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

Supplement to: Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015; published online Feb 23. http://dx.doi.org/10.1016/S2213-2600(15)00042-9.

SUPPLEMENTARY APPENDIX

Reslizumab for inadequately controlled asthma with elevated blood

eosinophils

Castro M, MD, MPH; Zangrilli J; Wechsler ME; Bateman ED, MD, FRCP; Brusselle

GG, MD, PhD; Bardin P; Murphy K; Maspero J; O’Brien C; Korn S

Contents

Part A – Study Investigators

Part B – Supplementary Methods and Results

Eligibility Criteria

Randomisation

Study schema

Statistical analyses

Study Drugs

Prohibited and Restricted Medications

Efficacy Endpoints

Immunogenicity Testing

Hierarchal Fixed-Sequence Multiple-testing Procedure

Details of Anaphylactic Reactions

1

Part C – Supplementary Figures

Supplementary Figure S1. Change from Baseline in Asthma Control Questionnaire

Score over the 52-Week Treatment Period in (A) Study 1 and (B) Study 2 (Intention-

to-Treat Population).

Supplementary Figure S2. Change from Baseline in Asthma Symptom Utility Index

Score over the 52-Week Treatment Period in (A) Study 1 and (B) Study 2 (Intention-

to-Treat Population).

Supplementary Figure S3. Scatter Plot of Blood Eosinophil Count over the 52-

Week Treatment Period in (A) Study 1 and (B) Study 2 (Intention-to-Treat

Population).

Supplementary Figure S4. Pooled sub-analyses of FEV1 least-squares means at

over the first 16 weeks and from baseline to study end (week 52) for patient

populations with different concomitant medication profiles.

Supplementary Figure S5. Pooled sub-analyses (accros trials) of CAE rate ratios

(at week 52) by prior CAE history in the last 12 months (1–≥4 excaserbations)

Supplementary Figure S6. Pooled sub-analyses (accros trials) of CAE rate ratios

(at week 52) by baseline eosinophil level

Part D – Supplementary Table

Supplementary Table S1. Supplementary Table S1. CAE and FEV1 Results Based

on Background Medication (Pooled Study 1 ad Study 2).

Supplementary Table S2. Integrated analyses over 52 weeks

Supplementary Table S3. Actual measures key parameters at baseline and Week 52

Supplementary Table S4. Frequency of Clinical Asthma Exacerbations (CAEs) During the 52-Week Treatment Period by Consistency of Screening Blood Eosinophil Counts and Treatment Group-Adjudicated Data

2

Randomized Patients

Supplementary Table S5. Frequency of Asthma Exacerbations During the 52-Week Treatment Period by Treatment Group-Adjudicated Data Sensitivity Analysis (Not excluding Exacerbation Duration from the Offset) Randomized Patients Supplementary Table S6. Participating countries

Part A – Study Investigators

Study 1 Investigator and affiliation Sub-investigator(s) name Bleecker, Eugene, MD Wake Forest University School of Medicine Medical Center Blvd Winston-Salem, NC 27157 USA

Rodolfo Pascual, MD Jeffrey Krings, FNP Wendy Moore, MD Victor Ortega, MD

Bernstein, David I., MD Bernstein clinical Research Center, LLC 8444 Winton Rd Cincinnati, OH 45231 USA

Jonathan A. Bernstein, MD

Fahrenholz, John, MD Vanderbilt University Medical Center 2611 West End Ave, Ste 120 Nashville, TN 37203 USA

S. Bobo Tanner, MD Cindy Kate Anderson, MSN, FNP

Moss, Mark H., MD University of Wisconsin School of Medicine and Health 600 Highland Ave, H4.582 Clinical Science Center Madison, WI 53792 USA

Hiba Bashir, MD Mark J. Biagtan, MD Amaziah T. Coleman, MD Jared I. Darveaux, MD James E. Gern, MD Daniel J. Jackson, MD Robert F. Lemanske, Jr, MD Amy O’Brian Thomas, MD Frederick J. Rubner, MD Christine M. Seroogy, MD Ravi K. Viswanathan, MD Lindell R. Gentry, MD

3

Investigator and affiliation Sub-investigator(s) name Storms, William W, MD 1625 Medical Center, Ste 190 Colorado Springs, CO 80907 USA

Matthew S. Bowdish, MD Jill E. Smothers, NP-BC Julia Mesnikoff, NP-BC Kathryn A. Blair, NP-BC Carol F Halle, NP-BC

Miller, Beth A., MD University of Kentucky Health Care Division of Allergy, Immunology, Asthma, Allergy and Sinus Clinic 135 E Maxwell, Ste 250 Lexington, KY 40508 USA

Joalyce Hoil, ARNP, MSN, RN, AE-C

Tarpay, Martha M., MD 4200 W Memorial Rd, Ste 206 Oklahoma, OK 73120 USA

Elena Cutter, PA-C Meredith Pruirr, PA-C

Cernadas, Manuela, MD 75 Francis St Boston, MA 02115 USA (formerly Wechsler, Kazani, and Israel)

Elliot Israel, MD Mandeep Hundal, MD Kathleen Haley, MD

Ayesu, Kwabena, MD 324 E Par St Orlando, FL 32804 USA

Jay Chanmugam, DO Samuel Ogle, MD

Pacin, Michael, MD 9035 Sunset Dr, #202 Miami, FL 33173 USA

Heana Rodicic, MD Adriana Bonansea-Frances, MD

Greiner, Alexander N., MD Allergy and Asthma Medical Group and Research Center, APC 5776 Ruffin Rd San Deigo, CA 92123 USA (previously Meltzer, Eli, MD)

Michael J. Welch, MD, CPI Nancy K. Ostrom, MD, CPI Susan S. Laubach, MD Barbara S. Goergen, FNP, CPNP

Manning, Michael E., MD 7514 E Monterey Way, Ste IA Scottsdale, AZ 85251 USA

Aaron J. Davis, MD Jean A. Nelson, MS, FNP-C

Fuentes, David, MD 114 Trade Ave Boerne, TX 78006 USA

Richard E. Martinez, MD

Murphy, Kevin, MD Boys Town National Research Hospital 14000 Boys Town Hospital Rd Boys Town, NE, 68010 USA

Rosemary Jean Pauley-Hunter, APRN Jennifer Banfield, APRN

Pollard, Stephen, MD Family Allergy and Asthma Research Institute 1700 Bluegrass Ave, Ste 400 Louisville, KY 40215 USA

Maria Petrick, MD James Wesley Sublett, MD

4

Investigator and affiliation Sub-investigator(s) name Rosch, Meffrey M. MD 501 Howard Ave, Ste A201 Altoona, PA 16601 USA

Michael J. Davies, MD Michael J. Prematta, MD Tracy R. Prematta, MD

Condemi, John J., MD AAIR Research Center 300 Meridian Centre, Ste 305 Rochester, NY 14618 USA

Peter MG Deane, MD Emmanuel A. Quaidoo, MD Antole K. Kleiner, MD

Castro, Mario, MD, MPH 660 S Euclid Ave Campus Box 8052 St Louis, MO 63110 USA

Kaharu Sumino, MD, PhD Ajay Sheshadri, MD Adrian Shifren, MD

Rivas Matus, Patricia, MD Ave Libertador Bernardo O’Higgins N 611 (2841959) Rancague Chile

Lucy Edith San Martin Villalon, MD Carlos Julio Bisbal Malig, MD

Arias Alarcon, Maria, MD Portales N 287 Temuco (4781156) Chile

Ana Celia Toledo Vera, MD Sonia Edith Saavedra Solis, MD Armando Ivan Baeza Gonzalez, MD

Calvo Gil, Mario, MD Simpson N 850 Valdivia (5090145) Chile

Karin Grob Bedecarratz, MD

Soler Vasquez, Tamara, MD Ave Salvador N 95, Ste 908| Providencia (7500710) Santiago Chile

Viviana Rosa Jara Beltran, MD

Cartagena Salinas, Claudia, MD San Ignacio N 725 Valparaiso (2341131) Chile

Manuel Jose Barros Monge, MD Monica Teresa Gutierrez Claveria, MD

Duran Silva, Maruricio, MD Fundacion Neumologica Colombiana Carrera 13B 161-85 Bogota Colombia

Carlos Arturo Torress Duque, MD Jenny Libeth Juarado Hernandez, MD

Fernández Trujillo, Liliana, MD Fundacion Valle de Lili Carrera 98 No 18-49 Cali-Valle Colombia

William Martinez Guzman, MD

Matiz Bueno, Carlos, MD Calle 134 7-8, Room 333 Bogota, Bogota DC 11021 Colombia

Alejandro Ruiz Ordonez, MD

5

Investigator and affiliation Sub-investigator(s) name Brusselle, Guy, Prof, Dr Universitair Ziekenhuis Gent Department of reporatory medicine, De Pintelaan 185, Gent 9000 Belgium

Julie Carreeuw, Dr Sarah Desyne, Dr Eva Van Bracckel, Dr

Michils, Alain, Prof, Dr Hopital Erasme Pneumology Department Route de Lennik 808 Brussels 1070 Belgium

Benjamin Bondue, Dr

Martinot, Jean-Benoit, Dr Cabinet Medical Pegase Pneuocare Sprl Rue des Fabriques 6 Gembloux 5030 Belgium

John Silliard

Louis, Renaud, Dr CHU de Liege Ave de l’Hopital n1 Domaine Universitaire du Sart Tilman, Batiment B35 4000 Liege Belgium

Jean-Louis Corhay, Dr Florence Schleich, Dr Raluca Asandei, Dr

Pilette, Charles, Dr Cliniques Universitaire Saint-Luc Pneumology Department Ave Hippocrate 10 Brussels 1200 Belgium

Francoise Pirson, Dr

Bystron, Jaromir, MUDr Fakultní nemocnice Olomouc Oddělení alergologie a klinické imunologie IP Pavlova 6 775 20 Olomouc Czech Republic

Eva Henklova, MUDr

Skrickova, Jana, MUDr Fakultní nemocnice Brno Klinika nemoci plicnich a tuberkulozy Jihlavska 20 625 00 Brno Czech Republic

