Supplementary appendix This 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.
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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
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
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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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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)**
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
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
Investigator and affiliation Sub-investigator(s) name Mihaltan, Florin Dumitru, MD, PhD, Prof. “Marius Nasta” Institute of Pneumology 90 Viilor Road Bucharest 050159 Romania
Vladimir, Simanenkov, MD, PhD St. Petersburg State Budget Institution of Healthcare “City Hospital #26”, 2, Ulitsa Kostyusko St. Petersburg 196247 Russia
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
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
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
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
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
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
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
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
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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
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
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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 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.
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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
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