Supplementary webappendixThis webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Calverley PMA, Rabe KF, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374: 685–94.

1

Webappendix

Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised

clinical trials

Peter M A Calverley,* Klaus F Rabe,* Udo-Michael Goehring, Søren Kristiansen, Leonardo M Fabbri,† Fernando J Martinez,† for the

M2-124 and M2-125 study groups

*First authors

†Last authors

School of Clinical Sciences, Liverpool, UK (Prof P M A Calverley MD); University of Michigan Health System, Ann Arbor, MI, USA (Prof

F J Martinez MD); University of Modena and Reggio Emilia, Modena, Italy (Prof L M Fabbri MD); Leiden University Medical Centre,

Leiden, Netherlands (Prof K F Rabe MD PhD); and Nycomed, Konstanz, Germany (U-M Goehring MD, S Kristiansen PhD)

Contents Collaborators

Investigators in the M2-124 and M2-125 trials

On-line Table 1. Primary and secondary endpoints for study M2-124 and study M2-125

On-line Table 2: Exclusion criteria for M2-124 and M2-125 studies

On-line Table 3: Countries involved in the M2-124 and M2-125 studies

On-line Table 4. A) An analysis of FEV1 for the subgroup of completers based on the repeated measures analysis of covariance model. B) A

Poisson regression analysis of annualised exacerbation rate for the subgroup of completers.

On-line Table 5. Body weight changes from baseline to last visit in pooled data from M2-124 and M2-125 A) patients with or without

gastrointestinal adverse events and/or headache and B) change in body weight (kg) by body-mass index (BMI) at baseline.

On-line Table 6: Point estimate (according to Hodges-Lehmann; HL) change from baseline to last measurement in mean heart rate in

patients in roflumilast and placebo groups at selected sites in study M2-125

On-line Table 7: Difference in point estimate (according to Hodges-Lehmann; HL) change from baseline to last measurement in mean heart

rate between patients in the roflumilast and placebo groups at selected sites in study M2-125.

On-line Table 8: Frequency of permanent atrial fibrillation at baseline and at patient’s last visit in patients in the roflumilast and placebo

groups at selected sites in study M2-125

On-line Table 9: Routine laboratory data for biochemistry and haematology values in A) the M2-124 study and B) the M2-125 study (the

variables were ordered alphabetically by biochemistry first and then haematology)

Sample patient diary card

2

Collaborators (578) Mohamed Sabeer Abdool-Gaffar, Ismail Aboobaker Abdullah, Ismail Abdullah, M. Glenn Abernathy, Salim Abou Jaoude, Martin Adler,

Adesubomi B. Agoro, Imtiaz Ahmad, Magbool Ahmed, Tahir Ahmed, Paul Ainsworth, Zaurbek Aisanov, Imu Aisiku, Lo'ay Al-Asadi,

Lawrence K. Alwine, Luminita Ambert, Emad Amer, Devendra Amin, Julio Ancochea, M Anderson, Charles Andrews, John Anthony,

Yury Antonovsky, Maurice Archuleta, Robert Grady Ashley, Anthony R. Atkinson, Aubier, Nilkanth Awad, Allan Bailey, James Baker,

Albert M. Baker, Beatrix Bálint, Edward A. Balli, Adolfo Baloira, Rainer Bamberg, Mark Barber, Richard Barbers, Philip Bardin, Anthony

Bartkowiak, Eric Bateman, Halina Batura-Gabryel, Rebecca Baumbach, Malik Baz, Ekkehard Beck, Jens C. Becker, Stewart Behiels,

William Beliveau, Cyntia Bell, George Bensch, Pilar Berlinches, Lucien Bernabeu, David I. Bernstein, John Bertley, Alain Bettendorf, Salil

Bhargava, Graham Bishop, Stephanie Bitter-Suermann, Mark Blagden, Rafael Blanquer, Eugene Bleecker, Barry Blumenthal, Miron

Bogdan, William Booth, Joseph Boscia, Warren Botnick, Pierre Boucher, Nina Boulytcheva, Simon Bowler, Guy-René Boyer, Dominique

Boz, James K. Bradley, Alfred Brannen, Wesley Bray, Shari Anne Brazinsky, Kathleen Brennan, Andrew Brockmyre, Terri-Ann Brogan,

Robert Broker, Robert Brownlie, Hans Brüggen, Timothy E Bruya, Marc Bure, John R. Burk, John A. Butler, Denis Caillaud, Pamela

Camosy, Francisco Candal, Kent Carpenter, José Celdrán, Stefano Centanni, Isa Cerveri, Pascal Chanez, Jacqueline Chang, Glyn Chapman,

Nataliya Konstantinovna Chereyskaya, Michael Chia, Kenneth Chinsky, Michael Chisdak, Dariusz Chrostowski, Aleksandr Chuchalin,

Patrick G. Clay, Kenneth Cohen, Ronald Collette, Kathleen L. Collins, Marco Confalonieri, J. Allen D. Cooper, Jr., Edward Cordasco,

Luther Corley, lll, Corne, Jonathan Corren, Claudia Cote, Pierre Coulet, Henry Covelli, Peter Cowen, Bob Cowie, Timothy J. Craig, Elsbeth

Crothers, Csanadi, Alberto Cukier, Andrea Cummings, James Daly, Suresh Daniel, Adrian Darrah, Carolyn Daul, Leon Davis, Carlos

Alberto De Assis Viegas, Charles De Busk, Irma de Godoy, Ronald G DeGarmo, John P. Delgado, Guy Deslauriers, Janet Despot, Luis De-

Teresa Parreno, Edward Diamond, Anthony DiMarco, Christopher Dixon, John Dineen, Anna Doboszynska, James Doris, Mark T

Dransfield, George D'Souza, Jacques Dupouy, Anthony D'Urzo, Leonid Dvoretski, Joel Eade, Stephanie Eaton, José Echave, Andrey

Vladimirovich Efimov, Tony Egerton, David Elkayam, Jörg Eller, W. Travis Ellison, Kathi Ellstrom, Donald R. Elton, Joel D. Epstein,

David Erb, Neil A. Ettinger, Franco Falcone, Richard Fei, Edward Fein, Gregory Feldman, Dan F. Fennell, Tharwat Fera, Gary Ferguson,

Linda Ferguson, Luiz Fernando Ferreira Pereira, Wolfram Feußner, Mark Fisher, Robert Fisher, Elie Fiss, Jussara Fiterman, Mark

Fitzgerald, Eugene C. Fletcher, Laurent Fouquert, Peter Franklin, Carlos Cezar Fritscher, Andreas Fritzsche, David Fuentes, Fernando

Fuentes, Jacek Gabrys, Michel Gagnon, Dan Gainaru, Anna Galustyan, Raul E. Gaona, Jr., German Garcia de Vinuesa, Jean Sébastien

Gauthier, Umberto Gehling, Thibaut Gentina, Wayne Gibert, Johen Gillies, Ronald M. Gilman, Loenard Ginns, Khalad Girgis, John Given,

Henry Gong Jr., Gregory Gottschlich, Veeranna Gowda, Geoffrey Grambau, Gary Greenwald, James Greenwald, Philippe Grellier, Nicholas

Gross, Eduardo Grunvald, Paul Gustman, Peter-Uwe Haase, David Hagaman, Jonathan Hamling, Don Hammett, Nicola Hanania, Val

Hansen, Rafal Harat, James Harris, Anthony Harris, Robert Hartmann, Stephen Hellems, William Henderson, Richard E. Henry, Jose Luis

Heredia, Bertrand Herer, Jorge Lima Hetzel, Albrecht M. Heyder, David Hill, Frederick Charles Hiller, ll, Nausad Hirani, Wolfgang Höller,

Mark Holmes, Lawrence Homik, Stanley R. Horner, Ira D. Horowitz, Peter Howarth, Gary W. Hunt, Thomas Hyers, Patrick Hyvernat, Ijaz

M. Iqbal, E. M. Irusen, Tatyana Ivanova Ishina, Rama Padmanabhan Iyer, K. Jagannath, Subin Jain, Herbert Jamnig, Mark Janes, Jacob J.

Jansen, José Roberto De Brito Jardim, John Jayne, Carol Johnson, Stephen Jones, James Joubert, Glen E. Journeay, Herve Jullian, Cynthia

Jumper, Thomas D. Kaelin, Jr., Henri Kafé, Christian Kähler, Frederick W. Kahn, Jeffrey Kaladas, Allen Kaplan, Jill Karpel, Jeff Karrasch,

Srinivas Katragadda, Fadi Adam Kawley, Mitchell G. Kaye, Teréz Kecskés, Paul Keith, Allan Kelly, Steven Kelsen, Michael Kerkering,

Edward M. Kerwin, Yekaterina Khronusova, Sandhya Khurana, Stephan H. Kimura, H. Kinch, Jeffrey Kingsley, Eric Christophoer Kleerup,

W. Ken Kleinsteuber, Alan Knox, Steven Koenig, Alexander Komlev, Jack Kooy, Nelson P. Kopyt, Margit Korduan, Tamas Kormos,

Andreas Koser, Firas Koura, László Kovács, Raymond J. Kovalski, Monica Kraft, Jeevana Krishna, Peter Krumpe, Zoltan Kuberka, T.

Mohan Kumar, Shahrukh Kureishy, Ware Kuschner, Christopher Kyle, David Lahasky, Greg Lakin, Andy Lam, Sy Lam, David Laman,

Edward Lane, John Langan, Randall C. Lanier, José Roberto Lapa, Pierre Larivée, Michael Larj, Joe Lasky, Edgar Lau, Reiner Laumen,

James F. Lawless, Bernard Le Brozec, Jean-Jacques Leduc, Theodore Lee, Daniel Lee, William Leeds, Dominique Lejay, Robert Lenox,

Gysbert Charl Liebenberg, David Liebman, Anneliese Linnhoff, Edward E. Lisberg, Mark C. Liu, Eleuterio Llorca, Richard F. Lockey,

Dwight C. Look lll, Andrea Ludwig-Sengpiel, William R. Lumry, Fernando Luiz Cavalcante Lundgren, Frank P. Maggiacomo, P. A.