Dagmar Kindlova, MUDr Martina Doubkova, MUDr

Kasl, Milan, MUDr Klokoska 106 Tabor 39001 Czech Republic

Darina Kaslova, MUDr Jana Linhartova, MUDr

6

Investigator and affiliation Sub-investigator(s) name Barinova, Monika, MD Alergologie a klinicka imunologie Bratri Mrstiku 38 Breclav 690 74 Czech Republic

Jana Teturova, MD

Sedlak, Vratislav, MUDr Fakultní nemocnice Hrsdec Kralove, Plinci klinika Sokolska 581 Czech Republic

Zdenka Parakova, MUDr

Vytiska, Jiri, MUDr Krajska nemocnice Liberec as Oddeleni tuberkulozy a respiracnich nemoci Husova 10 Liberec 460 63 Czech Republic

Tomas Vencalek, MUDr Petr Placek, MUDr

Rohovsky, Tomas, MUDr Hornmed sro Charbulova 8 Brno 618 00 Czech Republic

Zuzana Matyasova, MUDr, PhD Katerina Kurthova, MUDr

Bjerring, Niels Odense Universitets Hospital Lungemedicinsk Forskningsafdeling J Sdr Blvd 29, indgang 87-88 DK-5000 Odense C Denmark

Hanne Madsen Jesper Davidsen David Sherson

Suppli Ulrik, Charlotte Hvidovre Hospital, Hjerte-Lunge afdelingen Kettegard Alle 30 2650 Hvidovre Denmark

Mia Moberg Ejvind Frausing

Póczi, Magdolna, Dr Dr Kenessey Albert Korhaz Rendelointezet Tudogyogyaszat Rakoczi Fejedelem ut 125-127 2660 Balassagyrmat Hungary

Katalin Gomori, Dr

Bártfai, Zoltán, Dr soproni Erzsebet Oktato Korhaz es Rehabilitacios Intezet Tudogyogyaszati Ostaly gyori ut 15 9400 Sopron Hungary

Abdallah Dakhlaqui, Dr Petra Braz, Dr

Szalai, Zsuzsanna, Dr Karolina Korhaz Tudogyogyaszat Regi Vamhaz ter 2-4 9200 Mosonmagyarovar Hungary

Zsuzsanna Horvath, Dr

7

Investigator and affiliation Sub-investigator(s) name Márk, Zsuzsanna, Dr Tudogyogyintezet Torobalint, III Osztaly Munkacsy Mihaly utca 70 2045 Torokbalint Hungary

Edit Dulka, Dr Erzsebet Fajt, Dr Zsuzsanna Putz, Dr

Kivity, Shmuel, Prof, MD Allergy and Asthma Clinic Tel aviv Sourasky Medical Center 6 Weitzman St Tel Aviv 64239 Israel

Yehuda A. Schwarz, MD Laliv Shamshins, MD Amir Bar-Shai, MD Kobi (Jacob) Sade, MD

Fink, Gershon, MD Pulmonary Unit Kaplan Medical Center, PO Box 1 Rehovot 76100 Israel

Alexander Yarmolovsky, MD Avi Gilad, MD Daniel Starobin, MD Eliezer Lainman, MD, Prof Rafi Wishnitzer, MD Itzhak Rosenberg, MD Said Elkrinawi, MD

Kramer, Mordechai, MD, Prof Pulmonary Unit Rabin Medical Center Beilinson Campus, Jabotinsky St Petach Tikva 49100 Israel

Abdel Rahman Nader, MD Dorit Shitenberg, MD Dror Rosengarten, MD Leonardo Fuks, MD Sonia Schneer, MD Victoria Rusahov, MD

Vilayi-Weiler, Zeev, MD Pulmonary Unit Barzilai Medical Center 2 Hahistadrout St Ashkelon 78278 Israel

Nelly Poliakov, Dr

Izbicki, Gabriel, MD Pulmonary Unit, Shaare Zedek Medical Center 12 Shmuel Deit, PO Box 3235 Jerusalem 91031 Israel

Nissim Arish, MD Ariel Rokach, MD Hava Azulai, MD

Shitrit, David, MD Department of Pulmonary Medicine Meir Medical Center 59 Tchernichovsky St Kfar Saba 44281 Israel

Alona Matveitchouk MD Olga Talker, MD Alexander Guber, MD

Breuer, Raphael, Prof, MD Pulmonary Unit Hadassah University Hospital Ein Kerem Kiryat Hadassah PO Box 12000 Jerusalem 91120 Israel

Neville Berkman, MD Uri Laxer, MD Zvi-Gregorio Fridlender, MD Liran Levy, MD

8

Investigator and affiliation Sub-investigator(s) name Yigla, Mordechai, MD Pulmonary Unit Rambam Medical Center 8 Haaliya Hashniya St 31096 Haifa Israel

Anna Solomonov, MD Emilya Hardak,MD

Adir, Yochai, MD Pulmonary Division The Lady Davis Carmel Medical Center 7 Michal St, Haifa 34362 Israel

Anat Amital, MD Assaf Carmeli Jacobi, MD Amir Abramovich, MD Michal Shteinberg, MD

Reshef, Avner, MD Department of Allergy, Immunology and Angioedema The Chain Sheba Medical Center Tel-Hashomer, Ramat Gan 52621 Israel

Mona Iancovici Kidon, MD

Asankowicz - Bargiel, Beata, MD Specjalistyczna Poradnia Pulmonologiczna ul Limanowskiego 20/22 61-400 Ostrow Wielkopolski Poland

Violetta Balicka, MD Michal Bargiel, MD

Kachel, Tomasz, MD, PhD Specjalistyczny Zespol Chorob Pluc i Gruzlicy Oddzial Pulmonologiczno Alergologiczny ul Falata 2 43-360 Bystra Poland

Ewelina Jaworska, MD Pawel Pecikiewicz, MD

Majorek-Olechowska, Bernadetta, MD Alergo-Med specjalistyczna Przychodnia Lekarska Ap zoo ul PCK 26 33-100 Tarnow Poland

Wieslaw Olechowski, MD, PhD Bozena Ciaston-Dudek, MD

Siergiejko, Zenon, Prof Prywatny Gabinet Internistyczno Alergologiczny ul Ogrodowa 5 15-010 Bialystok Poland

Grzegorz Siergiejko, MD, PhD Piotr Siegiejko, MD

Rybacki, Cezary, MD, PhD 10 Wojskowy Szpital Kliniczny Oddzial Klinkzny Pulmunologi i Alergologii ul Powstancow Warszawy 5 85-681 Bydgoszcz Poland

Iwona Patyk, MD Agata Kalicka, MD

9

Investigator and affiliation Sub-investigator(s) name Springer, Ewa, MD, PhD SNZOZ Alergologia Plus Osrodek Diagnostyki I Terapii Uczulen ul Drobnika 49, 60-693 Pozan Poland

Izabella Pawlik, MD, PhD Malgorzata Rzymkowska, MD, PhD Anna Sokolowska-Zietek, MD

Kuzubova, Natalia, MD, PhD, Dr Med Sci State Educational Institution of Higher Professional Education St Petersburg State Medical University na IP Pavlov of Roszdrav (new title: State Budget Educational Institution of Higher Professional Education St Petersburg State Medical Univeristy na IP Pavlov of Minzdravsotcrazvitiya of Russia, Pulmonary Research Institute (legal) 6/8 ul Lva Tolstogo affilate1 St Petersburg 197022 Russia (actual) 12, ul Roentgena St Petersburg 197022 Russia

Titova Olga, MD, Phd, Dr Med Sci Egotova Natalia, MD Privalova Elena, MD, PhD

Martynenko, Tatiana, MD, PhD, Dr Med Sci Prof Municipal Institution of Healthcare City Hospital #5, 75 Zmeinogorskiy Trakt Barnaul, 65045 Russia Altai State Medical University Chair of therapy and family medicine with the course of clinical immunology and allergology within the physicians’ professional development faculty, 40 Prospect Lenia Barnaul 65638 Russia

Ganova Olga, MD Skalozub Elena, MD Paraeva Olga, MD Popkova Liubov, MD

Yakusevich, Vladimir, MD, PhD, Dr Med Sci, Prof Municipal Institution of Healthcare Clinical Emergency Hospital na NV Soloviev 11 ul Zagorogniy Sad, Yaroslavl 150003 Russia State Educational Institution of Higher Professional Education Yaroslavl State Medical Academy of Minzdravsotcrazvitiya of Russia 5, ul Revolutsionnaya, Yaroslvl 150000 Russia

Petrochenko Alexander, MD, PhD Kadochnikova Veronika, MD Smirnova Natalia, MD Kabanov Andrey, MD Lebedeva Natalia, MD Goncharuk Olga, MD

Barbarash, Olga, MD, PhD Dr Med Sci Prof Federal State Budget Institution Research Institute of Complex Cardiovascular Pathology RAMS Siberian Affiliate, 6, Sosnovyj Bulvar Kemerovo 650002 Russia Municipal Budget Institution of Healthcare Kemerovo Cardiology Dispensary, 6, Sosnovyj Bulvar Kemerovo 650002 Russia

Evgeny Bazdyrev, MD, PhD Yulia Savostianova, MD

10

Investigator and affiliation Sub-investigator(s) name Lenskaya, Liudmila, MD, PhD, Dr Med Sci Regional State Institution of Healthcare Tomsk Regional Clinical Hospital, 96, ul Ivana Chernykh Tomsk, 634063 Russia

Sanzharovskaya Maria, MD, PhD Budankova Ekaterina, MD Ustyuzhanina Elena, MD, PhD Varvyanskaya Natalia, MD, PhD Shepeleva Evgeiya, MD, PhD Grigorieva Tatyana, MD

Kondyurina, Elena, MD, PhD, Dr Med Sci, Prof State Educational Institution of Higher Professional Education Novosibirsk State Medical University of Roszdrav (new title: State Institution of Higher Professional Education Novosibirsk State Medical University of Minzdrava of Russia, 52 Krasiny Prospekt Novosibirsk, 630091 Russia

Tatarenko Yuliya, MD kukhtinova Natalya, MD, PhD Gulevskaya Natalya, MD

Mitha, Essack, Dr Newtown Clinical Research Centre, Ste 3 Newgate Centre Jeppe St, Newtown Johannesburg 2113 South Africa

