Multi-center, randomized, placebo-controlled trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease: a study protocol for the INOX trial

Yves Lacasse, Sarah Bernard, Frédéric Sériès, Van Hung Nguyen, Jean Bourbeau, Shawn Aaron, François Maltais, International Nocturnal Oxygen (INOX) Research Group, Marcel Mallet, Jean Bourbeau, Bruno Paradis, François Maltais, Richard Lecours, Pierre Larivée, Marc Baltzan, François Corbeil, Christine Drapeau, Guy Cournoyer, Shawn Aaron, Denis O'Donnell, Martha Shepertecky, Eric Wong, Jeremy Road, Paula Simão, Miguel Guimarães, Cristina Bárbara, Paula Pinto, Joaquim Moita, Cidália Rodrigues, João Munhá, Salete Valente, Carlos Javier Egea Santaolalla, Araceli Abad Fernández, Irene Cano, Javier Sayas Catalán, Cristóbal Esteban, Amaia Garcia-Loizaga, Jean-Claude Meurice, Alain Palot, Pascal Chanez, Jésus Gonzalez, Antoine Guerder, Yves Lacasse, Sarah Bernard, Frédéric Sériès, Van Hung Nguyen, Jean Bourbeau, Shawn Aaron, François Maltais, International Nocturnal Oxygen (INOX) Research Group, Marcel Mallet, Jean Bourbeau, Bruno Paradis, François Maltais, Richard Lecours, Pierre Larivée, Marc Baltzan, François Corbeil, Christine Drapeau, Guy Cournoyer, Shawn Aaron, Denis O'Donnell, Martha Shepertecky, Eric Wong, Jeremy Road, Paula Simão, Miguel Guimarães, Cristina Bárbara, Paula Pinto, Joaquim Moita, Cidália Rodrigues, João Munhá, Salete Valente, Carlos Javier Egea Santaolalla, Araceli Abad Fernández, Irene Cano, Javier Sayas Catalán, Cristóbal Esteban, Amaia Garcia-Loizaga, Jean-Claude Meurice, Alain Palot, Pascal Chanez, Jésus Gonzalez, Antoine Guerder

Abstract

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. LTOT is usually provided by a stationary oxygen concentrator and is recommended to be used for at least 15-18 h a day. Several studies have demonstrated a deterioration in arterial blood gas pressures and oxygen saturation during sleep in patients with COPD, even in those 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. The primary objective of the International Nocturnal Oxygen (INOX) trial is to determine, in patients with COPD not qualifying for LTOT but who present significant nocturnal arterial oxygen desaturation, whether nocturnal oxygen provided for a period of 3 years decreases mortality or delay the prescription of LTOT.

Methods: The INOX trial is a 3-year, multi-center, placebo-controlled, randomized trial of nocturnal oxygen therapy added to usual care. Eligible patients are those with a diagnosis of COPD supported by a history of past smoking and obstructive disease who fulfill our definition of significant nocturnal oxygen desaturation (i.e., ≥ 30% of the recording time with transcutaneous arterial oxygen saturation < 90% on either of two consecutive recordings). Patients allocated in the control group receive room air delivered by a concentrator modified to deliver 21% oxygen. The comparison is double blind. The primary outcome is a composite of mortality from all cause or requirement for LTOT. Secondary outcomes include quality of life and utility measures, costs from a societal perspective and compliance with oxygen therapy. The follow-up period is intended to last at least 3 years.

Discussion: The benefits of LTOT have been demonstrated whereas those of nocturnal oxygen therapy alone have not. The INOX trial will likely determine whether supplemental oxygen during sleep is effective in reducing mortality, delaying the need for LTOT and improving health-related quality of life in patients with COPD who desaturate overnight.

Trial registration: Current Controlled Trials ISRCTN50085100 ; ClinicalTrials.gov NCT01044628 (date of registration: January 6, 2010).

Keywords: COPD; Mortality; Oxygen therapy; Randomized trial; Sleep.

