). 
The design of a ranùomized controlled  trial of nocturnal 
oxyge.n  taises  important   methodological  p robl ems  in  the 
choice of the primai')' outcome. ln such a trial. wharever the 
treatrnent receiveù, the condition  of participants  may d terio- 
rate to the point  that LTOT is rcquired. This siruanon  is par- 
ticularly  problematic   because  LTOT  compulsorily  includes 
sleep rime (and therefore nocturnal oxygen therapy). LTOT 
would rhus represcnt an itnJXlttant contaminant and  a tlucat 
J to the validity of the trial. Therefore, a composite of morta liry 
or progression to LTOT would constitute the primary outcomc 
of the trial. The choice of a composi te outcome  requircs that 
its components are of sim ilar importance,  occur  with  similar 
frcquency and  have similar RR reduction  (JO). Whether dis- 
case progression requir ing LTOT has the same weight as dearh 
for  pat ients  with  severe  COPD  is d ebarable. Howevcr,  we 
know thar the prescription of LTOT is a marker of disease pro- 
gression and a srrong predicror ofmortality (31-33). l t is abo 
a:;,;ociated with poor funct iona l status, impaired quality of life 
and depression 04). Of nore, in a tr ia l by Chaouar et a l  (16), 
morrality and progression to LTOT wcre weil balanccd in pro- 
portion, and moved  in the same direction. 
 
Can Respir J Vol 14 No 6 September 2007 

020CT2013 
Appendix to protocol
Multi-center  randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease - The
International  Noctumal  Oxygen (INOX) trial. 
Lacasse, Yves 
 
 
.. 
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.. 
.. 
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Amount requested in year 1 = $2 039 554 
Appendices to Research proposal 
 
 
 
 
 
Nocturnaloxygen in COPO 
 
1000 
 
 
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900 
 
800 
 
700 
 
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500 
 
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4      6    8     10    12   14    16  18    20 
Change ln event rate Intervention - 
.. 
-  lt l!L I!!III!I,! !!, I!41   1    ltiJ@CJICf!O!II!Tl   l 
Figure   4)   Noccumal ox<mecry  trllClngs m  pauems wzch   chrontc 
ob,tructive  pulmonary disease not qunlifying for long-cerm uxygen ch,>r- 
a/)y. A Noccurnal OX)' gm desaturaunn (30% or more  of che recording 
rime wich an oxygen sa11;racion lower  chan 90%) with nonperilldical 
variarion in saHtrarion throughotu sleep. This tracing is nm - ltggescive 
of sleep apnea . B Ncx-ncmal oxygen desaturation with cydical changes 
in saturmion Sltggesting slee p a[me(l . S pO1Arrerial oxyg ..,.,t satuTation 
 
 
on the  basis of oximetry tracings only. Given the  l imited  access 
to d iagnostic facilities for pa tients  with  suspected sleep apnea 
in Canada (38), this argues  in favour  of a pragmaric approach 
for  the  inclusion of patie n ts in  the study on the basis of rhe 
prerest p robability of sleep apnea and  the  resulrs  of ox imetry 
                                                                                                                 
control groups, 
Figure  3) Sample sizes (number of >atients  peT group) required  to 
detecc absolute risk differences betu. en treated and uncreared  patients, 
tâch two-sided  signifù;ance level of 0.05  and varying study  powers 
(0.75, 0.85 and 0.95). The risk  of a major clinicat "'"'' in  che 
uncreated group i> assumed w be 40% 
 
 
The  resu lts of  our  survey  prov idcd  useh1l  informat ion  for 
the  planning of th e CANOX tria l. We wcre  particularll' intet· 
ested in detennining what  Canad ian  respirologists considc r as 
the minima l importantdiffcrenœ in major event rare (ie, mor- 
tality  or  progression   to LTOT)   bctween tmtreared patients 
(room air)  and  rreated  patients (noctumal oxygen). Our  find - 
ing  of a poor .concordance  berween   the  compu.red  NNT and 
thar  direct!y elici ted  by the  questionnaire was of  no surprise. 
Prcvious   studies   (21,35,36)  aIso  suggested   thar   physic ians' 
emhusiasm for therapy varies when the data are presented with 
the   NNT  compared  with  the  absol ute   r isk   reducti on. 
Assuming a major  eve nt  rate  of 40% in  the untreated group, 
we determ ined  that   221  patients per  group  were  need ed  to 
demonsrratc a 14% difference in evenc  rates  between the t\\'O 
study groups  (power  85%;  alpha  errer  5%,  two-sided) (37). If 
the sa mple si ze was inc reased  to 300 patients per group,  the dif- 
ference to be detected is 12%. Figure 3 i llumates th a r small 
change> in the d ifference  to be detccted have a hugc impact on 
the  needed  sample si ze. 
We clarified other componenrs of rhe CANOX trial's  prc•- 
rocol  from   the   results of  the   present survey.  The first  one 
relates to the diagnosis of sleep apnea  in patients with  severe 
COPD and   the   routine  use  of  polysomnography  i n  such 
patients. Approximately 60% of the  respondenrs would accept 
to confidently diagnose nocturna l oxygen  desaturarion alone 
 
Can Respir J Vol 14  No 6 Septem ber 2007 
tracings  (Figure 4). The second issue relates to th e inclusion of 
active smokers in  the  trial. Forty-one per cent of the  respon- 
dents  woukl prescr ibc  nocturnal ox ygen  therapy  to  acti ve 
smokers. Although Jess than  desirable (39),  this situat ion  is a 
rdlection of n1rrcnt practices i n Canada rhat  are nor about to 
cha nge. The currcm vcr.<ion of  the  srudy  protocol  docs  not 
exclude current smohrs from the triaL A srratificd ranJomiza- 
tion  process should be used to ensure thar smokets a re equally 
distributed in tre;oted and  untreat,-d patients. 
Fi nally, thar lOS respi rologisrs expresscd  thei r wilhngness ro 
participate i n a multkenr.re tri<1l of nocturnal ox ygen therapy is 
wry suppottive and ckarly demonsrrares the interest raised by 
the  problem   of  nocturna l  ox ygen  desmuration  in  COPD 
rariems, Our findi ng of variations in cli nical  prac rices in sev- 
era! aspec[S of the manage ment  of noctumaJ ox ygen desatura.. 
rion  is also an  i ndication thar further research is warranted, 
The  present survey   provided   important informati on  for  the 
planning of a na tiona l randomized, placebo-controllcd  t r ia l of 
nocrumal oxygen therapy in COPD. 
 
ACKNOWLEDGEMENT:  We thank   the   resrirologists   who 
tobk the ti mc to rcpl y ro our survey. 
 
REFERENCES 
L Long tcrm domioliary ox.rge-n  rhtmpy in cluonk hypoxic ("(lf 
pulmonal.: c0mplicating chronic bmnchitis  nd  emphyscma. 
Report cf the Mt•. dical Re&earch Council \Vorking Pany. L<tncet 
198!:L6Sl-6. 
. ContimK)us or nocwrnal ox ·ge-n thernp·in hypoxemk chronic 
ob5tructive l ung discase:.A cllni c.al trial.  Noctumal Oxygen 
Thcrapy TrialGroup.t\nnlncern Med 1980:93:391-8. 
3. l..eitch AG.Clancy  L), Legg.:n R), Tweedd,,lc  r, i);,wson P, Evan>  Ji. 
ArteriRI blood ga.) tt!nsi ons, hydrogcn  ion, and clecuœncephall'J,'l<lm 
duri ng sl :er in rat ients wîth chronic \'tntilatory failure. Thorax 
1976;31:730-5. 
 