Mahesh, C. Kees Mahutte, Anthony Malanga, Osman Malik, Francois Maltais, Michael Mandel, Adel Manur, Renato Marciel, Samuel

Marcushamer, George A. Mark, Joseph Martinelli, Richard Martinez, Maria Mascolo, Giuseppe Mazza, I. Mc Coll, McCaughey, John

McConnell, Richard McDavid, Charlene McEvoy, E. Regis McFadden, Hugh McGoldrick, Andrew McIvor, Carol McKinnon, Arturo

Meade, Curtis Mello, A. M. Mesquita, James Meyer, Armin Meyer, Robert Mezey, Mark W. Millard, David Miller, Thomas Mirzai,

Wolfgang Mitlehner, Gernot Moder, Martin Mollen, Peter Mooney, Joseph Morelli, Timothy Moriarty, A. Morice, Neal J. Moser,

Dominique Mounier, Dominique Muller, Hilger Müller, Boris Murillo, Kevin Murphy, Mohammed Nadeemullah, C. Nagaraja, Piotr

Nalepa, Analene Nel, Harold S. Nelson, Jeffrey Newman, Richard Nielson, Igor Nikitins, Pramod Niphadkar, Thomas Nolen, Vladimir

3

Nonikov, Vladislav Grigorievich Novojenov, Thomas Nussdorfer, Akbar Obaray, J. A. O'Brien, Júlio Oliveira, Dario Olivieri, Mario

Olivieri, Dan Olson, Michael F. J. O'Mahony, William O'Mahony, Robert F. Onder Jr., Stephan Ong, Ian Orpen, Edgardo Osea, Michael

Pacin, Ralph J. Panos, Ian Parker, Amit Patel, Prashant Patil, James L. Pearle, Georges Pecastaing, Sunil Perera, Luis Alejandro Pérez de

Llano, Matthew Peters, Gregory Peterson, Joachim Pettenkofer, Michael W. Pfeifer, Martin Phillips, Robert Piasecki, Keith Pierce,

Wladyslaw Pierzchala, Ronald Pieters, Bernard Pigearias, Massimo Pistolesi, Emilio Pizzichini, Rick Player, Magdolna Póczi, Wolfgang

Pohl, Octavius Polk, Jr., Veronika Popova, Keith Popovich, Rachakonda Prabhu, M. Prins, Anna Prokop-Staszecka, Svetlana Proninia,

Krishna Pudi, Charles Pue, John Pullman, George Louis Raad, Rana Rab-Hasan, Marianna Rakvács, Pattabhi Raman, N. Ramraje, Gerhard

Ras, Praveen Rastogi, Paul Ratner, Janusz Regula, Syed M. Rehman, Paolo Renzi, Gary J. Richmond, Dennis Riff, Michael T. Robinson,

Jose Ramon Rodriguez Suarez, William Rodriguez-Cintron, Andrea Rossi, Wyatt Rousseau, Tushar Sahasrabudhe, R. C. Sahoo, Carmen

Salvaterra, Sundeep Salvi, Mercedes Samson, Gerardo San Pedro, Ignacio Sánchez, Fernando Sànchez Toril, R. M. Sarnaik, George Sarosi,

Rüdiger Sauer, Davang Savani, Paul D. Scanlon, E. Neil Schachter, Gordon Schacter, Judit Schlezak, David Schneider, C. Eric Schroeder,

Dan Schuller, Graham Scott, Paul Seale, Irina Sedavnykh, Sudhir Sehgal, Richard Sellman, José Antonio Serrano, Christian Sevette, Dennis

Shale, Paul Shapero, Amir Sharafkhaneh, Raj Sharma, Joseph Shaver, Charles Sherman, Francis Sheski, John Scott Sibille, Irina V.

Sidorenko, Barry Sigal, Rodney Luiz Frare Silva, Amy Silverthorn, Vladimir Simanenkov, Virendra Singh, Deren M. Sinkowitz, Sayed

Sirajuddeen, Steve Sitar, Emil Skobeloff, Teresa Sligh, David Small, Christopher Smith, Philip Snell, Brian Snyder, Juan Jose Soler,

Mohunlall Soowamber, Antonio Spanevello, Selwyn Spangenthal, K. Srikanth, Nanyam Srinivaso Rao, Mark Stang, Heiner Steffen, Chris

Steinfort, George E. Stewart, Roberto Stirbulov, James M. Stocks, William W. Storms, Barry Streit, Russel Struble, Robert Strzinek, Randy

A. S. Stubbs, Patrick Sturm, Harald Sudhoff, John Suen, Robert Sussman, Rajesh Swarnakar, Mahmud Sweilem, Zsuzsanna Szalai, Yaga

Szlachcic, Miroslaw Szmidt, Zsuzsanna Sztancsik, Ricardo Tan, Cristina Tanaseanu, Coman Tanasescu, Martha Tarpay, Wanda Terlecka,

Bernard Terol, Rene Therrien, Frank Thien, Philip Thompson, David Thornton, Ray Tidman, A. Judson Tillinghast, William Tillis, Mihaly

Timar, Diego Torres II, John Trapp, Hermann A. Trauth, Ewa Trebas-Pietras, Jonathon Truwit, Chantal Turotte, Richard Tytus, John D.

Updegrove, Camil Vallieres, István Várkonyi, Wolf-Uwe Venske, Christophe Verkindre, Eduardo Viera, Johann J. Viljoen, Ilona Vinkler,

Sanet Visser, Lutz von Versen, Robert Voves, John Wade, Thomas M. Wade, Thomas A. Wade, Alan Wanderer, Henrik Watz, Dave E.

Webster, Anette Weihrich, Stefan Wesolowski, Gloria Westney, Martha V. White, Alexander White, Sandra K. Willsie, John A. Winder,

Robert Wolfe, Douglas Young, Roger Yusen, Jeffrey D. Yusim, Noe Zamel, Tomasz Ziedalski, Ekaterina Zorina, Pierre Zuck, John

Zwetchkenbaum

4

Investigators in the M2-124 and M2-125 trials

Australia Paul Seale, Royal Prince Alfred Hospital; Philip Thompson, Sir Charles Gairdner Hospital; Mark Holmes, Royal Adelaide Hospital; Philip

Bardin, Monash Medical Centre; Matthew Peters, Concord Repatriation General Hospital; Martin Phillips, Sir Charles Gairdner Hospital;

Michael Chia, Burnside War Memorial Hospital; Chris Steinfort, Geelong Clinical Research Centre; Igor Nikitins, Adelaide Medical

Research; Jeff Karrasch, Peninsula Clinical Research Centre; Simon Bowler, Mater Medical Centre; Frank Thien, Epworth Eastern Medical

Centre

Austria Wolfgang Pohl, Gänserndorf; Mahmud Sweilem, Hallein; Robert Voves, Feldbach; Wolfgang Höller, Linz; Gernot Moder, Spittal an der

Drau; Herbert Jamnig, Natters; Christian Kähler, Innsbruck

Brazil Elie Fiss, Faculdade de Medicina do ABC; Alberto Cukier, Hospital das Clínicas Uni. SP / INCOR; José Roberto De Brito Jardim, Hospital

São Paulo EPM-UNIFESP; Roberto Stirbulov, Irmandade Santa Casa de Misericórdia-SP; José Roberto Lapa, Hospital Universitário

Clementino -UFRJ; Emilio Pizzichini, Hospital Universitário - UFSC; Carlos Cezar Fritscher, Hospital São Lucas - PUC-RS; Jussara

Fiterman, Hosp. de Clínicas de Porto Alegre HC-RS; Rodney Luiz Frare Silva, Hosp. de Clín. Univ. Fed. Parana -UFPR; Jorge Lima

Hetzel, Imandada Santa Casa de Misericórdia; Júlio Oliveira, Universidade Federal de Juiz de Fora; Irma de Godoy, Faculdade de Medicina

de Botucatu - UNES; Luiz Fernando Ferreira Pereira, Faculdade de Medicina da Universidade; Renato Marciel, IPSEMG Hospital

Governador Pinhairo; Carlos Alberto De Assis Viegas, Hospital Universitário de Brasília; Fernando Luiz Cavalcante Lundgren, Hospital

Otávio de Freitas

Canada Francois Maltais, Hospital Laval; Nausad Hirani, Calgary General Hospital; Tharwat Fera, Sherbrooke, QC; Jean Sébastien Gauthier, Q & T

Research; Graham Bishop, Dr. Graham Bishop; Andrew McIvor, St. Joseph's Hospital-McMaster Universit; Noe Zamel, Mount Sinai

Hospital; Pierre Larivée, Universite de Sherbrooke; William Booth, Antigonish; David Small, SMBD Jewish General Hospital; Emad Amer,

Mississauga, ON; Michel Gagnon, CHUM Notre-Dame Hospital; Allan Kelly, Hermitage Medical Centre; Pierre Boucher, Invascor Clincal

Research; Lawrence Homik, Concordia Hospital; Paolo Renzi, Centre de recherche du CHUM; Jack Kooy, PCT Networks Inc.; John

Anthony, Scarborough,ON; Paul Keith, MCMaster University Health Sciences; Edgar Lau, Richmond Health Services; Michael F. J.

