Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Rabe KF, Martinez FJ, Ferguson GT, et al. Triple inhaled therapy at two glucocorticoid doses in
moderate-to-very-severe COPD. N Engl J Med. DOI: 10.1056/NEJMoa1916046
Supplementary Appendix

1. Trial investigators ......................................................................................................................... 2

2. METHODS .................................................................................................................................... 9

Figure S1. Order of hypothesis testing for Type I error control: US and ex-US approaches. ............. 15

Figure S2. Forest plots for time-to-first event analyses. ...................................................................... 16

Figure S3. Change from baseline in SGRQ total score over 52 weeks. .............................................. 17

Figure S4. Rate of moderate or severe COPD exacerbations by eosinophil subgroups. ..................... 18

Figure S5. Rate of moderate or severe COPD exacerbations by blood eosinophil count.................... 19

Table S1. Pre-specified endpoints in the ETHOS trial protocol. ......................................................... 20

Table S2. Additional baseline demographics....................................................................................... 24

Table S3. Prior COPD-related inhaled therapies. ................................................................................ 25

Table S4. Secondary and other pre-specified symptom and health-related quality of life endpoints .. 26

Table S5. Summary of adjudicated causes of death............................................................................. 28

Table S6. Subgroup analyses of the rate of moderate or severe COPD exacerbations by exacerbation

history, ICS use at screening, and reversibility .................................................................................... 29

Table S7. Time to first MACE and time to first confirmed pneumonia .............................................. 31

Table S8. Incidence of MACE and pneumonia adverse events. .......................................................... 32

Table S9. Adverse events occurring in ≥2% of patients in any treatment group (by preferred term) . 33

Table S10. Adverse events of special interest occurring in ≥1% of patients in any treatment group (by

category). .............................................................................................................................................. 34

References ........................................................................................................................................... 35

1
1. Trial investigators

Argentina

Hector Hugo Altieri, Norma Aramayo, Germán Arce, Miguel Bergna, Xavier Bocca, Horacio Budani, Victor
Hugo Cambursano, Cristian Carminio, Fernando Antonio de la Riestra, Maria De Salvo, Héctor Defranchi,
Ricardo del Olmo, Andrés Luis Echazarreta, Pedro Elías, Cristián Fazio, Marcelo Fernández, Gabriel García,
Adriana Gosn, Virginia Larivey, Luis Larrateguy, Veronica Patricia Lawriwskyj, Martin Maillo, Fernando
Massola, Walter Mattarucco, Andrea Medina, Alicia Beatriz Molina Bonetto, Laura Nardone, Juan Facundo
Nogueira, Angel Esteban Piacenza, Federico Promencio, Miguel Quiroga, Luisa Beatriz Rey, Mariana
Rivera, Alicia Rodriguez, Juan José Rodriguez Moncalvo, Ramón Rojas, Gonzalo Saenz, Pablo Sáez,
Damián Silva, Adriana Sosso, Jorge Taborda, Alberto Tolcachier, Nora del Valle Vega, Fernando Verra,
Luis Wehbe

Australia

Simon Bowler, Peter Bremner, Patrick Carroll, Michael Chia, Huw Davies, Mark Holmes, Jeff Karrasch,
Matthew Peters, Frederick Graham Simpson, Anna Tai, Francis Thien, Peter Wark, John Wheatley

Austria

Othmar Ablinger, Bernhard Forstner, Michael Studnicka, Mahmud Sweilem, Norbert Vetter, Robert Voves,
Josef Würtz, Peter Würtz

Belgium

Luc Capiau, Benoit Colinet, Ulrike Himpe, Eduard Janssens, Jean Benoit Martinot, Jaak Mortelmans, Rudi
Peche, Thierry Pieters, Luc van Zandweghe, Guy Vereecken, Geert Vileyn

Brazil

Marina Andrade Lima, Alexandre Cardoso, Claudia Costa, Alberto Cukier, Elie Fiss, Jussara Fiterman,
Guilherme Garcia, Irma Godoy, José Roberto Jardim, Marli Knorst, Fernando Lundgren, Waldo Mattos,
Danuza Ávila de Mello, Maria Eunice Moraes de Oliveira, Marcio Neis, Karina Oliveira, Andreia Pez,
Emilio Pizzichini, Marcelo Rabahi, Adalberto Rubin, Roberto Stirbulov

Canada

Syed Anees, François Blouin, Guy Chouinard, Guy Deslauriers, Anthony Dowell, Anthony D'Urzo, Francis
Ervin, Tharwat Fera, Murdo Ferguson, Sam Henein, Lawrence Homik, Allan Kelly, Patrick Killorn, François
Maltais, Darcy Marciniuk, Giuseppe Mazza, Andrew McIvor, Lyle Melenka, Denis O'Donnell, Bonavuth
Pek, Sean Peterson, George Philteos, Claude Poirier, Dennis Reich, Don Sin, Eric St-Amour, John Taliano,
Guy Tellier, Arthur Vasquez, Brian Zidel

2
Chile

Manuel Barros, Claudia Cartagena, Juan Cristóbal Celis Carrasco, Germán Cruz, Patricia Fernández, Roxana
Fuentes, José Fuentes, Paula Galleguillos, Victor Martinez, Roxana Maturana, Eduardo Mendez, Laura
Mendoza, Juan Carlos Palma Carvajal, Juana Pavie, Carlos Quilodran, Andrés Rosenblut, Patricia
Schonffeldt, Rafael Silva, Sergio Vargas

China

Xiaoyue Chang, Gang Chen, Hong Chen, Rongchang Chen, Juan Du, Ganzhu Feng, Jiaxi Feng, Yingyun Fu,
Xiuhua Fu, Xiwen Gao, Zhancheng Gao, Yuhai Gu, Wei Gu, Yubiao Guo, Zhongliang Guo, Xiaowen Han,
Huijie He, Zhiyi He, Jian-an Huang, Jin Huang, Mao Huang, Shujuan Jiang, Mingyan Jiang, Jian Kang,
Jiulong Kuang, Yali Li, Yingxiang Lin, Zeying Liu, Xiaoju Liu, Chuntao Liu, Dongming Liu, Shuying Liu,
Qiaofa Lu, Bailing Luo, Zhuang Luo, Xiaodong Mei, Zongxing Ou, Wenjun Pei, Dejun Sun, Yuling Tang,
Haoyan Wang, Changhui Wang, Dexi Wang, Limin Wang, Guangfa Wang, Xuefen Wang, Liping Wei, Bin
Wu, Xixin Yan, Ting Yang, Lan Yang, Yang, Hongzhong Yang, Kejing Ying, Changhe Yu, Xiangyan
Zhang, Min Zhang, Guohou Zhao, Xiangdong Zhou, Huili Zhu, Lei Zhu, Shuyang Zhu

Czech Republic

Masroor Ali, Michal Bláha, Jana Bursová, Martina Čmakalová, Josef Frátrik, Elena Güttlerová, Stanislav
Holub, Daniela Kopecká, Jaromír Musil, Ilona Pavlišová, Alexandra Popelková, Lenka Povýšilová, Jolana
Presperinova, Josef Veverka, Jiří Votruba, Jiří Vytiska

France

Alain Boye, Ari Chaouat, Gilles Devouassoux, Dominique Lejay, Mathieu Larrousse, Charles Le Merre,
Hervé Pegliasco

Germany

Sabine Ballenberger, Robert Bals, Ekkehard Beck, Peter Berg, Burkhard Bewig, Hans Christian Blum, Lutz
Bollmann, Hans Brüggen, Falk Brunner, Stephan Budweiser, Klaus Dalhoff, Andres de Roux, Regina
Deckelmann, Andreas Deimling, Rolf Dichmann, Frank Eberhardt, Tamara Eckermann, Martin Ehlers,
Andreas Eich, Moritz Erlinger, Guido Ern, Jan Feimer, Frank Feldmeyer, Karin Forster, Andreas Forster,
Karl Heinz Franz, Andreas Fritzsche, Christian Gessner, Thomas Ginko, Peter-Uwe Haase, Peter Hammerl,
Hans Peter Hauber, Stefan Heindl, Gerd-Ulrich Heinz, Rudolf Hennig, Peter Hofbauer, Martin Hoffmann,
Gerhard Hoheisel, Gabriele Illies, Margret Jandl, Matthias John, Thomas Jung, Josef Junggeburth, Frank
Käßner, Frank Kanniess, Claus Keller, Joachim Kirschner, Anne-Marie Kirsten, Uwe Kleinecke-Pohl,
Andrea Koch, Hans-Joachim König, Stephanie Korn, Claus Kroegel, Matthias Krull, Petra Kühne, Evelin
Liefring, Anneliese Linnhoff, Andrea Ludwig-Sengpiel, Matthias Luttermann, Silke Mronga, Ingomar F. K.
Naudts, Ruth Nischik, Axel Overlack, Ronald Redlich, Peter Ruckert, Heiner Saueressig, Axel Schaefer,
3
Christian Schäfer, Lennart Schaper, Isabelle Schenkenberger, Volker Schlegel, Christian Schlenska, Olaf
Schmidt, Gerhard Scholz, Michael Sebert, Helena Sigal, Heiner Steffen, Inga Steinebach, Christoph Stolpe,
Liebhild Stratmann, Harald Sudhoff, Hilke Temme, Lutz Volgmann, Volker von Behren, Christian von
Mallinckrodt, Jürgen Wachter, Matthias Waltert, Sabina Wehgartner-Winkler, Joachim Weimer, Tobias
Welte, Jörg Winkler, Stefan Zielen