Dr Yakub Moosa Essack

Vermeulen, Jan, Dr Panorama Medical Centre, Room 113 Hennie Winterback St Panorama Cape Town, Western Cape 7500 South Africa

Daphne Charlotte (Danelle) Richter, Dr

Manjra, Ahmed, Dr Paediatric Allergy and Asthma Centre 218 Hiway Medical Center Spine Rd, Westville, Durban, KwaZulu Natal, 3630 South Africa

Andre Stephen Botha, Dr

Fulat, Muhammed, Dr Global Clinical Trialsl (Pty), Ltd Shop 29, Nedbank Plaza Steve Biko St, Pretoria 0001 South Africa

Imtiaz Hoosen, Dr

Irusen, Elvis, Prof University of Stellenbosch Respiratory Research Unit Dept of Medicine, Tygerberg Campus, Francie van Zikl Dr Parow, Cape Town Western Cape 7505 South Africa

Firdows Noor, Dr Coenraad F Koegelenberg, Dr

Vawda ZFV, Dr 343 Randles Rd Sydenham, Durban 4091 South Africa

Suleman Hassen Mahomedy, Dr Nazimddin Aboo, MD

11

Investigator and affiliation Sub-investigator(s) name Bateman, Eric Donn, Prof UCT Lung Institute George St, Mowbray 7700 Cape Town South Africa

Mary Elizabeth Bateman, Dr Gregory Louis Calligaro, Dr Gregory John Symons, Dr Aliasgar Sadaqali Gulamhussein Esmail, Dr Richard Nellis van Zyl-Smit, Dr Jeanette Holtlzhausen, Dr

Engelbrecht, Ingrid, Dr Engelbrecht Research PTY Ltd, 174 Craddock Ave Lyttleton 0157 Pretoria South Africa

Nicolene Elizabeth Robinson, Dr

Breedt, Johannes, Dr Ste 02, jackaranda Hospital 213 Middleberg St Muckleneuk, Pretoria 001 South Africa

Dorelle Lucille Kristen, Dr

Bhorat, Qasim Ebrahim, Dr House 1900 Sycamore St Diamini Ext 2 Soweto 1818 Gauteng South Africa

As’ad Ebrahim Bhorat, Dr

Curiac, Dan me3plus Clinical Trials Molndalsvagen 30C SE-412 63 Goteborg Sweden

Carl-Peter Anderberg Monica Eriksson

Nyström Kronander, Ulla Universitetsjukhuset I Linkoping Allergicentrum Se-581 85 Linkoping Sweden

Lennart Nilsson Eva Millinger Abul kashem Munir Agnetha Karlsson Ulrica Wikner

Lötvall, Jan Krefting Research Center Medicinaregatan 1F, Box 424 Goteborg 405 30 Sweden

Anders Bjerg Stig Hagstad Bo Lundback Jonas Eriksson

Bardin, Phil, A/Prof Monash Medical Center 246 Clayton Rd Clayton VIC 3168 Australia

Paul King, Dr Joy Lee, Dr Yvonne Ng, Dr Yee Tung Kuo, Dr Jyotika Prasad, Dr AKM Nizam Uddin, Dr

Langton, David, A/Prof Frankston Hospital Hastings Rd Frankston VIC 3199 Australia

Juan Mulder, Dr Melinda Wilson, Dr Chee Yoong Choy, Dr

12

Investigator and affiliation Sub-investigator(s) name Thompson Phillips, Martin, Dr Lung Institute of Western Australia Ground Floor, E Block Sir Charles Gairdner Hospital Hospital Ave Nedlands WA 6009 Australia

Jelena maricevic, Dr Li Ping Chung, Dr Margaret Stevens, Dr Peter Bremner, Dr Gerard Ryan, Dr Yuben Moodley, A/Prof Elisabeth Tropiano, Dr

Baraket, Melissa, Dr Liverpool Hospital Department of Respiratory Medicine Elizabeth St Liverpool NSW 2170 Australia

Guy Marks, Prof Jonathan Williamson, Dr

Harun, Roslan bin Department of Medicine Universiti Kebangsaan Malaysia Medical Centre Jalan Yaacob latif, Bandar Tun Razak 56000 Kuala Lumpur Malaysia

Andrea Ban Yu-Lin Norziha Zainul Abidin Norita Idris Azira Ahmad Kamil Nur Amani Aris Rose Azzlinda Osman

Ali, Irfhan Ali Bin Hyder Department of Respiratory Hospital Pulau Pinang Jalan Residensi 10990 Pulau Pinang Malaysia

Lalitha A/P Pereirasamy Kumaresh Raj Lachmanan

Pang, Yong-Kek Department of Medicine University Malaya Medical Centre Lembah Pantal 59100 Kuala Lumpur Malaysia

Liam Chong Kin Chua Keong Tiong Lai Nai Lang Lim Yue Ching Suzanna Hani Hussein Siti Khadijah binti Baharuddin

How, Soon Hin Hospital Tengku Ampuan Afzan Jalan Tanah Putih 25100 Kuantan Phang Malaysia

Kuan Yeh Chunn Gowri Sundaram Leong Seng Tai Yow Sim Yee Mohd Zulkarnain bin Ahmad

A Muthukumaru, Umadevi Medical Department Hospital Taiping Jalan Taming Sari 34000 Taiping, Perak Malalysia

Mangayarkarasi a/p Ramanathan, Dr Nur Fatin Raihanah bt Abdullah Rosales Venoo a/l Kuppusamy Sivatharsini a/p Aruugam Mohd Norhazani Che Hamzah

13

Investigator and affiliation Sub-investigator(s) name Ismail, Ahmad Izuanuddin Bin Level 4, Bangunan Klinik Pakar Faculty of Medicine Universiti Teknologi MARA Jalan Prima Selayang 7 68100 Batu Caves, Selangor Malaysia

Tengku Saifudin Bin Tengku Ismail Mohd Arif Bin Mohd Zim Asmah Mohd Nor Nur Atifah Zakaria Nur Asimah Zainal Abidin Muhammad Afandi Arippin Siti Noor Aishah Zahari

Beasley, Charles Richard, Prof Medical Research Institute of New Zealand Level 7, CSB Building Wellington Hospital Riddiford St, Newtown Wellington 6021 New Zealand

Philippa Shirtcliffe, Dr Irene Braithwaite, Dr Steven Walker, Dr

Wong, Conroy, Dr Respiratory Department Middlemore Hospital Hospital Rd, Private Bag 93311 Otahuhu, Auckland 1640 New Zealand

Elaine Yap (Li Ching), Dr Brendon Ah Chan, Dr Fiona Horwood, Dr Stuart Jones, Dr Conor O’Dochartaigh, Dr

Reid, James, Associate Prof RMC Medical Research Ltd 285 South Rd, Dunedin 9012 New Zealand

Gordon Dean Millar-Coote, Dr Naomi Jayne Motterhead, Dr

Chang, Catherina, Dr Waikato Hospital, Pembroke St Hamilton 3204 New Zealand

Leong Leow, Dr Andres Davies, Dr Janice Wong, Dr Noel Karalus, Dr Eskanarain Shafuddin, Dr

Santiaguel, Joel, Dr 2F, Clinical Trials Unit Quirino Memorial Medical Center Katipunan Rd cor JP Rizal St Project 4 Quezon City 1009 Philippines

Arturo C. Patanao, Je, Dr Alvel Tang-Manga, Dr

Custodio, Val O., Dr Room 211 and 220 2F Marian Building Far Eastern University Nicanor Reyes Medical Foundation Regaldo Ave, West Fairview Quezon City 1118 Philippines

Maya M. Castillo, Dr

De Guia, Teresita, Dr G/F Pulmonary Division Philipine Heart Center East Ave, Quezon City 1100 Philippines

Bernice Ong-de la Cruz, Dr

14

Investigator and affiliation Sub-investigator(s) name Gonong, Joven Roque, Dr Room 1214 Research Room G/F Lung Center of the Philippines Quezon Ave, Quezon City 1004 Philippines

Lawrence O. Raymond, Dr Cosme A. Galasgas, Jr, Dr

Chantaphakul, Hiroshi, Assistant Prof Chulalongkorn University Hospital Division of Allergy/Immunology Department of Medicine Bangkok 10330 Thailand

Sawad Boonpiyathad, MD

Sangsayunh, Piamlarp, Dr Division of Respiratory Medicine Central Chest Institute of Thailand 39 Tiwanon Rd, Amphur Muang Nonthaburi 11000 Thailand

Kittima Bangpattanasiri, MD

Wiwatworapan, Tawatchai, MD Pulmonary Unit Department of Internal Medicine Maharaj Nakhonratchasima Hospital Muang Nakhonratchasima 30000 Thailand

Thanakorn Anantasetagoon, MD

Study 2 Investigator and affiliation Sub-investigator(s) name Stahlman, Jon E., MD, CPI 565 Old Norcross Road, Suite 102 Lawrenceville, GA 30046 USA

Deidre Crocker, MD Pamela Crowe, RN Mary Beth McKinney, CRC Christina Stein, NP

Hill, David G., MD 170 Grandview Avenue Waterbury, CT 06708 USA

Bunny Albanese Katie Cleveland Sandra J. Dock, PA-C Karen Floyd, BS, CRT, RPFT Hilary Thomas Kawecki, BS, RT, RRT Deborah M. Parks, CRT Richard Scott Silverman, MD Erinn Tiernan Ferdinando Urbano, MD

15

Investigator and affiliation Sub-investigator(s) name Korenblat, Phillip E., MD, CPI The Clinical Research Center, LLC 1040 N Mason Rd, Ste 112 St. Louis, MO 63141 USA

Jeffrey P. Tillinghast, MD, CPI

Mariano, Hipolito G., Jr., MD 3636 N First St., Suite 141 Fresno, CA 93726 USA

Brenda Abbott Paramjit S. Fagoora, MD Antonio Negrete

Wasserman, Richard, L., MD, PhD 7777 Forest Lane, Suite B-332 Dallas, TX 75230 USA

Angela R. Hague, PA-C Rebecca L. Martin, RRT, CCRC Linda K. Miars, LVN Joanna Rolen, PA-C Stacy Silvers, MD Robert W. Sugerman, MD Jessica Zidik, MS

