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Lancet. 2009 Aug 29;374(9691):685-94. doi: 10.1016/S0140-6736(09)61255-1.

Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.

Collaborators (1160)

Abdool-Gaffar MS, Abdullah IA, Abdullah I, Abernathy MG, Jaoude SA, Adler M, Agoro AB, Ahmad I, Ahmed M, Ahmed T, Ainsworth P, Aisanov Z, Aisiku I, Al-Asadi L, Alwine LK, Ambert L, Amer E, Amin D, Ancochea J, Anderson M, Andrews C, Anthony J, Antonovsky Y, Archuleta M, Ashley RG, Atkinson AR, Aubier, Awad N, Bailey A, Baker J, Baker AM, Bálint B, Balli EA, Baloira A, Bamberg R, Barber M, Barbers R, Bardin P, Bartkowiak A, Bateman E, Batura-Gabryel H, Baumbach R, Baz M, Beck E, Becker JC, Behiels S, Beliveau W, Bell C, Bensch G, Berlinches P, Bernabeu L, Bernstein DI, Bertley J, Bettendorf A, Bhargava S, Bishop G, Bitter-Suerman S, Blagden M, Blanquer R, Bleecker E, Blumenthal B, Bogdan M, Booth W, Boscia J, Botnick W, Boucher P, Boulytcheva N, Bowler S, Boyer GR, Boz D, Bradley JK, Brannen A, Bray W, Brazinsky SA, Brennan K, Brockmyre A, Brogan TA, Broker R, Brownlie R, Brüggen H, Bruya TE, Bure M, Burk JR, Butler JA, Caillaud D, Camosy P, Candal F, Carpenter K, Celdrán J, Centanni S, Cerveri I, Chanez P, Chang J, Chapman G, Chereyskaya NK, Chia M, Chinsky K, Chisdak M, Chrostowski D, Chuchalin A, Clay PG, Cohen K, Collette R, Collins KL, Confalonieri M, Cooper JA Jr, Cordasco E, Corley L 3rd, Corne, Corren J, Cote C, Coulet P, Covelli H, Cowen P, Cowie B, Craig TJ, Crothers E, Csanadi, Cukier A, Cummings A, Daly J, Daniel S, Darrah A, Daul C, Davis L, Viegas CA, De Busk C, de God I, DeGarmo RG, Delgado JP, Deslauriers G, Despot J, Parreno LD, Diamond E, DiMarco A, Dixon C, Dineen J, Doboszynska A, Doris J, Dransfield MT, D'Souza G, Dupouy J, D'Urzo A, Dvoretski L, Eade J, Eaton S, Echave J, Efimov AV, Egerton T, Elkayam D, Eller J, Ellison WT, Ellstrom K, Elton DR, Epstein JD, Erb D, Ettinger NA, Falcone F, Fei R, Fein E, Feldman G, Fennell DF, Fera T, Ferguson G, Ferguson L, Pereira LF, Feussner W, Fisher M, Fisher R, Fiss E, Fiterman J, Fitzgerald M, Fletcher EC, Fouquert L, Franklin P, Fritscher CC, Fritzsche A, Fuentes D, Fuentes F, Gabrys J, Gagnon M, Gainaru D, Galustyan A, Gaona RE Jr, de Vinuesa GG, Gauthier JS, Gehling U, Gentina T, Gibert W, Gillies J, Gilman RM, Ginns L, Girgis K, Given J, Gong H Jr, Gottschlich G, Gowda V, Grambau G, Greenwald G, Greenwald J, Grellier P, Gross N, Grunvald E, Gustman P, Haase PU, Hagaman D, Hamling J, Hammett D, Hanania N, Hansen V, Harat R, Harris J, Harris A, Hartmann R, Hellems S, Henderson W, Henry RE, Heredia JL, Herer B, Hetzel JL, Heyder AM, Hill D, Hiller FC 2nd, Hirani N, Höller W, Holmes M, Homik L, Horner SR, Horowitz ID, Howarth P, Hunt GW, Hyers T, Hyvernat P, Iqbal