Hungary

Anna Bartha, Ildikó Breining, Valéria Csajbók, Katalin Gömöri, Zsuzsanna Mark, Imre Mészáros, Lajos
Molnár, János Mucsi, Eva Radeczky, Marianna Rakvács, Judit Schlezák, Mihály Tímár, Erika Unger, István
Várkonyi, Hilda Zibotics

Italy

Elena Bacci, Bianca Beghé, Francesco Blasi, Damiano Capaccio, Mauro Carone, Stefano Centanni, Isa
Cerveri, Alfredo Chetta, Giuseppe Fiorentino, Antonio Foresi, Maria Pia Foschino Barbaro, Francesco
Mazza, Stefano Nava, Paolo Palange, Giovanni Passalacqua, Claudio Pedone, Stefano Picciolo, Massimo
Pistolesi, Renato Prediletto, Paola Rogliani, Alessandro Sanduzzi Zamparelli, Nicola Scichilone, Antonio
Spanevello

Japan

Tomoki Kimura, Masaharu Kinoshita, Hiroyuki Nakamura, Hiroyuki Ohbayashi, Hironori Sagara, Yuji
Tohda, Takashi Yamada, Eiji Yamagata

Mexico

Moisés Acuña, Sylvia Colmenero, Dante Hernández, Luis Natera, Alejandra Ramírez Venegas, Alicia
Ramírez, Jorge Rosas, Héctor Glenn Valdez López

Netherlands

Mazin Alhakim, Paul Bresser, Robert Costongs, Frank Custers, Remco Djamin, Michiel Eijsvogel, Steven
Gans, Martijn Goosens, Christian Melissant, Sunil Ramlal, M.A. Tiemessen, Hans Timmer, Vivienne van de
Walle, Jan Willem van den Berg, Maarten van den Berge, Pascal Wielders

New Zealand

Benedict Brockway, Simon Carson, Catherina Chang, Paul Dawkins, Michael Epton, John Kolbe, Paul
Noonan, Dean Quinn, John Richmond, Andrew Veale

Peru

4
José Cabrera, Oscar Carbajal, Socorro Castro, William Chávez, Octavio Cubas, Silvia Giovana del Pilar
Cubas Durango, Javier Diaz, Rolando Estrella, Maria Faverio, Ronal Gamarra, Alfredo Guerreros, Carlos
Iberico, Alberto Matsuno, Ramon Mendoza, Fernando Roberto Rodriguez Chariarse, Danilo Salazar, César
Villarán, José Antonio Zaga Ortega

Poland

Adam Śmiałowski, Anna Biełous-Wilk, Anna Bogusz, Kornelia Ciekalska, Krystyna Folcik, Hanna
Gęsińska, Tomasz Kaziród, Violetta Łabij, Danuta Mądra-Rogacka, Bernadetta Majorek-Olechowska,
Janusz Milanowski, Robert Mróz, Władysław Pierzchała, Robert Staniszewski, Marzenna Tarnowska-
Matusiak, Sławomir Tokarski

Russia

Elena Alexeeva, Gregory Arutyunov, Alexander Averyanov, Alexander Bezlepko, Natalia Galvas, Mikhail
Ilkovich, Sergey Mikhailov, Elena Ovchinnikova, Valery Podzolkov, Elena Polkanova, Irina A. Semenova,
Natalia Shaporova, Vasilii Trofimov, Elena Vishneva, Anna Zateyshchikova

Serbia

Ivan Cekerevac, Vesna Dopudja Pantic, Aleksandra Ilic, Ivan Kopitovic, Zorica Lazic, Ivana Mikavica,
Branislava Milenkovic, Dragica Mirkovic, Natasa Petrovic-Stanojevic, Gorana Sovljanski, Ivana Stankovic,
Ana Stojanovic, Miodrag Vukcevic, Vladimir Zugic, Dejan Zujovic, Biljana Zvezdin

South Africa

Ismail Aboobaker Abdullah, Ismail Abdullah, Paul Abrahams, Luthando Adams, David Bernhardi, Johannes
Breedt, Nazira Carrim-Ganey, Douwe De Jong, Nyda Fourie, Elvis Irusen, Dirkie Janse van Rensburg,
Umesh Lalloo, Johan Lombaard, Hannelie Lottering, Ismael Mitha, Essack Mitha, Mohamed Salim
Mookadam, Murimisi Mukansi, Chantal Muller, Haylene Nell, Trevenesan Padayachee, Gerhard Ras,
Danelle Richter, Susanna Roux, Saadiya Seedat, Mohammed Tayob, Michael van der Linden, Eugene Van
der Walt, Albie Van Zyl, Richard van Zyl-Smit, Marianne Elizabeth Viljoen, Agatha Wilhase

South Korea

Joong Hyun Ahn, Min Kwang Byun, Jung Hyun Chang, Jaehwa Cho, Hee Soon Chung, Seung Joon Kim,
Yee Hyung Kim, Kwan Ho Lee, Sang Yeub Lee, Yong Chul Lee, Sang Haak Lee, Sung Soon Lee, Sung-
Chul Lim, Seong Yong Lim, Choon Sik Park, Seungsoo Sheen, Jae Jeong Shim, Soojung Um, Sukjoong
Yong, Chul-Gyu Yoo, Kwang Ha Yoo, Hyoungkyu Yoon, Hoil Yoon, Ho Kee Yum

Spain

5
Macarena Arroyo, Ferran Barbé, Miguel Barrueco, Albert Boada Valmaseda, José Luis de la Cruz Ríos, Luis
de Teresa, José Echave-Sustaeta, Xavier Farrès, Antonio Ferrer, Juan Luis García Rivero, Javier Hueto Pérez
de Heredia, José María Ignacio García, Jordi Juanola Pla, Luis Lores, José María Marin, Pyrene Martínez,
Carlos Martínez Rivera, Luis Mateos Caballero, Fernando Molina Nieto, Eduard Monsó, Elsa Naval Sendra,
Jacinto Ortiz, Juan Ortiz de Saracho Bobo, Mercè Pérez Vera, Germán Peces-Barba, Luis Puente-Maestu,
David Ramos Barbón, Ana Rañó, José Miguel Rodriguez González-Moro, Juan Roldán, Fernando Sánchez-
Toril López, Antonio Santa Cruz, José Gregorio Soto Campos, Zoran Stojanovic, Pere Torán-Monserrat,
José Luis Velasco Garrido

Sweden

Johan Berglund, Ulla-Britt Ericsson, Pekka Koskinen, Anders Luts, Åke Olsson, Stefan Rustscheff, Ines
Vinge

Taiwan

Shih-Lung Cheng, Wen-Feng Fang, Liang-Wen Hang, Jeng-Yuan Hsu, Ming-Shyan Huang, Yu Chih Liu,
Yu-Feng Wei, Cheng Ta Yang, Chong-Jen Yu

United Kingdom

Joshua Asubiaro, Ronnie Beboso, Mark Blagden, John Calvert, Gourab Choudhury, Rebecca Clark, David
Collier, Anthony Gunstone, John Hurst, Paul Ivan, Venkata Kondagunta, Brian Leaker, Ravi Mahadeva,
Gerry McKaig, Damien McNally, Monica Nordstrom, Babatunde Oyesile, Janice Patrick, Elizabeth Sapey,
Dinesh Saralaya, Rex Sarmiento, Dave Singh, Johnston Stewart, Usha Sukumaran, Amrit Takhar, Alice
Turner, Dennis Wat, Jadwiga Wedzicha, Mark Wilkinson, Andrew Wilson