O'Mahony, London Road Diagn. Clinic & Med.Centre; Mohunlall Soowamber, Scarborough,ON; Anthony D'Urzo, Primary Care Lung

Clinic; Guy Deslauriers, St-Jerome; Andy Lam, West Lincoln Memorial Hospital; Samuel Marcushamer, Edmonton; Giuseppe Mazza,

Clinique Medicale Langelier; William O'Mahony, Corruna Research Centre; Sy Lam, Calgary West Medical Center; Richard Tytus,

Hamilton Medical Research Group; Stewart Behiels, Belvedere Medicentre; Rama Padmanabhan Iyer, Chatham, ON; Gordon Schacter,

London, ON; Rene Therrien, Centre de Rhumatologie St. Louis; Ronald Collette, Burnaby, BC; Chantal Turotte, Mediclub; Allan Bailey,

BioQuest Research; Bob Cowie, Calgary, Alberta; Linda Ferguson, Colchester Research Group; Camil Vallieres, Pro-Research,

Polyclinique des Ponts; John Bertley, St. Catharines; Allen Kaplan, Richmond Hill; Anthony R. Atkinson, Bridgewater; Csanadi, Fort Erie

France Pascal Chanez, Hôpital Arnaud de Villeneuve; Aubier, Hôpital Bichat; Christian Sevette, Centre Hospitalier; Patrick Hyvernat, Cabinet

Hyvernat; Pierre Zuck, Hôpital du Bon Secours; Georges Pecastaing, Cabinet Médical; Henri Kafé, Cabinet de Pneumologie; Jacques

Dupouy, Cabinet de Pneumologie; Pierre Coulet, Cabinet de Pneumologie; Bernard Pigearias, Cabinet de Pneumologie; Bernard Le Brozec,

Cabinet de Pneumologie; Herve Jullian, Centre Hospitalier General; Dominique Lejay, Lejay Dominique; Philippe Grellier, Clinique les

Fleurs; Laurent Fouquert, Cabinet de Pneumologie; Guy-René Boyer, Centre de Consultation; Lucien Bernabeu, Centre Hospitalier de

Chauny; Christophe Verkindre, Centre Hospitalier de Béthune; Alain Bettendorf, Dr. Alain Bettendorf; Marc Bure, CH Lens; Bertrand

Herer, Centre des Forcilles; Thibaut Gentina, Cabinet de Pneumologie / Allergologie; Denis Caillaud, C.H.U. Clermont-Ferrand, Hopital;

Dominique Boz, Dr. Marc Denis; Dominique Mounier, Dr Dominique MOUNIER; Bernard Le Brozec, Dr. Le Brozec Bernard; Dominique

Muller, Dr. Dominique Muller; Bernard TEROL, Cabinet Médical; Jean-Jacques LEDUC, Hôpital Saint Vincent de Pau

5

Germany Wolfram Feußner, Kassel; Hermann A. Trauth, Marburg; Umberto Gehling, Schwetzingen; Hans Brüggen, Deggendorf; Reiner Laumen,

Fulda; Jens C. Becker, Lübeck; Heiner Steffen, Landsberg/Lech; Wolf-Uwe Venske, Oschersleben; Anneliese Linnhoff, Berlin; Margit

Korduan, Berlin; Lutz von Versen, Berlin; Joachim Pettenkofer, Berlin; Wolfgang Mitlehner, Berlin; Jörg Eller, Berlin; Robert Hartmann,

Regensburg; Andreas Fritzsche, Berlin; Stephanie Bitter-Suermann, Hamburg; Henrik Watz, Hamburg; Ekkehard Beck, Rüdersdorf; Andrea

Ludwig-Sengpiel, Großhansdorf; Harald Sudhoff, Berlin; Anette Weihrich, Neuruppin; Rüdiger Sauer, Ulm; Peter-Uwe Haase, Halle;

Michael W. Pfeifer, Donaustauf; Hilger Müller, Potsdam; Rainer Bamberg, Potsdam

Hungary Magdolna Póczi, Dr.Kenessey Albert Kórház Rendelointézet; Zsuzsanna Szalai, Karolina Hospital a. Outpatients Clinic; Mihaly Timar,

Magyar Honvedseg Központi Honvedkorhaz; István Várkonyi, Kenézy Gyula Kórház; Judit Schlezak, Selye Janos Korhaz RI.; Zsuzsanna

Sztancsik, Bekes Megyei Kepviselo Tudokorhaza; Beatrix Bálint, Csongrad Megyei Onkormanyzat Szakkorhaza; Tamas Kormos, Fövárosi

Bajcsy Zsilinszky Kórház; Marianna Rakvács, Magyarorszagi Reformatus Egyhaz Mosdosi; Ilona Vinkler, SzSzB Megyei Önkormányzat;

Teréz Kecskés, Egyesített Egészségügyi Intézmények; Zoltan Kuberka, Gyógyír XI. Kht.; László Kovács, Városi Kórház Rendelöintézet

India Nilkanth Awad, LTMG (Sion) Hospital; Virendra Singh, SMS Hospital (Consultation Office); George D'Souza, St. Johns Medical College

& Hospital; T Mohan Kumar, Shree Ramakrishna Hospital; Pattabhi Raman, Kovai Medical Centre & Hospital; A. M. Mesquita, Goa

Medical College; K. Jagannath, Chennai Thoracic Research Institute; K. Srikanth, PSG Hospitals; Pramod Niphadkar, Asthma & Allergy

Centre; R. C. Sahoo, KMC Hospital; C. Nagaraja, Rajiv Gandhi Institute; Prashant Patil, Government Medical College; Nanyam Srinivaso

Rao, Osmania General Hospital; N. Ramraje, JJ Group of Hospitals; Sundeep Salvi, Chest Research Foundation; R. M. Sarnaik, Leela

Mores Chest Clinic; Veeranna Gowda, Victoria Hospital; Sayed Sirajuddeen, Yenopaya Medical College Hospital; P. A. Mahesh, Allergy,

Asthma & Chest Center; Tushar Sahasrabudhe, Opposite Ramakrishna More Auditorium; Rajesh Swarnakar, Get Well Hospital & Research

Institute; Salil Bhargava, Gyan Pushp Research Center for Chest & A

Italy Dario Olivieri, Ospedale Rasori; Franco Falcone, Ospedale Bellaria-Azienda USL, Citta di; Andrea Rossi, Ospedali Riuniti di Bergamo;

Marco Confalonieri, Ospedale Cattinara; Isa Cerveri, Policlinico San Matteo; Stefano Centanni, Ospedale San Paolo; Massimo Pistolesi, AO

Careggi; Claudio Donner, Fond.Maugeri,IRCCS-Inst.Scient.diVeruno; Mario Olivieri, Policlinico G.B.Rossi; Antonio Spanevello,

Fondazione S.Maugeri

New Zealand Johen Gillies, P3 Research Ltd

Poland Ewa Trebas-Pietras, Wojewodzki Szpital im. Kardynala; Anna Doboszynska, Cent. Leczniczo-Rehabilitacyjne; Miroslaw Szmidt,

Wojewodzki Szpital Specjalis.; Wanda Terlecka, Wojewodzki Szpital Specjalisty; Wladyslaw Pierzchala, Klinika Pneumonologii; Stefan

Wesolowski, Instytut Grulicy I Chorób Puc; Jacek Gabrys, Dr. n med. Jacek Gabrys; Rafal Harat, Oddzial Chorób Pluc; Anna Prokop-

Staszecka, II Oddzial Chorób Pluc; Halina Batura-Gabryel, Dr. hab. Halina Batura-Gabryel; Janusz Regula, Oddzial Chorób Wewnetrznych;

Piotr Nalepa, I Oddzial Chorób Pluc

Romania Cristina Tanaseanu, Sf. Pantelimon Emergency Clin. Hopitla; Coman Tanasescu, Colentina Clinical Hospital; Miron Bogdan, Marius Nasta

Institute of Pneumophtisi; Dan Gainaru, Sana Medical Center; Luminita Ambert, Dr. Victor Babes Clinical Hospital

6

Russia Svetlana Proninia, City Clinical Hospital #13; Tatyana Ivanova Ishina, City Clinical Hospital N61; Yury Antonovsky, Moscow City

Hospital 23; Irina Sedavnykh, City Outpatient Clinic 51; Nina Boulytcheva, Moscow City Hospital 1; Leonid Dvoretski, Moscow

Outpatient Clinic 7; Alexander Komlev, Center Emergency Radiation Med; Aleksandr Chuchalin, Hosp. 57 City Clinical Room 509;

Ekaterina Zorina, Dep. of Pulmonology 1/3/358; Vladimir Nonikov, Central Clinical Hospital; Irina V. Sidorenko, City Hospital 7; Anna

Galustyan, Pediatric Medical Academy St. Petersburg; Vladimir Simanenkov, Med. Acadmey of Postgraduate Education; Veronika Popova,

St. George Hospital #4; Nataliya Konstantinovna Chereyskaya, Moscow Regional Research Clinical Instit; Vladislav Grigorievich

Novojenov, Moscow City Hospital #29; Zaurbek Aisanov, Research Institute of Pulmology; Andrey Vladimirovich Efimov, Third Central

Military Hospital

South Africa M. Prins, Universitas Hospital; Eric Bateman, UCT Lung Institute; Jacob J. Jansen, Vergelegen Medi Clinic; Analene Nel, Medinel Clinical

Trial Center; James Joubert, Tiervlei Trial Centre; Ismail Aboobaker Abdullah, Saint Augustine Medical Centre 2; Mohamed Sabeer

Abdool-Gaffar, Kingsway Clinical Trial Centre; Sanet Visser, Waterkloof Ridge; Gerhard Ras, Muelmed Medical Centre; Ismail Abdullah,

Gatesville Medical Centre; Gysbert Charl Liebenberg, Durbanville Medic-Clinic; Johann J. Viljoen, Genclin Corporation; E. M. Irusen,

Respiratory Research Dep. of Int. Med.; JA O'Brien, Christiaan Barnard Memorial Hospital

Spain Ignacio Sánchez, Hospital General Uni. Guadalajara; Julio Ancochea, Hospital de la Princesa; José Echave, Hospital 12 de Octubre; José