IM, Irusen EM, Ishina TI, Iyer RP, Jagannath K, Jain S, Jamnig H, Janes M, Jansen JJ, Jardim JR, Jayne J, Johnson C, Jones S, Joubert J, Journeay GE, Jullian H, Jumper C, Kaelin TD Jr, Kafé H, Kähler C, Kahn FW, Kaladas J, Kaplan A, Karpel J, Karrasch J, Katragadda S, Kawley FA, Kaye MG, Kecskés T, Keith P, Kelly A, Kelsen S, Kerkering M, Kerwin EM, Khronusova Y, Khurana S, Kimura SH, Kinch H, Kingsley J, Kleerup EC, Kleinsteuber WK, Knox A, Koenig S, Komlev A, Kooy J, Kopyt NP, Korduan M, Kormos T, Koser A, Koura F, Kovács L, Kovalski RJ, Kraft M, Krishna J, Krumpe P, Kuberka Z, Kumar TM, Kureishy S, Kuschner W, Kyle C, Lahasky D, Lakin G, Lam A, Lam S, Laman D, Lane E, Langan J, Lanier RC, Lapa JR, Larivée P, Larj M, Lasky J, Lau E, Laumen R, Lawless JF, Le Brozec B, Leduc JJ, Lee T, Lee D, Leeds W, Lejay D, Lenox R, Liebenberg GC, Liebman D, Linnhoff A, Lisberg EE, Liu MC, Llorca E, Lockey RF, Look DC 3rd, Ludwig-Sengpiel A, Lumry WR, Lundgren FL, Maggiacomo FP, Mahesh PA, Mahutte CK, Malanga A, Malik O, Maltais F, Mandel M, Manur A, Marciel R, Marcushamer S, Mark GA, Martinelli J, Martinez R, Mascolo M, Mazza G, Mc Coll I, McCaughey, McConnell J, McDavid R, McEvoy C, McFadden ER, McGoldrick H, McIvor A, McKinnon C, Meade A, Mello C, Mesquita AM, Meyer J, Meyer A, Mezey R, Millard MW, Miller D, Mirzai T, Mitlehner W, Moder G, Mollen M, Mooney P, Morelli J, Moriarty T, Morice A, Moser NJ, Mounier D, Muller D, Müller H, Murillo B, Murphy K, Nadeemullah M, Nagaraja C, Nalepa P, Nel A, Nelson HS, Newman J, Nielson R, Nikitins I, Niphadkar P, Nolen T, Nonikov V, Novojenov VG, Nussdorfer T, Obaray A, O'Brien JA, Oliveira J, Olivieri D, Olivieri M, Olson D, O'Mahony MF, O'Mahony W, Onder RF Jr, Ong S, Orpen I, Osea E, Pacin M, Panos RJ, Parker I, Patel A, Patil P, Pearle JL, Pecastaing G, Perera S, Pérez de Llano LA, Peters M, Peterson G, Pettenkofer J, Pfeifer MW, Phillips M, Piasecki R, Pierce K, Pierzchala W, Pieters R, Pigearias B, Pistolesi M, Pizzichini E, Player R, Póczi M, Pohl W, Polk O Jr, Popova V, Popovich K, Prabhu R, Prins M, Prokop-Staszecka A, Proninia S, Pudi K, Pue C, Pullman J, Raad GL, Rab-Hasan R, Rakvács M, Raman P, Ramraje N, Ras G, Rastogi P, Ratner P, Regula J, Rehman SM, Renzi P, Richmond GJ, Riff D, Robinson MT, Suarez JR, Rodriguez-Cintron W, Rossi A, Rousseau W, Sahasrabudhe T, Sahoo RC, Salvaterra C, Salvi S, Samson M, San Pedro G, Sánchez I, Toril FS, Sarnaik RM, Sarosi G, Sauer R, Savani D, Scanlon PD, Schachter EN, Schacter G, Schlezak J, Schneider D, Schroeder CE, Schuller D, Scott G, Seale P, Sedavnykh I, Sehgal S, Sellman R, Serrano JA, Sevette C, Shale D, Shapero P, Sharafkhaneh A, Sharma R, Shaver J, Sherman C, Sheski F, Sibille JS, Sidorenko IV, Sigal B, Silva RL, Silverthorn A, Simanenkov