United States

Chandar Abboy, Ladly Abraham, Roger Abrahams, Amable R. Aguiluz, Bassil Aish, Mohamed Ali, Karen
Allen, Gregory Allen, Jr., William F. Alleyne, II., Jose Alvarez, Rajasekaran Annamalai, Rami Arfoosh,
Ahmed Arif, Samir Arora, Robby Ayoub, Francisco Badar, Anil Badhwar, Peggy Barnhill, Glenn Beard,
Richard Beasley, George Bensch, Peter Bercz, Larry Berman, David Bernard, David I. Bernstein, Saligrama
Bhat, Maria Blahey, Joseph A. Boscia, III., Susan Bottone, Cynthia Bowman-Stroud, Shari Brazinsky,
Gregory Brooks, Barry Buffman, John R. Burk, Robert Buynak, William Byars, James Cain III, Ronald
Caldwell, Robert Call, Jose F. Cardona, James Carswell, Ivan Castano, Ravi Chandran, Christopher Chappel,
Eric Chenworth, Kenneth Chinsky, Jim Christensen, Bertrand Cole, Jeremy Cole, Clinton Corder, Bruce
Corser, Maria C. Cubillas, Richard Cutchin, Nizar Daboul, Jerome Daniel, Timothy Dao, Enrique Davis,
Gilda M. De La Calle, Luis De La Cruz, Ronald DeGarmo, Samuel DeLeon, Michael B. Denenberg, Sandip
Desai, Ernesto Diaz, Jose Diaz, Robert Dillon, Calvin Dixon, Leonard Dunn, Hugh Durrence, Timothy
Elder, Kirk Elliott, David Erb, Neil Ettinger, Emeka Eziri, Faisal Fakih, Richard Fei, Gregory Feldman,

6
Jeremy Feldman, Gary Ferguson, Maria Fernandez, Herbon Fleming, Charles Fogarty, Rodney Folz, Miguel
Franco, George Freeman, Stephen Fritz, David Fuentes, Gregory Funk, Nashwa Gabra, Bernard Garcia,
Francisco Garcia, Robert Garver, Padmaja Reddy Gayam, Arthur Gelb, Marcy Goisse, William Gonte,
Learned Gonzales, Robert Gordon, Brian Gotkin, Gregory Gottschlich, Kanakadurga Govindaraju, Richard
Gower, Joseph Graif, Benny Green, Gary Greenwald, Darin Gregory, Kevin Grullon, Sridhar Guduri,
Giancarlo Guido, Tarsem Gupta, James Haaksma, Ghassam Hadi, Kenneth S. Haft, Michael Hagan, Athir
Hajjar, Gregory Hammond, Hoadley Harris, Aaron Hartman, Ernest Hendrix, Carlos Herrera, Mitzie Hewitt,
Albrecht Heyder, Jeffrey Hirschfield, James Hitchcock, John Holcomb, Donald Howard, Cathy Hurley,
Iftikhar Hussain, Thomas Hyers, Abraham Ishaaya, Younus Ismail, Richard Jackson, Joshua Jacobs, Ajay
Jain, Ahmad Jalloul, Mikell Jarratt, Frank Johnson, Stephen Jones, Rebecca Jordan, John Joseph, Kishor
Joshi, Thomas Kaelin, Monroe Karetzky, Najmuddin Karimjee, Robert Kaufmann, Mitchell Kaye, Edward
Kerwin, Ahtaram Khan, Sohail Khan, Yasuko Kidokoro, Jeffrey Kingsley, Gaylon Kipp, Ryan Klein,
Andras Koser, Raymond Kovalski, James Krainson, Camil Kreit, Kannappan Krishnaswamy, Shana
Krstevska, Ted Kubicki, Steven Kulback, Amrendra Kumar, Sanjeev Kumar, Ritsu Kuno, Mitchell
Kuppinger, Shahrukh Kureishy, Joseph Labuda, Albert Lai, Mitchell Douglas Lee, Lawrence Levinson,
Vadim Leyenson, Joseph Lillo, Govinda Lohani, Aslam Loya, Peter Lutz, Lon Lynn, Sharan Mahal, Naveed
Mahfooz, Sashi Makam, Rickey Manning, Lyndon Mansfield, Abbas Mansour, Hipolito Mariano, David
Marks, Jennifer Martin, Mark Martin, Rafael Martinez, Cindy Martinez, Maria Mascolo, Samuel Mast,
Jonathan Matz, David Maybee, James McDonnell, Isaac Melamed, Curtis Mello, Eric Melvin, Kevin
Merkes, Peter Meyers, Bernard Michlin, Magdy Mikhail, Thomas Minor, Gowdhami Mohan, Jason Mohr,
Elizabeth Mones, Anthony Montanaro, Eliot Moon, Emily Morawski, Nabil Morcos, Courtney Morgan,
Timothy Moriarty, Scott Morin, Nidal Morrar, Felix Morris, Alvaro Murcia, Alexander Murray, Murtaza
Mussaji, Salil Nadkarni, Pedro Nam, Cheta Nand, Ikeadi Maurice Ndukwu, Brooke Nevins, Rachel Nisbet,
Timothy L. Norcross, Daniel Norman, Thomas Nugent, Lazaro Nunez, David Nyanjom, Dany Obeid,
Onwura Obiekwe, Thomas O’Brien, Joseph Ojile, Ikechi Okwara, Robert Onder, Robert Orr, David
Ostransky, Raidel Oviedo, Ward Paine, Mikhail Palatnik, Michael Palumbo, Jorge Paoli-Bruno, Kaushik
Patel, Amit Patel, Nancy L.S. Patel, Christopher Perry, Shirin Peters, Michael Pfeffer, David Pham, Jean
Philippe, Regina Pillai, Jennifer M. Piwowarski, Joe Pouzar, Bruce Prenner, Kevin Pritchett, Raman
Purighalla, George Pyrgos, Syed Rahman, William Randall, Orlando Rangel, Syed Rehman, Robert Remler,
A Lynn Ridgeway, Ernie Riffer, Eustace Riley, Clifford Risk, Demetrius Rizos, Emory Robinette, Lilia
Rodriguez, Hugo Romeu, Bridgett Ronan, Shari Rozen, Timothy Rummel, Gary Ruoff, Eugene Ryan,
Stephen Ryan, Boris Sagalovich, Satinder Saini, Robert Salazar, Victor Salcedo, D. Andrew Sams, Mercedes
Samson, Jay Sandberg, William Sargeant, Alan Schecter, Eric Schenkel, Jay Schmidt, C. Andrew Schroeder,
James Schultz, Jeffrey Scott, Anita Scribner, Michael Seep, Sudhir Sehgal, Sudhir Sekhsaria, Jean-Louis
Selam, John Sensenbrenner, Marvin Sexton, Amit Shah, Suresh Shah, Ajit Shah, Vipul Shah, Ranjan Shah,
Heena Shah-Patel, Paul Shapero, Timothy Shepherd, Lawrence Sher, James R Shoemaker, John Scott
Sibille, Ather Siddiqi, Barry Sigal, Vinay Sikand, Thomas Siler, William Sims, Naresh Singh, David Smith,
Stephen Keith Smith, Clark Soderlund, Royce Solano, Guillermo Somodevilla, Weily Soong, John Southard,

7
Clyde Southwell, Selwyn Spangenthal, Roy St. John, Thomas Stern, Asha Stern, Gary Steven, Vijay
Subramaniam, Sever Surdulescu, Ricardo Tan, Tonny Tanus, Horia Tatu, Gilbert Teixeira, Alan Thomas,
Charles Thompson, Ernest Thompson, Jr, Letitia Thompson-Hargrave, Craig Thurm, Raymond Tidman,
Louis A. Torres Jr., Rodolfo Trejo, Miguel Trevino, Barry Troyan, John Updegrove, Sanjay Vadgama, Sunil
Verma, Manuel Villareal, Srinivas Vodnala, Andrew Wachtel, George Walker, Luke Webb, Dave E
Webster, Paul Weinberg, Terry Wells, Howard Wenocur, Jan Westerman, Bram Wieskopf, Hugh Windom,
David Winslow, Robert Wise, Bryan Wolf, Patrick Wright, Daniel Yang, Douglas Young, Thomas Yunger,
Irfanullah Yusufzai, Zahid Zafar, Joseph Zaky

8
2. METHODS

Trial Procedures

For budesonide/glycopyrrolate/formoterol 320/18/9.6 µg, budesonide/glycopyrrolate/formoterol 160/18/9.6

µg, glycopyrrolate/formoterol 18/9.6 µg, and budesonide/formoterol 320/18/9.6 µg, the doses of 18 µg

glycopyrrolate and 9.6 µg formoterol fumarate are equivalent to 14.4 µg of glycopyrronium and 10 µg of

formoterol fumarate dihydrate, respectively. Patients were instructed to take two inhalations in the morning

and two in the evening (approximately 12 hours apart). Doses represent the sum of two inhalations (i.e., the

doses per actuation were 160 or 80 µg budesonide, 9 µg glycopyrrolate, and 4.8 µg formoterol fumarate,

resulting in a total daily dose of 640 or 320 µg budesonide, 36 µg glycopyrrolate, and 19.2 µg formoterol

fumarate).

