Feltes et al. – Supplemental Material

The Motavizumab Cardiac Study Group

Austria: U. Salzer-Muhar, Medical University of Vienna, Vienna; J. I. Stein, Medical University of Innsbruck, Innsbruck; G. Tulzer, General Hospital of Linz, Linz

Belgium: A. Benatar, Academic Hospital, Free University of Brussels, Brussels; H. Dessy, Queen Fabiola Children's University Hospital, Brussels; D. De Wolf, Ghent University Hospital, Ghent; M. Gewillig, University Hospitals Leuven, Leuven; M. Massin, Regional Center Hospital Citadelle, Liege; T. Sluysmans, St. Luke’s Clinic Catholic University of Leuven, Brussels; B. Suys, Antwerp University Hospital, Edegem; P. Vandenberghe, Queen Paola Children’s Hospital, Antwerp

Bulgaria: M. N. Bosheva, E. D. Ghenev, M. Krasteva, University Multiprofile Hospital for Active Treatment "St.Georgi", Plovdiv; P. Chakarova, Multiprofile Hospital for Active Treatment "Stara Zagora", Stara Zagora; S. Dachev, Regional Dispensary for Pulmonary Diseases with Inpatient sector-Ruse, Ruse; I. Galabov, Multiprofile Hospital for Active Treatment "St. Marina", Varna; A. Georgieva, Multiprofile Hospital for Active Treatment “Plovdiv”, Plovdiv; E. Hristova, Specialized Hospital for Active Treatment of Pediatric Diseases, Sofia; V. Nedkova-Kolarova, R. Rosmanova, University Multiprofile Hospital for Active Treatment "Dr. Georgi Stranski", Pleven; M.R. Tzonzarova, Specialized Hospital for Active Treatment of Cardiovascular Diseases, Sofia

Canada: A. Kakadekar-Sankaran, K. Sankaran-Kakadekar, Royal University Hospital, Saskatoon; J. Langley, Clinical Trials Research Center, IWK Health Center, Halifax; M. Lebel, Sainte Justine Hospital, Montreal; K.-J. Lee, The Hospital for Sick Children, Toronto; J. McDonald, McGill University Health Centre, Montreal; J. Robinson, Stollery Children’s Hospital, University of Alberta, Edmonton; H. Rosenberg, Children’s Hospital of Eastern Ontario, Ottawa; A. Singh, Children and Women’s Hospital of British Columbia, Vancouver

Czech Republic: J. Biolek, Most Hospital, Most; R. Brabec, Motol Teaching Hospital, Prague; M. Cihar, Na Bulovce Teaching Hospital, Prague; P. Jehlicka, Pilsen Teaching Hospital, Pilsen- Lochotin; Z. Kokstein, Hradec Kralove Teaching Hospital, Hradec Kralove; K. Liska, Prague General Teaching Hospital, Prague; Z. Stranak, The Institute for Care of Mother and Child, Prague

Denmark: B. Windelborg Nielsen, Aarhus University Hospital, Skejby, Aarhus

France: I. Denjoy, Robert Debre Hospital, Paris; E. Dumas de la Roque, Bordeaux Children's Hospital, Bordeaux; B. Escande, Hospital Hautpierre, Strasbourg; J.-M. Lupoglazoff, Marie Lannelongue Surgical Center, Le Plessis Robinson; F. Marcon, Subscribers’ Hospital, Vandoeuvre Les Nancy; P. Morville, American Memorial Hospital, Reims; D. Semama, University Hospital of Dijon, Dijon; U. Simeoni, Hospital of the Conception, Marseille

Germany: R. Dalla Pozza, H. Netz, Ludwig Maximilian University Hospital, Munich; S. Dittrich, University Hospital of the Friedrich-Alexander University Erlangen-Nuremberg, Erlangen; M. Hofbeck, Tübingen University Hospital, Tübingen; D. Kececioglu, Heart and

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Diabetes Center North Rhine-Westphalia, Bad Oeynhausen; M. F. Knuf, Johannes-Gutenberg University, Mainz; H.-H. Kramer, Schleswig Hostein University Hospital, Kiel; R. Motz, Oldenburg Hospital, Oldenburg; T. Paul, Georg-August University Gottingen, Gottingen; M. Peuster, Rostock University Hospital, Rostock, Ruhr University Bochum, Bad Oeynhausen; A. Wessel, Hannover Medical School, Hannover