Sepulveda, Pedro, MD 910 San Pedro Avenue San Antonio, TX 78212 USA

Peter Fornos, MD Teresa Phillips, FNP-BC

Shapero, Paul A., MD 700 Mt. Hope Avenue, Suite 430 Bangor, Maine 04401 USA

Michelle Doucette, RN Pamella Oertel Kelly Webb, CMA

Katial, Rohit, MD National Jewish Health 1400 Jackson St Denver, CO 80206 USA

Holly Currier, RN Flavia Hoyte, MD Kim McPeak, RN

Sindel, Lawrence J., MD Pulmonary Associates of Mobile, P.C. 6701 Airport Boulevard, Suite B-131 Mobile, AL 36608 USA

Greg Anthony Cowan, RRT, CCRC Letoya P. Craig Michele Hemphill, RN, CCRC Pam Rowe, RN Allan F. Seibert, MD Vicki Wren, RN

Averill, Francis MD 802 North Belcher Road Clearwater, FL 33765 USA

Tracy Balentine, RN Mary Reilly, RN Michele Shatz, RN

Daul, Carolyn B., MD, PhD Clinical Research Specialists 3939 Houma Blvd, Bldg 6-Suite 20 Metairie, LA 70006 USA

Anne-Marie Fremin, RN, MN, FNP Michele G. Slattery

16

Investigator and affiliation Sub-investigator(s) name Mansfield, Lyndon E., MD Western Sky Medical Research 2121 Wyoming Ave El Paso, TX 79903 USA

Valerie W. Acosta, DNP, MSN, FNP-C, FPMHNP Rachelle Eastwood, CCRC Ruby Maynes, CCRC Catherine R. Posey, CCRC

Dowell, Anthony, MD 269 Blvd. St-Jean Suite 213 Pointe-Claire, Quebec, H9R 3J1 Canada

Ronald Dandurand, MD Maryse Dowell Marisa Mardegan

Henein, Sam, MD SKDS Research Inc. 221-679 Davis Drive Newmarket, Onario, L3Y 5G8 Canada

Ahsan Ahmad Norman Kalyniuk, MD Grishma Patel

Dhar, Anil, MD, MB, BS, FRCPC, FCCP 150-1720 Howard Avenue Windsor, Ontario N8X 5A6 Canada

Winston David Rajkumar, MD, MB, BS, FRCPC, FCCP

Gamberale, Ana María, MD Av. Cabildo 1548 1° “A”/6° “B” Av. Cabildo 1536 5° “B” CABA, CABA C1426ABP Argentine

Marcela Mariana Moreira Cedeño, MD Maria Cristina De Salvo, MD Vanessa María Luzardo Palacios, MD

Máspero, Jorge Fernando, MD Billinghurst 1677, 3er piso, (C1425DTG), Ciudad Autónoma de Buenos Aires Argentina

Maria Ines Antunez Gabriel Osvaldo Benhabib, MD Claudia Beatriz Boquete Mónica Silvia De Gennaro, MD Cynthia Jaquelina Erazo Marta Eugenia Lampert, MD Fernando Ariel Serrano, MD Mariana Foa Torres

de la Riestra, Fernando Antonio, MD Córdoba 2392, Piso 1, (S2000KZD) Rosario, Santa Fe Argentina

Daniel Hugo Bulijubasich, MD Silvina Estela Mannarino, MD Rogelio Alberto Pendino, MD

Fiterman, Jussara Costa, MD Av. Ipiranga, 6690 - 4° andar 90610-000-Porto Alegre – RS Brazil

Daniela Cavalet Blanco, MD Danila Inocente Fabiane Kahan, MD Denise Antunes Padilha Kroth, MD Édna Thais Jeremias Martins

17

Investigator and affiliation Sub-investigator(s) name Fiss, Elie MD Av. Principe de Gales, 821 09060-650-Santo André – 5P Brazil

Quézia Priscila Rocha Cavalcante Flávio Marques Valente Correa Andrea Gimenez, MD Nadine Cristina Machado Marcio Abreu Neis, MD Selma Denis Squassoni Thabata Silva Veiga

Teixeira, Paulo José Zimermann MD Rua Professor Annes Dias, 295-Pavilhão Pereira Rilho - 1° andar 90020-090-Porto Alegre-RS Brazil

Luciano Müller Corrêa da Silva, MD Marilia Giotti Bianca Gubert Lucelia Hernandes Lima Luciana Batista Severo

de Mattos, Waldo Luis Leite Dias MD, PhD Avenida Francisco Trein, 596-Ambulatório de Pneumologia-Sala 4014B 91350-200-Porto Alegre-RS Brazil

Carolina Borchardt Heidtmann, MD Alana Durayski Ranzi Stephanie Rocha

Dalcin, Paulo de Tarso Roth, MD Rua Ramirco Barcelos, 2350 - 2° Andar – Sala 2050 90035-903 – Porto Alegre-RS Brazil

Cristiane Dupont Bandeira, MD Gerson Guerra Alice Manica Muller Helena Souza van der Laan, MD

Pizzichini, Emilio MD Campus Universitário – Trindade 88040-970-Florianópolis-SC Brazil

Andria Machado da Silva Maira Perraro Cristiane Cinara Rocha Leila John Marques Steidle, MD Fernanda Agapito Pássaro Wilmer

Kaldman, Moises Acuña Blvd, Luis Encinas SN Colonia Centro CP 83000 Hermosillo Sonora Mexico

Jesus Torres Gomez Dennise Olivarez Miranda

Díaz, Alberto Manuel Servin MD Avenida Paseo de los Héroes No. 10999 Consultorio 701, Zona Río, C.P. 22010 Tijuana, Baja California México

Ruth Manso Alma Rosa Zatarain Robles, MD Erika Trapero

Daniel, Hernandez Colin Dante MD Penitenciaria No. 20, Col. Centro, C.P. 44100, Guadalajara, Jalisco México

Miguel Angel Mora Delgadillo Ana Torres Leon, MD Maria Esther Marmolejo, MD Mireya Orozco Vela, MD Griselda Coracero Zuñiga

18

Investigator and affiliation Sub-investigator(s) name Melendez, Alvaro Pedroza MD Insurgentes Sur 3700C, Col. Insurgentes Cuicuilco Delegación Coyoacan, C.P. 04530 México Distrito Federal México

Sandra Guadalupe Bautista García, MD

Diaz, Sandra Nora Gonzalez MD Av. Francisco I. Madero Pte. s/n y Av. Gonzalitos Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo León México

Claudia Ivonne Gallego Corella, MD Alfredo Arias Cruz, MD Arya Yannel Gonzalez Gonzalez, MD Alejandra macias Weinmann, MD

Fuchigami, Alberto Matsuno MD Compiejo Hospitalario San Pablo Avenida El Polo 789, Santiago de Surco Lima Lima 33 Peru

Yudy Gamio Cardenas Silvia Elizabeth Aiva Peña Alejandro Manuel Peña Villalobos, MD

Viladegut, Rolando Alfonso Estrella MD Hospital Nacional “Luis N. Saénz” de la Policia Nacional del Perú Avenida Brasil Cuadra 26 S/N, Jesús María, Lima Lima 11 Peru

Santiago Vizcardo Bendezu, MD Oscar Alexis Carbajal Paulet, MD Jimmy Robert Fernandez Perez, MD Valentin Leonidas Velasquez Sierra Miguel Angel Arteaga Morón Milagros Guadalupe Madrid Quiñones

Ore, Danilo Joel Salazar MD Avenida Honorio Delgado 262 Lima Lima 31 Peru

Carlos Alberto Salazar del Carpio, MD Enrique Renzo Morello Bustios, MD Victor Alberto Herrera Arana, MD

Benavides, Alfredo Gilberto Guerreros MD Avenida Garcilazo de la Vega 1420 Lima Lima 01 Peru

Eneyda Giuvanela Llerena Zegarra, MD Karla Ysabel Sanchez Vallejos, MD Cinthya Ballona Valdivia

Bernardini, Socorro Ursina Castro MD Avenida Guardia Civil 337, San Borja Lima Lima 41 Peru

Carlos Enrique Mendoza Armaez, MD Hercilia Gomez Rodriguez Jannet Karina Castro Angeles

Frias, William Wilfredo Chavez MD Avenida Sucre 134 Pueblo Libre Lima Lima 21 Peru

Erick John Ramirez Aranda, MD Miguel Oswaldo Rojas Villegas, MD Ofelia Mendoza De Los Santos, MD

Kikumoto, Miguel Tsukayama MD Centro de Investigación Ricardo Palma Calle Ricardo Angulo 130, San Isidro Lima Lima 27 Peru

Rosalba Lupe Asako Maekawa Ykehara, MD Natalia Rocio Naomi Vasquez Arakaki, MD Eduardo Jose Carcausto Huamani, MD Cesar Augusto Noriega Rocca, MD Judith Esther Armas Mejia Ana Sofia Espinoza Cuadros Paola Melissa Casas Cauti

19

Investigator and affiliation Sub-investigator(s) name Ortega, Jose Antonio Zaga MD Avenida Edgardo Rebagliati Martins 490 Lima Lima 11 Peru

Carmen Rossana Ortiz Santilla, MD Monica Elizabeth Del Portal Gonzales Martha Cecilia Domenack Sanchez

Bourdin, Arnaud, MD Service des maladies respiratories Hôpital Arnaud de Villeneuve 371, avenue du Doyen G. Giraud 34295 Montpeilier Cedex 5 France

Raphaël Chiron, MD Lahouari Meziane, MD Anne-Sophie Gamez-Dubuis, MD

Chanez, Pascal, PR Service de Pneumologie – Unité des maladies respiratories Hôpital Nord Chemin des Bourrelys 13015 Marseille France

Céline Tummino, MD Khuder Alagha, MD Tunde Sofalvi, MD

Linnhoff, Anneliese, MD Research Center for Medical Studies Hohenzollerndamm 2 10717 Berlin Germany

Carina Claudius-Bork, MD Birgit Stresow Dljana Hegic

Korn, Stephanie MD Klinische-Forschung Pneumologie, III. Medizinische Klinik, Universitätsklinikum, Gebäude 406 Langenbeckstraße 1 55131 Mainz Germany