Figures

Fig. 1
Fig. 1
Nocturnal oximetry tracings in patients with COPD not qualifying for LTOT. a Significant nocturnal oxygen desaturation (>30% of the recording time with a saturation < 90%) without periodic variations in saturation, a tracing not suggestive of sleep apnea. b Significant nocturnal oxygen desaturation with cyclical changes in saturation suggesting sleep apnea, a tracing suggestive of sleep apnea
Fig. 2
Fig. 2
Diagnostic procedures. In case of oximetry tracing suggestive of sleep apnea, patients are excluded, unless sleep apnea is ruled out on the basis of a formal sleep study (either of Type-1 or Type-2 – shaded area) performed off-protocol
Fig. 3
Fig. 3
Nocturnal oxygen flow titration procedure

References

    1. Hill K, Goldstein RS, Guyatt GH, Blouin M, Tan WC, Davis LL, Heels-Ansdell DM, Erak M, Bragaglia PJ, Tamari IE, et al. Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care. CMAJ. 2010;182(7):673–8. doi: 10.1503/cmaj.091784.
    1. Statistics_Canada: The 10 leading causes of death, 2011. Statistics Canada 2011. []. Accessed 11 Dec 2016.
    1. Nocturnal_Oxygen_Therapy_Trial_Group Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93(3):391–8. doi: 10.7326/0003-4819-93-3-391.
    1. Medical_Research_Council_Party Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet. 1981;1(8222):681–6.
    1. O'Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk DD, Balter M, Ford G, Gervais A, Goldstein R, Hodder R, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2007 update. Can Respir J. 2007;14(Suppl B):5B–32. doi: 10.1155/2007/830570.
    1. Fleetham JA, Mezon B, West P, Bradley CA, Anthonisen NR, Kryger MH. Chemical control of ventilation and sleep arterial oxygen desaturation in patients with COPD. Am Rev Respir Dis. 1980;122(4):583–9.
    1. Tatsumi K, Kimura H, Kunitomo F, Kuriyama T, Watanabe S, Honda Y. Sleep arterial oxygen desaturation and chemical control of breathing during wakefulness in COPD. Chest. 1986;90(1):68–73. doi: 10.1378/chest.90.1.68.
    1. Fletcher EC, Scott D, Qian W, Luckett RA, Miller CC, Goodnight-White S. Evolution of nocturnal oxyhemoglobin desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mm Hg. Am Rev Respir Dis. 1991;144(2):401–5. doi: 10.1164/ajrccm/144.2.401.
    1. Chaouat A, Weitzenblum E, Kessler R, Charpentier C, Ehrhart M, Levi-Valensi P, Zielinski J, Delaunois L, Cornudella R, Moutinho dos Santos J. Sleep-related O2 desaturation and daytime pulmonary haemodynamics in COPD patients with mild hypoxaemia. Eur Respir J. 1997;10(8):1730–5. doi: 10.1183/09031936.97.10081730.
    1. Lacasse Y, Series F, Vujovic-Zotovic N, Goldstein R, Bourbeau J, Lecours R, Aaron SD, Maltais F. Evaluating nocturnal oxygen desaturation in COPD--revised. Respir Med. 2011;105(9):1331–7. doi: 10.1016/j.rmed.2011.04.003.
    1. Sergi M, Rizzi M, Andreoli A, Pecis M, Bruschi C, Fanfulla F. Are COPD patients with nocturnal REM sleep-related desaturations more prone to developing chronic respiratory failure requiring long-term oxygen therapy? Respiration. 2002;69(2):117–22. doi: 10.1159/000056313.
    1. Block AJ, Boysen PG, Wynne JW. The origins of cor pulmonale; a hypothesis. Chest. 1979;75(2):109–10. doi: 10.1378/chest.75.2.109.
    1. Flenley DC. Clinical hypoxia: causes, consequences, and correction. Lancet. 1978;1(8063):542–6. doi: 10.1016/S0140-6736(78)90564-0.
    1. Fletcher EC, Levin DC. Cardiopulmonary hemodynamics during sleep in subjects with chronic obstructive pulmonary disease. The effect of short- and long-term oxygen. Chest. 1984;85(1):6–14. doi: 10.1378/chest.85.1.6.
    1. Weitzenblum E, Muzet A, Ehrhart M, Ehrhart J, Sautegeau A, Weber L. Nocturnal changes in blood gases and pulmonary arterial pressure in chronic bronchitis patients with respiratory insufficiency (author's transl) Nouv Presse Med. 1982;11(15):1119–22.
