Clinical trial NCT01044628: The International Nocturnal Oxygen (INOX) Trial
Official title: Multi-Center Randomized Placebo-controlled Trial of Nocturnal Oxygen Therapy in Chronic Obstructive Pulmonary Disease. The International Nocturnal Oxygen (INOX) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Obstructive Pulmonary Disease
Nocturnal Desaturation
Keywords: COPD
Oxygen therapy
Nocturnal
Desaturation
INOX
Lead sponsor: Laval University
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2010-01-08
Enrollment: 243
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: This multicenter randomized placebo controlled trial aims to determine if in patients with COPD not qualifying for LTOT but presenting significant nocturnal arterial oxygen desaturation, whether nocturnal oxygen therapy provided for a period of 4 years decreases mortality or delay the prescription of LTOT.

Detailed description: Background Long-term oxygen therapy (LTOT) is the only component of the management of chronic obstructive pulmonary disease (COPD) that improves survival in patients with severe daytime hypoxemia (defined as an arterial oxygen pressure \[PaO2\] measured in stable state \<= 55 mmHg or in the range 56-59 mmHg when clinical evidence of pulmonary hypertension or polycythemia are noted). In Canada, LTOT is usually provided by a stationary oxygen concentrator and is recommended to be used for at least 15-18 hours a day. Several studies have demonstrated a deterioration in arterial blood gas pressures and oxygen saturation during sleep in patients with COPD. Sleep-related oxygen desaturation often occurs in patients not qualifying for LTOT. The suggestion has been made that the natural progression of COPD to its end stages of chronic pulmonary hypertension, severe hypoxemia, right heart failure, and death is dependent upon the severity of desaturation occurring during sleep. This is an attractive hypothesis and is supported by the fact that hypoxemic episodes during sleep are accompanied by substantial increases in pulmonary arterial pressure and often by important cardiac arrhythmias. Supplemental nocturnal oxygen alleviates both the acute increases in pulmonary arterial pressure and the cardiac arrhythmias. It has been suggested that, over the long run, nocturnal oxygen therapy (N-O2) may halt the progression of long-standing cor pulmonale and prolong survival. Probably due to the fact that the recommendations of scientific societies regarding the indications for and use of N-O2 in COPD not qualifying for conventional LTOT are presently imprecise, a number of patients are currently treated with N-O2 although the beneficial effects of this therapy have not been confirmed.

Objectives Primary objective: To determine, in patients with COPD not qualifying for LTOT but who present significant nocturnal arterial oxygen desaturation, whether N-O2 provided for a period of 4 years decreases mortality or delay the prescription of LTOT.

Secondary objectives: To estimate, in the same population, the cost-utility ratio of nocturnal oxygen therapy over a 4-year period.

Hypotheses In patients with COPD not qualifying for LTOT but who present significant nocturnal arterial oxygen desaturation, N-O2 provided for a period of 4 years is effective in decreasing mortality or delaying the requirement for LTOT; and is cost-effective and favorably compares to other medical interventions.

Research plan Study design: We propose a 4-year, multi-center, placebo-controlled, randomized trial of nocturnal oxygen therapy added to usual care in patients presenting sleep-related oxygen desaturation who do not qualify for LTOT.

Inclusion criteria: (1) patients with a diagnosis of COPD supported by an history of past smoking and obstructive disease with FEV1/FVC \< 70%; (2) presence of mild-to-moderate daytime hypoxemia with a daytime PaO2 in the range of 56-69 mmHg; (3) patients fulfilling our definition of nocturnal oxygen desaturation: \>= 30% of the recording time with transcutaneous arterial oxygen saturation \< 90% on two consecutive recordings.

Intervention:

Nocturnal oxygen therapy: N-O2 will be delivered overnight to allow the oxygen saturation to be \> 90%.

Placebo: The patients allocated in the control group will receive room air delivered by defective concentrator. The comparison will be double blind.

Primary outcomes The primary outcomes of this trial are mortality from all cause or requirement for LTOT (composite outcome).

Secondary outcomes Secondary outcomes will include quality of life and utility measures, costs from a societal perspective and compliance with oxygen therapy. Trial duration: The follow-up period lasts at least 4 years. We expect this trial to be completed within 8 years.

Eligibility criteria: 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;
* SpO2 at rest \< 95%;
* 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 ot give informed consent.