Univ.-Prof. Dr. med. Roland Buhl Timo Schiffer Carolin Vasiliadis Manuel Klöser Sonja Bamberger Matthias Jung Tanja Kremer Ursula Kirmair Tatjana Reshetnykova Adriana Magureanu Luminita Cervis

Stock, Philippe, MD Klinik für Pädiatrie mit Schwerpunkt Pneumologie und Immunologie Charité Campus Virchow-Klinikum Augustenburger Platz 1 13353 Berlin Germany

Holger Kaiser, MD Kirn Parasher, MD Marion Trentmann

Maus, Olga Synexus Clinical Research GmbH Johannisplatz 1 04103 Leipzig Germany **Degtyareva, Elizaveta (Former PI)**

Kristin Kreutzmann, MD Simone Gleitsmann Antje Giersch Peggy Kranz Uta Schröter Rita Paschmionka, MD

20

Investigator and affiliation Sub-investigator(s) name Kornmann, Marc Oliver, MD IKF GmbH & Co KG, Institut für klinische Forschung Pneumologie, Clinical Research Center Respiratory, Standort IFS-Interdisziplinäres Facharztzentrum Stresemannallee Stresemannallee 3, 60596 Frankfurt Germany

Andreas Eich, MD Berthold Michels, MD Elke Ehresmann Carina Klassen

Jandl, Margret, MD Hamburger Institut für Therapieforschung GmbH Colonnaden 72 20354 Hamburg Germany

Diana Daher Matthias Eichler, MD Hartmut Timmermann, MD Jeannette Kotzur Svenja Pahlke Sandra Weiss Beatrix Harmel

Koch, Andrea, MD University Hospital Bochum-Bergmannsheil Medical Clinical III for Pneumology, Allergology, Sleep- and Respiratory Medicine Bürkle-de-la-Camp Platz 1 44789 Bochum Germany

David Jungck Tatyana Zhelezova Erna Brandenburger Cornelia Kmiez

Schmidt, Olaf, MD KPPK GmbH – Studienzentrum Dr. Kroker und Dr. Schmidt Innere Medizin / Pneumologie, Emil-Schüller-Straße 29 56068 Koblenz Germany

Axel Kroker, MD Michele Lobo-Becker, MD Nina Mehlem Ulrike Hürter Christine Oberhardt Sonja Denner

Gaga, Mina Athens Chest Hospital “Sotiria” 7th Department of Respiratory Medicine and Asthma Centre 152 Mesogion Avenue – 11527 Athens Greece

Eleftherios Zervas Konstantinos Samitas Maria Kokkala

Man, Milena Adina, MD, PhD “Leon Daniello” Pneumophtisiology Clinical Hospital 6 BP Hasdeu Street Cluj Napoca Cluj 400731 Romania

Gabriela Rusu, MD Elena Busuioceanu, MD Maria Victoria Ruta, MD

Ureche, Corina, MD, PhD Emergency Clinical County Hospital Targu-Mures 50 Gh. Marinescu Street Targu-Mures Mures 540136 Romania

Katalin Mako, MD

Bumbacea, Dragos, MD, PhD “Novo Medica” SRL 6A Costache Negri Entrance Bucharest 050554 Romania

Marina Lazar, MD

21

Investigator and affiliation Sub-investigator(s) name Mihaltan, Florin Dumitru, MD, PhD, Prof. “Marius Nasta” Institute of Pneumology 90 Viilor Road Bucharest 050159 Romania

Oana Claudia Deleanu, MD Ioana Munteanu, MD Elena-Iuliana Balasa, MD

Vladimir, Simanenkov, MD, PhD St. Petersburg State Budget Institution of Healthcare “City Hospital #26”, 2, Ulitsa Kostyusko St. Petersburg 196247 Russia

Ilyashevich Inna, MD, PhD Ledovaya Alla, MD, PhD Konovalova Natalia, MD Sharova Alevtina Dmitrii Svirido, MD

Trofimov, Vasiliy, MD, PhD State Educational Institution of Higher Professional Education St. Petersburg State Medical University n.a. I.P. Pavlov of Roszdrav 6/8, ulitsa Lva Tolstogo affiliate 1, St. Petersburg 197022 Russia

Zhanna Savitskaya, MD, PhD Olga Ivanova, MD, PhD Valentina Nazarova, MD, PhD Zhila Ivan, MD Zhila Oxana, MD

Alexander, Chuchalin, MD, PhD Federal State Institution Research Pulmonology Institute of Federal Medical and Biology Agency of Russia 32/61, Odinnadtsataya Parkovaya Ulitsa, korp.4, Moscow 105077 Russia

Zaurbek Aisanov, MD, PhD Olga Stulova, MD, PhD Elena Kalmanova, MD, PhD Nina Dostueva Elena Plekhanova

Alexander, Sinopalnikov, MD, PhD Moscow City State Institution of Healthcare City Clinical Hospital n.a. S.P. Botkin 5, Vtoroy Botkinskiy Proezd, Moscow 125284 Russia

Belotserkovskaya Yulia, MD, PhD

Sidorenko, Irina, MD, PhD Moscow City State Institution of Healthcare City Clinical Hospital #7 4, Kolomenskiy Proezd, Moscow 115446 Russia

Tatiana Zakharzhevskaya, MD, PhD Vyacheslav Treskunov, MD, PhD Sergey Zenokhov, MD

Alekseeva, Elena, MD, PhD Federal State Institution Outpatient Clinic #3 of Russian President Administration 31, Grokholskiy Pereulok, Moscow 129090 Russia **Oleynichenko, Ekaterina (Former PI)**

Ekaterina Oleynichenko, MD Tatyana Shipova, MD Elena Sultanova, MD

Goncharova, Svetlana, MD Municipal Budgetary Institution of Healthcare of Novosibirsk city 155, ulitsa Turgenyeva, Novosibirsk 630008 Russia

Lidiya Petrovicheva, MD Olesya Levchenko, MD Tatyana Belyaeva, MD

22

Investigator and affiliation Sub-investigator(s) name Goryachkina, Ludmila, MD, PhD State Budget Educational Institution of Additional Professional Education of Minzdravsotsrazvitiya of Russia 2/1 build.1, ulitsa Barrikadnaya, Moscow 123995 Russia

Olga Drobik, MD, PhD Daria Fomina, MD, PhD Marina Voronova, MD

Mikhailov, Sergey, MD Non-governmental Institution of Healthcare 84, Volokolamskoe Shosse, Moscow 125367 Russia

Dmitry Spozito, MD Valery Smirin, MD

Hrebenar, Slavomir, MD Plucna ambulancia Hrebenar, s.r.o. Fabiniho 15 052 01 Spisska Nova Ves Slovak Republic

Denisa Kavkova, MD Dana Denesova Anna Baronova Lenka Barnova

Plutinsky, Jan, MD, PhD ZAPA JJ, s.r.o. SNP 19 934 01 Levice Slovak Republic

Ivan Marget, MD

Plutinska, Jarmila, MD ANA JJ, s.r.o. Ambulancia alergologie a imunologie Ulica 17, novembra 1300 955 01 Topolcany Slovak Republic

Jan Plutinsky, MD, PhD Marcela Daruova Miloslava Spaldonova Simona Jancovicova

Lescisinova, Helena, MD NsP Sv. Jakuba n.o. Bardejov Ambulancia pneumologie a ftizeologle ul. Sv. Jakuba 21 085 01 Bardejov Slovak Republic

Ladislav Urge, MD

Blazhko, Viktor MI of Health Care “Kharkiv City Clinical Hospital #13” Department of Pulmonology #2, Prospekt Gagarina, 137 Kharkiv Kharkivska obl. 61124 Ukraine

Ganna Tymchenko Iana Sendetska

Pertseva, Tetyana State Institution “Dnipropetrovsk Medical Academy of the Ministry of Health of Ukraine” Chair of Facultative Therapy and Endocrinology on base Sixth City Clinical Hospital, Department of Therapy with Pulmonological beds Batumska Str., 13, Dnipropetrovsk 49074 Ukraine

Kateryna Gashynova Gateryna Bogatska

23

Investigator and affiliation Sub-investigator(s) name Dziublyk, Oleksandr State Institution “National Institute of Phthisiology and Pulmonology n.a. F.G. Yanovsky under NAMS of Ukraine” Department of Treatment Technologies of Nonspecific Lung Disease, Amosova Str., 10, Kyiv 03680 Ukraine

Vsevolod Kliagin Oleksandr Mukhin Rostyslav Sukhin Sergii Simonov Anton Gryshylo

Feshchenko, Yuriy SI “NI of Phthisiology and Pulmonology of NAMS of Ukraine” Department of Pulmonology Amosova Str., 10 Kyiv, Kyivska obl. 03680 Ukraine

Oleksandr Adamchuk Lesia Kuryk Oleksandr Kanarskyy Olena Krylach

Gavrysyuk, Volodymyr State Institution “National Institute of Phthisiology and Pulmonology n.a. F.G. Yanovsky under NAMS of Ukraine”, Clinical and Functional Department, Amosova Str., 10, Kyiv 03680 Ukraine

Olga Strafun Olga Shadrina

Iashyna, Liudmyla State Institution “National Institute of Phthisiology and Pulmonology n.a. F.G. Yanovsky under NAMS of Ukraine” Department of Diagnostic, Therapy and Clinical Pharmacology of Lung Diseases, Amosova Str., 10, Kyiv, 03680 Ukraine

Svitlana Moskalenko Inna Zvol Maryna Polianska

Mostovoy, Yuriy Vinnytsya National Medical University n.a. M.I. Pyrohov, Chair of Propedeutics of Internal Medicine on base City Clinical Hospital #1, Department of Pulmonology, Khmelnytske shoes, 96, Vinnytsya 21029 Ukraine

Anna Demchuk Tetiana Konstantinovych

Monogarova, Nadiya Donetsk National Medical University n.a. M. Horkyy, Chair of Internal Diseases n.a. A.Ya, Gubergryts on base Municipal treatment and Prophylactic Institution “Donetsk Regional Clinical Territorial Medical Association”, Department of Pulmonology, Prospekt Illicha, 14, Donetsk 83099 Ukraine