    1. Boysen PG, Block AJ, Wynne JW, Hunt LA, Flick MR. Nocturnal pulmonary hypertension in patients with chronic obstructive pulmonary disease. Chest. 1979;76(5):536–42. doi: 10.1378/chest.76.5.536.
    1. Tirlapur VG, Mir MA. Nocturnal hypoxemia and associated electrocardiographic changes in patients with chronic obstructive airways disease. N Engl J Med. 1982;306(3):125–30. doi: 10.1056/NEJM198201213060301.
    1. Flick MR, Block AJ. Nocturnal vs diurnal cardiac arrhythmias in patients with chronic obstructive pulmonary disease. Chest. 1979;75(1):8–11. doi: 10.1378/chest.75.1.8.
    1. Wijkstra PJ, Guyatt GH, Ambrosino N, Celli BR, Guell R, Muir JF, Prefaut C, Mendes ES, Ferreira I, Austin P, et al. International approaches to the prescription of long-term oxygen therapy. Eur Respir J. 2001;18(6):909–13. doi: 10.1183/09031936.01.00202301.
    1. Orth M, Walther JW, Yalzin S, Bauer TT, de Zeeuw J, Kotterba S, Baberg HT, Schultze-Werninghaus G, Rasche K, Duchna HW. Influence of nocturnal oxygen therapy on quality of life in patients with COPD and isolated sleep-related hypoxemia: a prospective, placebo-controlled cross-over trial. Pneumologie. 2008;62(1):11–6. doi: 10.1055/s-2007-980129.
    1. Chaouat A, Weitzenblum E, Kessler R, Charpentier C, Enrhart M, Schott R, Levi-Valensi P, Zielinski J, Delaunois L, Cornudella R, et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J. 1999;14(5):1002–8. doi: 10.1183/09031936.99.14510029.
    1. Fletcher EC, Luckett RA, Goodnight-White S, Miller CC, Qian W, Costarangos-Galarza C. 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(5):1070–6. doi: 10.1164/ajrccm/145.5.1070.
    1. Cranston JM, Crockett AJ, Moss JR, Alpers JH. Domiciliary oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;4
    1. Hosselet J, Ayappa I, Norman RG, Krieger AC, Rapoport DM. Classification of sleep-disordered breathing. Am J Respir Crit Care Med. 2001;163(2):398–405. doi: 10.1164/ajrccm.163.2.9808132.
    1. Levi-Valensi P, Weitzenblum E, Rida Z, Aubry P, Braghiroli A, Donner C, Aprill M, Zielinski J, Wurtemberger G. Sleep-related oxygen desaturation and daytime pulmonary haemodynamics in COPD patients. Eur Respir J. 1992;5(3):301–7.
    1. Lacasse Y, Series F, Martin S, Maltais F. Nocturnal oxygen therapy in patients with chronic obstructive pulmonary disease: a survey of Canadian pulmonologists. Can Respir J. 2007;14(6):343–8. doi: 10.1155/2007/487831.
    1. Lewis CA, Eaton TE, Fergusson W, Whyte KF, Garrett JE, Kolbe J. Home overnight pulse oximetry in patients with COPD: more than one recording may be needed. Chest. 2003;123(4):1127–33. doi: 10.1378/chest.123.4.1127.
    1. American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep. 1999;22(5):667–89. .
    1. Jensen HH, Godtfredsen NS, Lange P, Vestbo J. Potential misclassification of causes of death from COPD. Eur Respir J. 2006;28(4):781–5. doi: 10.1183/09031936.06.00152205.
    1. Ernst PP, Bourbeau J, Rainville B, Benayoun S, Suissa S. Underestimation of COPD as a cause of death. Eur Respir J. 2000;16(Suppl. 31):13s.
    1. Neff TA, Conway WA, Lakshiminarayan S. ACCP-NHLBI National Conference on oxygen therapy. Chest. 1984;86(2):234–47. doi: 10.1378/chest.86.2.234.
    1. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis. 1992;145(6):1321–7. doi: 10.1164/ajrccm/145.6.1321.
    1. Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J. 2002;19(3):398–404. doi: 10.1183/09031936.02.00063702.
    1. Schunemann HJ, Griffith L, Jaeschke R, Goldstein R, Stubbing D, Guyatt GH. 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(12):1170–6. doi: 10.1016/S0895-4356(03)00115-X.
    1. Ware JE, Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473–83. doi: 10.1097/00005650-199206000-00002.
    1. McHorney CA, Ware JE, Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31(3):247–63. doi: 10.1097/00005650-199303000-00006.
    1. Brazier J, Usherwood T, Harper R, Thomas K. Deriving a preference-based single index from the UK SF-36 Health Survey. J Clin Epidemiol. 1998;51(11):1115–28. doi: 10.1016/S0895-4356(98)00103-6.
