The International Nocturnal Oxygen (INOX) Trial
The International Nocturnal Oxygen (INOX) Trial
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.
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.
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.