Tamila Bilokon Viktoriya Noreyko Olena Semendyayeva

Ostrovskyy, Mykola Regional Centre of Phthisilogy and Pulmonology, State Higher Educational Institution “Ivano-Frankivsk National Medical University” Chair of Phthisiology and Pulmonology with the course of Occupational Diseases I.Franka Str., 17, Ivano-Frankivsk 76018 Ukraine

Oleksandr Varunkiv Mariana Kulynych-Miskiv Iryna Savelikhina Svitlana Savaryn

Lysenko, Iryna Municipal Institution “Zaporizhzhia Regional Clinical Hospital” of Zaporizhzhia Regional Council, Regional Centre of Allergology and Clinical Immunology, Orekhivske Shose, 10, Zaporizhzhia 69600 Ukraine

Roman Sychov Nataliia Kargalska Kseniia Porublova

24

Investigator and affiliation Sub-investigator(s) name Kraydashenko, Oleg Municipal Institution “Zaporizhzhya City Clinical Hospital #6” Therapeutical Department 34, Stalevariv Str. Zaporizhzhya, Zaporizhzhya region 69035 Ukraine

Aleksandr Kremzer Roman Stets

Krakhmalova, Olena SI “Institute of Therapy n.a. L.T. Malaya of NAMS of Ukraine” Department of Cardiopulmonolgy, Postysheva, 2-a Ave. Kharkiv, Kharkivska obl. 61039 Ukraine

Olena Kolesnikova Olena Hetman Daria Kalashnyk Liudmyla Tsedryk

Kim, Changhwan Kangdong Sacred Heart Hospital 150 Sungahn-ro, Gangdong-gu Seoul 134 701 Korea

Eun Kyung Mo Yong Bum Park Jeng Yun Jang Youn Jung Lee Sul Hee Sim Su Eun Jang Eun Jung Nam Won Kyung Park Sewon Jang Haet Nim Huh Hyun Mi Kim

Shim, Jae Jeong Korea University Guro Hospital Division of Pulmonary 97 Guro-dong gil, Guro-gu Seoul 152-703 Korea

Choi, Inseon Chonnam National University Hospital 42 Jebongro, Dong-gu Gwangju 501 757 Korea

Eui-Ryoung Han Young A Koh un young Lee Eun Jeong Choi Kyoung-bin Cho Hyun Ryu Su Kyoung Park

Park, Jung-Won Severance Hospital 50 Yonsei-ro, Seodaemun-gu Seoul 120 752 Korea

Jae-Hyun Lee Nam Ju Kang JiWon Yoo Junghee Park JiSun Lee Sangmi Kim Ye Jin Kim Hee Na Kim

Park, Hae-Sim Ajou University Hospital 164, World Cup-ro, Yeongtong-gu Suwon 443-380 Korea

Hyun-Jung Shin Ji Sung Na Young Jin Chung Yun Jeong Kim

25

Investigator and affiliation Sub-investigator(s) name Cho, Sang-Heon Seoul National University Hospital 101 Daehak-ro, Jongno-gu Seoul 110-744 Korea

So Jung Park Su jung Kim Ji Young Lee Hong Won Jang jin-ah Lee Min Kyoung Kim Hyang Mi Park Seong Hwan Kim Jan Dee Kim

Kuo, Han-Pin MD No. 5, Fu-Shing St., Gueishan Township Chang Gung Medical Foundation Linkou Branch Taoyuan County 333 Taiwan

Chien-Da Huang, MD Horng-Chyuan Lin, MD Shu-Min Lin, MD Chun-Hua Wang, MD Wan-Yan Jiang Hsiao-Fang Fan

Part B – Supplementary Methods and Results

Eligibility Criteria

Inclusion Criteria

Patients enrolled in either study had to meet the following inclusion criteria:

• Male or female patients aged 12 to 75 years with a previous diagnosis of asthma.

• At least one asthma exacerbation requiring oral, intramuscular, or intravenous

corticosteroid use for ≥ 3 days over the past 12 months before screening.

• Current blood eosinophil level of ≥ 400 per microliter (at screening).

• Airway reversibility of ≥ 12% to beta-agonist administration.

o Airway reversibility was demonstrated by withholding long-acting beta-agonist

(LABA) therapy for ≥ 12 hours and short-acting beta-agonist therapy (SABA) for

≥ 6 hours before measuring forced expiratory volume in 1 second (FEV1), and

26

then repeating the FEV1 measurement after receiving SABA therapy (up to four

puffs). If a patient’s FEV1 improved by ≥ 12% between the two tests, the patient

was deemed as having airway reversibility. One retest was permitted during the

screening period.

• Asthma Control Questionnaire (ACQ) score of ≥ 1.5 at screening and at baseline

(before the first dose of study drug).

• Use of inhaled fluticasone at a dosage of ≥ 440 micrograms, or equivalent, daily.

o Chronic oral corticosteroid use (≤10 milligrams per day of prednisone or

equivalent) was allowed. If a patient was on a stable dose (e.g. ≥ 2 weeks of

oral corticosteroid treatment) at the time of enrollment, the patient had to

remain on this dose throughout the study.

o The patient’s baseline asthma therapy regimen (including, but not limited to,

inhaled corticosteroids, oral corticosteroids [up to a maximum dose of 10

milligrams of prednisone daily or equivalent], leukotriene antagonists, 5-

lipoxygenase inhibitors, or cromolyn sodium) had to be stable for 30 days prior

to screening and baseline, and had to continue without dosage changes

throughout the study.

• All female patients had to be surgically sterile, 2 years postmenopausal, or have a

negative beta-human chorionic gonadotropin (ß-HCG) pregnancy test at

screening (serum) and at baseline (urine).

• Female patients of childbearing potential (not surgically sterile or 2 years

postmenopausal) had to use a medically accepted method of contraception and

agree to continued use of this method for the duration of the study and for 30 days

after completing the trial.

27

o Acceptable methods of contraception included the barrier method with

spermicide, abstinence, an intrauterine device (IUD), and steroidal

contraceptives (oral, transdermal, implanted, or injected).

o Partner sterility alone was not acceptable for inclusion.

• Provision of written informed consent.

o Patients aged 12 to 17 years had to provide assent.

• Reasonable health (except for the diagnosis of asthma), as judged by the

investigator, and as determined by a medical history, medical examination,

electrocardiogram evaluation (at screening), and serum chemistry, hematology,

and urinalysis.

• Willing and able to understand and comply with study restrictions, requirements,

and procedures, as specified by the study center, and to remain at the study

center for the required duration during the study period, and be willing to return to

the center for the follow-up evaluation as specified in the protocol.

• Patients who experienced an asthma exacerbation during the screening period

were considered to have failed screening and were not randomized to study

treatment.

o Patients could only be rescreened once.

Exclusion Criteria

Patients who met any of the following criteria were excluded from the studies:

• Any clinically meaningful comorbidity that could interfere with the study schedule

or procedures, or compromise safety.

• Known hypereosinophilic syndrome.

28

• Another confounding underlying lung disorder (e.g. chronic obstructive pulmonary

disease, pulmonary fibrosis, or lung cancer).

o Patients with pulmonary conditions with symptoms of asthma and blood

eosinophilia (e.g. Churg-Strauss syndrome or allergic bronchopulmonary

aspergillosis) were excluded.

• Current smoker (i.e. had smoked within the last 6 months prior to screening).

• Current use of systemic immunosuppressive, immunomodulating, or other

biologic agents (including, but not limited to, anti-immunoglobulin E monoclonal

antibodies, methotrexate, cyclosporine, interferon-α, or anti-tumor necrosis factor

[anti-TNF] monoclonal antibodies) within 6 months prior to screening.

• Prior use of an anti-human interleukin-5 monoclonal antibody (e.g. reslizumab,

mepolizumab, or benralizumab).

• Any inadequately controlled, aggravating medical factors (e.g. rhinitis, gastro-

esophageal reflux disease, or uncontrolled diabetes).

• Participation in any investigative drug or device study within 30 days prior to

screening, or any investigative biologics study within 6 months prior to screening.

• Female patients who were pregnant, nursing, or, if of childbearing potential, not

using a medically accepted effective method of birth control (e.g. barrier method

with spermicide, abstinence, IUD, or steroidal contraceptive [oral, transdermal,

implanted, or injected]).

o Partner sterility alone was not considered an acceptable form of birth control.

• Concurrent infection or disease that prevented assessment of active asthma.

• History of concurrent immunodeficiency (human immunodeficiency virus [HIV],

acquired immunodeficiency syndrome [AIDS], or congenital immunodeficiency).

29

• Current suspected drug and alcohol abuse, as specified in the Diagnostic and

Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-

TR).

• Active parasitic infection within 6 months prior to screening.

• Receipt of any live attenuated vaccine within the 12-week period prior to

screening.

• History of allergic reactions to or hypersensitivity to any component of the study

drug.

• An infection within 4 weeks prior to screening or during the screening period

necessitating admission to hospital for ≥ 24 hours, or treatment with intravenous

or oral antibiotics.

• History of exposure to water-borne parasites within 6 weeks prior to screening or

during the screening period, or a history of diarrheal illness of undetermined

etiology within 3 months prior to screening or during the screening period.

• Requirement for treatment for an asthma exacerbation within 4 weeks of

screening or during the screening period.

RANDOMISATION

Patients were randomly assigned to treatment through a qualified randomization

service provider (eg, interactive response technology [IRT]). Upon receiving the

required patient identification, region (US vs other) and using oral corticosteroids at

enrollment (yes or no), the IRT assigned the patient to the next available

randomization code within the randomization stratum according to the specified

30

sequence. The randomization code was generated by the NA Clinical Supply Chain

at Teva following specifications from the Biometrics Department. A statistician not

assigned to the study was responsible for review and approval of the randomization

code.

STUDY SCHEMA

STATISTICAL ANALYSES

Efficacy endpoints were evaluated in the intention-to-treat population (all randomized

patients) and safety endpoints were assessed in the safety population (all patients

receiving ≥1 dose of study medication). A hierarchal, fixed-sequence multiple-testing

procedure was used to test the primary and secondary endpoints. Exacerbation

frequency (primary endpoint) was analyzed using a negative binomial regression

31

model, including treatment arm and randomization stratification factors as model

factors, and logarithm of follow-up time excluding the summed duration of

exacerbations in the treatment period as an offset variable. Rate ratios versus

placebo and 95% confidence intervals (CI) were estimated from the model.