347 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
APPENDIX 3 
 
PREVALENCE AND DETERMINANTS OF NOCTURNAL OXYGEN DESATURATION IN 
CHRONIC OBSTRUCTIVE PULMONARY DISEASE 
Yves Lacasse1  MD, MSc, Nada Vujovic-Zotovic2  MD, Roger Goldstein2  MB ChB, Jean Bourbeau3 
MD, MSc, Frédéric Sériès1  MD, Richard Lecours4  MD, Shawn Aaron5  MD, MSc, François Maltais1 
MD 
1Centre de recherche, Hôpital Laval, Institut universitaire de cardiologie et de pneumologie de 
l’Université Laval, Québec; 2West Park Hospital, Department of Medicine and Physical Therapy, 
University of Toronto; 3Montreal Thoracic Institute, McGill University, Montreal; 4Service de 
pneumologie, Centre hospitalier affilié de l’Hôtel-Dieu de Lévis, Lévis ; 5Ottawa Health Research 
Institute, University of Ottawa. 
Background: The proportion of patients with moderate/severe COPD not qualifying for long-term 
oxygen therapy (LTOT) who present nocturnal oxygen desaturations is not well characterized.   This 
statistic is of outmost importance in our planning of a randomized trial of nocturnal oxygen therapy in 
COPD (the International Nocturnal Oxygen – INOX - trial).  The feasibility of this trial as well as the 
resources allocation depend on the proportion of patients with moderate/severe COPD not qualifying 
for LTOT who present nocturnal oxygen desaturation. 
Objectives: To determine, in patients with moderate-to-severe COPD not qualifying for long-term 
oxygen therapy (LTOT), the proportion of nocturnal desaturators. 
Desing: Cross-sectional study. 
Setting: 5 clinical sites that are planning the INOX trial. 
Patients:  The inclusion (and exclusion) criteria for this pilot study were the same as those that will 
apply in the INOX trial.  Briefly, we included patients: (1) with a diagnosis of COPD supported by an 
history of past or current smoking and obstructive disease with an FEV1 < 50% predicted, an 
FEV1/FVC < 60% and a total lung capacity > 80% predicted; (2) with mild-to-moderate daytime 
hypoxemia with a daytime paO2 in the range of 56-69 mmHg; and (3) stable COPD at the time of the 
study, as demonstrated by no acute exacerbation and no change in the medication for at least 6 weeks 
before the enrollment in the study.  Preliminary data obtained from a small convenience sample of 
patients (n = 12) indicated that about 25% of the patients with moderate-to-severe COPD meeting these 
criteria are nocturnal desaturators (unpublished data).  We determined that a sample size of 128 patients 
is needed for the precision of the proportion of desaturators to be no more than  7.5% 
Measurements: Within 1 month of the first nocturnal oximetry, we obtained baseline clinical 
characteristics, pulmonary function tests (including spirometry, lung volumes and carbon monoxide 
diffusion capacity).  We measured arterial blood gases while patients were breathing at room air. 
Nocturnal  saturation  (SaO2)  monitoring  was  obtained  with  a  continuous  digital  recording  system 
(Nonin Medical Inc., Plymouth, MN, USA). For each patient, two oximetries were obtained over a 2- 
week period.  Patients were classified in 3 categories according to the same criteria that will apply in 
the INOX trial: (a) no nocturnal desaturation (i.e., < 30% of the recording time with an oxygen 
saturation < 90% on both oximetries); (b) nocturnal desaturation (i.e.,  30% of the recording time with 
an  oxygen  saturation  <  90%)  with  suspicion  of  associated  sleep  apnea  (i.e.,  cyclical  changes  in 
saturation in addition to the desaturations on either of the oximetries); (c) nocturnal desaturation (i.e., 
30% of the recording time with an oxygen saturation < 90%) without suspicion of associated sleep 
apnea  (i.e.,  steady  tracing  with  non-periodic  variation  in  saturation  throughout  sleep  on  both 
oximetries). 
Results:  128  patients  (62% male;  mean  age:  70;  SD:  8);  mean  FEV1%predicted:  37%;  SD:  11) 
contributed to the analysis.  The recording time with an oxygen saturation < 90% in both oximetries 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
was highly correlated (r = 0.84; p < 0.0001), indicating consistency in desaturation captured on 
consecutive oximetry recordings.  Fifty-one of the 128 patients were classified as nocturnal desaturators 
without suspicion of sleep apnea (40%; 95% confidence interval: 31 – 49).  These patients represent 
those eligible in the INOX trial.   In addition, 16 patients (13%) were classified as desaturators with 
suspicion of sleep apnea.  In the INOX trial, these patients may be submitted to polysomnography in 
order to rule out sleep apnea.   Baseline characteristics and results of physiological measures are 
compared in Table 1 and 2 respectively.  We found no significant difference in baseline characteristics 
or physiological measures among the 3 groups that could predict nocturnal desaturation without 
suspicion of sleep apnea, with the exception of body mass index.  The most significant predictor of 
nocturnal oxygen desaturation was baseline saturation measured at the opening of the oximeter (Table 
3). 
Conclusions: A significant proportion (40%) of patients with moderate-to-severe COPD not qualifying 
for LTOT has nocturnal oxygen desaturation without evidence of sleep apnea.   This phenomenon 
cannot be reliably predicted by any simple anthropometric or physiological measure. 
 
 Table 1: Baseline characteristics (n = 128)                                                                                                
Nocturnal 
desaturation 
without 
suspicion of 
sleep apnea 
Nocturnal 
desaturation 
with 
suspicion of 
sleep apnea 
 
 
 
 
No nocturnal 
desaturation 
  
(n = 51)  
(n = 16)  
(n = 61)  
P value   
 
Age 
68.4 (7.7) 
68.0 (8.6) 
71.0 (7.8) 
0.09 
Gender (% male) 
52.9 
75.0 
65.6 
0.2 
 
BMI 
 
24.9 (4.8) 
30.8 (6.4) 
24.3 (5.0) 
0.0007 
 
Current smokers (%) 
 
17.6 
18.8 
14.8 
0.9 
 
Pack-years 
 
49.5 (24.5) 
61.8 (30.3) 
48.9 (23.9) 
0.2 
 
Theophyline 
 
9.8% 
12.5% 
23.0% 
0.2 
 
Tiotropium 
 
82.4% 
68.8% 
83.6% 
0.4 
 
LABA 
 
92.2% 
87.5% 
83.6% 
0.4 
 
Inhaled steroids (ICS) 
 
62.7% 
62.5% 
65.6% 
0.9 
 
Combinations (LABA + ICS) 
 
45.1% 
50.0% 
50.8% 
0.8 
 
Prednisone 
 
5.9% 
6.3% 
4.9% 
1.0 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
Table 2 : Arterial blood gases and pulmonary function tests results (n = 128) 
Nocturnal 
desaturation 
without 
suspicion of 
sleep apnea 
Nocturnal 
desaturation 
with 
suspicion of 
sleep apnea 
 
 
 
 
No nocturnal 
desaturation 
  
(n = 51)  
(n = 16)  
(n = 61)  
P value   
 
pH 
7.4 (0.4) 
7.4 (0.03) 
7.4 (0.02) 
0.12 
 
pCO2 
42.6 (4.9) 
45.2 (5.9) 
42.1 (4.3) 
0.20 
pO2 
63.7 (4.1) 
65.2 (3.4) 
65.8 (2.9) 
0.03 
Hb 
144.5 (14.6) 
142.3 (9.5) 
146.1 (13.8) 
0.6 
 
FEV1 % 
35.3 (11.7) 
35.3 (11.8) 
35.5 (10.0) 
0.7 
 
FVC % 
80.0 (16.9) 
69.4 (21.6) 
78.8 (22.4) 
0.08 
 
FEV1 / FVC 
34.3 (10.6) 
42.5 (13.7) 
35.2 (9.5) 
0.05 
 
FRC % 
166.1 (31.3) 
151.3 (33.2) 
165.9 (35.7) 
0.4 
 
TLC % 
127.0 (18.3) 
116.4 (19.3) 
127.5 (22.9) 
0.2 
 
RV % 
193.3 (43.9) 
182.2 (52.6) 
192.9 (56.8) 
0.7 
 
DLCO % 
41.1 (13.2) 
56.4 (20.0) 
45.5 (16.7) 
0.03 
 
 
Table 3: Nocturnal oximetry results[1] (n = 128) 
Nocturnal 
desaturation 
without 
suspicion of 
sleep apnea 
 
 
Nocturnal 
desaturation 
with 
suspicion of 
sleep apnea 
 
 
 
 
 
 
No nocturnal 
desaturation 
  
(n = 51)  
(n = 16)  
(n = 61)  
P value   
 
Recording time (hours) 
7.5 (1.4) 
7.3 (1.1) 
7.4 (1.4) 
0.8 
 
Desaturation index 
5.4 (4.1) 
23.8 (16.0) 
5.5 (5.9) 
< 0.0001 
 
Baseline saturation 
88.6 (2.3) 
89.0 (3.6) 
92.0 (1.2) 
< 0.0001 
 
Average saturation 
85.8 (2.7) 
84.8 (3.3) 
89.0 (1.9) 
< 0.0001 
 
% recording time with saturation 90% 
60.6 (25.7) 
62.8 (24.6) 
10.4 (12.8 
< 0.0001 
 