Exacerbations

A COPD exacerbation was defined as a change in the patient’s usual COPD symptoms that lasted 2 or more

days, was beyond normal day-to-day variation, was acute in onset, and may have warranted a change in

regular medication. The change in symptoms must have included at least one major COPD symptom and at

least one other major or minor symptom from the list below:

- Major COPD symptoms: dyspnea, sputum volume, and sputum color

- Minor COPD symptoms: cough, wheeze, sore throat, cold symptoms (rhinorrhea or nasal congestion),

and fever without other cause.

All moderate or severe COPD exacerbations were captured using the COPD Exacerbation electronic

case report form. Mild COPD exacerbations were captured based on symptoms as recorded by the patient in

an electronic diary. COPD exacerbations of any severity were considered to be expected trial endpoints and

were not reported as adverse events unless considered a serious adverse event.

The investigator was required to justify the decision for defining the event as an exacerbation, and

record it in the electronic case report form if symptoms were acute or progressed rapidly and required

treatment less than 2 days from onset of symptoms, or if a patient’s symptoms and the overall clinical

9
findings supported the diagnosis of a COPD exacerbation, but the patient did not experience a worsening of

at least one major COPD symptom and at least one other major or minor symptom.

Pulmonary Function Tests

All pulmonary function tests were performed in accordance with American Thoracic Society criteria.1 All

trial staff responsible for performing pulmonary function testing received standardized training, and all

technicians were required to demonstrate proficiency in the use of the equipment and the ability to perform

technically acceptable pulmonary function tests prior to performing testing on trial patients. Spirometry

assessments were required to meet protocol-specified acceptability and repeatability criteria.

At Visit 1, a single spirometry assessment was conducted. At Visits 2 and 3, spirometry was

conducted 60 and 30 minutes prior to bronchodilator administration and at 30 minutes post-bronchodilator.

For patients participating in the 4-hour pulmonary function sub-study, additional spirometry assessments

were conducted at Visits 4, 5, 7, 10, 12, and 14 (Day 1 and Weeks 4, 12, 24, 36, and 52). At these visits,

spirometry was conducted at 60 and 30 minutes prior to trial drug administration and at 15 and 30 minutes,

and 1, 2, and 4 hours after trial drug administration. An additional spirometry assessment was conducted at 5

minutes after trial drug administration at Visit 4 (Day 1) only.

Pneumonia

To adequately assess and characterize the risk of pneumonia in patients in a nonbiased manner, an external

clinical endpoint committee (CEC) reviewed all adverse events reported as pneumonia to ensure appropriate

pre-defined and clinically consistent pneumonia criteria were met.

A clinically consistent definition of pneumonia was implemented, requiring all of the following criteria:

1. Clinical diagnosis of pneumonia by the investigator

2. Documentation of chest imaging obtained within 14 days of the diagnosis of pneumonia that was

compatible with the diagnosis of pneumonia

3. Treatment with antibiotics (and/or appropriate antiviral and/or antifungal agents)

10
 4. At least two of the following clinical signs, symptoms, or laboratory findings: increased cough,

increased sputum purulence or production, adventitious breath sounds on auscultation, dyspnea or

tachypnea, fever, elevated white blood cell counts, and hypoxemia.

The CEC could request any additional information, including copies of chest X-rays or CT scans, if

needed, to confirm the pneumonia diagnosis. Radiographs were evaluated locally, and the results (infiltrate

compatible with pneumonia) were documented within the source document at the sites. If the investigator

became aware that a diagnosis of pneumonia was made without a chest image having been performed, he or

she was to obtain a chest X-ray (frontal and lateral) up to 10 to 14 days after the date of pneumonia

diagnosis.

Statistical Analysis

Sample Size

The probability of demonstrating differences for 320 µg-budesonide triple therapy versus both dual therapies

with a P-value of <0.005 was approximately 78% (87% for each comparison). These calculations assumed

yearly rates of moderate or severe exacerbations of 1.14, 1.21, 1.34, and 1.34 with 320 µg-budesonide triple

therapy, 160 µg-budesonide triple therapy, glycopyrrolate/formoterol, and budesonide/formoterol,

respectively. The sample size was increased from 8000 to 8400 following a blinded sample size re-

estimation.2

Populations and Estimands

The intent-to-treat (ITT) population included all patients who were randomized and received any amount of

trial treatment. Patients were analyzed according to randomized treatment group, and efficacy data obtained

after discontinuation of treatment but prior to withdrawal from the trial were included. The modified ITT

(mITT) population was a subset of the ITT population that included all patients with post-randomization data

obtained prior to discontinuation from treatment. Any data collected after completion of, or discontinuation

from, randomized trial medication was excluded from the mITT analysis but included in the ITT analysis.

The safety population was similar to the mITT population, but patients were analyzed according to treatment

received rather than treatment randomized, and patients with no post-dose safety assessments were excluded.

The per-protocol population was a subset of the mITT population defined as all patients with post-

11
randomization data obtained prior to any major protocol deviations and was used for non-inferiority

analyses. The primary estimand of interest was the efficacy estimand, which assumed continuation of

randomized treatments for the trial duration, regardless of actual compliance. A secondary analysis of the

primary endpoint was performed using the attributable estimand, which accounted for patients who

discontinued treatment because of lack of efficacy or tolerability by imputing missing data. The treatment

policy estimand, i.e. the effect of randomized treatment over the study period regardless of whether

randomized treatment was continued, was assessed using the ITT population, in which all observed data

were utilized regardless of whether patients remained on randomized treatment.

Type I Error Control

All treatment comparisons were made for superiority, except for 160 µg-budesonide triple therapy to

budesonide/formoterol, which was for non-inferiority followed by superiority. However, attaining statistical

significance in the superiority comparison was not a pre-requisite to proceeding down the testing hierarchy

(Figure S1).

This trial had a planned interim efficacy analysis overseen by an external data monitoring

committee. Because the criteria for unequivocal efficacy were not met for the interim analysis, and the trial

continued until all participants completed, the one-sided α criteria for the final analysis was adjusted based

on the percentage of the information available at the interim analysis such that the overall Type I error was

controlled at a one-sided α of 0.025. The final analysis one-sided critical level of significance was 0.023,

thereby making the two-sided level 0.046.

For both registration approaches, US and ex-US, and for each dose of triple therapy, if the primary

and first secondary measures were statistically significant for all comparisons, then Type I error for the

remainder of the secondary measures with the exception of time to death (all-cause) was to be controlled by

using Hochberg within each comparison.3 If all of the secondary measures were significant, then time to

death (all-cause) was to be tested within each comparison.

Non-Inferiority Margins

12
For the comparison of 160 µg-budesonide triple therapy to budesonide/formoterol, the non-inferiority

margins were as follows (all for two-sided 95% CIs): for exacerbation endpoints, a rate ratio of 1.1 for the

upper bound; for Transition Dyspnea Index (TDI) focal score, –0.75 units for the lower bound; for rescue

medication use, 0.75 puffs/day for the upper bound; for St. George’s Respiratory Questionnaire (SGRQ), 3.0

units for the upper bound; for SGRQ responders, 10 percentage points for the upper bound; for the

EXAcerbations of Chronic pulmonary disease Tool (EXACT) total score, 1.5 units for the upper bound.

Analysis Methods

The rate of moderate or severe COPD exacerbations and the rate of severe exacerbations were

analyzed using negative binomial regression, adjusting for baseline post-bronchodilator percent predicted

FEV1 and log baseline blood eosinophil count as continuous covariates and baseline COPD exacerbation

history, ICS use at screening, and region (US and Canada; Asia; Western Europe; Eastern Europe; Mexico,

Central America, and South America; Australia, New Zealand, and South Africa) as categorical covariates.

Time at risk was used as an offset variable. The Cox regression model for time to first moderate or severe

COPD exacerbation included the same covariates.

TDI focal score and SGRQ total score were analyzed using linear repeated measures analysis of

covariance (ANCOVA) models including treatment, visit, and the treatment by visit interaction, and ICS use

at screening as categorical covariates and log baseline blood eosinophil count, baseline score, baseline post-

bronchodilator percent predicted FEV1, and percent reversibility to bronchodilator as continuous covariates.

The mean change from baseline in EXACT total score was analyzed using a similar repeated measures

model as for TDI, but using the corresponding baseline mean score instead of the Baseline Dyspnea Index as

a covariate.

Change from baseline in rescue medication use was analyzed using a linear repeated measures

ANCOVA model including treatment, 4-week time interval, the treatment by time interval interaction, and

screening ICS use as categorical covariates and baseline post-bronchodilator percent predicted FEV1,

baseline rescue medication use, log baseline blood eosinophil count, and percent reversibility to

bronchodilator as continuous covariates.

13
 For the SGRQ responder analysis, logistic regression was used to compare the treatment groups with

baseline SGRQ score, log baseline blood eosinophil count, and baseline post-bronchodilator percent

predicted FEV1 and percent reversibility to bronchodilator as continuous covariates and treatment, and ICS

use at screening as categorical covariates.

Time to death was analyzed using a Cox regression model, adjusting for baseline post-

bronchodilator percent-predicted FEV1 and baseline age as covariates.