Celdrán, Hospital Ntra. Sra. Del Prado; Jose Ramon Rodriguez Suarez, Hosp. Clínico Universitario de Santiago; Pilar Berlinches, Hospital

Ntra. Sra. del Rosell; Jose Luis Heredia, Hospital Mutua de Terrasa; Eleuterio Llorca, Hospital General de Elda; Fernando Sànchez Toril,

Hospital Arnau de Vilanova; German Garcia de Vinuesa, Hospital de Merida; Fernando Fuentes, Hospital Universitario Infanta Cristina;

Rafael Blanquer, Universitario Doctor Peset; Juan Jose Soler, General de Requena; José Antonio Serrano, Hospital Universitario de Getafe;

Adolfo Baloira, Hospital Montecelo; Luis De-Teresa Parreno, Clínica Mediterránnea de Neurociencias; Luis Alejandro Pérez de Llano,

Hospital de Calde

UK Martin Adler, Belmont Health Centre; Alan Knox, Nottingham City Hospital; Mark Blagden, Avondale Surgery; Jonathan Hamling,

Oldfield Surgery; Peter Mooney, The Burngreave Surgery; Peter Howarth, Southampton General Hospital; Carol McKinnon, Castemilk

Health Centre; John Langan, Baillieston Health Centre; Robert Brownlie, Valleyfield Health Centre; Peter Calverley, University Hospital

Aintree; Paul Ainsworth, Sherbourne Medical Centre; Ian Orpen, St. James Surgery; Adel Manur, Solihull Hospital, Netherwood House;

Tony Egerton, Springhill Surgery; Glyn Chapman, Sunbury Health Centre Group Practise; Ronald Pieters, Whitstable Health Centre; M

Anderson, Old School Surgery; Elsbeth Crothers, Old School Surgery; Hugh McGoldrick, The Health Centre; A Morice, Academic Dept. of

medicine; Christopher Kyle, Glengormley Medical Practice; Corne, Queens Medical Centre Nottingham; Ian Parker, Beehive Surgery; I Mc

Coll, Mc Coll Medical Practice; McCaughey, Randalstown Medical; H Kinch, Sidley Surgery; Christopher Dixon, Sidley Surgery; Andrea

Cummings, Holywood Road Surgery; Adrian Darrah, Notting Hill Medical Practice; Dennis Shale, Department of Respiratory Medicine;

Raj Sharma, Dr Elias & Partners Pebsham Surgery

USA Edward Cordasco, Remington-Davis Inc; Salim Abou Jaoude, Forum Health-Western Reserve Care System; Jonathan Corren, Allergy

Research Foundation, Allergy Med; David Elkayam, Bellingham Asthma, Allergy & Immunology; Gary Greenwald, Advances in Medicine;

James Harris, South Bend Clinic; Michael Pacin, Florida Center for Allergy and Asthma Re; Francisco Candal, North Shore Research

Associates; Richard Sellman, Montana Medical Research; Steven Koenig, University of Virginia; Jonathon Truwit, University of Virginia;

Shari Anne Brazinsky, Institute of HealthCare Assessment, Inc.; Neil A. Ettinger, Cardio-Pulmonary Associates; Robert Sussman,

Pulmonary Allergy Associates; Mark C. Liu, John Hopkins Asthma & Allergy Center; William R. Lumry, AARA Research Center; James

Baker, Allergy, Asthma and Dermatology; Theodore Lee, New Horizons Health Research; Ira D. Horowitz, Delaware Valley Clinical

Research; Kevin Murphy, Midwest Allergy and Asthma As; Robert Wolfe, Office of Robert N. Wolfe, MD; Carolyn Daul, Clinical

Research Specialists, LLC; Gregory Gottschlich, New Horizons Clinical Research; James Greenwald, MEDEX Healthcare Resarch, Inc.;

7

Glen E. Journeay, Austin Clinical Research, Inc.; Paul Shapero, Paul Shapero, MD; John Scott Sibille, Sunset Medical Research; Frank P.

Maggiacomo, New England Center for Clinical Research; Claudia Cote, Bay Pines VA Medical Center; Eugene Bleecker, Cloverdale

Research Facility; David Lahasky, Pharmaseek; Charles Sherman, Safe Harbor Clinical Research; Ronald M. Gilman, Safe Harbor Clinical

Research; Nicholas Gross, Hines VA Hospital; Dan Olson, Medical University of Ohio; Frederick W. Kahn, Montana Health Research

Institute; Kathleen Brennan, Temple University Hospital; Peter Krumpe, VA SNHCS-Reno; James L. Pearle, California Research Medical

Group, Inc.; Wesley Bray, Marietta Pulmonary Medicine; Timothy Moriarty, Emerald Coast Research Associates; W. Ken Kleinsteuber,

Bluegrass Clinical Research, Inc.; John Trapp, Somnos Laboratories, Inc.; Joe Lasky, Tulane University; Curtis Mello, Infinity Medical

Research, Inc.; Ricardo Tan, Calif. Allergy & Asthma Med. Group; Mitchell G. Kaye, Minnesota Lung Center; Mark Stang, Minnesota

Lung Center; Henry Covelli, Pulmonary and Internal Medicine; Brian Snyder, Southgate Medical Group; Gregory Peterson, Diagnostic &

Critical Care Medicine, PC; Martha V. White, Institute for Asthma and Allergy, P.C.; William Henderson, Danville Regional Medical

Center; Barry Blumenthal, Medical Research Unlimited; Terri-Ann Brogan, Pharmaceutical Research Associates, Inco; C. Eric Schroeder,

Consultants in Pulmonary Medicine; James K. Bradley, Consultants in Pulmonary Medicine; George Louis Raad, Metrolina Medical

Research; Keith Popovich, Keith J Popovich; Robert Grady Ashley, Florida Research Network; Michael Chisdak, United Health Services

Hospitals, Inc.; John Zwetchkenbaum, AAPRI Clinical Research Institute; Barry Sigal, Piedmont Medical Research Associates; Thomas

Hyers, C.A.R.E. Clinical Research; Nicola Hanania, Baylor College of Medicine; Gary J. Richmond, Dr. Gary J. Richmond; Robert Broker,

Hillcrest Family Practice; Gerardo San Pedro, Lousiana State University Health Science; Mercedes Samson, Assiciated Pharmaceutical

Reseach Center; Graham Scott, Coastal Carolina Research Center; Albrecht M. Heyder, Atlantic Pulmonary Associates; John D. Updegrove,

Trinity Clinic; Maurice Archuleta, Front Range Clinical Research, LLC; David Erb, Gaffney Pharmaceutical Research; Greg Lakin, PRN of

Kansas; Leon Davis, Extended Ann Research; Thomas Nolen, TOMAC, Inc.; John R. Burk, Pulmonary Consultants of Texas PA; David

Fuentes, TTS Research; Richard Martinez, TTS Research; Mark W Millard, Baylor Martha Foster Lung Care Cente; Amir Sharafkhaneh,

VA Medical Center; Dave E. Webster, Team Research of Texas; Dan F. Fennell, Pulmonary Consultants; Edward Lane, The Connecticut

Sinus Center; Michael Mandel, Pulmonary & Sleep Specialist; Joseph Martinelli, St. Luke's / Whiteside Research; Russel Struble, Great

Lakes Research Group, Inc.; Peter Cowen, Medical Specialists of the Palm Beaches; Stephan H. Kimura, Emerald Coast Clinical Reserach;

Gregory Feldman, South Carolina Pharmaceutical Research; Wayne Gibert, Multi- Specialty Clinical Research; Stephan Ong, MD Medical

Research / Org Medical Center; Amit Patel, Integrated Research Group, Inc; Krishna Pudi, UPR; Rana Rab-Hasan, AIM Research; Michael

T. Robinson, Provinence Medical Group; Imu Aisiku, Medical Research Initiatives, Inc.; Janet Despot, Cardinal Respiratory Medicine;

Anthony DiMarco, Geauga Medical Arts; Khalad Girgis, College Park Family Care Center Multi-Sp; Deren M. Sinkowitz, Peninsula

Pulmonary Medical Associates; Robert Strzinek, Texas Familcare Clinical Research; David Thornton, Pinehurst Medical Clinic, Inc; E.

Regis McFadden, The Metro Heatlh System; Lawrence K. Alwine, Dowingtown Family Medicine; John P. Delgado, Intergrated Medical

Research P.C.; Ware Kuschner, VA PAHCS; Donald R. Elton, Mid Carolina Internal Med Associates, LL; Timothy E Bruya, Spokane

Respiratory Consultants; Thomas Mirzai, Desert Center for Allergy & Chest Diseas; David Miller, Bond Clinic, PA; Philip Snell,

MountainView Clinical Research; Charlene McEvoy, Regions Hospital; Robert Piasecki, Pulmonory Partners; Praveen Rastogi, Pinnacle;

Anthony Harris, Harris & Associates, PC; Rick Player, Jefferson Clinic, PC; Imtiaz Ahmad, Allergy Sleep & Lung Care; Dariusz

Chrostowski, Health Sciences Research Center; Kenneth Cohen, New West Physicians; James Doris, Lovelace Scientific Resources Inc.;

Richard Fei, Bendel Medical Research; Gary Ferguson, Pulmonary Institute; Henry Gong Jr., Rancho Los Amigos Research and Education;

Yaga Szlachcic, Rancho Los Amigos Research and Education; Stephen Hellems, Ridgewood Medical Group; Carol Johnson, Clinical

Research Consultans; Nelson P Kopyt, Northeast Clinical Research Center, Inc.; Raymond J. Kovalski, PMA Medical Specialist LLC;

Monica Kraft, Duke University School Medical Center; Richard F. Lockey, USF Asthma & Allergy Immunology CRU; Magbool Ahmed,

Mohave Pulmonary & Sleep Disorder Clinic; George A. Mark, Marion Associates; Mark Fisher, Fisher Clinical Research; Eric Christophoer

Kleerup, UCLA; Ralph J. Panos, University Internal Medicine Associates; Anthony Bartkowiak, Blair Medical Associates, Inc.; Randall C.