V, Singh V, Sinkowitz DM, Sirajuddeen S, Sitar S, Skobeloff E, Sligh T, Small D, Smith C, Snell P, Snyder B, Soler JJ, Soowamber M, Spanevello A, Spangenthal S, Srikanth K, Rao NS, Stang M, Steffen H, Steinfort C, Stewart GE, Stirbulov R, Stocks JM, Storms WW, Streit B, Struble R, Strzinek R, Stubbs RA, Sturm P, Sudhoff H, Suen J, Sussman R, Swarnakar R, Sweilem M, Szalai Z, Szlachcic Y, Szmidt M, Sztancsik Z, Tan R, Tanaseanu C, Tanasescu C, Tarpay M, Terlecka W, Terol B, Therrien R, Thien F, Thompson P, Thornton D, Tidman R, Tillinghast AJ, Tillis W, Timar M, Torres D 2nd, Trapp J, Trauth HA, Trebas-Pietras E, Truwit J, Turotte C, Tytus R, Updegrove JD, Vallieres C, Várkonyi I, Venske WU, Verkindre C, Viera E, Viljoen JJ, Vinkler I, Visser S, von Versen L, Voves R, Wade J, Wade TM, Wade TA, Wanderer A, Watz H, Webster DE, Weihrich A, Wesolowski S, Westney G, White MV, White A, Willsie SK, Winder JA, Wolfe R, Young D, Yusen R, Yusim JD, Zamel N, Ziedalski T, Zorina E, Zuck P, Zwetchkenbaum J, Seale P, Thompson P, Holmes M, Bardin P, Peters M, Phillips M, Chia M, Steinfort C, Nikitins I, Karrasch J, Bowler S, Thien T, Pohl W, Sweilem M, Voves R, Höller W, Moder G, Jamnig H, Kähler C, Fiss E, Cukier A, Jardim JR, Stirbulov R, Lapa JR, Pizzichini E, Fritscher CC, Fiterman J, Silva RL, Hetzel JL, Oliveira J, de Godoy I, Pereira LF, Marciel R, Viegas CA, Lundgren FL, Maltais F, Hirani N, Fera T, Gauthier JS, Bishop G, McIvor A, Zamel N, Larivée P, Booth W, Small D, Amer E, Gagnon M, Kelly A, Boucher P, Homik L, Renzi P, Kooy J, Anthony J, Keith P, Lau E, O'Mahony MF, Soowamber M, D'Urzo A, Deslauriers G, Lam A, Marcushamer S, Mazza G, O'Mahony W, Lam S, Tytus R, Behiels S, Iyer RP, Schacter G, Therrien R, Collette R, Turotte C, Bailey A, Cowie B, Ferguson L, Vallieres C, Bertley J, Kaplan A, Atkinson AR, Csanadi, Chanez P, Aubier, Sevette C, Hyvernat P, Zuck P, Pecastaing G, Kafé H, Dupouy J, Coulet P, Pigearias B, Le Brozec B, Jullian H, Lejay D, Dominique L, Grellier P, Fouquert L, Boyer GR, Bernabeu L, Verkindre C, Bettendorf A, Bure M, Herer B, Gentina T, Caillaud D, Boz D, Mounier D, Le Brozec B, Muller D, Terol B, Leduc JJ, Feussner W, Trauth HA, Gehling U, Brüggen H, Laumen R, Becker JC, Steffen H, Venske WU, Linnhoff A, Korduan M, von Versen L, Pettenkofer J, Mitlehner W, Eller J, Hartmann R, Fritzsche A, Bitter-Suermann S, Watz H, Beck E, Ludwig-Sengpiel A, Sudhoff H, Weihrich A, Sauer R, Haase PU, Pfeifer MW, Müller H, Bamberg R, Póczi M, Szalai Z, Timar M, Várkonyi I, Schlezak J, Sztancsik Z, Bálint B, Kormos T, Rakvács M, Vinkler I, Kecskés T, Kuberka Z, Kovács L, Awad N, Singh V, D'Souza G, Kumar TM, Raman P, Mesquita AM, Jagannath K, Srikanth K, Niphadkar P, Saho RC, Nagaraja C, Patil P, Rao NS, Ramraje