Analyses of the rate of moderate or severe exacerbations according to eosinophil count were

performed using generalized additive modeling, combining nonparametric regression for the relationship of

eosinophil levels to response with a negative binomial model.

14
Figure S1. Order of hypothesis testing for Type I error control: US and ex-US approaches.

All comparisons of BGF MDI 160 versus BFF MDI are for non-inferiority using the per-protocol estimand followed by superiority. Superiority is not
required to advance to the next comparison. All other comparisons are for superiority and use the efficacy estimand unless otherwise stated. Endpoints are at
Week 24 for the US approach and over 24 weeks for the ex-US approach wherever applicable (lung function, SGRQ score, and symptoms). Hochberg-
controlled secondary endpoints were the time to first moderate or severe COPD exacerbation, rescue medication use, rate of severe COPD exacerbation,
SGRQ total score (ex-US), SGRQ responders (US), EXACT total score (ex-US), and TDI focal score (ex-US). BFF MDI denotes budesonide/formoterol
fumarate metered dose inhaler, BGF MDI 160 budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler 160/18/9.6 µg, BGF MDI 320
budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler 320/18/9.6 µg, COPD chronic obstructive pulmonary disease, exac. exacerbations,
EXACT EXAcerbations of Chronic pulmonary disease Tool, GFF MDI glycopyrrolate/formoterol fumarate metered dose inhaler, SGRQ St. George’s
Respiratory Questionnaire, TDI transition dyspnea index.

15
Figure S2. Forest plots for time-to-first event analyses.

Panel A shows the time to first moderate or severe COPD exacerbation in the modified intent-to-treat population (efficacy estimand), and Panel B the time to
death (all-cause) in the intent-to-treat population (treatment policy estimand). Error bars represent 95% confidence intervals. Hazard ratios are plotted on a
logarithmic scale. BFF MDI denotes budesonide/formoterol fumarate metered dose inhaler, BGF MDI budesonide/glycopyrrolate/formoterol fumarate
metered dose inhaler, COPD chronic obstructive pulmonary disease, GFF MDI glycopyrrolate/formoterol fumarate metered dose inhaler.

16
Figure S3. Change from baseline in SGRQ total score over 52 weeks (efficacy estimand; modified intent-to-treat population).

The I bars represent standard errors. Total scores on the SGRQ range from 0 to 100, with lower scores indicating better health-related quality of life; the
minimum clinically important difference is 4 units4. BFF MDI denotes budesonide/formoterol fumarate metered dose inhaler, BGF MDI
budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler, GFF MDI glycopyrrolate/formoterol fumarate metered dose inhaler, SGRQ St George’s
Respiratory Questionnaire.

17
Figure S4. Rate of moderate or severe COPD exacerbations by eosinophil subgroups (efficacy estimand; modified intent-to-treat population).

Error bars represent 95% confidence intervals. Hazard ratios are plotted on a logarithmic scale. BFF MDI denotes budesonide/formoterol fumarate metered
dose inhaler, BGF MDI budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler, COPD chronic obstructive pulmonary disease, GFF MDI
glycopyrrolate/formoterol fumarate metered dose inhaler.

18
Figure S5. Rate of moderate or severe COPD exacerbations by blood eosinophil count (modified intent-to-treat population).

Banded areas indicate 95% confidence intervals. BFF MDI denotes budesonide/formoterol fumarate metered dose inhaler; BGF MDI
budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler; COPD chronic obstructive pulmonary disease; GFF MDI glycopyrrolate/formoterol
fumarate metered dose inhaler.

19
Table S1. Pre-specified endpoints in the ETHOS trial protocol.

Reported in Not reported in

Endpoints this manuscript this manuscript
or supplement or supplement
Primary endpoint

Rate of moderate or severe COPD exacerbations X

Secondary endpoints

Time to first moderate or severe COPD exacerbation X

Change from baseline in average daily rescue medication use X

over 24 weeks

TDI focal score over 24 weeks (ex-US) X

Change from baseline in EXACT total score over 52 weeks X

(ex-US)

Change from baseline in SGRQ total score over 24 weeks X

(ex-US)

Percentage of participants achieving an MCID of 4 units or X

more in SGRQ total score at Week 24 (US)

Time to death (all-cause) X

Rate of severe COPD exacerbations X

Other endpoints

Rate of COPD exacerbations of any severity X

Time to first COPD exacerbation of any severity X

Time to first severe COPD exacerbation X

Change from baseline in average daily rescue medication use X

over 52 weeks

Time to death (respiratory) X

Time to treatment failure (treatment discontinuation for any X

cause, moderate or severe exacerbation, or death)

Change from baseline in the EXACT total score over 24 weeks X

and over each 4-week interval of the 52-week treatment period

Change from baseline in the E-RS total score over 24 weeks, X

over 52 weeks, and over each 4-week interval of the 52-week
treatment period

Percentage of days with “no rescue medication use” X

TDI focal score over 24 weeks (US) X

20
 Reported in Not reported in
Endpoints this manuscript this manuscript
or supplement or supplement
TDI focal score over 52 weeks, and at each post-randomization X
visit

Percentage of participants achieving an MCID threshold of 1 X

unit or more on average over 24 weeks in TDI focal score

Percentage of participants achieving an MCID threshold of 1 X

unit or more on average over 52 weeks in TDI focal score

Change from baseline in SGRQ total score over 52 weeks, and X

at each post-randomization visit

Percentage of participants achieving an MCID of 4 units or X

more in SGRQ total score at Week 52

Percentage of participants achieving an MCID of 4 units or X

more in SGRQ total score over 52 weeks and over 24 weeks

EQ-5D-5L variables, including the EQ-5D index score, the EQ- X

5D VAS, and each of the five-dimension single item 5-level
responses at each post-randomization visit.

Pulmonary function tests sub-study endpoints

Primary endpoints

Change from baseline in morning pre-dose trough FEV1 at X

Week 24 (US) for the comparisons of triple therapies to
glycopyrrolate/formoterol

Change from baseline in morning pre-dose trough FEV1 over 24 X

weeks (ex-US) for the comparisons of triple therapies to
glycopyrrolate/formoterol

FEV1 AUC0-4 at Week 24 (US) for the comparisons of triple X

therapies to budesonide/formoterol

FEV1 AUC0-4 over 24 weeks (ex-US) for the comparisons of X

triple therapies to budesonide/formoterol

Other endpoints

Change from baseline in morning pre-dose trough FEV1 over X

24 weeks, over Weeks 12 to 24, over 52 weeks and at each post-
randomization visit

FEV1 AUC0-4 over 24 weeks, over Weeks 12 to 24, over X

52 weeks and at each post-randomization visit where measured

Peak change from baseline in FEV1 over 24 weeks, over Weeks X

12 to 24, over 52 weeks and at each post-randomization visit
where measured

Rate of decline in pre-dose FEV1 over 52 weeks X

21
 Reported in Not reported in
Endpoints this manuscript this manuscript
or supplement or supplement
Rate of decline in FEV1 AUC0-4 over 52 weeks X

Time to onset of action on Day 1 X

24-h Holter monitoring sub-study endpoints

Primary endpoint

Change from baseline in mean heart rate averaged over X

24 hours

Secondary endpoints

Change from baseline in mean nighttime (22:00 to 06:00) and X

daytime (06:00 to 22:00) heart rate

Change from baseline in the maximum 24-hour heart rate X

Change from baseline in the minimum 24-hour heart rate X

Change from baseline in the frequency of isolated ventricular X

ectopic events (including a single PVC)

Change from baseline in the frequency of ventricular couplets X

(defined as two PVCs preceded or followed by regular beats)

Change from baseline in the frequency of ventricular runs X

(defined as three or more PVCs preceded or followed by regular
beats)

Change from baseline in the frequency of supraventricular X

ectopic beats

Change from baseline in the frequency of isolated X

supraventricular ectopic events

Change from baseline in the frequency of supraventricular X

couplets

Change from baseline in the frequency of supraventricular runs X

Incidence of withdrawal criteria being met during 24-hour X

Holter monitoring

Incidence of atrial fibrillation with a rapid ventricular response X

(>100 bpm)

Other endpoints

Proportion of participants with maximum heart rate >180, X

>160−180, >140−160, >120−140, >100−120, and 100 bpm or
less

The proportion of participants with a minimum heart rate >60, X

>50−60, >40−50, and ≤40 bpm

22
 Reported in Not reported in
Endpoints this manuscript this manuscript
or supplement or supplement
The proportion of participants in each category of change from X
baseline in the number of PVCs per hour (no change, increase
of >0−<60, 60−<120, and ≥120, and decrease of >0−<60,
60−<120, and ≥120)

Healthcare resource utilization assessments X

AUC0–4 denotes area under the curve from 0 to 4 hours, bpm beats per minute, COPD chronic obstructive
pulmonary disease, EQ-5D-5L EuroQol 5 Dimensions 5 Levels health questionnaire, E-RS EXACT-
Respiratory Symptoms, EXACT EXAcerbations of Chronic pulmonary disease Tool, FEV1 forced expiratory
volume in 1 second, MCID minimal clinically important difference, SGRQ St. George’s Respiratory
Questionnaire, PVC premature ventricular contraction, TDI Transition Dyspnea Index, VAS Visual Analog
Score.