Lanier, Affinity Health Group; Cyntia Bell, Anchor Research Center; Michael Larj, University of Rochester; David Liebman, Southeastern

Research Associates, Inc.; Alfred Brannen, Augusta Lung Assosiate LLC; Boris Murillo, Berkshire Medical Center; Richard Nielson,

Crystal Lake Health Clinic; John Dineen, St. Joseph Office Park; Andrew Brockmyre, Holston Medical Group; Joseph Shaver, Southeastern

Clinical Research Institute; Randy A. S. Stubbs, The Pressure Company, Inc.; Eduardo Grunvald, The Regents of the University of CA;

John Wade, Baptist Clinical Research; Paul Gustman, Pulmonary Physicans of South Florida LLC; Cynthia Jumper, Texas Tech University

Health Science; John A. Butler, John A. Butler, MD; Kathi Ellstrom, VA Loma Linda Healthcare System; William Rodriguez-Cintron, San

Juan VA Medical Center; Loenard Ginns, Massachusetts General Hospital; Sudhir Sehgal, Research Solutions; Edward Fein, Pulmonary &

Critical Care Associates; Richard Barbers, Keck School of Medicine At USC; John McConnell, Kentuckiana Pulmonary Association; Neal

J. Moser, Internal Medicine Associates; Thomas Nussdorfer, Medical Research Associates; Roger Yusen, Barnes-Jewish Hospital Investig

Pharmacy; Jeevana Krishna, Cumming Family Research; Wyatt Rousseau, Presbyterian Hospital of Dallas; Jeffrey Kingsley, Southeast

8

Regional Research Group; Maria Mascolo, Southeast Lung & Critical Care; James Meyer, Meyer, James; Tomasz Ziedalski, Providence

Everett Medical Center; Gloria Westney, Morehouse School of Medicine; Syed M. Rehman, Asthma and Allergy Center; Patrick Sturm,

Tri-State Pulmonary Medicine; Francis Sheski, Outpatient Clinical Research; Amy Silverthorn, AZ Pulmonary Specialists, Ltd.; Steve Sitar,

Orange County Clinical Trials; Adesubomi B. Agoro, Health First Medical Group; A. Judson Tillinghast, Arizona Pulmonary Specialists,

LTD; Davang Savani, Chest Critical Care Consultants; Dan Schuller, Creighton University; George E. Stewart, Allergy & Asthma Care of

Florida; David I. Bernstein, Berstein Clin. Research Center; Harold S. Nelson, National Jewish Medical+Research Center; University

Clinical Research; Emil Skobeloff, Consortium Clinical Research, Ltd.; John A. Winder, Toledo Center for Clinical Research; William

Beliveau, Clinical Partners LLC; Edward Diamond, Alexian Brothers Center for Clinical Re.; Charles Andrews, Diagnostics Research

Group; Timothy J. Craig, M.S. Hershey Medical Center; Edward M. Kerwin, Clin. Research Inst. of Southern Oregon; George Bensch,

Bensch Reseach Associates; Edward E. Lisberg, Asthma & Allergy Center of Chicago; Alexander White, Coastal Medical Research; Jeffrey

Kaladas, Urgentmed Family Medical Center; John Pullman, Mercury Street Medical Research Clinic; Raul E. Gaona, Jr., Quality Assurance

Research Center; Sandra K. Willsie, Kansas City University; Patrick G. Clay, Kansas City University; David Hill, Waterbury Pulmonary

Associates; Paul Ratner, Sylvana Research Associates; Thomas D. Kaelin, Jr., Lowcountry Lung & Critical Care, PA; W. Travis Ellison,

Radiant Research- Greer; Albert M. Baker, Lynchburg Pulmon. Associates, Inc.; Ray Tidman, River Birch Research; Tahir Ahmed, Mount

Sinai Med. Center-Pulmon. Div.; J. Allen D. Cooper, Jr., Birmingham VA Medical Center; Joel D. Epstein, Southern California Clinical

Trials; Frederick Charles Hiller, ll, University of Arkansas for Med. Sciences; Stanley R. Horner, Allergy, Asthma, Immunology Services;

Jill Karpel, Northshore- LIJ Health System; Steven Kelsen, Temple University Hospital; C. Kees Mahutte, Long Beach VA Medical Center;

David Hagaman, Vanderbilt ASAP; Selwyn Spangenthal, American Health Research; Devendra Amin, Bay Area Chest Physicians; Gary W.

Hunt, Horizon Research Center, Inc.; Fadi Adam Kawley, F. Adam Kawley, MD, PA; Martha Tarpay, Allergy, Asthma & Clinical Research

Cent; John Given, Allergy & Respiratory Center; Stephanie Eaton, Northside Respiratory Care; John Jayne, Asthma & Pulmonary

Diagnostic Associates; Mark Janes, Medical Associates Clinic, P.C.; Malik Baz, ABM Research; Rebecca Baumbach, Synergy Med. Ed.

Alliance-Clin. Res. Dep; Alan Wanderer, Allergy & Asthma Consultants of Montana; Keith Pierce, Michigan Institute of Medicine; Kent

Carpenter, University Med. Associates, PA; Robert F. Onder Jr., Midwest Clinical Research LLC; Richard E. Henry, Asthma & Allergy of

Idaho; The Regents of the University of Califor; Joel Eade, Internal Medicine Research; Yekaterina Khronusova, Advanced Biomedical

Research of America; Kenneth Chinsky, Square l Clin. Research; Martin Mollen, Arizona Research Center; Ronald G DeGarmo, DeGarmo

Institute; Sunil Perera, Allergy Medical Group of North Area; Mark T Dransfield, UAB Lung Health Center; Christopher Smith, Health

Acience Research Center at Asthma; James M. Stocks, University of Texas; Kathleen L. Collins, Christi Clinic Clinical Research Departm;

Mark Fitzgerald, TTS Research; William W. Storms, The William Storms Allergy Clinic; Diego Torres II, Peninsula Research, Inc; Paul D.

Scanlon, Mayo Clinic Rochester dba Mayo; Edgardo Osea, Interlink Research Institute; Barry Streit, Central Medical Group, P.A; Warren

Botnick, Pulmonary & Sleep Specialists, PC; Eduardo Viera, Research Center of Florida; Dwight C Look lll, University of Iowa; Dennis

Riff, Advance Research Institute; Teresa Sligh, Providence Clinical Research; Pamela Camosy, Wellmed Medical Management Clinical

Rese; Joseph Boscia, Union Pharmaceutical Research; Robert Fisher, Community Research Center, LLC; Lo'ay Al-Asadi, CAMC Health

Foundation & Research Inst.; Edward A. Balli, Edward A. Balli, MD, PA; Mark Barber, Crystal Lake Health Clinic; Luther Corley, lll,

Huntsville Lung Association; Suresh Daniel, Kelsey-Seybold Clinic; Eugene C. Fletcher, Eugene Fletcher, MD; Peter Franklin, St. Mary's

Duluth Clinic Health System; Geoffrey Grambau, Midwest Consultants for Clin. Trials LLC; Ijaz M. Iqbal, Mostellar Medical Center;

Michael Kerkering, Spokane Internal Medicine; Shahrukh Kureishy, Metroplex Pulmonary & Sleep Center, P.A.; James F. Lawless, FFM

Clinical Research; Mohammed Nadeemullah, Brighton Internal Medicine; Jeffrey Newman, QualityCare Medical Center; Jeffrey D. Yusim,

QualityCare Medical Center; Thomas M. Wade, Investig. Clin. Research of Indiana, LLC; Douglas Young, Northern California Research;

Charles De Busk, Heartland Medical PC; Srinivas Katragadda, ID Clinical Research, Ltd.; Firas Koura, Kentucky Lung Clinic; David

Laman, Consolidated Clinical Trials; Daniel Lee, Dwight David Eisenhower Army Med Center; Robert Lenox, SUNY Upstate Medical

Univ; Osman Malik, Veritas Clinical Specialities; William Leeds, Veritas Clinical Specialities; Armin Meyer, Greenville Hospital

System/Lung Ce; Rachakonda Prabhu, Redrock Research; David Schneider, Rx R&D; Stephen Jones, IPC Clinical Research; James Daly,

Southeast Lung & Critical Care Specialis; Sandhya Khurana, Syracuse VA Medical Center; Akbar Obaray, R Reasearch; Carmen

Salvaterra, Pulmonary Disease&Critical Care Associat; Thomas A. Wade, Columbus Clinic; Don Hammett, Center for Research; Val

Hansen, IPC Clinical Research/DBA Avila Clinical; Subin Jain, Louisville Pulmonary Care, PLLC; Anthony Malanga, Pulmonary and

Critical Care Assoc.; George Sarosi, Roudebush Veteran's Administration; William Tillis, Peoria Pulmonary Associates Group; John Suen,

Suen; M. Glenn Abernathy, Southeastern Research Associates, Inc.; Nassau Queens Pulmonary Association; Robert Mezey, Pulmonary

Physicians of South FL, LLC; Richard McDavid, Appalachian Medical Research; Charles Pue, Remington Davis Inc.; Arturo Meade,

Sparks Health System; Joseph Morelli, Joseph Morelli, DO; Octavius Polk, Jr., Providence Clinical Research; Andreas Koser, Greenville

Pharmaceutical Research

9

On-line Table 1. Primary and secondary endpoints for study M2-124 and study M2-125 Primary efficacy endpoints

• The following variables will serve as primary endpoints: • Mean change in pre-bronchodilator FEV1 from baseline (V2) to each post-randomization visit during

the treatment period • Mean rate of COPD exacerbations requiring oral or parenteral glucocorticosteroids or requiring

hospitalization or leading to death, per patient per year (moderate or severe COPD exacerbations) Key secondary efficacy endpoints