Hungary: K. Adamovich, University of Pecs, Pecs; L. Barkai, Borsod-Abaúj-Zemplén Megyei County Hospital and University Teaching Hospital, Miskolc; F. Dicso, Andrew Josa Teaching Hospital, Nyiregyhaza; M. Katona, University of Szeged, Szeged; A. Miklós, Petz Aladar County Teaching Hospital, Gyor; S. Miklós, Semmelweis University, Budapest; A. Nagy, University of Debrecen Medical and Health Center, Debrecen; E. Szabo, Csolnoky Ferenc Hospital, Veszprem; A. Szatmari, Gottsegen Gyorgy National Institute of Cardiology, Children’s Center, Budapest

Israel: S. S. Ashkenazi, Schneider Children's Medical Center of Israel, Petach Tikva; A. Barzilai, The Chaim Sheba Medical Center, Tel Hashomer; I. Berger, F. B. Mimouni, Tel-Aviv Sourasky Medical Center, Tel Aviv; R. Dagan, Soroka University Medical Center, Beer Sheva; D. Engelhard, Hadassah University Hospital Ein Kerem, Jerusalem; I. Kassis, Rambam Medical Center, Haifa; Y. Schlesinger, Shaare Zedek Medical Center, Jerusalem; E. Somekh, Edith Wolfson Medical Center, Holon

Lebanon: F. F. Bitar, American University of Beirut Medical Center, Beirut; L. Daou, Hotel Dieu De France, Beirut; R. Sacy, St. George University Hospital, Ashrafieh

Poland: G. Dawid, Tadeusz Sokołowski Autonomous Public Clinical Hospital No. 1 of the Pomeranian Medical Academy, Szczecin; J. S. Gadzinowski, Gynecological-Maternity Hospital of the Medical University of Poznan, Poznan; G. Gornicka, Professor Anthony Gebali Children’s Clinical Hospital, Lublin; B. Kassur-Siemienska, Children’s Health Center Institute, Warsaw; A. Kojro-Wojcieszonek, K. Mackowska, Provincial Children's Hospital of Bydgoszcz, Bydgoszcz; P. Korbal, Dr. John Biziela Independent Public Health Hospital, Bydgoszcz; A. Sysa, Institute of Polish Mother’s Health Center, Lodz; M. Szczepanski, Independent Public Hospital of the Medical University of Bialystok, Bialystok; M. A. Wojtalik, Charles Jonschera Hospital of the University of the Medical Sciences, Poznan

Russia: N. B. Baltserovich, City Outpatient Clinic #113, St. Petersburg; V. Bulatov, Kazan State Medical University, Kazan; A. N. Galustyan, St. Petersburg State Pediatric Medical Academy; K. V. Gorbatikov, Regional Clinical Hospital Tyumen, Tyumen; S. N. Ivanov, Research Cardiology Institute of Tomsk Scientific Center, Tomsk; V. G. Lyubomudrov, O. A. Solovieva, St. Petersburg City Children’s Hospital #1, St. Petersburg; S. A. Shadrin, Kuban State Medical Academy, Krasnodar; Y. S. Sinelnikov, Meshalkin Research Institute of Blood Circulation, Novosibirsk

Spain: J. Casaldaliga, Vall d’Hebron University Hospital, Barcelona; J. F. Exposito, Maternal and Child Hospital Jaen, Jaen; I. Fernandez-Santamarina, Vigo General Hospital, Vigo; D. García de la Calzada, Miguel Servet University Hospital, Zaragoza; L. García-Guereta, Hospital La Paz, Madrid; J. M. Guia, The Virgin of Arrixaca University Hospital, El Palmar; J. M.

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Guzman Cabañas, Queen Sofia Hospital, Cordoba; M. A. Izquierdo, Donostia Hospital, San Sebastian; E. Maroto, Gregorio Maranon Hospital, Madrid; C. Medrano, Juan Canalejo Hospital, La Coruna; J. Ortiz, Jerez Hospital, Jerez de la Frontera; A. Perez, October 12 Hospital, Madrid; C. Planell, Josep Trueta Hospital, Girona; M. Rissech, St. Joan of God Hospital, Esplugas de Llobregat; M. D. Rodriguez, Virgin of the Snow University Hospital, Granada; J. Santos, Virgen del Rocio University Infant Hospital, Seville; A. Valls-i-Soler, Hospital of the Cross, Barakaldo; I. Zabala, Maternal and Infant Hospital, Malaga