N, Salvi S, Sarnaik RM, Gowda V, Sirajuddeen S, Mahesh PA, Sahasrabudhe T, Swarnakar R, Bhargava S, Olivieri D, Falcone F, Rossi A, Confalonieri M, Cerveri I, Centanni S, Pistolesi M, Donner C, Olivieri M, Spanevello A, Gillies J, Trebas-Pietras E, Doboszynska A, Szmidt M, Terlecka W, Pierzchala W, Wesolowski S, Gabrys J, Harat R, Prokop-Staszecka A, Batura-Gabryel H, Regula J, Nalepa P, Tanaseanu C, Tanasescu C, Bogdan M, Gainaru D, Ambert L, Proninia S, Ishina TI, Antonovsky Y, Sedavnykh I, Boulytcheva N, Dvoretski L, Komlev A, Chuchalin A, Zorina E, Nonikov V, Sidorenko IV, Galustyan A, Simanenkov V, Popova V, Chereyskaya NK, Novojenov VG, Aisanov Z, Efimov AV, Prins M, Bateman E, Jansen JJ, Nel A, Joubert J, Abdullah IA, Abdool-Gaffar MS, Visser S, Ras G, Abdullah I, Liebenberg GC, Viljoen JJ, Iruse EM, O'Brien JA, Sánchez I, Ancochea J, Echave J, Celdrán J, Suarez JR, Berlinches P, Heredia JL, Llorca E, Toril FS, de Vinuesa GG, Fuentes F, Blanquer R, Soler JJ, Serrano JA, Baloira A, Parreno LD, de Llano LA, Adler M, Knox A, Blagden M, Hamling J, Mooney P, Howarth P, McKinnon C, Langan J, Brownlie R, Calverley P, Ainsworth P, Orpen I, Manur A, Egerton T, Chapman G, Pieters R, Anderson M, Crothers E, McGoldrick H, Morice A, Kyle C, Corne, Parker I, Mc Coll I, McCaughey, Kinch H, Dixon C, Cummings A, Darrah A, Shale D, Sharma R, Cordasco E, Jaoude SA, Corren J, Elkayam D, Greenwald G, Harris J, Pacin M, Candal F, Sellman R, Koenig S, Truwit J, Brazinsky SA, Ettinger NA, Sussman R, Liu MC, Lumry WR, Baker J, Lee T, Horowitz ID, Murphy K, Wolfe R, Daul C, Gottschlich G, Greenwald J, Journeay GE, Shapero P, Sibille JS, Maggiacomo FP, Cote C, Bleecker E, Lahasky D, Sherman C, Gilman RM, Gross N, Olson D, Kahn FW, Brennan K, Krumpe P, Pearle JL, Bray W, Moriarty T, Kleinsteuber WK, Trapp J, Lasky J, Mello C, Tan R, Kaye MG, Stang M, Covelli H, Snyder B, Peterson G, White MV, Henderson W, Blumenthal B, Brogan TA, Schroeder CE, Bradley JK, Raad GL, Popovich K, Ashley RG, Chisdak M, Zwetchkenbaum J, Sigal B, Hyers T, Hanania N, Richmond GJ, Broker R, San Pedro G, Samson M, Scott G, Heyder AM, Updegrove JD, Archuleta M, Erb D, Lakin G, Davis L, Nolen T, Burk JR, Fuentes D, Martinez R, Millard MW, Sharafkhaneh A, Webster DE, Fennell DF, Lane E, Mandel M, Martinelli J, Struble R, Cowen P, Kimura SH, Feldman G, Gibert W, Ong S, Patel A, Pudi K, Rab-Hasan R, Robinson MT, Aisiku I, Despot J, DiMarco A, Girgis K, Sinkowitz DM, Strzinek R, Thornton D, McFadden ER, Alwine LK, Delgado JP, Kuschner W, Elton DR, Bruya TE, Mirzai T, Miller D, Snell P, McEvoy C, Piasecki R, Rastogi P, Harris A, Player R, Ahmad I, Chrostowski D, Cohen K, Doris J, Fei R, Ferguson G, Gong H Jr, Szlachcic Y, Hellems S, Johnson C, Kopyt NP, Kovalski RJ, Kraft M, Lockey