• Mean change in post-bronchodilator FEV1 [L] from baseline (V2) to each post-randomization visit during the treatment period

• Time to mortality due to any reason • Natural log-transformed CRP [mg/L] (mean change from baseline (V2) to last scheduled study visit) • Mean TDI Focal score during the treatment period

Secondary efficacy endpoints COPD exacerbations

• Mean rate of COPD exacerbations per patient per year (mild; moderate; severe; mild, moderate or severe; COPD exacerbations treated with systemic steroids and/or antibiotics; COPD exacerbations treated with antibiotics only; and CRF COPD exacerbations)

• Proportion of patients experiencing a COPD exacerbation (mild; moderate; severe; moderate or severe; mild, moderate or severe; COPD exacerbations treated with systemic steroids and/or antibiotics; COPD exacerbations treated with antibiotics only; and CRF COPD exacerbations)

• Time to first COPD exacerbation (mild; moderate; severe; moderate or severe; mild, moderate or severe; COPD exacerbations treated with systemic steroids and/or antibiotics; COPD exacerbations treated with antibiotics only; and CRF COPD exacerbations)

• Mean number of COPD exacerbation days (mild; moderate; severe; moderate or severe; mild, moderate or severe; COPD exacerbations treated with systemic steroids and/or antibiotics; COPD exacerbations treated with antibiotics only; and CRF COPD exacerbations)

• Duration of COPD exacerbations (mild; moderate; severe; moderate or severe; mild, moderate or severe; COPD exacerbations treated with systemic steroids and/or antibiotics; COPD exacerbations treated with antibiotics only; and CRF COPD exacerbations)

• Time to second COPD exacerbation of moderate or severe COPD exacerbations • Number needed to treat (NNT) of moderate or severe COPD exacerbations

Lung function variables (pre- and post-bronchodilator)

• FVC [L] (mean change from baseline (V2) to each post-randomization visit during the treatment period)

• FEF25-75% [L/s] (mean change from baseline (V2) to each post-randomization visit during the treatment period)

• FEV3 [L] (mean change from baseline (V2) to each post-randomization visit during the treatment period)

• FEV6 [L] (mean change from baseline (V2) to each post-randomization visit during the treatment period)

• FEV1/FVC [%] (mean change from baseline (V2) to each post-randomization visit during the treatment period)

• FEV1/FEV6 [%] (mean change from baseline (V2) to each post-randomization visit during the treatment period)

• PEF [L/min] (mean change from baseline (V2) to each post-randomization visit during the treatment period)

BDI/TDI

• Mean TDI component scores (functional impairment, magnitude of task, magnitude of effort) over the treatment period

• Proportion of patients with clinically relevant improvements in the TDI Focal score Mortality

10

• Time to mortality due to a COPD exacerbation Diary

• Use of rescue medication (mean change from baseline (W0) to each post-randomization week during the treatment period)

• COPD symptom scores: score sum, cough, sputum (mean change from baseline (W0) to each post-randomization week during the treatment period)

• Proportion of symptoms free days / rescue medication free days Time to study withdrawal

• Time to study withdrawal during the treatment period • Time to withdrawal due to a COPD exacerbation during the treatment period • Time to study withdrawal due to an adverse event (AE) during the treatment period

EuroQoL (EQ-5D)

• EQ-5D total score during the treatment period • Visual analog scale (VAS) during the treatment period

Endpoints for safety and tolerability

• Adverse events • Standard laboratory parameters • Vital signs (blood pressure, pulse rate) • 12-lead electrocardiogram • 24 hour holter monitoring (at selected centers in the US, in a subset of patients) • Hemoccult (guaiac) testing • Body weight and body mass index • Routine physical examination

11

On-line Table 2: Exclusion criteria for M2-124 and M2-125 studies

Exclusion criteria

COPD exacerbation (indicated by corticosteroid treatment of hospitalisation) unresolved at initial visit (4 weeks pre-baseline)

Asthma or other relevant lung disease

Clinically significant cardiopulmonary abnormalities not related to COPD

Clinically relevant abnormal laboratory findings

Pregnant or planned pregnancy or breast feeding

Females of child-bearing potential not using or not willing to use a medically reliable method of contraception

Chronic gastrointestinal (GI) disorders with a history of recurrent GI bleeds within the previous 1 year

Participation in another clinical trial within 30 days of the run-in period

Current participation in or completion within 3 months of the run-in period of a pulmonary rehabilitation programme

Use of disallowed drugs

Use of immunosuppressive medications within 4 weeks prior to baseline

Known alpha-1-antitrypsin deficiency

Known HIV infection and/or active hepatitis

Diagnosis or history of any cancer (other than basal cell carcinoma) within 5 years of study start

Clinically relevant ECG findings not related to COPD and requiring further evaluation

Alcohol or drug abuse

Suspected hypersensitivity or contraindication to study medication

Unable to follow study procedures (e.g. language difficulties, psychological disorders)

Suspected non-compliance

12

On-line Table 3: Countries involved in the M2-124 and M2-125 studies

M2-124 M2-125

Australia Canada

Austria Germany

France India

Germany Italy

Hungary Poland

New Zealand Spain

Romania South Africa

Russia USA

UK

USA

13

On-line Table 4. A) An analysis of FEV1 for the subgroup of completers based on the repeated measures analysis of covariance model. B) A Poisson regression

analysis of annualised exacerbation rate for the subgroup of completers.

Repeated measurements (FEV1) All patients Completers only

Between difference p-value (2-sided) Between difference p-value (2-sided)

M2-124 39 mL 0·0003 42 mL 0·0008

M2-125 58 mL <0·0001 73 mL <0·0001

Poisson regression

(exacerbations)

All patients Completers only

Change p-value (2-sided) Change p-value (2-sided)

M2-124 –14·9% 0·0278 –11·6% 0·1365

M2-125 –18·5% 0·0035 –15·4% 0·0306

14

On-line Table 5. Body weight changes from baseline to last visit in pooled data from M2-124 and M2-125 A) patients with or without gastrointestinal adverse events

and/or headache and B) change in body weight (kg) by body-mass index (BMI) at baseline.

A)

Treatment Adverse event pattern* n Mean (SD) 95% CI

Roflumilast

No 1302 –2.02 (4.008) –2.238, –1.802

Yes 196 –2.60 (3.721) –3.124, –2.076

Placebo

No 1421 0.08 (3.514) –0.103, 0.263

Yes 89 0.07 (2.922) –0.546, 0.686 *At least one gastrointestinal event (defined by diarrhoea, nausea and vomiting) and/or headache with onset or end of the

adverse event occurring during the treatment period. CI, confidence interval. SD, standard deviation. n denotes the number

of patients with data available

15

B)

BMI Category Roflumilast Placebo Roflumilast vs Placebo

Baseline Last visit – baseline

Baseline Last visit – baseline Last visit – baseline

n Mean (SD) Mean (SD) n Mean (SD) Mean (SD) Mean (95% CI)

All data 1498 73.65 (18.67) –2.09 (3.98) 1510 73.28 (18.18) 0.08 (3.48) –2.17 (–2.437, –1.903)

Underweight

(BMI �18) 134 45.60 (6.82) –0.73 (2.50) 127 45.83 (5.89) 1.28 (4.20) –2.01 (–2.848, –1.172)

Normal weight

(BMI 18–�25) 572 62.74 (8.39) –1.64 (3.21) 605 62.43 (8.50) 0.12 (2.98) –1.76 (–2.114, –1.406)

Overweight

(BMI 25–�30) 475 78.99 (9.05) –2.02 (3.65) 462 79.00 (8.39) 0.07 (3.18) –2.09 (–2.529, –1.651)

Obese

(BMI >30) 317 97.18 (15.29) –3.57 (5.51) 316 96.72 (14.11) -0.46 (4.28) –3.11 (–3.880, –2.340)

Baseline, last measurement prior to first intake of double-blind study medication; CI, confidence interval; SD, standard deviation; last visit, last post-randomisation measurement (including last observation carried forward method);n denotes the number of patients with data available; .

16

ECG Holter monitoring data from 19 centres in the M2-125 study

On-line Table 6: Point estimate (according to Hodges-Lehmann; HL) change from baseline to last

measurement in mean heart rate in patients in roflumilast and placebo groups at selected sites in study

M2-125 Variable Roflumilast Placebo

Mean heart rate, beats/minute

Change from baseline, HL point estimate (95% confidence intervals)

1.5 (–1.5, 6.5)

(n = 18)

0.0 (–5.5, 8.0)

(n = 14)

On-line Table 7: Difference in point estimate (according to Hodges-Lehmann; HL) change from baseline

to last measurement in mean heart rate between patients in the roflumilast and placebo groups at selected

sites in study M2-125. Variable Difference between treatments P value

Mean heart rate, beats/minute

Change from baseline, HL point estimate (95%

confidence intervals)

2.0 (–5.0, 8.0)

(roflumilast, n = 18; placebo, n = 14)

0.556

On-line Table 8: Frequency of permanent atrial fibrillation at baseline and at patient’s last visit in

patients in the roflumilast and placebo groups at selected sites in study M2-125 Frequency of atrial fibrillation, n (%) Roflumilast

(n=33)

Placebo

(n=22)

Baseline 1 (3.0) 0 (0.0)

Last visit 1 (3.0) 1 (4.5)

17

On-line Table 9: Routine laboratory data for biochemistry and haematology values in A) the M2-124 study and B) the M2-125 study (the variables were ordered

alphabetically by biochemistry first and then haematology)

A) Variable Roflumilast Placebo

Baseline Last visit Change Baseline Last visit Change

Biochemistry

Alanine aminotransferase, U/L 24.2 (17.8)

(n=691)

22.4 (11.7)

(n=691)

–1.8 (16.4)