Sweden: A. Jonzon, Uppsala University Hospital, Uppsala; E. Pesonen, Lund University Hospital, Lund; J. Sunnegardh, Sahlgrenska University Hospital, Goteborg; P. Winberg, Karolinska University Hospital, Stockholm

United Kingdom: M. Blackburn, Leeds General Infirmary, Leeds; F. A. Bu’Lock, University Hospitals of Leicester, Leicester; F. Casey, Royal Belfast Hospital for Sick Children, Belfast; P. Daubeney, Royal Brompton Hospital, London; B. Jani, Medway Maritime Hospital, Gillingham; M. J. Marsh, Southampton General Hospital, Southampton; R. Tulloh, Bristol Royal Hospital for Children, Bristol

United States: M. Aouthmany, Mercy Children's Hospital, St. Vincent Mercy Medical Center, Toledo, OH; A. Arrieta, G. Goodman, Children's Hospital of Orange County, Orange, CA; A. Atz, Medical University of South Carolina, Charleston, SC; V. Balaraman, Kapiolani Medical Center for Women and Children, Honolulu, HI; J. Bolivar, Miami Children’s Hospital, Miami, FL; D. Bratcher, Children’s Mercy Hospital, Kansas City, MO; R. Breitbart, Children’s Hospital Boston, Boston, MA; J. Brenner, Johns Hopkins Hospital, Baltimore, MD; D. Burchfield, University of Florida School of Medicine, Shands Children's Hospital, Gainesville, FL; A. Cabalka, Mayo Clinic, Rochester, MN; M. Camitta, Duke University Medical Center, Durham, NC; K. Chintala, Children’s Hospital of Michigan, Detroit, MI; W. Covitz, Wake Forest University Health Sciences Center, Winston-Salem, NC; L. Cripe, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; P. Dennehy, Rhode Island Hospital, Providence , RI; J. Domachowske, SUNY Upstate Medical University, Syracuse, NY; K. Dooley, Children’s Healthcare of Atlanta, Atlanta, GA; J. Englund, Children;s Hospital and Regional Medical Center, Seattle, WA; R. Fedderly, Children’s Hospital of Wisconsin, Milwaukee, WI; T. Hoffman, Nationwide Children’s Hospital Research Institute, Columbus, OH; J. Fergie, Driscoll Children’s Hospital, Corpus Christi, TX; J. Finnigan, Children’s Cardiology Associates PLLC, Austin, TX; R. Fox, University of Maryland, Baltimore, MD; D. Freeman, Arkansas Pediatric Clinic, Little Rock, AR; A. Friedman, Yale New Haven Children’s Hospital, New Haven, CT; R. Gajarski, University of Michigan, Ann Arbor, MI; D. Gremmels, Children’s Hospital and Clinic, Minneapolis, MN; S. Gullquist, Virginia Commonwealth University Health System, Richmond, VA; C. Hall, University of Rochester, Rochester, NY; F. Henderson, University of North Carolina, Chapel Hill, NC; P. Hughes, M. Lepow, Albany Medical Center, Albany, NY; F. Ing, Children’s Hospital and Health Center, San Diego, CA; J. Johns, Vanderbilt Children’s Hospital, Nashville, TN; G. Johnson, K. Rosen, Penn State Milton S. Hershey Medical Center, Hershey, PA; A. Kantak, Akron Children’s Hospital, Akron, OH; D. Kaufman, University of Virginia, Charlottesville, VA; L. Krilov, Winthrop University Hospital, Mineola, NY; K. Kuehl, Children’s National Medical Center, Washington, DC; G. Kung, Children’s Hospital Los Angeles, Los Angeles, CA; C. Lamprecht, Nemours Children’s Clinic Biomedical Research