 
 
1 Only the results of the second oximetry are shown. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
 
APPENDIX 4 
 
NOCTURNAL  OXIMETRY  ALONE  OR  POLYSOMNOGRAPHY  TO  RULE  OUT  SLEEP 
APNEA IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE?  A VALIDATION STUDY 
Yves Lacasse MD, SMc, François Maltais MD, Frédéric Sériès MD.  Centre de recherche, Centre de 
Pneumologie, Hôpital Laval, Institut universitaire de cardiologie et de pneumologie de l’Université 
Laval, Québec, Canada. 
Background :  Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are 
common conditions.  The combination of COPD and OSA is referred to as the “overlap syndrome”. 
We recently demonstrated that 40% of patients with COPD and moderate hypoxemia (daytime paO2 in 
the range of 56-69 mmHg) exhibit nocturnal oxygen desaturation.  Two different patterns of nocturnal 
oxygen desaturation are seen on oximetry tracings: (1) steady nocturnal desaturation with non-periodic 
variation  in  saturation  throughout  sleep;  and  (2)  nocturnal  desaturation  with  cyclical  changes  in 
saturation.   Typical tracings are shown in Appendix 11.   Whether the diagnosis or the exclusion of 
obstructive sleep apnea must rely on a laboratory or ambulatory polysomnography is uncertain. 
Objectives : To determine the accuracy of home nocturnal oximetry to distinguish between OSA and 
nocturnal oxygen desaturation alone in patients with moderate-to-severe COPD who exhibit significant 
nocturnal oxygen desaturation. 
Methods: This study involved, in a blind comparison of home nocturnal oximetry and laboratory 
polysomnography in patients with nocturnal oxygen desaturation.   Patients:  We conducted in 2006 a 
multi-centre cross-sectional study with the objective to determine, in an unselected population of 
patients with COPD and moderate daytime hypoxemia, the proportion of nocturnal oxygen desaturators 
and the predictors of this phenomenon.  Five clinical centres in Quebec and Ontario participated in this 
study that enrolled 128 patients.  Forty-nine (49) patients from Laval Hospital contributed to this 
analysis.   Among these 49 patients, 23 had significant nocturnal oxygen desaturation diagnosed by 
home oximetry alone.   Home oximetry: For the purpose of the cross-sectional study, we obtained 
continuous nocturnal saturation (SaO2) monitoring with a digital recording system (Nonin Medical Inc., 
Plymouth,  MN,  USA).    Recordings  of  at  least  4  hours  were  mandatory.    For  each  patient,  two 
oximetries were obtained over a maximal period of 2 weeks.  We defined “nocturnal desaturation” as 
30% of the recording time (time in bed) with a transcutaneous arterial oxygen saturation < 90%.  Each 
patient was then classified in one of 2 categories on the basis of 2 consecutive recordings, according to 
the recording time with an oxygen saturation < 90% along with the visual inspection of the printed 
report: (1) nocturnal desaturation without suspicion of associated sleep apnea (i.e., steady SaO2 tracing 
with  non-periodic  variation  in  saturation  throughout  sleep  on  either  of  the  oximetries);  and  (2) 
nocturnal desaturation with suspicion of associated sleep apnea (i.e., cyclical changes in saturation in 
addition to the stable desaturations on either of the oximetries).  All reports were reviewed by a sleep 
specialist (FS) with extensive experience and special interest in oximetry assessment for final patient 
classification. We recalled these 23 patients to obtain an in-lab polysomnography to validate our 
classification by home nocturnal oximetry alone. For the purpose of this validation study, we obtained 
an additional oximetry with the same system in order to ascertain the desaturation pattern of these 
patients.    Gold standard: polysomnography  : Within 2 weeks of the home nocturnal oximetry, each 
patient  underwent  a  polysomnographic  study.     The  polysomnographic  recordings  consisted  in 
continuous acquisition of electroencephalogram, electroocculogram, submental electromyogram, naso- 
oral airflow with thermistors, nasal pressure with nasal cannula), chest and abdominal movements with 
impedance 
plethysmography 
(RespitraceÆ, 
Ambulatory 
Monitoring 
Inc, 
Ardsley, 
NY), 
electrocardiogram, and breath sounds by means of two microphones connected to a calibrated sound 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
analyzer.  Sleep position was continuously assessed by the attending technician on the monitor of an 
infrared camera. All variables were digitally recorded (Sandman EliteTM system, Mallinckrotd, 
Kenilworth, NJ). Sleep and respiratory variables were scored according to standard criteria.   Sleep 
apnea was considered to be significant when the apnea/hypopnea index  15/h. 
Results: From the 23 patients identified as nocturnal desaturators in cross-sectional study, 18 were 
available for this study; 11 underwent an in-lab sleep study (Figure 1, next page).  Details of the results 
are provided in Table 1.   Upon reevaluation in the validation study, one patient (No. 9) had normal 
oximetry whereas she previously desaturated in the cross-sectional study.  Her sleep recording was 
normal.   This patient was excluded from further analysis. In the 10 other patients, the results of the 
home oximetry recordings were concordant with those of the cross-sectional study.  OSA was ruled out 
in the 5 patients who were classified as “nocturnal desaturators without suspicion of associated OSA”. 
In the 5 patients who were classified as “nocturnal desaturators with suspicion of OSA” on oximetry 
recordings, OSA was confirmed in 3 (Table 2). 
 
Table 1. Patients’ classification according to nocturnal oximetry and polysomnography 
 
 
Patient 
no. 
Classification in the 
cross-sectional study by 
oximetry alone 
Validation study 
Classification by 
oximetry 
 
 
Result of 
polysomnography 
1 
No OSA suspected 
No OSA suspected 
OSA - 
2 
No OSA suspected 
No OSA suspected 
OSA - 
3 
No OSA suspected 
No OSA suspected 
OSA - 
4 
No OSA suspected 
OSA suspected 
OSA - 
5 
No OSA suspected 
No OSA suspected 
OSA - 
6 
OSA suspected 
OSA suspected 
OSA + 
7 
OSA suspected 
OSA suspected 
OSA + 
8 
OSA suspected 
OSA suspected 
OSA + 
9 
No OSA suspected 
No significant desaturation 
OSA - 
10 
No OSA suspected 
No OSA suspected 
OSA - 
11 
OSA suspected 
OSA suspected 
OSA - 
 
Table 2.  Accuracy of home nocturnal oximetry to detect sleep apnea in COPD 
 
Polysomnography (gold standard) 
 
 
OSA 
No OSA 
Total 
Home nocturnal 
OSA suspected
3 
2 
5 
Oximetry 
No OSA suspected
0
5 
5
 
Total
3 
7 
10 
 
Conclusion : In patients with significant nocturnal oxygen desaturation, home nocturnal oximetry has 
high negative predictive value for the diagnosis of OSA : OSA may be ruled out in patients with 
oximetry tracings demonstrating significant nocturnal desaturation with non-periodic variation in 
saturation throughout sleep.  However, home nocturnal oximetry has a poor positive predictive value 
for the diagnosis of OSA. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
Figure 1. 
 
 
 