RF, Ahmed M, Mark GA, Fisher M, Kleerup EC, Panos RJ, Bartkowiak A, Lanier RC, Bell C, Larj M, Liebman D, Brannen A, Murillo B, Nielson R, Dineen J, Brockmyre A, Shaver J, Stubbs RA, Grunvald E, Wade J, Gustman P, Jumper C, Butler JA, Ellstrom K, Rodriguez-Cintron W, Ginns L, Sehgal S, Fein E, Barbers R, McConnell J, Moser NJ, Nussdorfer T, Yusen R, Krishna J, Rousseau W, Kingsley J, Mascolo M, Meyer J, Ziedalski T, Westney G, Rehman SM, Sturm P, Sheski F, Silverthorn A, Sitar S, Agoro AB, Tillinghast AJ, Savani D, Schuller D, Stewart GE, Bernstein DI, Nelson HS, Skobeloff E, Winder JA, Beliveau W, Diamond E, Andrews C, Craig TJ, Kerwin EM, Bensch G, Lisberg EE, White A, Kaladas J, Pullman J, Gaona RE Jr, Willsie SK, Clay PG, Hill D, Ratner P, Kaelin T Jr, Ellison WT, Baker AM, Tidman R, Ahmed T, Cooper JA Jr, Epstein JD, Hiller FC 2nd, Horner SR, Karpel J, Kelsen S, Mahutte CK, Hagaman D, Spangenthal S, Amin D, Hunt GW, Kawley FA, Tarpay M, Given J, Eaton S, Jayne J, Janes M, Baz M, Baumbach R, Wanderer A, Pierce K, Carpenter K, Onder RF Jr, Henry RE, Eade J, Khronusova Y, Chinsky K, Mollen M, DeGarmo RG, Perera S, Dransfield MT, Smith C, Stocks JM, Collins KL, Fitzgerald M, Storms WW, Torres D 2nd, Scanlon PD, Osea E, Streit B, Botnick W, Viera E, Look DC 3rd, Riff D, Sligh T, Camosy P, Boscia J, Fisher R, Al-Asadi L, Balli EA, Barber M, Corley L 3rd, Daniel S, Fletcher EC, Franklin P, Grambau G, Iqbal IM, Kerkering M, Kureishy S, Lawless JF, Nadeemullah M, Newman J, Yusim JD, Wade TM, Young D, De Busk C, Katragadda S, Koura F, Laman D, Lee D, Lenox R, Malik O, Leeds W, Meyer A, Prabhu R, Schneider D, Jones S, Daly J, Khurana S, Obaray A, Salvaterra C, Wade TA, Hammett D, Hansen V, Jain S, Malanga A, Sarosi G, Tillis W, Suen J, Abernathy MG, Mezey R, McDavid R, Pue C, Meade A, Morelli J, Polk O Jr, Koser A.

Erratum in

  • Lancet. 2010 Oct 2;376(9747):1146.

Abstract

BACKGROUND:

The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD.

METHODS:

In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 microg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125.

FINDINGS:

Patients were assigned to treatment, stratified according to smoking status and treatment with longacting beta(2) agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV(1) increased by 48 mL with roflumilast compared with placebo (p<0.0001). The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast and 1.37 with placebo (reduction 17% [95% CI 8-25], p<0.0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was -2.17 kg.

INTERPRETATION:

Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies.

FUNDING:

Nycomed.

PMID:
19716960
DOI:
10.1016/S0140-6736(09)61255-1
[Indexed for MEDLINE]
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