(n=691)

22.7 (12.7)

(n=693)

24.1 (18.4)

(n=693)

1.4 (16.3)

(n=693)

Alkaline phosphatase, U/L 79.3 (25.1)

(n=691)

81.0 (24.0)

(n=691)

1.7 (17.4)

(n=691)

79.1 (23.0)

(n=695)

79.6 (32.1)

(n=695)

0.5 (27.9)

(n=695)

Aspartate aminotransferase, U/L 23.3 (12.6)

(n=691)

22.9 (12.7)

(n=691)

–0.4 (12.8)

(n=691)

22.6 (12.7)

(n=693)

24.1 (17.3)

(n=693)

1.4 (13.3)

(n=693)

Billirubin, µmol/L 8.5 (4.3)

(n=690)

8.3 (4.7)

(n=690)

–0.2 (3.9)

(n=690)

8.7 (4.9)

(n=691)

8.5 (5.0)

(n=691)

–0.1 (4.6)

(n=691)

Cholesterol, mmol/L 5.4 (1.1)

(n=691)

5.3 (1.1)

(n=691)

–0.1 (0.9)

(n=691)

5.4 (1.1)

(n=695)

5.3 (1.1)

(n=695)

–0.1 (0.9)

(n=695)

Creatinine, µmol/L 80.3 (19.1)

(n=656)

81.5 (20.0)

(n=656)

1.2 (13.3)

(n=656)

81.9 (24.2)

(n=655)

82.7 (21.4)

(n=655)

0.9 (19.0)

(n=655)

Creatinine kinase, U/L 116.4 (86.9)

(n=691)

111.8 (82.5)

(n=691)

–4.6 (78.3)

(n=691)

109.9 (80.9)

(n=693)

107.8 (103.3)

(n=693)

–2.0 (103.6)

(n=693)

C-reactive protein, mg/L 8.052 (14.278)

(n=695)

9.192 (19.136)

(n=695)

1.140 (21.086)

(n=695)

6.813 (11.224)

(n=691)

9.543 (19.458)

(n=691)

2.730 (20.689)

(n=691)

Gamma glutamyl transferase, U/L 40.4 (54.2)

(n=691)

39.6 (46.9)

(n=691)

–0.8 (37.8)

(n=691)

38.1 (54.1)

(n=694)

43.9 (83.4)

(n=694)

5.8 (69.1)

(n=694)

Glucose, mmol/L 5.77 (1.79)

(n=655)

5.94 (1.76)

(n=655)

0.18 (1.80)

(n=655)

5.67 (1.67)

(n=653)

5.84 (1.80)

(n=653)

0.17 (1.82)

(n=653)

High-density lipoprotein, mmol/L 1.7 (0.5)

(n=691)

1.6 (0.5)

(n=691)

0.0 (0.4)

(n=691)

1.6 (0.5)

(n=694)

1.6 (0.6)

(n=694)

0.0 (0.4)

(n=694)

Low-density lipoprotein, mmol/L 3.0 (1.0)

(n=671)

2.9 (0.9)

(n=671)

-0.1 (0.7)

(n=671)

3.0 (0.9)

(n=678)

3.0 (0.9)

(n=678)

0.0 (0.8)

(n=678)

Potassium, mmol/L 4.6 (0.4) 4.5 (0.5) –0.1 (0.5) 4.6 (0.5) 4.6 (0.5) 0.0 (0.5)

18

(n=657) (n=657) (n=657) (n=652) (n=652) (n=652)

Sodium, mmol/L 141.7 (3.3)

(n=692)

141.4 (3.6)

(n=692)

–0.3 (3.8)

(n=692)

141.7 (3.2)

(n=695)

141.3 (3.6)

(n=695)

–0.4 (3.5)

(n=695)

Triglycerides, mmol/L 1.7 (1.1)

(n=690)

1.5 (0.9)

(n=690)

–0.2 (0.8)

(n=690)

1.7 (1.1)

(n=695)

1.6 (1.2)

(n=695)

–0.1 (1.1)

(n=695)

Haematology

Basophils, G/L 0.03 (0.03)

(n=686)

0.03 (0.02)

(n=686)

0.00 (0.03)

(n=686)

0.03 (0.02)

(n=688)

0.03 (0.03)

(n=688)

0.00 (0.03)

(n=688)

Basophils/leukocytes, % 0.40 (0.25)

(n=686)

0.41 (0.26)

(n=686)

0.01 (0.32)

(n=686)

0.38 (0.23)

(n=688)

0.40 (0.29)

(n=688)

0.02 (0.33)

(n=688)

Eosinophils, G/L 0.20 (0.16)

(n=686)

0.19 (0.16)

(n=686)

–0.01 (0.14)

(n=686)

0.21 (0.20)

(n=688)

0.20 (0.19)

(n=688)

–0.01 (0.18)

(n=688)

Eosinophils/leukocytes, % 2.48 (2.01)

(n=686)

2.42 (1.99)

(n=686)

–0.06 (1.74)

(n=686)

2.63 (2.43)

(n=688)

2.58 (2.44)

(n=688)

–0.05 (2.33)

(n=688)

Erythrocytes, T/L 4.69 (0.50)

(n=694)

4.63 (0.48)

(n=694)

–0.06 (0.33)

(n=694)

4.74 (0.45)

(n=692)

4.70 (0.48)

(n=692)

–0.04 (0.33)

(n=692)

Haematocrit, % 43.9 (4.1)

(n=686)

43.4 (4.3)

(n=686)

–0.5 (3.2)

(n=686)

44.2 (4.0)

(n=684)

43.9 (4.4)

(n=684)

–0.2 (3.2)

(n=684)

Haemoglobin, mmol/L 9.1 (0.8)

(n=694)

9.0 (0.9)

(n=694)

–0.1 (0.6)

(n=694)

9.2 (0.8)

(n=692)

9.1 (0.9)

(n=692)

0.0 (0.6)

(n=692)

Leukocytes, G/L 8.29 (2.48)

(n=695)

8.22 (2.51)

(n=695)

–0.07 (2.26)

(n=695)

8.26 (2.33)

(n=692)

8.24 (2.64)

(n=692)

–0.02 (2.34)

(n=692)

Lymphocytes, G/L 2.05 (0.75)

(n=686)

2.01 (0.81)

(n=686)

–0.05 (0.62)

(n=686)

2.10 (0.89)

(n=688)

1.99 (0.94)

(n=688)

–0.11 (0.64)

(n=688)

Lymphocytes/leukocytes, % 25.50 (7.87)

(n=686)

25.16 (8.45)

(n=686)

–0.34 (6.96)

(n=686)

25.89 (7.66)

(n=688)

24.98 (8.48)

(n=688)

–0.91 (7.40)

(n=688)

Monocytes, G/L 0.57 (0.23)

(n=686)

0.55 (0.21)

(n=686)

–0.02 (0.22)

(n=686)

0.55 (0.21)

(n=688)

0.55 (0.23)

(n=688)

0.00 (0.21)

(n=688)

Monocytes/leukocytes, % 7.00 (2.43)

(n=686)

6.91 (2.38)

(n=686)

–0.09 (2.24)

(n=686)

6.77 (2.24)

(n=688)

6.80 (2.29)

(n=688)

0.04 (2.31)

(n=688)

Neutrophils, G/L 5.46 (2.15)

(n=686)

5.45 (2.19)

(n=686)

–0.01 (2.08)

(n=686)

5.37 (1.84)

(n=688)

5.47 (2.31)

(n=688)

0.10 (2.22)

(n=688)

19

Neutrophils/leukocytes, % 64.58 (9.07)

(n=686)

65.08 (9.65)

(n=686)

0.49 (8.48)

(n=686)

64.30 (8.74)

(n=688)

65.19 (9.79)

(n=688)

0.90 (9.26)

(n=688)

Platelets, G/L 273.4 (72.0)

(n=688)

276.0 (79.2)

(n=688)

2.6 (59.2)

(n=688)

274.2 (75.0)

(n=687)

263.7 (75.1)

(n=687)

–10.5 (61.1)

(n=687)

All values are mean (standard deviation) unless otherwise stated. n denotes the number of patients with data available at baseline and last visit (including last observation carried forward method).

20

B) M2-125 Variable Roflumilast Placebo

Baseline Last visit Change Baseline Last visit Change

Biochemistry

Alanine aminotransferase, U/L 23.2 (14.4)

(n=682)

22.6 (14.6)

(n=682)

–0.6 (14.5)

(n=682)

23.6 (21.1)

(n=691)

23.9 (21.0)

(n=691)

0.3 (26.0)

(n=691)

Alkaline phosphatase, U/L 82.7 (23.5)

(n=685)

83.0 (24.0)

(n=685)

0.4 (17.3)

(n=685)

81.5 (24.2)

(n=691)

80.0 (30.9)

(n=691)

–1.5 (27.7)

(n=691)

Aspartate aminotransferase, U/L 23.5 (13.3)

(n=683)

22.7 (11.6)

(n=683)

–0.7 (10.8)

(n=683)

23.5 (17.4)

(n=691)

23.1 (12.0)

(n=691)

–0.3 (17.8)

(n=691)

Billirubin, µmol/L 8.5 (4.3)

(n=682)

7.9 (3.9)

(n=682)

–0.5 (3.6)

(n=682)

8.6 (4.4)

(n=689)

8.2 (4.6)

(n=689)

–0.4 (4.0)

(n=689)

Cholesterol, mmol/L 5.1 (1.1)

(n=684)

5.0 (1.1)

(n=684)

–0.1 (0.8)

(n=684)

5.2 (1.1)

(n=691)

5.1 (1.1)

(n=691)

0.0 (0.9)

(n=691)

Creatinine, µmol/L 82.7 (20.3)

(n=645)

83.1 (22.5)

(n=645)

0.5 (15.5)

(n=645)

83.3 (20.4)