23  Patients with significant nocturnal oxygen desaturation in the cross-sectional study 
 
1  moved away 
2  were prescribed CONT-O2 
2  died 
 
18  Patients available for the validation study 
 
4  refusals 
3 exacerbations at the time of the study 
 
  11  Patients in the validation study  
 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
APPENDIX 5 
 
UTILITY SCORES IN PATIENTS WITH OXYGEN-DEPENDENT COPD 
Yves Lacasse MD, MSc, Sylvie Martin MSc, François Maltais MD. Centre de recherche, Centre de 
Pneumologie, Hôpital Laval, Institut universitaire de cardiologie et de pneumologie de l’Université 
Laval, Québec, Canada. 
Background :  The comparison of health-related quality of life among patients with different chronic 
health condition is essential to the prioritization of limited health resources from cost-effectiveness 
analyses.   To do so, utility measures use a preference-based or value-based approach to express the 
health-related quality of life of an individual using a single number. This number incorporates the overall 
assessment of health-related quality of life and the values attached to it. This number is usually between 0 
and 1. The two extreme values are anchored to specific states, most commonly death (0) and full health 
(1).   The utility of patients with oxygen-dependent chronic obstructive pulmonary disease (COPD) is 
unknown. 
Objectives: To determine the utility of patients with oxygen-dependent COPD. 
Design: Cross-sectional study. 
Patients: We surveyed patients with oxygen-dependent COPD registered at the Quebec City area 
Respiratory home care program.   This program is funded by the Quebec universal medical insurance 
plan and delivers home care (mainly home oxygen therapy and related services) to registered patients 
with any chronic lung disease.  Oxygen dependence was defined as severe hypoxemia (PaO2  55 
mmHg; OR PaO2  59 mmHg with clinical evidence of at least one of the following: (1) pulmonary 
hypertension; (2) right ventricular hypertrophy; (3) cor pulmonale; (4) hematocrit  55%1) requiring 
continuous oxygen therapy (CONT-O2, i.e., ≥ 18 hours per day). 
Measures: We used the SF-6D2, a preference-based single index derived from the SF-36. 
Results:  105 patients were surveyed; 3 did not provide complete SF-36 data.  The clinical characteristics 
of the 102 patients who did complete the SF-36 are summarized in Table 1.  The mean utility score was 
0.60 (SD: 0.11). Women (n = 43) and men (n = 59) had similar utility scores (0.59 vs. 0.61 respectively, p 
= 0.37).  For comparison, utility scores associated with several health conditions are provided in Table 2 
(below). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1  Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a 
clinical trial. Ann Intern Med 1980; 93: 391-398. 
2 Brazier J, Usherwood T, Harper R, et al. Deriving a preference-based single index from the UK SF-36 Health Survey. J Clin Epidemiol 
1998; 51: 1115-28. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
Characteristics 
(n = 102)
Gender 
59 males : 43 females
Age (years) 
71 (65 - 77)
Mean FEV1 (% pred.) 
34% (25 - 44)
Past medical history (number of major medical diagnoses, excluding
COPDb) 
0 (0 - 1)
Time since the introduction of continuous oxygen therapy (months)
19 (9 – 32)
Number of drug prescriptions 
7 (6 - 10)
Leaving with spouse 
73%
Table 1. Clinical characteristics of patientsa 
 
 
 
 
 
 
 
 
 
 
 
 
 
a For clarity and uniformity, results are presented (unless otherwise specified) as medians (interquartile range); 
b Six diagnostic categories were considered: heart failure, ischaemic heart disease, diabetes, stroke, musculoskeletal disease, 
and cancer. 
Interpretation: Health-related quality of life of patients with oxygen-depend COPD is severely impaired. 
The prescription of CONT-O2 is a critical step in the life of patients with severe COPD. 
Discussion: implication for the construction of the INOX trial’s composite outcome - an example 
from the cardiovascular literature: A composite outcome is an event that is considered to have occurred 
if one of several different events or outcomes is observed3.  Although a composite outcome may increase 
the event rate (and thus the statistical power) of the study, it may mislead if its components are of widely 
differing importance to patients, the number of events in its component of greater importance is small, or 
if the magnitude of effects differs markedly across its components4. 
Utility scores may be used to explore the extent to which components of composite outcomes in 
randomized controlled trials vary in importance to patients. In a systematic review of cardiovascular trials 
published in 2002-2003, Ferreira-Gonzalez and collaborators first developed a hierarchical categorization 
of importance to patients for the components end points included in the eligible studies5.  Published 
estimates of utility associated with the outcomes guided this process6.  Five categories were hence created 
(Table 2): death, critical, major, moderate and minor. 
Table 2.  Component outcomes by category of importance to patients 
 
End point 
Utility score (from 
Tengs and Wallace) 
I. Death 
0.0 
All cause mortality 
Mortality not otherwise defined 
Cardiac death not otherwise defined 
Cardiac death due to coronary heart disease not otherwise
defined 
II. Critical 
0.7 – 0.8 
Large myocardial infarction 
Stroke leaving permanent moderate deficit
Cardiac arrest followed by resuscitation manoeuvres
Dissecting or ruptured aortic aneurysm 
III. Major 
0.8 – 0.9 
Non-fatal myocardial infarction 
 
3 Meinert CL.  Clinical trials dictionary.  Baltimore : the Johns Hopkins Center for Clinical Trials; 1996. 
4 Montori VM, Permanyer-Miralda G, Ferreira-Gonzalez I, et al. Validity of composite end points in clinical trials. BMJ 2005; 330: 594-6. 
5 Ferreira-Gonzalez I, Busse JW, Heels-Ansdell D, et al.  Problems with the use of composite endpoints n cardiovascular trials: systematic 
review of randomised controlled trials.  BMJ. 2007; 334: 786. 
6 Tengs TO, Wallace A.  One thousand health-related quality of life estimates.  Med Care 2000; 38: 583-637. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
 
Stroke leaving permanent deficit, severity not defined 
Coronary artery bypass grafting 
Cerebrovascular event not otherwise defined
IV. Moderate 
0.9 – 0.95 
Coronary revascularisation not otherwise specified
Coronary revascularisation—angioplasty/stenting
Non-fatal angina needing hospital admission
Hospital admission not otherwise specified
V. Minor 
Non-fatal angina, not defined 
> 0.95 
Non-fatal arrhythmias, not otherwise specified
Dyspnoea, not otherwise defined 
Change in blood pressure 
To describe the gradient of importance to patients among the components end points, Ferreira-Gonzalez 
and collaborators considered a large gradient to be present if the composite outcome combined outcomes 
from categories I or II (fatal or critical) with outcomes from category V (minor).   They considered a 
moderate gradient to be present if the composite outcome combined outcomes from categories I or II (fatal 
or critical) with outcomes from category IV (moderate).  They assigned a minor (or absent) gradient to 
composite outcomes not included in the other two categories.  From 114 trials, only 14 (12%) included a 
composite outcome with either no gradient or minor gradient in importance to patients.  The pooled 
treatment effects of interventions on fatal and critical outcomes were similar.  The authors concluded that 
confident interpretation of composite outcomes requires small gradients of importance to patients and 
similar risk reduction across components. 
Conclusion: From this scheme of categorization and from the results of our study, the prescription of 
CONT-O2 would therefore be classified as “critical”.   The gradient of importance to patients between 
death and prescription of LTOT is minor.  The composite of death and requirement for CONT-O2 is 
appropriate. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
APPENDIX 6 
 
SYSTEMATIC REVIEW AND META-ANALYSIS OF NOCTURNAL OXYGEN THERAPY IN 
COPD 
Yves Lacasse, Sylvie Martin.  Centre de recherche, Centre de Pneumologie, Hôpital Laval, Institut 
universitaire de cardiologie et de pneumologie de l’Université Laval, Québec, Canada 
Background: A systematic review / meta-analysis of domiciliary oxygen in COPD was published in 
2005 in the Cochrane Library[7].  In this review, the studies of continuous oxygen therapy (provided for 
at least 15 hours per day) were considered separately from those of nocturnal oxygen therapy alone. 
Only 2 small randomized controlled trials of nocturnal oxygen therapy were uncovered.  The analysis 
was limited to the outcome of mortality.  Almost four years have elapsed since the publication of this 
meta-analysis. 
Objectives: General objective: To update/expand Cranston’s systematic review and meta-analysis of 
nocturnal oxygen therapy in COPD. 
Specific objectives: (1) to locate any additional unpublished or ongoing trial on nocturnal oxygen 
therapy in COPD; (2) to determine the effect of nocturnal oxygen therapy on survival and disease 
progression in patients with COPD. 
Methods: Search strategy: We accessed, in January 2009, the Cochrane Library with the following 
search strategy: ((Oxygen* or O2) and (home* or domicil* or long-term or “long term”)) or LTOT. 
The  Medline,  Embase  and  CINHAL  databases  were  also  reviewed  using  these  search  words: 
«“nocturnal oxygen therapy” [all fields]» from 2005 to 2009.  Lastly, we hand-searched the 2005, 2006, 
2007, and 2008 American Thoracic Society, American College of Chest Physicians and European 
Respiratory Society meeting abstracts. 
Selection criteria: Two reviewers (YL and SM) independently assessed the titles and abstracts of all 
citations obtained to only select randomized controlled trials of nocturnal oxygen therapy in patients 
with COPD.  Control groups received either conventional care or any other nocturnal therapy.  If the 
title of an article and its abstract suggested any possibility that it might be relevant, the paper was 
retrieved and independently assessed by the same reviewers for a final decision about its inclusion into 
the meta-analysis. 
Data  collection  and  analysis:  Pooled  statistics  were  calculated  as  Peto  Odds  Ratios  with  95% 
confidence intervals (CI). 
Results: Literature search (Figure): 986 separate publications were retrieved.  Both reviewers located 
and agreed to include only the same 2 randomized trials retrieved by Cranston et al.[7] .  These two trials 
compared nocturnal oxygen therapy to usual care; one was an open trial[8] whereas the other was 
placebo-controlled[9].    The  agreement  between  the  reviewers  was  substantial  (quadratic  weighted 
Kappa: 0.77; 95% CI: 0.45 – 0.80). 
Effects of nocturnal oxygen therapy on mortality and disease progression: In the meta-analysis, there 
was no difference in mortality between the treated and the control groups.  Considering mortality as the 
only outcome, the pooled odds ratio was 0.97 (95% CI: 0.41 – 2.31; p homogeneity  = 0.69).   Also, we 
expanded Cranston et al.’s review by conducting a meta-analysis of the composite outcome (i.e., 
 