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Department, Orlando, FL; J. Lieberman, Miller Children’s Hospital, Long Beach, CA; C. Meissner, Tufts New England Medical Center, Boston, MA; S. Miller, Children’s Hospital of Pittsburgh, Pittsburgh, PA; A. Mott, Texas Children’s Hospital, Houston, TX; S. Nachman, State University of New York at Stony Brook University Medical Center, Stony Brook, NY; V. Nizet, University of California San Diego Pediatric Pharmacology Research Unit, San Diego, CA; D. Null, Primary Children’s Medical Center, Salt Lake City, UT; S. Paridon, Children’s Hospital of Philadelphia, Philadelphia, PA; M. Parrish, University of California Davis Medical Center, Sacremento, CA; M . Polak, West Virginia University, Morgantown, WV; A. Qureshi, G. Rosenthal, Cleveland Clinic, Cleveland OH; M. Reller, Oregon Health & Science University, Portland, OR; J. Romero, University of Nebraska Medical Center, Creighton University, Omaha, NE; L. Rubin, North Shore Long Island Jewish Health, Schneider Children’s Hospital, New Hyde Park, NY; Z. Saba, Children’s Hospital and Research Center at Oakland, Oakland, CA; P. Sanchez, University of Texas Southwestern Medical Center, Dallas, TX; C. Sang, Jr, East Carolina University School of Medicine, Greenville, NC; V. San Joaquin, Children’s Hospital of Oklahoma, Oklahoma City, OK; R. Schelonka, University of Alabama Birmingham, Birmingham AL; T. Scholz, University of Iowa Children’s Hospital of Iowa, Iowa City, IA; A. Sharkey, Washington University School of Medicine, St. Louis, MO; M. Silio, Tulane University Health Sciences Center, New Orleans, LA; H. Sondheimer, The Children’s Hospital, Aurora, CO; J. Stevens, James Whitcomb Riley Hospital for Children, Indianapolis, IN; J. Sullivan, Kosair Charities Pediatric Research Unit, Louisville, KY; C. Tan, J. Lieberman, Miller Children’s Hospital, Long Beach, CA; R. Welliver, Women & Children’s Hospital, Buffalo, NY; G. Wetzel, University of Tennessee Health Science Center, LeBonheur Children’s Medical Center, Memphis, TN; R. White, Memorial Hospital of South Bend, South Bend, IN; L. Wolkoff, Connecticut Children’s Medical Center, Hartford, CT; R. Yetman, University of Texas Health Science Center at Houston Medical School, Houston, TX; R. Yogev, Children’s Memorial Hospital, Chicago, IL

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Supplemental Methods

Exclusion Criteria

Patients not eligible for enrollment included those with unstable cardiac or respiratory status, including severe cardiac defects with unanticipated survival or with anticipated cardiac transplantation; hospitalization, unless discharge was anticipated within 21 days; cardiac surgery anticipated within 2 weeks of randomization; any requirement for mechanical ventilation, extracorporeal membrane oxygenation, continuous positive airway pressure, or other mechanical respiratory or cardiac support; any associated noncardiac anomalies or end organ dysfunction resulting in anticipated survival of <6 months or unstable abnormalities of end organ function; acute respiratory illness, or other acute infection or illness (patients with respiratory symptoms were tested for RSV before randomization and were excluded if they were positive); chronic seizure or neurologic disorder; immunodeficiency; mother with human immunodeficiency virus

(HIV) infection (unless the child was negative for HIV infection); known allergy to any immunoglobulin products; receipt of any polyclonal antibody or palivizumab within 3 months before randomization; use of any investigational agents other than those commonly used during cardiac surgery or the immediate postoperative period; or current participation in any other investigational protocols.

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Table S1. CHD Stratification of Patients by Primary Cardiac Lesion (ITT Population)

CHD Stratum Motavizumab Palivizumab Total Cardiac Lesion (n=623) (n=612) (N=1235) Cyanotic*, n (%) 346 (55.5) 319 (52.1) 665 (53.8)

Tetralogy of Fallot 107 (17.2) 94 (15.4) 201 (16.3)

Single ventricle 99 (15.9) 90 (14.7) 189 (15.3) Pulmonary atresia with VSD 39 (6.3) 34 (5.6) 73 (5.9) Tricuspid atresia 26 (4.2) 34 (5.6) 60 (4.9) DORV with transposed great arteries 25 (4.0) 17 (2.8) 42 (3.4) d-TGA with/without VSD and 21 (3.4) 18 (2.9) 39 (3.2) with/without pulmonary stenosis Pulmonary atresia with intact septum 20 (3.2) 16 (2.6) 36 (2.9) Ebstein anomaly 9 (1.4) 16 (2.6) 25 (2.0) Other**, n (%) 277 (44.5) 293 (47.9) 570 (46.2) VSD 130 (20.9) 154 (25.2) 284 (23.0) Atrioventricular septal defect 44 (7.1) 54 (8.8) 98 (7.9) Atrial septal defect 37 (5.9) 28 (4.6) 65 (5.3) All other defects 66 (10.6) 57 (9.3) 123 (10.0)

CHD=congenital heart disease; DORV=double outlet right ventricle; d-TGA=dextro- transposition of the great arteries; ITT=intent-to-treat; VSD=ventricular septal defect. *Pulmonary atresia with VSD, pulmonary atresia with intact ventricular septum, tetralogy of Fallot, single ventricle including hypoplastic left or right heart, tricuspid atresia, DORV, Ebstein anomaly, or d-TGA with/without VSD, with/without pulmonary stenosis. **Children who did not have one of the designated diagnoses to be included in the cyanotic stratum (above) were classified as “Other” anticipating that this group would largely be made up of children with acyanotic CHD lesions.