Likelihood-based Chi-square tests (two-sided, α = 0.05) were used to test for

between-group differences. The summed duration of an exacerbation was excluded

based on a FDA advice that since new exacerbations cannot occur during an extant

exacerbation, the offset term for each patient in your negative binomial generalized

linear model should exclude the summed duration of exacerbations during the

reporting period. Results of the sensitivity analysis using an offset variable that did

not exclude the summed duration of CAEs from the follow-up time were analyzed for

both studies and given in Table S5.

It was estimated that 480 (Study 1; 240 per arm) and 460 (Study 2; 230 per arm)

patients would provide approximately 90% power (two-sided, α=0.05) to detect a

33% reduction in exacerbation frequency with reslizumab versus placebo. This

estimate was based on an assumption that the mean (variance) annual exacerbation

rate in the placebo arm was ≥1.2 [Pavord et al 2012], and that there would be a

maximum 10% false-positive rate for the blood eosinophil test at enrollment and a

9% drop-out rate. The sample size for Study 1 is slightly larger, as it was originally

powered to accommodate improvement in FEV1 as a co-primary endpoint.

A mixed-effect model for repeated measures was used to compare overall least-

squares mean changes from baseline in lung function, patient-reported asthma

32

outcomes, SABA use, and blood eosinophil counts, with treatment, visit, treatment–

visit interaction, and stratification factors as fixed effects, patient as a random effect,

and baseline value as a covariate. The analysis for secondary efficacy variables was

prespecified for the 16 week time point for analysis of FEV1 and for overall effect at

16 weeks for lung function, patient-reported asthma outcomes, SABA use, blood

eosinophil counts, time to first CAE and CAE requiring use of systemic

corticosteroids. Type I error was controlled for these predefined secondary endpoints

and was not controlled for other time points and analyses. An analysis of covariance

model was used to compare least-squares mean changes from baseline to end-of-

treatment endpoint for the above outcomes with fixed effects for treatment and

stratification factors, and baseline value as a covariate. For all lung function

variables, gender was added to the models as a fixed effect, and height as a

covariable. Kaplan-Meier methodology was used to estimate and compare the

distributions of time to clinical asthma exacerbation. For the purpose of the Kaplan-

Meier analysis, CAEs occurring after randomization and up to 2 weeks after the end

of treatment (EOT) phase were included, and time to the event was calculated

appropriately. Patients without CAEs within this time frame were censored at

2◦weeks after the treatment completion date or study discontinuation, whichever

came first. Distribution differences were analyzed using a log-rank test adjusted for

the stratification factors. A stratified Cochran-Mantel-Haenszel test was used to

analyze the proportion of patients achieving a ≥0.5-point improvement from baseline

in AQLQ total score and a ≥0.5-point reduction in ACQ score. These changes

represent minimal clinically important differences [Juniper et al 1994; Juniper et al

2005].

33

Data from the two studies was pooled on a patient by patient basis. Pooled data was

used to perform sub-group analyses (Table S2) for CAE and FEV1 analysis. The

statistical model used for the analysis within each subgroup was the same model

used for the analysis of the predefined endpoints.

Study Drugs

Study drugs were provided as sterile solutions for infusion. Reslizumab was

presented as 100 milligrams (10 milliliters) per vial, formulated at 10 milligrams per

milliliter in in pH 5.5 buffered solution. Placebo was presented as 10 milliliters per

vial, formulated in pH 5.5 buffered solution. Both study drugs were added and mixed

with sterile saline for infusion and then administered via an intravenous infusion line

outfitted with a sterile, non-pyrogenic infusion, single-use, low-protein binding filter

(0.20 to 1 micrometer in diameter). Prior to use, reslizumab and placebo were stored

in a refrigerator at a controlled temperature (2° to 8° Celsius).

34

Prohibited and Restricted Medications

Use of any anti-human interleukin-5 monoclonal antibodies (e.g. reslizumab,

mepolizumab, or benralizumab) was prohibited. Patients were also prohibited from

using omalizumab and all other biologic therapies within the 6-month period prior to

screening. Other medication restrictions included the use of: any

immunosuppressive or immunomodulatory agents (including, but not limited to,

methotrexate, cyclosporine, and interferon-α), or anti-TNF monoclonal antibodies

within 6 months prior to screening; any live attenuated vaccines within 12 weeks

prior to screening; and systemic corticosteroids (excluding oral corticosteroids up to

a maximum dose of 10 milligrams of prednisone daily or equivalent, if the dosage

had been stable for 30 days prior to screening and continued without dosage

changes throughout the study) and all other non-biologic investigational drugs within

30 days prior to screening. If the patient was taking a SABA or LABA, they were

asked to withhold these medicines for 6 and 12 hours, respectively, prior to any

study visit that included spirometry or airway reversibility testing, including the

screening visit.

Efficacy Endpoints

Primary Endpoint

The primary endpoint in both studies was the frequency of clinical asthma

exacerbations reported for each patient during the 52-week treatment period. An

exacerbation event was considered to be a clinical asthma exacerbation if the patient

met either or both of the following criteria: (1) use of systemic corticosteroids or an

increase in the use of inhaled corticosteroid treatment for ≥ 3 days (for patients

35

already treated with systemic or inhaled corticosteroids, the dose of corticosteroids

had to be increased by at least two-fold for ≥ 3 days); or (2) asthma-related

emergency treatment, including at least one unscheduled visit to the physician’s

office for nebulizer treatment or other urgent treatment to prevent worsening of

asthma symptoms, visit to the emergency room for asthma-related treatment, or

asthma-related hospitalization. These criteria had to be corroborated with at least

one other measurement to indicate worsening clinical signs and symptoms of

asthma, as follows: a decrease in forced expiratory volume in 1 second (FEV1) of

≥ 20% from baseline; a decrease in the peak expiratory flow rate by ≥ 30% from

baseline on 2 consecutive days; or worsening of symptoms or other clinical signs per

physician evaluation of the event.

Clinical asthma exacerbations that occurred between the completion of the first dose

of study drug and 2 weeks after the end-of-treatment/early withdrawal visit were

included in the analysis. The primary analysis of clinical asthma exacerbations was

based on adjudicated data. The frequency of asthma exacerbations requiring

courses of systemic corticosteroids prescribed for ≥ 3 days was analyzed similarly.

Secondary Efficacy Endpoints

The secondary endpoints in both trials were: overall change from baseline in FEV1

over 16 weeks; overall change from baseline in Asthma Quality of Life Questionnaire

(AQLQ) total score to week 16; overall change from baseline in ACQ score over 16

weeks; overall change from baseline in Asthma Symptom Utility Index (ASUI) score

over 16 weeks; overall change from baseline in SABA use over 16 weeks; and

overall change from baseline in blood eosinophil count over 16 and 52 weeks.

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Other Efficacy Endpoints

Other efficacy endpoints included: change from baseline to weeks 4, 8, 12, 16, 20,

24, 28, 32, 36, 40, 44, 48, and 52, or early withdrawal in lung function (FEV1, percent

predicted FEV1, forced vital capacity [FVC], and forced expiratory flow at 25% to

75% FVC [FEF25%-75%]); AM and PM peak expiratory flow rate [PEFR], change from

baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, or early

withdrawal in ASUI score; change from baseline to weeks 4, 8, 12, 16, 20, 24, 28,

32, 36, 40, 44, 48, and 52, or early withdrawal in ACQ score; change from baseline

to weeks 16, 32 and 52, or early withdrawal in AQLQ score; change from baseline to

weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, or early withdrawal in

SABA use; and change from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40,

44, 48, and 52, and follow-up, or early withdrawal in blood eosinophil count. All lung

function endpoints were measured using spirometry according to American Thoracic

Society standards. At scheduled study visits, prebronchodilator spirometric testing

was performed after withholding SABA therapy for ≥ 6 hours and LABA therapy for ≥

12 hours.

Immunogenicity Testing

The immunogenicity of reslizumab was assessed by measuring for the presence of

anti-reslizumab antibodies at baseline and at the week 16, 32, 48, and 52 visits or

early withdrawal visit. Blood samples for anti-reslizumab antibodies assessment

were also obtained from all patients (inside or outside of the US) experiencing a

serious adverse event, an adverse event leading to withdrawal, or an exacerbation of

asthma symptoms.

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Serum samples for were analyzed by Teva (Teva Biopharmaceuticals USA,

Rockville, MD) using a validated homogeneous solution-based bridging ELISA

(Mikulskis et al 2011, Qui et al 2010). All cut point calculations were performed

according to the statistical methods recommended in current industry white papers

(Gupta et al 2011, Shankar et al 2008). The analysis includes identification and titer

measurement of positive samples.

The analysis of anti-reslizumab antibody in patient serum consisted of 3 tiers of

assays for screening, confirmation, and titer analysis:

• In the screening assay, biotin- and digoxigenin-conjugated drug was used

to detect anti-drug antibodies (ADA) (Qui et al 2010, Mikulskis et al 2011).

• The positive screening samples were further analyzed in the confirmatory

assay with 2 sequential steps:

− immune-competition with an excess amount of reslizumab to confirm

binding specificity to reslizumab, and

− blocking IL-5 crosslink by a rabbit anti-human IL-5 polyclonal antibody

to rule out false positive samples due to the presence of IL-5

The specific binding capability to reslizumab, excluding the binding of the IL-5, was

defined as ADA positive.

• Confirmed ADA-positive samples were then analyzed in a titration assay

for the determination of anti-reslizumab antibody titer.

If a patient had a treatment-emergent ADA response (ie, ADA positive at any of the

postdose time points but negative at the baseline visit predose timepoint) or if there

was a treatment-boosted ADA response (defined as a greater than 4-fold increase

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from a positive baseline ADA response (Shankar et at 2014), the patient was

classified as overall ADA positive.