 
7  Cranston JM, Crockett AJ, Moss JR, et al.   Domiciliary oxygen for chronic obstructive pulmonary disease.  Cochrane 
Database Syst Rev 2005; Oct 19; CD001744. 
8  Chaouat A, Weitzenblum E, Kessler R, et al.   A randomized trial of nocturnal oxygen therapy in chronic obstructive 
pulmonary disease patients. Eur Respir J 1999; 14: 1002-8. 
9  Fletcher EC, Luckett RA, Goodnight-White S, et al.   A double-blind trial of nocturnal supplemental oxygen for sleep 
desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mm Hg.  Am Rev Respir 
Dis 1992; 145: 1070-76. 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
mortality or requirement for continuous oxygen therapy, a marker of disease progression).  There was 
no difference in the composite outcome between the treated and the control groups (pooled odds ratio 
was 1.57 [95% CI: 0.75 – 3.26]; p homogeneity) = 0.47). 
Conclusions: Current evidence in the literature does not support the prescription of nocturnal oxygen 
therapy to improve survival or slow down disease progression in patients with COPD.  However, the 
confidence intervals around the pooled treatment effects are wide, and clinically significant effects are 
plausible.  More research is needed. 
 
 
 
 
Figure: Study selection 
 
 
Cochrane Airways Group 
Specialised Register of 
Trials in COPD 
 
440 titles 
 
Meeting Abstracts 
 
546 titles 
 
 
 
 
 
Excluded : 
983 
  Not COPD : 
211 
  Not nocturnal oxygen therapy: 
743 
  Not randomized controlled trial: 
28 
  Not mortality / LTOT prescription:  1 
 
 
Full papers 
(n = 3) 
 
 
2 papers reported on the same study 
 
 
 
Trials included in the meta-analysis 
(n = 2) 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
APPENDIX 7 
 
OXYGEN (OR PLACEBO) TITRATION PROCESS 
 
 
 
 
 
 
 
 
* At this point of the trial, if no patient is randomized to N-O2, then the final prescription is by default 
2 liters/minute, without further testing. 

Multi-center randomized trial ofnocturnal oxygen therapy in chronic obstructive pulmonary disease- The
International Noctumal Oxygen (INOX) trial. 
Lacasse, Yves 
020CT2013 
Appendix to protocol
 
 
Amount requested in year  1 = $2 039  554 
Appendices to Research proposal 
APPENDIX8 
 
 
LETTER OF AGREEMENT- LABORATOIRE  DE TÉLÉMATIQUE 
 
 
 
 
DIRECTEUR 
Dr Yves Berthiaume 
Centre de reche'Che, pavillon Masson 
Hôtel D1eu de Montréal 
3850 SamtUltain 
Mootréal, Qc   H2W 1TS 
Téléphooe.   (514) 890 8000 pst 12922 
Télé<oopieur: (514) 4127204 
yves.berthaiume@umootreal . ca 
 
DIRECTEUR-ADJOINT 
Dr BaS!!Petrof 
 
REGROUPEMENTS STRATÉGIQUES 
 
Apnée  obstructive du smnmeil et 
facteurs de morbidité 
cardiovasrulaires 
Dr Frédénc Sénes 
 
Asthme et obésité 
Dr Lo..usPh!lippeBoo!et 
 
Bioaérosols et santé respiratoire 
Dre Caroline Duchaine 
 
Fibrose kystique 
Dr André  Cantin 
 
Infections respiratoires et virus 
émergents 
DrGuyBoivm 
 
Soins  critiques respiratoires 
Dr Phihppe Jouvet 
 
Maladies pubnonaires obstructives 
chronique 
Dr Jean Bourbeau 
 
INFRASTRUCTURES 
 
Banque de tissus 
Dr M1chel Laviolette 
 
Laboratoire deTélématique 
Biomédicale 
Dr Éric Rousseau 
 
Plateforme génmnique 
Dre Catht!'ineLapri se 
 
Ce llule éthique 
Dr Bruno Aw is:si 
 
Formation 
Dr Yvon Corm ier 
 
DIRECTEUR ADMINISTRATIF 
Dr Bnmo Aw issi 
Unité d'ép1dérrnolog ie resp iratoire 
Université McGill 
3650 Samt-Urtam 
Mootréal, Qc H2X 2P4 
Téléphone    (5 14) 8432210 
Té!é<oop1eur: (5 14) 843-2083 
Coume!   bruno aw issi@mqpl! ca 
 
SITE WEB 
http:1/www .rsr_ chus. qc. ca 
Sherbrooke, le 24 Janvier 2009. 
 
Dr Yves Lacasse 
Pneumologue 
Hôpital Laval, Québec 
 
Bonjour Dr Lacasse, 
 
Nous  avons  évalué  le  temps  requis  pour  réaliser   votre  projet  " Multi-center 
randomized placebo-controlled trial of noctumal oxygen therapy in chronic obstructive 
pulmonary disease" (CANOX) et avec ce que nous avons comme information, un 
délai de 16 semaines  de travail  serait requis. Le document  d'analyse  sommaire 
est allilexé. 
 
Au  tarif  de notre  analyste-programmeur actuel,  la portion  à budgéter  pour  la 
programmation de l'application serait : 
 
16 semaines à 35 heures/semaines= 560 heures 
560 heures à 24,70 $/heure = 13 832,00 $ 
à ceci s'ajoute les avantages sociaux  et autres bénéfices marginaux (2904,72  $), 
soit un total de 16 736,72.00 $ 
 
Tel  que  mentiollilé  dans  votre  message,  l'ajout   de  fonctionnalités tel  que  le 
"Serious  adverse  events  module"  et  le "Arborescent screening log"  n'est  pas 
compris  dans  cette  estimation.   Pour  ces  modules  supplémentaires, il faudrait 
compter une  somme   de 4000 $. 
 
De plus, il faut prévoir des frais de 1000 $qui se détaillent  comme suit: 
1-  un  tarif  armuel  récurrent   pour  l'hébergement  sécurisé  de  l'application 
d'environ 150.00 $par armée sur le serveur du réseau. 
2-  des  frais de déplacement en  début et fin de projet  pour  notre  analyste- 
programmeur  de l'ordre de 450 $ 
3-  des frais pour l'extraction des données en fin de projet de l'ordre  de 400 $ 
Pour un grand total estimé à 21736,72  $ 
En espérant le tout conforme à vous attentes. Cordialement vôtre. 
 
 
Éric Rousseau 
L aboratoire de Télématique Biomédicale 
Réseau en Santé Respiratoire  du FRSQ 
819 564-5306 

Multi-center randomized trial ofnocturnal oxygen therapy in chronic obstructive pulmonary disease- The
International Noctumal Oxygen (INOX) trial. 
Lacasse, Yves 
020CT2013 
Appendix to protocol
 
 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal 
APPENDIX9 
 
 
LETTER  OF   SUPPORT  OF   THE   CANADIAN RESPIRATORY CLINICAL  RESEARCH 
CONSORTIUM 
 
 
 
 
CR.CR.CCRCP 
CANADIAN   R  ES P I  RATOI Y        C  l iNI CA l  IESEARCH   CONSORTI U  N 
CO   N S  ORTIUM    CANADIEN   DE  UCHEICHE Cli NIQU  E     EN   PNEUNOLOGIE 
 
Februruy 3, 2009 
 
Yves Lacasse 
Centre de pneumologie 
Hôpital Laval 
2725 Chemin Ste-Foy 
Ste-Foy, P. Québec 
GlV 4G5 
Fax: 418-656-4762 
 
DearYves, 
 
On behalf of the Canadian Respiratory C linicat Research Consortium it is my pleasure to write a 
letter of support for your clinicat trial entitled: Mu!ti-center randomized placebo-controlled trial 
ofnoctumal oxygen therapy in chronic obstructive pulmonruy disease. 
 