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Table S2. Adverse Events Occurring in Approximately 5% of Patients in Both Groups

Preferred Term, n (%) Motavizumab Palivizumab (n=618) (n=612) Pyrexia 184 (29.8) 179 (29.2) Upper respiratory tract infection 169 (27.3) 172 (28.1) Cough 92 (14.9) 71 (11.6) Rhinitis 91 (14.7) 77 (12.6) Otitis media 77 (12.5) 70 (11.4) Gastroenteritis 70 (11.3) 66 (10.8) Diarrhea 70 (11.3) 65 (10.6) Nasopharyngitis 68 (11.0) 58 (9.5) Vomiting 60 (9.7) 51 (8.3) Bronchitis 49 (7.9) 48 (7.8) Rhinorrhea 49 (7.9) 45 (7.4) Teething 44 (7.1) 36 (5.9) Constipation 44 (7.1) 31 (5.1) Blood urea increased 39 (6.3) 34 (5.6) Viral infection 39 (6.3) 31 (5.1) Conjunctivitis 39 (6.3) 27 (4.4) Tetralogy of Fallot 38 (6.1) 50 (8.2) Pharyngitis 33 (5.3) 25 (4.1) Dermatitis diaper 32 (5.2) 31 (5.1) Ventricular septal defect 31 (5.0) 38 (6.2) Cyanosis 31 (5.0) 30 (4.9) Pneumonia 30 (4.9) 36 (5.9) Bronchiolitis 30 (4.9) 24 (3.9) Otitis media acute 28 (4.5) 19 (3.1) Nasal congestion 26 (4.2) 33 (5.4) Respiratory disorder 23 (3.7) 28 (4.6) Irritability 22 (3.6) 38 (6.2) Gastrooesophageal reflux disease 21 (3.4) 28 (4.6)

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Table S3. Preferred Terms for Skin Events of Interest by Nonspecific and Specific Event Terms

Nonspecific Preferred Terms Specific Preferred Terms Erythema Allergic edema Laryngotracheal edema Fixed eruption Anaphylactoid reaction Lip edema Generalized edema Angioedema Lip swelling Pruritis Angioneurotic edema Edema Pruritis generalized Bronchial edema Edema mouth Rash Circumoral edema Oropharyngeal swelling Rash erythematous Dermatitis allergic* Periorbital edema Rash macular* Drug eruption* Pharyngeal edema Rash maculopapular* Drug hypersensitivity* Pharyngeal ulceration Rash papular* Erythema annulare* Pruritis allergic Rash pruritic Erythema marginatum* Rash generalized Erythema multiforme* Skin swelling Eye edema Swelling Eye swelling Swelling face Eyelid edema Swollen tongue Face edema Tongue edema Flushing Tracheal edema Generalized erythema Urticaria Hypersensitivity* Urticaria generalized Laryngeal edema

*Additional terms designated by the medical monitor as indicative of a possible hypersensitivity reaction for the analysis of skin events “of interest”.

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Table S4. Motavizumab Trough Serum Concentrations

Mean Serum Concentration (μg/mL)* of Motavizumab

Population 1** Population 2† (n=618) (n=618) Pre-dose 1 n 543 536 Mean (SD) 0 (0.0) 0 (0.0)

30 Days post dose 1 n 521 521 Mean (SD) 46.90 (15.20) 46.61 (15.45)

30 Days post dose 2 n 228 237 Mean (SD) 60.94 (25.41) 60.19 (25.50)

30 Days post dose 3 n 203 232 Mean (SD) 66.59 (34.51) 65.62 (34.12)

30 Days post dose 4 n 378 442 Mean (SD) 77.87 (32.75) 79.01 (34.06)

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Figure S1. Disposition of patients

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Figure S2. Incidence of hypersensitivity events.

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