Hierarchal Fixed-Sequence Multiple-testing Procedure

A fixed-sequence multiple testing procedure was implemented to test the primary

and secondary endpoints (in the order specified in the Supplementary Appendix –

Efficacy Endpoints), while controlling the overall type 1 error rate at 0.05. If the

resulting two-sided p-value from the primary endpoint comparison was ≤ 0.05, the

next comparison of interest (first secondary endpoint) was to be interpreted

inferentially at 0.05. This process was to be continued through the secondary

endpoints until either all comparisons of interest were interpreted inferentially, or until

the point at which the resulting two-sided p-value for a comparison of interest was

> 0.05. At the point where P > 0.05, no further comparisons were to be interpreted

inferentially. No multiplicity adjustments were made for other efficacy analyses.

Details of Anaphylactic Reactions

Two patients in the reslizumab arm in Study 2 experienced an anaphylactic reaction

(investigator assessed). Both events were assessed as serious, considered

treatment-related and the two patients discontinued from the study.

The first patient was a 45 year old female with a current medical history of asthma,

contrast agent allergy, aspirin/salicylate pseudo anaphylaxis/intolerance, and

recurrent sinusitis. Concomitant medications included fluticasone/salmeterol 500/50

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combination inhaler, salbutamol prn, nasonex, singulair, Mizolastine, lorazepan,

fluoxetine, chlorprothixene, and zopiclone. Within 15 minutes of the second

reslizumab infusion the patient experienced dyspnea, flush, nausea, vomiting and

shivering. Tremor and paleness were reported but itching and hives were not

present. The patients blood pressure was normal to elevated (170/100) and her

pulse remained within the normal range. Blood oxygen saturation was as low as

89% at one point but her chest revealed no ‘spasticity’. She was treated with IV

corticosteroid, dimentidine (cimetidine), Ringer’s Lactate and lorazepam and

discharged from the clinic on oral prednisone and an antihistamine with full recovery.

This patient is ADA negative.

The second patient was a 48 year old female with a current listed history of asthma,

aspirin/salycilate pseudoanaphylaxis/intolerance, allergies to mold and animal hair,

allergic rhinitis, and recurrent sinusitis. Current medications included

fluticasone/salmeterol 500/50, maintenance prednisone, salbutamol, and birth

control pill. Twenty minutes after finishing the 12th reslizumab infusion the patient

experienced intense itching on the upper right arm and pressure in the lower

abdomen. Shortly after symptom onset, the itchiness spread to the upper left arm,

both legs, predominantly the thighs, popliteal space/cavity and the genital area. Vital

signs were stable throughout the anaphylactic reaction, no signs of circulatory

collapse/shock. Physical examination revealed an absence of dyspnea, sinus

rhythm (via ECG); vesicular breathing was identified in both lungs (but no spasms)

plus dorsal/basal wheezing (existent prior to IMP infusion). Blood oxygen saturation

was 97%. Treatment included IV systemic corticosteroid ranitidine, Fenistil, 1000 mL

Ringer infusion solution. The reaction had substantially regressed over 1.5 hours.

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The patient was discharged on oral corticosteroid with full recovery. This patient is

ADA negative.

Part C – Supplementary Figures

Supplementary Figure S1. Change from Baseline in Asthma Control

Questionnaire Score over the 52-Week Treatment Period in (A) Study 1 and (B)

Study 2 (Intention-to-Treat Population).

The panels show the least-square mean (standard error) change from baseline in Asthma

Control Questionnaire score over the 52-week study period and at end-of-treatment.

*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.

A

B

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Supplementary Figure S2. Change from Baseline in Asthma Symptom Utility

Index Score over the 52-Week Treatment Period in (A) Study 1 and (B) Study 2

(Intention-to-Treat Population).

The panels show the least-square mean (standard error) change from baseline in Asthma

Symptom Utility Index score over the 52-week study period and at end-of-treatment.

*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.

A

B

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Supplementary Figure S3. Scatter Plot of Blood Eosinophil Count over the 52-

Week Treatment Period in (A) Study 1 and (B) Study 2 (Intention-to-Treat

Population).

The panels show individual blood eosinophil counts in both treatment arms over the 52-week

study period and treatment follow-up. Patients were required to have a blood eosinophil

count of at least 400/µL at least once during the screening period prior to being randomized.

As this value did not necessarily occur at baseline, the baseline eosinophil counts depicted

for the randomized population in the figure include some patients with values below 400/µL.

Also see table S4 for analysis by screening eosinophil count.

A

B

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Supplementary Figure S4. Pooled sub-analyses (across trials) of FEV1 least-

squares means at over the first 16 weeks and from baseline to study end (week 52)

for patient populations with different concomitant medication profiles.

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Supplementary Figure S5. Pooled sub-analyses (across trials) of CAE rate ratios (at week 52) by prior CAE history in the last 12 months (1– ≥4 exacerbations)

Supplementary Figure S6. Pooled sub-analyses (across trials) of CAE rate ratios (at week 52) by baseline eosinophil level

45

Part D Supplementary Tables

Supplementary Table S1. CAE and FEV1 Results Based on Background Medication (Pooled Study 1 and Study 2).

Sub- population analysis (pooled Study 1 and Study 2 results) Adjudicated CAE rate

Placebo (n) Reslizumab Rate ratio (95% CI)†

n result n result ALL patients 476 1.8118 477 0.8359 0.4613 (0.37, 0.58) ***

LABA YES LABA NO

383 93

1.84 1.63

397 80

0.83 0.84

0.45(0.35, 0.58) 0.51(0.29, 0.89)

OCS dependent YES 73 2.04 404 0.69 0.32(0.18, 0.55) FEV1‡ Δ (95% CI)§ Overall change in FEV1 ALL patients (L)

Week 16 468

0.109 473

0.226 0.117 (0.073, 0.160)*** Week 52 0.115 0.224 0.110(0.066, 0.154)***

LABA NO patients Week 16

92 0.148

78 0.241 0.093(-0.001, 0.188)

Week 52 0.140 0.221 0.081(-0.020, 0.182) LABA YES patients

Week 16 376

0.109 395

0.230 0.120 (0.071, 0.169) Week 52 0.114 0.227 0.113(0.063, 0.162)

OCS YES patients Week 16

70 0.246

72 0.375 0.129(-0.005, 0.263)

Week 52 0.255 0.406 0.151(0.016, 0.286) *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. p-value were only calculated only for the entire population: it was not calculated for subgroup analyses. † The rate ratio represents the ratio of adjudicated CAE rates between the reslizumab and placebo arms. ‡Values shown are least-square mean changes from baseline. §The between-group difference is the absolute reduction in the reslizumab arm versus the placebo arm.

46

Supplementary Table S2. Integrated results for long and short versions of ACQ over 52 weeks

CI=confidence interval. ****p<0•0001.

Supplementary Table S3. Actual measures key parameters at baseline and Week 52 Study 1 Study 2 Parameter±SD Placebo Reslizumab Placebo Reslizumab Eosinophils, cells/μl

Baseline 624±590 696±768 688±682 610±412 Week 52 496±338 212±71 534±429 67±185

FEV1, L Baseline 1.93±0.79 1.89±0.73 2.00±0.67 2.13±0.78 Week 52 2.02±0.82 2.14±0.78 2.10±0.69 2.36±0.79

ACQ score Baseline 2.76±0.88 2.66±0.85 2.60±0.79 2.57±0.89 Week 52 1.82±1.09 1.45±1.05 1.73±1.02 1.36±0.89

AQLQ Baseline 4.16±1.09 4.30±1.12 4.22±1.08 4.35±1.02 Week 52 5.18±1.20 5.66±1.16 5.20±1.17 5.50±0.99

ASUI Baseline 0.61±0.20 0.63±0.019 0.65±0.19 0.65±0.20 Week 52 0.78±0.20 0.85±0.17 0.80±0.18 0.86±0.15

SABA Baseline 2.7±3.2 2.4±2.8 2.7±2.4 2.9±2.8 Week 52 2.1±2.7 1.8±2.9 2.2±1.9 2.2±2.6

ACQ= Asthma Control Questionnaire Score; SABA= Short-Acting Beta Agonist , AQLQ=Asthma Quality of Life Questionnaire. ASUI=Asthma Symptom Utility Index. SABA=short-acting beta-agonist. SD=standard deviation.

Study 1 + Study 2

Placebo

Reslizumab

treatment effect (95% CI)

ACQ-7 score -0.769 -1.019 -0.250 (-0.343, 0.156)***

ACQ-6 score -0.850 -1.087 -0.238 (-0.336,-0.140)****

ACQ-5 score -0.915 -1.169 -0.254 (-0.356, 0.152)****

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Supplementary Table S4. Frequency of Clinical Asthma Exacerbations (CAEs) During the 52-Week Treatment Period by Consistency of Screening Blood Eosinophil Counts and Treatment Group-Adjudicated Data Randomized Patients Study 1 + Study 2

Adjudicated CAE rate

Placebo

Reslizumab

Rate ratio

(95% CI)

At least 1 screening EOS<400 1.34 0.66 0.49(0.33, 0.73)*

All screening EOS>=400 2.10 0.93 0.45(0.34, 0.59)*

Supplementary Table S5. Frequency of Asthma Exacerbations During the 52-Week Treatment Period by Treatment Group-Adjudicated Data Sensitivity Analysis (Not excluding Exacerbation Duration from the Offset) Randomized Patients Adjudicated CAE rate

Placebo

Reslizumab

Rate ratio (95% CI)

Study 1 1.51 0.82 0.54(0.4098, 0.7085)*

Study 2 1.73 0.76 0.44 (0.3135, 0.6202)*

Episodes requiring systemic corticosteroid for ≥ 3 days

Study 1 1.34 0.66 0.49 (0.3613, 0.6583)*

Study 2 1.36 0.58 0.42 (0.2935, 0.6148)*

*p < 0.0001

• Supplementary Table S6. Participating countries

Study 1 Study 2

• Australia

• Belgium

• Chile

• Colombia

• Argentina

• Brazil

• Canada

• France

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• Czech Republic

• Denmark

• Hungary

• Israel

• Malaysia

• New Zealand

• Philippines

• Poland

• Russia

• South Africa

• Sweden

• Thailand

• United States

• Germany

• Greece

• Republic of Korea

• Mexico

• Peru

• Romania

• Russia

• Slovak Republic

• Taiwan

• Ukraine

• USA

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