Your study protocol was presented to our group at our Winter 2005 symposium and it was very 
weil received. In the meantime, you have continued to refine your protocol and complete severa! 
pilot studies which have demonstrated the relevance of the question to Canadian public h ealth, as 
weil as the feasibility ofthe ultimate clinicat trial. 
 
The Canadian Respiratory Clinicat Research Consortium (CRCRC), under the leadership of the 
Canadian Lung Association's Canadian Thoracic Society's clinicat trials comm ittee, is an umbrella 
organization of professional societies with a special interest in respiratory related clinicat 
research. The Consortium fonctions as a not for profit organization and is independent of 
industry. Representatives from ali of Canada's teaching centers are members of the consortium. 
Our consortium was developed to promote clinicat research that answers important questions 
arising in adult and pediatrie pulmonary medicine. The Consortium places particular emphasis 
on studies needed to increase or establish the leve!of evidence ofkey-recomm endations of 
treatment guidelines. 
 
We have chosen to support your trial as an important one that we wou ld particularly like to be 
involved with.  Our networl< of respiratory researchers across Canada is keen to be involved in 
this study, and our members are committed towards recruiting patients for your study. We wish 
you success with your CIHR grant applicat ion. This will be an exciting opportunity for a cross- 
Canada collaborative effort to better the lives of patients affected by COPD. 
 
 
Shawn Aaron, MD, MSc, FRCPC 
Cha.irman, CRCRC 

Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The
02OCT2013 
Appendix to protocol
 
 
International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal 
APPENDIX 10 
 
 
 
CO-INVESTIGATORS AND COLLABORATORS 
 
New Brunswick, Canada 
Dr. Marcel Mallet, Dr.-Georges-L.-Dumont University Hospital Centre, Moncton 
Quebec, Canada 
Dr. Jean Bourbeau, Montreal Chest Institute, Montreal 
Dr. Bruno Paradis, CSSS de Laval – Centre ambulatoire, Laval 
Dr. François Maltais, Institut universitaire de cardiologie et de pneumologie de Québec, 
Quebec 
Dr. Richard Lecours, Hôtel-Dieu de Lévis, Levis 
Dr. Pierre Larivée, Centre hospitalier universitaire de Sherbrooke, Sherbrooke 
Dr. Marc Baltzan, Mount Sinai Hospital, Montreal 
Dr. Christine Drapeau, Centre hospitalier régional de Trois-Rivières, Trois-Rivieres 
Dr. Guy Cournoyer, Hôpital régional de Saint-Jérôme, Saint-Jerome 
Ontario, Canada 
Dr. Shawn Aaron, The Ottawa Hospital – General Campus, Ottawa 
Dr. Denis O’Donnell, Kingston General Hospital, Kingston 
Manitoba, Canada 
Dr. Martha Shepertecky, St. Boniface General Hospital, Winnipeg 
Alberta, Canada 
Dr. Eric Wong, University of Alberta Hospital, Edmonton 
British Columbia, Canada 
Dr. Jeremy Road, Vancouver General Hospital, University of British Columbia, Vancouver 
Portugal 
Dr. Paula Simão, Hospital Pedro Hispano, Matosinhos 
Dr. Miguel Guimarães, Centro Hospitalar Vila Nova de Gaia / Espinho EPE, Vila Nova de 
Gaia 
Dr. Cristina Bárbara and Dr. Paula Pinto, Hospital Pulido Valente, CH de Lisboa Norte, Lisboa 
Dr. Joaquim Moita, Centro Hospitalar de Coimbra, Quinta dos Vales, Coimbra 
Dr. João Munhá, Centro Hospitalar do Barlavento Algarvio – EPE, Portimão 
Dr. Salete Valente, Centro Hospitalar Cova da Beira, Covilhã 
France 
Dr. Jean-Claude Meurice, CHU de Poitiers, Poitiers 
Dr. Alain Palot and Dr. Pascal Chanez, Hôpital Nord, Marseille 
Dr. Jésus Gonzalez, Groupe Hospitalier Pitié Salpêtrière, Paris 
Spain 
Dr. Carlos Javier Egea Santaolalla, Hospital Txagorritxu, Vitoria-Gasteiz 
Dr. Araceli Abad Fernández, Hospital Universitario de Getafe, Getafe 
Dr. Javier Sayas Catalán, Hospital Universitario 12 de Octubre, Madrid 
Dr. Cristóbal Esteban, Hospital Galdakao-Usansolo, Galdakao 

02OCT2013 
Appendix to protocol
 
 
Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease – The Canadian Nocturnal Oxygen (INOX) trial 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal 
 
APPENDIX 11 
 
NOCTURNAL OXIMETRY TRACINGS IN PATIENTS WITH COPD NOT QUALIFYING FOR CONTINUOUS OXYGEN THERAPY 
 
(A) 
Nocturnal oxygen desaturation (> 30% of the recording time with a saturation < 90%) with non-periodic 
variation in saturation throughout sleep.  This tracing is not suggestive of sleep apnea. 
 
 
 
 
 
(B) 
Nocturnal oxygen desaturation with cyclical changes in saturation suggesting sleep apnea. 

 
Lacasse, Yves   Multi-center randomized trial of noctumal oxygen therapy in chronic obstructive pulmonary disease 
Amount requested in year 1 = $1 794 000 
Appendices to Research proposal 
 
 
APPENDIX 12 
 
1 
PATIENT SCREENING: DIAGNOSIS OF  NOCTURNAL DESATURATION 
 
 
 
Home oximetry #1 
 
 
Home oximetry #2 
 
 
30% of the recording time with 
saturation < 90% on either of the oximetries 
 
 
 
 
 
 
Suspicion of sleep apnea 
on either of the oximetries 
 
 
 
 
 
 
Type-1 or Type-2 
sleep study 
available? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Shaded boxes: procedures performed off-protocol (see protocol, section 2.5.4 Noctumal desaturation: operational 
definition and patient selection). 
 
020CT2013 
Appendix to protocol 

Lacasse,Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease
Amount requested in year 1 = $1 794 000 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
 
APPENDIX 13 
 
 
 
AMERICAN ACADEMY OF SLEEP MEDICINE CLASSIFICATION SYSTEM FOR SLEEP APNEA EVALUATION 
STUDIES[1] 
 
 
 
Type 1: standard 
polysomnography 
Type 2: 
comprehensive 
portable 
polysomnography 
Type 3: 
modified 
portable sleep 
apnea testing 
Type 4: 
continuous single 
or dual parameter 
recording 
 
 
 
Parameters 
Minimum of 7, 
including EEG, 
EOG, chin EMG, 
ECG, airflow 
respiratory effort, 
O2 saturation 
Minimum of 7, 
including EEG, 
EOG, chin EMG, 
ECG, airflow 
respiratory effort, 
O2 saturation 
Minimum of 4, 
including 
ventilation, 
heart rae or 
ECG, O2 
saturation 
Mimimum of 1: 
O2 saturation, 
flow, or chest 
movement 
 
Body position 
Documented or 
objectively 
measured 
Possible 
Possible 
No 
 
Leg movement             EMG or motion 
sensor desirable 
but optional 
Optional 
Optional 
No 
 
Personnel in 
attendance 
Yes 
No 
No 
No 
 
Interventions during 
the study 
Possible 
No 
No 
No 
 
EEG: electroencephalography; EOG: electrooculography; EMG: electromyography; ECG: electrocardiography. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for 
syndrome definition and measurement techniques in clinical research. Sleep 1999; 22: 667-89. 