23
Table S2. Additional baseline demographics (modified intent-to-treat population).*

Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/

glycopyrrolate/ glycopyrrolate/ formoterol formoterol
formoterol formoterol 18/9.6 µg 320/9.6 µg
320/18/9.6 µg 160/18/9.6 µg (N = 2120) (N = 2131)
(N = 2137) (N = 2121)
Race — no. (%)
White 1819 (85.1) 1783 (84.1) 1808 (85.3) 1816 (85.2)
Asian 162 (7.6) 166 (7.8) 157 (7.4) 166 (7.8)
Black 78 (3.6) 88 (4.1) 75 (3.5) 64 (3.0)
American Indian/Alaska Native 33 (1.5) 40 (1.9) 30 (1.4) 39 (1.8)
Other 45 (2.1) 44 (2.1) 50 (2.4) 46 (2.2)
Body mass index — kg/m 2
27.6±6.2 27.5±6.3 27.6±6.2 27.1±6.2
COPD duration — yr 8.4±6.5 8.2±6.1 8.2±6.1 8.4±6.1
Reversibility to ipratropium
Change in FEV1 from pre-to post- 144.0±150.6 148.7±149.5 141.1±144.5 136.5±141.8
ipratropium — mL
Reversibility ≥ 12% and ≥ 200 633 (29.6) 634 (29.9) 599 (28.3) 598 (28.0)
mL, n (%)
Cardiovascular medical history†
No. of patients evaluated 2144 2124 2125 2136
≥1 cardiovascular risk factor 1511 (70.5) 1505 (70.9) 1492 (70.2) 1513 (70.8)
Hypertension 1272 (59.3) 1252 (58.9) 1250 (58.8) 1251 (58.6)
High total cholesterol 769 (35.9) 769 (36.2) 744 (35.0) 761 (35.6)
Diabetes 398 (18.6) 400 (18.8) 339 (16.0) 358 (16.8)

Plus–minus values are means ±SD. †Safety population. The doses of glycopyrrolate and formoterol fumarate are
*

equivalent to 14.4 µg of glycopyrronium and 10 µg of formoterol fumarate dihydrate, respectively. COPD denotes
chronic obstructive pulmonary disease, FEV1 forced expiratory volume in 1 second.

24
Table S3. Prior COPD-related inhaled therapies (safety population).

Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/ All patients

glycopyrrolate/ glycopyrrolate/ formoterol formoterol (N = 8529)
formoterol formoterol 18/9.6 µg 320/9.6 µg
320/18/9.6 µg 160/18/9.6 µg (N = 2125) (N = 2136)
(N = 2144) (N = 2124)
PRN SABA and/or 1 (<0.1) 1 (<0.1) 1 (<0.1) 1 (<0.1) 4 (<0.1)
SAMA only

Used MA only 24 (1.1) 19 (0.9) 23 (1.1) 21 (1.0) 87 (1.0)

LAMA 23 (1.1) 14 (0.7) 22 (1.0) 21 (1.0) 80 (0.9)
Used BA only 18 (0.8) 12 (0.6) 14 (0.7) 12 (0.6) 56 (0.7)
LABA 15 (0.7) 10 (0.5) 10 (0.5) 11 (0.5) 46 (0.5)
Used ICS only 9 (0.4) 6 (0.3) 4 (0.2) 7 (0.3) 26 (0.3)
Used MA and BA only 393 (18.3) 366 (17.2) 383 (18.0) 401 (18.8) 1543 (18.1)
LAMA/LABA 315 (14.7) 278 (13.1) 286 (13.5) 305 (14.3) 1184 (13.9)
Used ICS and BA only 681 (31.8) 695 (32.7) 677 (31.9) 706 (33.1) 2759 (32.3)
ICS/LABA 663 (30.9) 672 (31.6) 660 (31.1) 672 (31.5) 2667 (31.3)
Used ICS and MA only 27 (1.3) 31 (1.5) 39 (1.8) 37 (1.7) 134 (1.6)
ICS/LAMA 14 (0.7) 13 (0.6) 24 (1.1) 21 (1.0) 72 (0.8)
Used ICS, MA, and BA 986 (46.0) 991 (46.7) 981 (46.2) 949 (44.4) 3907 (45.8)
ICS/LAMA/LABA 839 (39.1) 840 (39.5) 846 (39.8) 833 (39.0) 3358 (39.4)
Did not use any ICS, 5 (0.2) 3 (0.1) 3 (0.1) 2 (<0.1) 13 (0.2)
MA, BA, or PRN
SABA or SAMA

Data are n (%). The components (e.g. ICS, MA, and/or BA) must have each been used for at least 30 days prior to
screening. Scheduled (non-PRN) use of SAMA or SABA was included in MA and BA categories, respectively. BA
denotes β2-agonist, COPD chronic obstructive pulmonary disease, ICS inhaled corticosteroid, LABA long-acting β2-
agonist, LAMA long-acting muscarinic antagonist, MA muscarinic antagonist, PRN as needed, SABA short-acting β2-
agonist, SAMA short-acting muscarinic antagonist.

25
Table S4. Secondary and other pre-specified symptom and health-related quality of life endpoints (efficacy estimand;

modified intent-to-treat population).

Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/

glycopyrrolate/ glycopyrrolate/ formoterol formoterol
formoterol formoterol 18/9.6 µg 320/9.6 µg
320/18/9.6 µg 160/18/9.6 µg (N = 2120) (N = 2131)
(N = 2137) (N = 2121)
Secondary endpoints
Change from baseline in average daily rescue medication use over 24 weeks*
No. of patients evaluated 1425 1389 1387 1426
Mean (SE) –1.2 (0.06) –1.0 (0.07) –0.7 (0.07) –0.8 (0.06)
320 µg-budesonide triple therapy versus comparators
Mean (95% CI) — –0.15 (–0.32 to 0.01) –0.51 (–0.68 to –0.34) –0.37 (–0.54 to –0.20)
160 µg-budesonide triple therapy versus comparators
Mean (95% CI) — — –0.35 (–0.53 to –0.18) –0.22 (–0.39 to –0.05)
Percentage of patients achieving a decrease of ≥ 4 units in SGRQ total score at Week 24
No. of patients evaluated 2119 2102 2096 2122
Responders, n (%) 1068 (50.4) 1024 (48.7) 893 (42.6) 949 (44.7)
320 µg-budesonide triple therapy versus comparators
Odds ratio (95% CI) — 1.1 (0.9 to 1.2) 1.4 (1.2 to 1.5) 1.2 (1.1 to 1.4)
160 µg-budesonide triple therapy versus comparators
Odds ratio (95% CI) — — 1.3 (1.1 to 1.5) 1.2 (1.0 to 1.3)
TDI focal score over 24 weeks
No. of patients evaluated 2044 2023 1983 2021
Mean (SE) 1.3 (0.06) 1.3 (0.06) 0.9 (0.06) 1.0 (0.06)
320 µg-budesonide triple therapy versus comparators
Mean (95% CI) — 0.03 (–0.12 to 0.19) 0.40 (0.24 to 0.55) 0.31 (0.15 to 0.46)
160 µg-budesonide triple therapy versus comparators
Mean (95% CI) — — 0.37 (0.21 to 0.52) 0.27 (0.12 to 0.43)
Change from baseline in EXACT total score over 52 weeks
No. of patients evaluated 2126 2109 2105 2120
Mean (SE) –1.8 (0.18) –1.6 (0.18) –0.7 (0.19) –0.8 (0.18)
320 µg-budesonide triple therapy versus comparators
Mean (95% CI) — –0.21 (–0.70 to 0.28) –1.14 (–1.64 to –0.65) –1.04 (–1.53 to –0.55)
160 µg-budesonide triple therapy versus comparators
Mean (95% CI) — — –0.93 (–1.43 to –0.44) –0.83 (–1.32 to –0.34)
Change from baseline in SGRQ total score over 24 weeks
No. of patients evaluated 2076 2056 2017 2056