(n=647)

85.4 (24.6)

(n=647)

2.1 (16.3)

(n=647)

Creatinine kinase, U/L 119.2 (117.1)

(n=684)

115.2 (96.1)

(n=684)

–4.1 (120.1)

(n=684)

113.9 (92.5)

(n=691)

112.2 (90.5)

(n=691)

–1.7 (95.7)

(n=691)

C-reactive protein, mg/L 7.681 (12.899)

(n=686)

10.651 (23.965)

(n=686)

2.970 (23.070)

(n=686)

9.435 (17.632)

(n=690)

9.739 (20.061)

(n=690)

0.305 (23.768)

(n=690)

Gamma glutamyl transferase, U/L 32.1 (46.4)

(n=685)

34.1 (89.2)

(n=685)

2.0 (69.5)

(n=685)

32.5 (33.6)

(n=691)

38.4 (78.9)

(n=691)

6.0 (70.7)

(n=691)

Glucose, mmol/L 5.84 (2.17)

(n=646)

6.08 (2.15)

(n=646)

0.24 (2.06)

(n=646)

5.80 (1.83)

(n=647)

6.24 (2.43)

(n=647)

0.45 (2.23)

(n=647)

High-density lipoprotein, mmol/L 1.5 (0.5)

(n=685)

1.5 (0.5)

(n=685)

0.0 (0.4)

(n=685)

1.5 (0.5)

(n=691)

1.5 (0.5)

(n=691)

0.0 (0.3)

(n=691)

Low-density lipoprotein, mmol/L 2.9 (0.9)

(n=667)

2.8 (0.9)

(n=667)

-0.1 (0.7)

(n=667)

2.9 (0.9)

(n=674)

2.9 (0.9)

(n=674)

0.0 (0.7)

(n=674)

Potassium, mmol/L 4.5 (0.5)

(n=641)

4.5 (0.5)

(n=641)

0.0 (0.5)

(n=641)

4.5 (0.5)

(n=646)

4.5 (0.5)

(n=646)

0.0 (0.5)

(n=646)

Sodium, mmol/L 140.8 (3.4)

(n=685)

141.2 (3.3)

(n=685)

0.4 (3.4)

(n=685)

140.7 (3.5)

(n=691)

141.0 (3.4)

(n=691)

0.2 (3.5)

(n=691)

21

Triglycerides, mmol/L 1.7 (1.1)

(n=685)

1.5 (0.9)

(n=685)

–0.1 (0.9)

(n=685)

1.7 (1.1)

(n=691)

1.6 (1.1)

(n=691)

0.0 (0.9)

(n=691)

Haematology

Basophils, G/L 0.03 (0.02)

(n=673)

0.03 (0.03)

(n=673)

0.00 (0.03)

(n=673)

0.03 (0.02)

(n=685)

0.03 (0.03)

(n=685)

0.00 (0.03)

(n=685)

Basophils/leukocytes, % 0.39 (0.25)

(n=673)

0.40 (0.28)

(n=673)

0.01 (0.34)

(n=673)

0.36 (0.20)

(n=685)

0.39 (0.26)

(n=685)

0.03 (0.29)

(n=685)

Eosinophils, G/L 0.24 (0.27)

(n=673)

0.24 (0.27)

(n=673)

0.01 (0.26)

(n=673)

0.22 (0.41)

(n=685)

0.23 (0.28)

(n=685)

0.01 (0.42)

(n=685)

Eosinophils/leukocytes, % 2.85 (2.82)

(n=673)

3.05 (3.21)

(n=673)

0.21 (3.00)

(n=673)

2.72 (3.22)

(n=685)

2.90 (3.00)

(n=685)

0.18 (3.25)

(n=685)

Erythrocytes, T/L 4.81 (0.52)

(n=677)

4.72 (0.53)

(n=677)

–0.09 (0.35)

(n=677)

4.79 (0.48)

(n=689)

4.73 (0.51)

(n=689)

–0.06 (0.34)

(n=689)

Haematocrit, % 44.3 (4.4)

(n=664)

43.3 (4.6)

(n=664)

–1.0 (3.3)

(n=664)

44.5 (4.5)

(n=680)

44.0 (4.7)

(n=680)

–0.6 (3.2)

(n=680)

Haemoglobin, mmol/L 9.1 (0.9)

(n=679)

8.9 (1.0)

(n=679)

–0.1 (0.7)

(n=679)

9.1 (0.9)

(n=691)

9.1 (1.0)

(n=691)

0.0 (0.6)

(n=691)

Leukocytes, G/L 8.39 (2.23)

(n=678)

8.32 (2.56)

(n=678)

–0.08 (2.32)

(n=678)

8.31 (2.47)

(n=689)

8.16 (2.45)

(n=689)

–0.15 (2.31)

(n=689)

Lymphocytes, G/L 2.10 (0.82)

(n=673)

1.99 (0.89)

(n=673)

–0.11 (0.67)

(n=673)

2.04 (0.80)

(n=685)

1.99 (0.80)

(n=685)

–0.05 (0.67)

(n=685)

Lymphocytes/leukocytes, % 25.39 (8.01)

(n=673)

24.58 (8.66)

(n=673)

–0.81 (7.60)

(n=673)

25.26 (8.12)

(n=685)

25.11 (8.34)

(n=685)

–0.16 (7.92)

(n=685)

Monocytes, G/L 0.55 (0.21)

(n=673)

0.54 (0.24)

(n=673)

–0.01 (0.23)

(n=673)

0.54 (0.21)

(n=685)

0.53 (0.22)

(n=685)

–0.01 (0.21)

(n=685)

Monocytes/leukocytes, % 6.70 (2.41)

(n=673)

6.70 (2.65)

(n=673)

0.00 (2.49)

(n=673)

6.74 (2.48)

(n=685)

6.72 (2.45)

(n=685)

–0.02 (2.42)

(n=685)

Neutrophils, G/L 5.50 (1.92)

(n=673)

5.51 (2.25)

(n=673)

0.01 (2.18)

(n=673)

5.47 (2.12)

(n=685)

5.38 (2.12)

(n=685)

–0.10 (2.19)

(n=685)

Neutrophils/leukocytes, % 64.64 (9.32)

(n=673)

65.17 (10.59)

(n=673)

0.53 (9.69)

(n=673)

64.85 (9.58)

(n=685)

64.80 (9.93)

(n=685)

–0.05 (10.17)

(n=685)

Platelets, G/L 273.7 (77.3) 278.9 (82.0) 5.2 (60.6) 267.9 (74.4) 257.8 (75.4) –10.2 (56.2)

22

(n=662) (n=662) (n=662) (n=667) (n=667) (n=667)

All values are mean (standard deviation) unless otherwise stated. n denotes the number of patients with data available at baseline and last visit (including last observation carried forward method).

Pharma

V0

EN

Please attach

tear-off identification sticker w

ith the CR

F ID

here

Please retu

rn th

is diary at th

e next reg

ular visit.

Investigator’s stam

p

Date an

d tim

e of

next visit

V1

V2

hrsm

inday

month

year

hrsm

inday

month

year

Patien

t Diary

BY

217/M2-125, H

ER

ME

S

final print v1.0:25-NO

V-2005

Exam

ple how to fill in the diary:

Co

mp

letion

of

the d

iary

♦E

ach entry page consists of3 sheets:

one white original and tw

o colored copies(pink and yellow

).As self-copying paper is being used,you should take care to the

following:

–P

lease make entries only on the w

hite original,and do not remove any pages.

–U

se a black

ball-point pen to ensure that entries are transcribed onto the copy.

♦P

lease enter the year on each page.

♦P

lease enter daily into the diary:

–D

ate (day and m

onth [dd

/mm

]).

–C

ough score and sputum production score.P

lease add up the numbers to

“Total”.

–N

umber of

puffs ofrescue m

edication you did inhale during the given 2 tim

e periods (num

ber ofpuff

means num

ber ofactua

tions taken from your rescue

medica

tion inhaler).Please add up the num

bers to “Total”.

Cough,

In the evening,please assess your symptom

s ofcough

sputum production:

and sputum production for the last 24 hours.

Please enter the num

ber “0”into the respective box if

you have had no symptom

s.

No.of

puffs rescue If

no rescue medica

tion was taken,enter the num

ber “0”m

edication:

into the respective box.

Thank you very m

uch for your cooperation.

Tim

e6:00

pm–

06:00 am

06:00 am

–06:00 pm

Total

202

No. of puffs rescue medication C

ough*

Sputum

production**

21Total

3

Da

teYearday

month

20

06

21

03

**Sp

utu

m p

rod

uctio

n: H

ow

mu

ch in

con

venien

ce was cau

sed b

y you

r sp

utu

m to

day?

0N

one (unnoticeable)

1M

ild (noticeable as a problem)

2M

oderate

(frequent inconvenience)

3S

evere (constant problem)

BY

217/M2-125,H

ER

ME

S/

V0

/1

*Co

ug

h: H

ow

was yo

ur co

ug

h to

day?

0N

o cough

1M

ild cough (at som

e time during the day)

2M

oderate cough (regularly during the day)

3S

evere cough (never free ofcough or feeling

free ofthe need to cough)

601

Da

teYearday

month

daym

onthday

month

daym

onthday

month

daym

onthday

month

daym

onthday

month

No. of puffs rescue medication

Ho

w m

any p

uffs o

fyo

ur rescu

e med

ication

did

you

take tod

ay? (R

ecord

the n

um

ber o

fp

uffs taken

du

ring

each tim

ep

eriod

no

ted).

Tim

e6:00

pm–

06:00 am

06:00 am

–06:00 pm

Total

Form 001 E

N

Cough

*

Sputum

production**

Total

No

te:P

lease add up your “Totals”for each day.

Please contact your study doctor w

henever your condition worsens,

for example:

–increased cough and

/or sputum–

increased need for rescue medica

tion