Lacasse,Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease
Amount requested in year 1 = $1 794 000 
Appendices to Research proposal
02OCT2013 
Appendix to protocol
 
 
 
APPENDIX 14 
 
A)   Prescription of long‐term oxygen therapy in stable patients 
(patients evaluated during a regular follow up visit) 
 
 
 
 
 
 
 
 
 
 
B)   Prescription of long‐term oxygen therapy in unstable patients 
(patients evaluated outside of the regular follow up visits, most likely in the course of an acute exacerbation) 
 
 
 
 
If this occurs within 30 days of 
the next protocol-based follow up 
visit, then this visit is 
 
 

02OCT2013 
Appendix to protocol
 
 
Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease 
Amount requested in year 1 = $1 794 000 
Appendices to Research proposal 
 
APPENDIX 15 
 
INOX’ CASE REPORT FORM 

02OCT2013 
Appendix to protocol
 
 
Lacasse, Yves 
Multi-center randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease 
Amount requested in year 1 = $1794 000 
Appendices to Research proposal 
 
APPENDIX 16 
 
SAMPLE SIZE 
 
1. Sample size requirements for secondary outcome analyses 
Disease-specific quality of life is  the secondary outcome of this trial.  Disease-specific quality of life will 
be measured using the  St. George’s Respiratory Questionnaire, an instrument that has been extensively 
validated in patients with all grades of respiratory disease including advanced COPD.  The questionnaire 
consists of 76 items divided into three domains (symptoms, activity, and impact).  Scores range from zero 
(perfect health) to 100 (worst possible) for each component; a total score which summarizes the responses 
to all items is obtained. A change in score of 4 units may be considered clinically significant. 
Disease-specific quality of life will be measured in 27 selected centers with specific facilities and 
expertise.  To decide on the number of selected centers and the target sample size in each of them, we 
computed the total sample size needed to give 80% chance of showing a statistically significant 
difference in SGRQ scores between two study periods, at a two-sided significance level of 5%, if the 
true  benefit  of  N-O2  reaches  the  minimal  clinically important  difference  (4 units on a 100-point 
scale[1,2]).  We derived baseline scores (and standard deviations) from 6 randomized trials of respiratory 
rehabilitation in COPD[3,4,5,6,7,8]  that enrolled patients whose baseline demographic and clinical 
characteristics were very similar to those who will meet the inclusion criteria of our trial.   In these 
randomized trials, baseline standard deviations were remarkably homogeneous (pooled SD: 14.74)[9]. 
From these specifications, we determined that 213 patients per group (total: 426) are needed, which is 
much smaller that the target sample size in the primary outcome analysis. 
2. Sample size requirements for economic analyses 
The objective of the INOX trial is not to demonstrate superiority of either of the treatment arm in terms 
of cost-effectiveness.  Rather, a secondary objective of the trial is to determine the cost-effectiveness 
ratio of nocturnal oxygen therapy over a 3-year period.  Non-parametric analyses (i.e., bootstrapping) 
will be used to derive confidence intervals for the incremental cost effectiveness ratio (see section 
2.16.2). 
 
 
1 Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD.  Eur Respir J 
2002; 19: 398-404. 
2 Schunemann HJ, Griffith L, Jaeschke R, et al.  Evaluation of the minimal important difference for the feeling thermometer 
and the St. George’s Respiratory Questionnaire in patients with chronic airflow obstruction. J Clin Epidemiol 2003; 56: 
1170-6. 
3 Engström CP, Persson LO, Larsson S, Sullivan M. Long-term effects of a pulmonary rehabilitation programme in 
outpatients with chronic obstructive pulmonary disease: A randomized controlled study. Scandinavian Journal of 
Rehabilitation Medicine 1999; 31: 207-13. 
4 Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, et al. Results at 1 year of outpatient 
multidisciplinary pulmonary rehabilitation: a randomized controlled trial. The Lancet 2000; 355: 362-8. 
5 Boxall A, Barclay L, Caplan G. A randomized controlled trial of home-based pulmonary rehabilitation for elderly, 
housebound COPD patients. In: Proceedings of the Thoracic Society ofAustralia & New Zealand, Annual Scientific 
Meeting, Adelaide, 4-9 April. 2003: P106. 
6 Finnerty JP, Keeping I, Bullough I, Jones J. The effectiveness of outpatient pulmonary rehabilitation in chronic lung 
disease. A randomized controlled trial.  Chest 2001; 119: 1705-10. 
7 Ringbaek TJ, Broendum E, Hemmingsen L, Lybeck K, Nielsen D, Andersen C, et al.  Rehabilitation of patients with 
chronic obstructive pulmonary disease. Exercise twice a week is not sufficient!. Respiratory Medicine 2000; 94: 150-4. 
8 Chlumsky J, Sterbova L, Smolikova L, Matous M, Salajka F. The effect of pulmonary rehabilitation on exercise tolerance 
and quality of life in patients with COPD. Preliminary data.  Eur Respir J 2001; 18:223s. 
9 Lacasse Y, Goldstein R, Lasserson TJ, Martin S. Pulmonary rehabilitation for chronic obstructive pulmonary disease. 
Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003793.pub2. DOI: 
10.1002/14651858.CD003793.pub2. 

02OCT2013 
Appendix to protocol
Lacasse, Yves 
Multi-center randomized placebo-controlled trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease
– The International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
 
 
APPENDIX 17 
 
CHARTER FOR DATA MONITORING COMMITTEE 
 
1. INTRODUCTION 
The International Nocturnal Oxygen (INOX) trial is a multi-centre randomized placebo-controlled trial 
of nocturnal oxygen therapy in patients with COPD that is funded by the Canadian Institutes for Health 
Research.  The INOX is registered at the U.S. National Institutes of Health (ClinicalTrials.gov – 
NCT01044628) and at the International Standard Randomised Controlled Trial Number (ISRCTN) 
Register (ISRCTN50085100). 
The objective of the INOX trial is to determine, in patients with chronic obstructive pulmonary 
disease (COPD) not qualifying for long-term oxygen therapy (LTOT) who exhibit significant nocturnal 
arterial  oxygen  desaturation,  whether  nocturnal  oxygen  therapy  provided  for  a  period  of  3  years 
decreases mortality or delay the requirement for LTOT.   A secondary objective of the trial is to 
determine the cost-utility ratio of nocturnal oxygen therapy over a 3-year period. 
The purpose of this document is to describe the roles and responsibilities of the independent 
Data Monitoring Committee (DMC) for the INOX trial, including the timing of meetings, methods of 
providing information to and from the DMC, frequency and format of meetings, statistical issues and 
relationships with other committees. 
 
2. ROLES AND RESPONSIBILITIES 
2.1 Aims of the committee 
     To assist and advise the Steering Committee so as to protect the validity and credibility of the trial. 
 
To  safeguard  the  interests  of  trial  participants  by  assessing  the  safety  and  efficacy  of  the 
interventions during the trial. 
     To monitor the overall conduct of the clinical trial. 
2.2 Terms of reference 
 
The DMC receives and reviews the progress and accruing data of the trial and provides advice on 
the conduct of the trial to the Steering Committee. 
     The DMC informs the Chair of the Steering committee if, in their view: 
(i) the results are likely to convince a broad range of clinicians, including those supporting the 
trial and the general clinical community, that one trial arm is clearly indicated or 
contraindicated; or 
(ii) it becomes evident that no clear outcome would be obtained. 
2.3 Specific roles of DMC 
 
To advise on protocol modifications suggested by the Steering Committee (e.g., to inclusion 
criteria, trial endpoints, or sample size). 
     To suggest additional data analyses. 
     To review the trial’s progress including updated figures on recruitment, data quality, and main 
outcomes and safety data. 
     To monitor: 
o recruitment figures and losses to follow-up; 
o compliance with the protocol by participants and investigators; 
o trial conduct – organization and implementation of trial protocol; 
o evidence for treatment differences in the main efficacy outcome measures; 
o evidence for treatment harm (e.g., toxicity data, serious adverse effects, deaths); 
o planned sample size assumptions; 

02OCT2013 
Appendix to protocol
Lacasse, Yves 
Multi-center randomized placebo-controlled trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease
– The International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
 
 
o compliance with previous DMC recommendations. 
     To assess the impact and relevance of external evidence. 
 
To  decide  whether  to  recommend  that  the  trial  continues  to  recruit  participants  or  whether 
recruitment should be terminated either for everyone or for some treatment groups and/or some 
participant subgroups. 
 
3. BEFORE OR EARLY IN THE TRIAL 
3.1 Decision to join the DMC 
All potential DMC members shall have sight of the protocol/outline before agreeing to join the 
committee.  Before recruitment begins, the trial will have undergone review by the funder, and local 
research ethics committee.   Therefore, if a potential DMC member has major reservations about the 
trial (e.g., the protocol or the logistics), he/she should report these to the trial office and may decide not 
to accept the invitation to join.  DMC members should be independent and constructively critical of the 
ongoing trial, but also supportive of aims and methods of the trial. 
DMC members formally register their assent by confirming (1) that they agree to be on the 
DMC and (2) that they agree with the contents of this Charter. 
3.2 Meeting before the start of the trial 
The DMC met in Toronto on April 22, 2010 before the trial to discuss the protocol and to have the 
opportunity to clarify any aspects with the principal investigators. 
 