26
 Mean (SE) –6.5 (0.25) –6.2 (0.25) –4.9 (0.25) –5.1 (0.25)
320 µg-budesonide triple therapy versus comparators
Mean (95% CI) — –0.34 (–0.99 to 0.30) –1.62 (–2.27 to –0.97) –1.38 (–2.02 to –0.73)
160 µg-budesonide triple therapy versus comparators
Mean (95% CI) — — –1.28 (–1.93 to –0.63) –1.04 (–1.68 to –0.39)
Other endpoints
Change from baseline in SGRQ total score at Week 52
No. of patients evaluated 1681 1680 1562 1631
Mean (SE) –6.4 (0.35) –6.0 (0.36) –4.5 (0.36) –4.9 (0.36)
320 µg-budesonide triple therapy versus comparators
Mean (95% CI) — –0.37 (–1.32 to 0.59) –1.88 (–2.84 to –0.91) –1.47 (–2.43 to –0.51)
160 µg-budesonide triple therapy versus comparators
Mean (95% CI) — — –1.51 (–2.48 to –0.54) –1.10 (–2.06 to –0.14)
Percentage of patients achieving a decrease of ≥ 4 units in SGRQ total score at Week 52
No. of patients evaluated 2119 2102 2096 2122
Responders, n (%) 937 (44.2) 907 (43.1) 766 (36.5) 832 (39.2)
320 µg-budesonide triple therapy versus comparators
Odds ratio (95% CI) — 1.0 (0.9 to 1.2) 1.4 (1.2 to 1.6) 1.2 (1.1 to 1.4)
160 µg-budesonide triple therapy versus comparators
Odds ratio (95% CI) — — 1.3 (1.2 to 1.5) 1.2 (1.0 to 1.3)

The means presented are least-squares means. *Rescue medication user population.

CI denotes confidence interval, EXACT EXAcerbations of Chronic pulmonary disease Tool, ICS inhaled
corticosteroid, SGRQ St. George’s Respiratory Questionnaire, TDI transition dyspnea index.

27
Table S5. Summary of adjudicated causes of death (safety population).

Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/ All

glycopyrrolate/ glycopyrrolate/ formoterol formoterol patients
formoterol formoterol 18/9.6 µg 320/9.6 µg (N = 8529)
320/18/9.6 µg 160/18/9.6 µg (N = 2125) (N = 2136)
(N = 2144) (N = 2124)
All causes
Total 27 (1.3) 42 (2.0) 47 (2.2) 35 (1.6) 151 (1.8)
On-treatment 19 (0.9) 28 (1.3) 35 (1.6) 29 (1.4) 111 (1.3)
Post-treatment 8 (0.4) 14 (0.7) 12 (0.6) 6 (0.3) 40 (0.5)
Cardiovascular
Total 11 (0.5) 16 (0.8) 28 (1.3) 11 (0.5) 66 (0.8)
On-treatment 10 (0.5) 11 (0.5) 22 (1.0) 10 (0.5) 53 (0.6)
Post-treatment 1 (<0.1) 5 (0.2) 6 (0.3) 1 (<0.1) 13 (0.2)
Respiratory
Total 7 (0.3) 13 (0.6) 8 (0.4) 6 (0.3) 34 (0.4)
On-treatment 4 (0.2) 9 (0.4) 6 (0.3) 4 (0.2) 23 (0.3)
Post-treatment 3 (0.1) 4 (0.2) 2 (<0.1) 2 (<0.1) 11 (0.1)
COPD
Total 5 (0.2) 7 (0.3) 5 (0.2) 5 (0.2) 22 (0.3)
On-treatment 4 (0.2) 5 (0.2) 3 (0.1) 4 (0.2) 16 (0.2)
Post-treatment 1 (<0.1) 2 (<0.1) 2 (<0.1) 1 (<0.1) 6 (<0.1)
Pneumonia
Total 2 (<0.1) 3 (0.1) 3 (0.1) 1 (<0.1) 9 (0.1)
On-treatment 0 2 (<0.1) 3 (0.1) 0 5 (<0.1)
Post-treatment 2 (<0.1) 1 (<0.1) 0 1 (<0.1) 4 (<0.1)
Cancer
Total 2 (<0.1) 6 (0.3) 3 (0.1) 7 (0.3) 18 (0.2)
On-treatment 1 (<0.1) 3 (0.1) 3 (0.1) 7 (0.3) 14 (0.2)
Post-treatment 1 (<0.1) 3 (0.1) 0 0 4 (<0.1)
Other
Total 7 (0.3) 7 (0.3) 8 (0.4) 11 (0.5) 33 (0.4)
On-treatment 4 (0.2) 5 (0.2) 4 (0.2) 8 (0.4) 21 (0.2)
Post-treatment 3 (0.1) 2 (<0.1) 4 (0.2) 3 (0.1) 12 (0.1)

Data are n (%).

COPD denotes chronic obstructive pulmonary disease.

28
Table S6. Subgroup analyses of the rate of moderate or severe COPD exacerbations by exacerbation history, ICS use

at screening, and reversibility (over 52 weeks; efficacy estimand; modified intent-to-treat population).

Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/

glycopyrrolate/ glycopyrrolate/ formoterol formoterol
formoterol formoterol 18/9.6 µg 320/9.6 µg
320/18/9.6 µg 160/18/9.6 µg (N = 2120) (N = 2131)
(N = 2137) (N = 2121)
Patients with ≥2 exacerbations in the previous year
No. of patients evaluated 1195 1187 1211 1217
Model-estimated rate 1.17 1.15 1.60 1.32
320 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — 1.02 (0.90 to 1.15) 0.73 (0.65 to 0.83) 0.89 (0.79 to 1.01)
160 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — 0.72 (0.64 to 0.81) 0.88 (0.77 to 0.99)
Patients using ICS at screening
No. of patients evaluated 1706 1729 1707 1704
Model-estimated rate 1.14 1.13 1.51 1.27
320 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — 1.01 (0.91 to 1.12) 0.76 (0.68 to 0.84) 0.90 (0.81 to 1.00)
160 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — — 0.75 (0.68 to 0.83) 0.89 (0.80 to 0.99)
Patients not using ICS at screening
No. of patients evaluated 431 392 413 427
Model-estimated rate 0.84 0.85 1.11 1.12
320 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — 0.99 (0.79 to 1.24) 0.75 (0.61 to 0.94) 0.75 (0.60 to 0.93)
160 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — — 0.76 (0.61 to 0.95) 0.76 (0.61 to 0.94)
Patients with reversibility to albuterol*
No. of patients evaluated 657 631 669 654
Model-estimated rate 1.03 1.12 1.70 1.28
320 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — 0.92 (0.77 to 1.09) 0.61 (0.51 to 0.72) 0.81 (0.68 to 0.96)
160 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — — 0.66 (0.56 to 0.78) 0.88 (0.74 to 1.04)
Patients without reversibility to albuterol*
No. of patients evaluated 1470 1486 1444 1472

29
 Model-estimated rate 1.10 1.05 1.29 1.22
320 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — 1.05 (0.94 to 1.17) 0.85 (0.76 to 0.95) 0.90 (0.80, 1.00)
160 µg-budesonide triple therapy versus comparators
Rate ratio (95% CI) — — 0.81 (0.73, 0.91) 0.86 (0.77, 0.96)

Reversible is defined as improvement in FEV1 post-albuterol administration compared to pre-albuterol of ≥ 12% and
*

≥ 200 mL. CI denotes confidence interval, COPD chronic obstructive pulmonary disease, ICS inhaled corticosteroid.

30
Table S7. Time to first MACE and time to first confirmed pneumonia (safety population).

Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/

glycopyrrolate/ glycopyrrolate/ formoterol formoterol
formoterol formoterol 18/9.6 µg 320/9.6 µg
320/18/9.6 µg 160/18/9.6 µg (N = 2125) (N = 2136)
(N = 2144) (N = 2124)
Time to first MACE
No. of patients with MACE, 31 (1.4) 30 (1.4) 44 (2.1) 23 (1.1)
n (%)
Percent of patients with MACE (95% CI) within
3 months 0.4 (0.2 to 0.8) 0.4 (0.2 to 0.8) 0.9 (0.6 to 1.4) 0.3 (0.1 to 0.7)
6 months 0.8 (0.5 to 1.3) 0.9 (0.6 to 1.4) 1.1 (0.7 to 1.7) 0.5 (0.3 to 0.9)
9 months 1.4 (1.0 to 2.0) 1.2 (0.8 to 1.8) 1.8 (1.3 to 2.6) 0.8 (0.5 to 1.3)
320 µg-budesonide triple therapy versus comparators
Hazard ratio (95% CI) — 1.00 (0.60 to 1.65) 0.63 (0.40 to 1.01) 1.25 (0.73 to 2.15)
P-value 0.99 0.05 0.42
160 µg-budesonide triple therapy versus comparators
Hazard ratio (95% CI) — — 0.64 (0.40 to 1.01) 1.25 (0.73 to 2.16)
P-value 0.06 0.41
Budesonide/formoterol versus comparators
Hazard ratio (95% CI) — — 0.51 (0.31 to 0.84) —
P-value 0.008
Time to first confirmed pneumonia
No. of patients with 90 (4.2) 75 (3.5) 48 (2.3) 96 (4.5)
pneumonia, n (%)
Percent of patients with pneumonia (95% CI) within
3 months 1.1 (0.7 to 1.7) 1.4 (1.0 to 2.0) 0.7 (0.4 to 1.2) 1.3 (0.8 to 1.8)
6 months 2.2 (1.6 to 2.9) 2.0 (1.5 to 2.7) 1.6 (1.1 to 2.3) 2.6 (2.0 to 3.5)
9 months 3.7 (3.0 to 4.7) 3.1 (2.4 to 3.9) 2.3 (1.7 to 3.1) 4.5 (3.7 to 5.6)
320 µg-budesonide triple therapy versus comparators
Hazard ratio (95% CI) — 1.23 (0.90 to 1.67) 1.78 (1.26 to 2.53) 0.89 (0.67 to 1.19)
P-value 0.20 0.001 0.43
160 µg-budesonide triple therapy versus comparators
Hazard ratio (95% CI) — — 1.46 (1.01 to 2.09) 0.73 (0.54 to 0.99)
P-value 0.04 0.04
Budesonide/formoterol versus comparators
Hazard ratio (95% CI) — — 2.00 (1.41 to 2.83) —
P-value <0.001

CI denotes confidence interval, MACE major adverse cardiovascular event.