Exclusion Criteria:

* Patients with severe hypoxemia fulfilling the usual criteria for continuous oxygen therapy at study entry: PaO2 \<=55 mmHg; or PaO2 \<= 59 mmHg with clinical evidence of at least one of the following: (1) with right ventricular hypertrophy (P pulmonale on ECG:3 mm leads ll, lll, aVf); (2) right ventricular hypertrophy; (3)Peripheral edema (cor pulmonale); (4) hematocrit \>=55%;
* Patients with proven sleep apnea (defined by an apnea/hypopnea index of \>=15 events/hour) or suspected sleep apnea on oximetry tracings;
* Patients currently using nocturnal oxygen therapy;
* 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.

Primary outcomes:
measure: Composite outcome: all-cause mortality or requirement for continuous oxygen therapy
timeFrame: From date of randomization until the date of prescription of continuous oxygen or date of death from any cause, whichever came first, assessed up to 48 months
Secondary outcomes:
measure: Disease-specific quality of life
timeFrame: 48 months
measure: Generic quality of life
timeFrame: 48 months
measure: Health economics
timeFrame: 48 months
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: St-Boniface General Hospital
state: Manitoba
city: Moncton
country: Canada
facility: Hôpital Dr Georges-L. Dumont
state: New Brunswick
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital (General Campus)
state: Ontario
city: Laval
country: Canada
facility: Centre de la santé et des services sociaux de Laval (Cité de la Santé de Laval)
state: Quebec
city: Lévis
country: Canada
facility: Hôtel-Dieu de Lévis
state: Quebec
city: Montreal
country: Canada
facility: Montreal Chest Institute
state: Quebec
city: Montreal
country: Canada
facility: Centre Hospitalier Mount-Sinai
state: Quebec
city: Montréal
country: Canada
facility: Hôpital du Sacré-Coeur de Montréal
state: Quebec
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)
state: Quebec
city: Saint-Jérôme
country: Canada
facility: Hôpital régional de Saint-Jérôme
state: Quebec
city: Sherbrooke
country: Canada
facility: CHUS, Fleurimont
state: Quebec
city: Trois-Rivières
country: Canada
facility: Centre de recherche Pneumomédic inc.
state: Quebec
city: Marseille
country: France
facility: Hôpital Nord de Marseille
city: Paris
country: France
facility: Groupe Hospitalier Pitié - Salpêtrière
city: Poitiers
country: France
facility: CHU de Poitiers
city: Portimao
country: Portugal
facility: Centro Hospitalar do Barlavento Algarvio - EPE
state: Algarve
city: Coimbra
country: Portugal
facility: Centro Hospitalar de Coimbra
city: Covilha
country: Portugal
facility: Centro Hospitalar da Cova da Beira
city: Lisboa
country: Portugal
facility: Hospital Pulido Valente - Centro Hospitalar Lisboa Norte
city: Matosinhos
country: Portugal
facility: Hospital Pedro Hispano Unidade Local de Saude de Matosinhos
city: Vila Nova de Gaia
country: Portugal
facility: Centro Hospitalara Vila Nova de Gaia-Espinho EPE
city: Galdakao
country: Spain
facility: Hospital Galdakao-Usansolo
state: Biskaia
city: Getafe
country: Spain
facility: Hospital Universitario de Getafe
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Vitoria-Gasteiz
country: Spain
facility: Hospital Txagorritxu
Study officials:
affiliation: Laval University
name: Yves Lacasse, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lacasse Y, Series F, Martin S, Maltais F. Nocturnal oxygen therapy in patients with chronic obstructive pulmonary disease: a survey of Canadian respirologists. Can Respir J. 2007 Sep;14(6):343-8. doi: 10.1155/2007/487831.
citation: Lacasse Y, Series F, Corbeil F, Baltzan M, Paradis B, Simao P, Abad Fernandez A, Esteban C, Guimaraes M, Bourbeau J, Aaron SD, Bernard S, Maltais F; INOX Trial Group. Randomized Trial of Nocturnal Oxygen in Chronic Obstructive Pulmonary Disease. N Engl J Med. 2020 Sep 17;383(12):1129-1138. doi: 10.1056/NEJMoa2013219.
citation: Lacasse Y, Bernard S, Series F, Nguyen VH, Bourbeau J, Aaron S, Maltais F; International Nocturnal Oxygen (INOX) Research Group. Multi-center, randomized, placebo-controlled trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease: a study protocol for the INOX trial. BMC Pulm Med. 2017 Jan 9;17(1):8. doi: 10.1186/s12890-016-0343-9.