4. COMPOSITION 
4.1 Membership and size of the DMC 
The members of the DMC for this trial are Dr. James Brophy (Cardiology and Clinical epidemiology, 
McGill University), Dr. Nick Anthonisen (Respiratory medicine, University of Manitoba), and Dr. 
Robin Roberts (Biostatistics, McMaster University). All three have experience in data monitoring. 
The members are independent of the trial.  They have not been involved with the trial in any 
other way or have some competing interest that could impact on the trial.  Any competing interests, 
both real and potential, should be declared.  These are not restricted to financial matters – involvement 
in  other  trials  or  intellectual  investment  could  be  relevant.    A  competing  interest  form  will  be 
completed and returned by the DMC members to the trial coordinating centre. 
4.2 Responsibilities of the DMC’s Chair 
The Chair should have previous experience of serving on DMCs and experience of chairing meetings, 
and should be able to facilitate and summarize discussions.     The Chair is expected to facilitate and 
summarize discussions. During the first DMC meeting, the members designated Dr. James Brophy as 
the Chair of the committee. 
4.3 Responsibilities of the statisticians 
     The reports to the DMC will be produced by the “Service de consultation statistique” of Laval 
University.  The trial statistician is independent from this service. 
     The DMC’s statistician (Dr. Robin Roberts) will not participate in the production of the reports to 
the DMC. 
     The DMC’s statistician will provide independent statistical expertise to further guide the other 
DMC members through the report. 
4.4 Responsibilities of the trial’s office team 
The trial office team (e.g., Trial Manager, etc) will only input to the production of the non-confidential 
sections of the DMC report. 
4.5 Responsibilities of the Principal investigator (PI) and Steering Committee 
The PI, may be asked, and should be available, to attend open sessions of the DMC meeting. The other 

02OCT2013 
Appendix to protocol
Lacasse, Yves 
Multi-center randomized placebo-controlled trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease
– The International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
 
 
Steering Committee’s members will not usually be expected to attend but can attend open sessions 
when necessary. 
4. 6. Final decisions: Relationships between the DMC and the Steering Committee 
The DMC does not make decisions about the trial, but rather makes recommendations to the Steering 
Committee. 
 
5. ORGANIZATION OF DMC MEETINGS 
5.1 Frequency 
The exact frequency of meetings will depend upon any statistical plans specified, and otherwise on trial 
events.  The wishes of the DMC and needs of the trial office will be considered when planning each 
meeting. 
5.2 Setting 
The first meeting will be face-to-face to facilitate full discussion and allow members to get to know 
each other.  Depending on the composition of the DMC, all subsequent meetings will be face-to-face if 
possible, with teleconference as a second option. 
5.3 Open and closed sessions 
A mixture of open and closed sessions will take place.  Only DMC members and others whom they 
specifically invite (e.g., the trial statistician), will be present in closed sessions.  In open sessions, all 
those attending the closed session will be joined by the principal investigator and/or any member of the 
Steering committee. 
 
6. TRIAL DOCUMENTATION AND PROCEDURES TO ENSURE CONFIDENTIALITY 
6.1 Material available 
During the first DMC meeting, the members decided to be unblinded to the allocation group throughout 
the trial.   Accordingly, all sessions will be open.   Therefore, the material will include efficacy and 
safety data by allocation group. 
 
Open sessions: Accumulating information relating performance standards (recruitment and data 
quality) will be presented.   This information will include screening logs, treatment compliance 
data, and data return rates).  .  Toxicity details based on pooled data will be presented and total 
numbers  of  events  for  the  primary  outcome  measure  and  other  outcome  measures  may  be 
presented, at the discretion of the DMC. 
 
Closed sessions: In addition to all the material available in the open session, the closed session 
material will include efficacy and safety data by coded allocation group. 
     The DMC members will receive the report at least 2 weeks before any meetings. 
6.2 Blinding 
The members of the DMC will decide whether they wish to be blinded or not to the allocation groups. 
During the first DMC meeting, the members decided to be unblinded to the allocation group throughout 
the trial. 
6.3 Confidentiality 
     DMC members do not have the right to share confidential information with anyone outside the 
DMC, including the PI. 
 
The DMC members should destroy their reports after each meetings.   Fresh copies of previous 
reports will be circulated with the newest report before each meeting. 
6.4 Documentation 
The principal investigator or the trials office team will collate any such information and provide it to 
the DMC members.  Identification of external evidence (e.g., from other trials/ systematic reviews) is 
not the responsibility of the DMC members. 

02OCT2013 
Appendix to protocol
Lacasse, Yves 
Multi-center randomized placebo-controlled trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease
– The International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
 
 
 
 
7. DECISION MAKING 
7.1 Possible recommendations 
Possible recommendations of the DMC could include: 
    No action needed, trial continues as planned; 
    Early stopping due, for example, to clear benefit or harm of a treatment, , or external evidence; 
 Extending recruitment (based on actual control arm response rates being different to predicted 
rather than on emerging differences) or extending follow-up; 
    Sanctioning and/or proposing protocol changes. 
7.2 Interim analysis schedule and procedures 
During its first meeting, the DMC members will finalize an interim analysis plan (schedule and rules). 
The Steering committee suggests that: 
     only one interim analysis be conducted; 
 
for efficacy, the composite outcome of mortality or progression to continuous oxygen therapy be 
monitored using the sequence of nominal significance levels of 0.001 and 0.05 (two-sided) [1,2]; 
 
safety be monitored every 6 months or more frequently if requested by the DMC.  Although no 
formal boundaries for safety monitoring are defined, clear evidence of net harm with no beneficial 
effect would be expected before the DMC recommends to terminate the trial. 
7.3 Voting 
Every effort will be made for the DMC to reach a unanimous decision.  If the DMC cannot achieve this, 
a vote may be taken, although details of the vote should not be included in the report to the Steering 
committee as these may inappropriately convey information about the state of the trial data. 
7.4 Quorum 
Effort should be made for all members to attend.  The trials office team will try to ensure that a date is 
chosen to enable this.  Members who cannot attend in person should be encouraged to attend by 
teleconference.  If, at short notice, any DMC members cannot attend at all then the DMC may still meet 
if at least one statistician and one clinician, including the Chair, will be present.  If the DMC is 
considering recommending major action after a meeting, the DMC Chair should talk with the absent 
members as soon after the meeting as possible to check they agree.   If they do not, a further 
teleconference should be arranged with the full DMC. 
7.5 Attendance 
If a member does not attend a meeting, it should be ensured that the member is available for the next 
meeting.  If a member does not attend a second meeting, they should be asked if they wish to remain 
part of the DMC.  If a member does not attend a third meeting, they should be replaced. 
 
8. REPORTING 
8.1 Communication of the decisions 
The DMC will report its recommendations in writing to Principal investigator within 24 hours.  The 
Steering Committee will be notified of any correspondence between the DMC and the Principal 
investigator within 2 weeks. 
8.2 Disagreement 
If the DMC has serious problems or concerns with the Steering committee decision, a meeting of these 
groups will be held.   The information to be shown will depend upon the action proposed and the 
DMC’s concerns.   Depending on the reason for the disagreement, confidential data may have to be 
revealed to all those attending such a meeting.  The meeting will be chaired by an external expert who 
is not directly involved with the trial. 

02OCT2013 
Appendix to protocol
Lacasse, Yves 
Multi-center randomized placebo-controlled trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease
– The International Nocturnal Oxygen (INOX) trial. 
Amount requested in year 1 = $2 039 554 
Appendices to Research proposal
 
 
9. AFTER THE TRIAL 
9.1 Final meeting 
At the end of the trial, there will be a meeting to allow the DMC to discuss the final data with the 
Steering committee and give advice about data interpretation. 
 
9.2 Publication 
DMC members will be named and their affiliations listed in the main report, unless they explicitly 
request otherwise.  During the first DMC meeting, the members agreed that neither their name nor their 
affiliations will be listed in the main report. 
A brief summary of the timings and conclusions of DMC meetings will be included in the body of this 
paper. 
The DMC will be given the opportunity to read and comment on any publications before 
submission.