31
Table S8. Incidence of MACE and pneumonia adverse events (safety population).

Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/ All

glycopyrrolate/ glycopyrrolate/ formoterol formoterol patients
formoterol formoterol 18/9.6 µg 320/9.6 µg (N = 8529)
320/18/9.6 µg 160/18/9.6 µg (N = 2125) (N = 2136)
(N = 2144) (N = 2124)
MACE
Patients with events 54 (2.5) 55 (2.6) 64 (3.0) 53 (2.5) 226 (2.6)
submitted to CEC
Number of events 57 56 70 56 239
submitted to CEC
Patients with confirmed 31 (1.4) 30 (1.4) 44 (2.1) 23 (1.1) 128 (1.5)
MACE
Non-fatal MI 9 (0.4) 13 (0.6) 17 (0.8) 8 (0.4) 47 (0.6)
Non-fatal stroke 12 (0.6) 6 (0.3) 6 (0.3) 6 (0.3) 30 (0.4)
Cardiovascular death 10 (0.5) 11 (0.5) 22 (1.0) 10 (0.5) 53 (0.6)
Pneumonia
Patients with events 115 (5.4) 100 (4.7) 66 (3.1) 118 (5.5) 399 (4.7)
submitted to CEC
Number of events 121 109 71 131 432
submitted to CEC
Patients with confirmed 90 (4.2) 75 (3.5) 48 (2.3) 96 (4.5) 309 (3.6)
pneumonia
At or before 24 weeks 43 (2.0) 40 (1.9) 29 (1.4) 43 (2.0) 155 (1.8)
After 24 weeks 48 (2.2) 38 (1.8) 22 (1.0) 59 (2.8) 167 (2.0)
Patients with serious 64 (3.0) 54 (2.5) 28 (1.3) 51 (2.4) 197 (2.3)
confirmed pneumonia

Data are n (%). CEC denotes clinical endpoint committee, MACE major adverse cardiovascular event, MI myocardial
infarction.

32
Table S9. Adverse events occurring in ≥2% of patients in any treatment group (by preferred term; safety population).
Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/ All patients
glycopyrrolate/ glycopyrrolate/ formoterol formoterol (N = 8529)
formoterol formoterol 18/9.6 µg 320/9.6 µg
320/18/9.6 µg 160/18/9.6 µg (N = 2125) (N = 2136)
(N = 2144) (N = 2124)
No. of Events (rate No. of Events (rate No. of Events (rate No. of Events (rate No. of Events (rate
patients, per 1000 patients, per 1000 patients, per 1000 patients, per 1000 patients, per 1000
n (%) patient-yr) n (%) patient-yr) n (%) patient-yr) n (%) patient-yr) n (%) patient-yr)
Nasopharyngitis 227 (10.6) 153.0 239 (11.3) 166.7 199 (9.4) 144.1 234 (11.0) 180.4 899 (10.5) 161.2
Chronic obstructive 203 (9.5) 135.1 221 (10.4) 139.2 219 (10.3) 151.4 242 (11.3) 163.5 885 (10.4) 147.1
pulmonary disease
Upper respiratory tract 123 (5.7) 78.6 137 (6.5) 93.1 102 (4.8) 72.9 115 (5.4) 83.9 477 (5.6) 82.3
infection
Pneumonia 98 (4.6) 53.3 85 (4.0) 49.2 61 (2.9) 37.3 107 (5.0) 63.8 351 (4.1) 51.0
Bronchitis 66 (3.1) 39.0 68 (3.2) 40.2 76 (3.6) 45.8 69 (3.2) 45.2 279 (3.3) 42.5
Hypertension 59 (2.8) 33.2 54 (2.5) 29.6 62 (2.9) 36.7 76 (3.6) 43.1 251 (2.9) 35.6
Back pain 67 (3.1) 35.9 65 (3.1) 37.0 55 (2.6) 31.1 64 (3.0) 37.6 251 (2.9) 35.5
Dyspnea 54 (2.5) 32.2 55 (2.6) 35.5 60 (2.8) 37.3 79 (3.7) 50.1 248 (2.9) 38.7
Headache 57 (2.7) 35.9 49 (2.3) 31.2 60 (2.8) 41.2 68 (3.2) 40.9 234 (2.7) 37.2
Sinusitis 56 (2.6) 33.2 61 (2.9) 38.6 47 (2.2) 28.2 55 (2.6) 33.8 219 (2.6) 33.6
Urinary tract infection 58 (2.7) 35.9 59 (2.8) 33.9 60 (2.8) 38.4 41 (1.9) 27.8 218 (2.6) 34.0
Influenza 63 (2.9) 34.8 52 (2.4) 29.1 42 (2.0) 25.4 61 (2.9) 37.1 218 (2.6) 31.7
Cough 58 (2.7) 34.3 48 (2.3) 27.5 50 (2.4) 31.1 51 (2.4) 33.8 207 (2.4) 31.7
Oral candidiasis 65 (3.0) 42.2 47 (2.2) 28.6 24 (1.1) 15.3 57 (2.7) 39.8 193 (2.3) 31.7
Muscle spasms 60 (2.8) 32.7 39 (1.8) 21.2 19 (0.9) 10.7 53 (2.5) 36.5 171 (2.0) 25.4
Diarrhea 44 (2.1) 24.3 28 (1.3) 15.3 37 (1.7) 22.0 38 (1.8) 22.3 147 (1.7) 21.0
Data are n (%).
33
Table S10. Adverse events of special interest occurring in ≥1% of patients in any treatment group (by category;
safety population).

Budesonide/ Budesonide/ Glycopyrrolate/ Budesonide/

glycopyrrolate/ glycopyrrolate/ formoterol formoterol All patients
formoterol formoterol 18/9.6 µg 320/9.6 µg (N = 8529)
320/18/9.6 µg 160/18/9.6 µg (N = 2125) (N = 2136)
(N = 2144) (N = 2124)
Cardiovascular conditions 95 (4.4) 110 (5.2) 137 (6.4) 93 (4.4) 435 (5.1)
Pneumonia 116 (5.4) 101 (4.8) 67 (3.2) 118 (5.5) 402 (4.7)
Lower respiratory tract 80 (3.7) 82 (3.9) 87 (4.1) 87 (4.1) 336 (3.9)
infections other than
pneumonia
Hypertension 75 (3.5) 70 (3.3) 72 (3.4) 93 (4.4) 310 (3.6)
Diabetes mellitus 72 (3.4) 65 (3.1) 53 (2.5) 61 (2.9) 251 (2.9)
Headache 61 (2.8) 56 (2.6) 63 (3.0) 71 (3.3) 251 (2.9)
Candidiasis 69 (3.2) 54 (2.5) 25 (1.2) 66 (3.1) 214 (2.5)
Bone fracture 46 (2.1) 38 (1.8) 44 (2.1) 46 (2.2) 174 (2.0)
Psychiatric effects 42 (2.0) 38 (1.8) 41 (1.9) 32 (1.5) 153 (1.8)
Agitation or anxiety 36 (1.7) 22 (1.0) 26 (1.2) 31 (1.5) 115 (1.3)
Dysphonia or aphonia 39 (1.8) 27 (1.3) 7 (0.3) 31 (1.5) 104 (1.2)
Ocular effects 19 (0.9) 28 (1.3) 27 (1.3) 25 (1.2) 99 (1.2)
Hypokalemia 25 (1.2) 17 (0.8) 21 (1.0) 29 (1.4) 92 (1.1)
Cerebrovascular conditions 30 (1.4) 12 (0.6) 13 (0.6) 23 (1.1) 78 (0.9)

Data are n (%).

34
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