    1. Nishimura K, Tsukino M. Clinical course and prognosis of patients with chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2000;6(2):127–32. doi: 10.1097/00063198-200003000-00008.
    1. Anthonisen NR, Wright EC, Hodgkin JE. Prognosis in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1986;133(1):14–20. doi: 10.1164/arrd.1986.133.1.14.
    1. Lachin JM. Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials. 1981;2(2):93–113. doi: 10.1016/0197-2456(81)90001-5.
    1. DAMOCLES_Study_Group A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet. 2005;365(9460):711–22. doi: 10.1016/S0140-6736(05)70939-9.
    1. Griffiths TL, Phillips CJ, Davies S, Burr ML, Campbell IA. Cost effectiveness of an outpatient multidisciplinary pulmonary rehabilitation programme. Thorax. 2001;56(10):779–84. doi: 10.1136/thorax.56.10.779.
    1. Montori VM, Permanyer-Miralda G, Ferreira-Gonzalez I, Busse JW, Pacheco-Huergo V, Bryant D, Alonso J, Akl EA, Domingo-Salvany A, Mills E, et al. Validity of composite end points in clinical trials. BMJ. 2005;330(7491):594–6. doi: 10.1136/bmj.330.7491.594.
    1. Ferreira-Gonzalez I, Busse JW, Heels-Ansdell D, Montori VM, Akl EA, Bryant DM, Alonso-Coello P, Alonso J, Worster A, Upadhye S, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334(7597):786. doi: 10.1136/.
    1. Lacasse Y, Bernard S, Martin S, Boivin M, Maltais F. Utility scores in patients with oxygen-dependent COPD: a case–control Study. COPD. 2015;12(5):510–5. doi: 10.3109/15412555.2014.995290.
    1. Tengs TO, Wallace A. One thousand health-related quality-of-life estimates. Med Care. 2000;38(6):583–637. doi: 10.1097/00005650-200006000-00004.
    1. Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med. 1985;6(4):651–61.
    1. Bednarek M, Plywaczewski R, Jonczak L, Zielinski J. There is no relationship between chronic obstructive pulmonary disease and obstructive sleep apnea syndrome: a population study. Respiration. 2005;72(2):142–9. doi: 10.1159/000084044.
    1. Masa JF, Montserrat JM, Duran J. Diagnostic access for sleep apnea in Spain. Am J Respir Crit Care Med. 2004;170(2):195. doi: 10.1164/ajrccm.170.2.950.
    1. Flemons WW, Douglas NJ, Kuna ST, Rodenstein DO, Wheatley J. Access to diagnosis and treatment of patients with suspected sleep apnea. Am J Respir Crit Care Med. 2004;169(6):668–72. doi: 10.1164/rccm.200308-1124PP.
    1. Scott AS, Baltzan MA, Wolkove N. Examination of pulse oximetry tracings to detect obstructive sleep apnea in patients with advanced chronic obstructive pulmonary disease. Can Respir J. 2014;21(3):171–5. doi: 10.1155/2014/948717.
    1. Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, Jemal A, Lee TA, Miravitlles M, et al. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J. 2006;27(1):188–207. doi: 10.1183/09031936.06.00024505.
    1. Chapman KR, Bourbeau J, Rance L. The burden of COPD in Canada: results from the Confronting COPD survey. Respir Med. 2003;97(Suppl C):S23–31. doi: 10.1016/S0954-6111(03)80022-7.
    1. Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, Marciniuk DD, Denberg T, Schunemann H, Wedzicha W, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179–91. doi: 10.7326/0003-4819-155-3-201108020-00008.
    1. GOLD. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2016. Available from: . Accessed 11 Dec 2016.
    1. Croxton TL, Weinmann GG, Senior RM, Wise RA, Crapo JD, Buist AS. Clinical research in chronic obstructive pulmonary disease: needs and opportunities. Am J Respir Crit Care Med. 2003;167(8):1142–9. doi: 10.1164/rccm.200207-756WS.
    1. Croxton TL, Bailey WC. Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for future research: an NHLBI workshop report. Am J Respir Crit Care Med. 2006;174(4):373–8. doi: 10.1164/rccm.200507-1161WS.

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