ARTICLES

Motavizumab for Prophylaxis of Respiratory Syncytial Virus in High-Risk Children: A Noninferiority Trial

AUTHORS: Xavier Carbonell-Estrany, MD, PhD,a Eric A. F. WHAT’S KNOWN ON THIS SUBJECT: Monthly prophylaxis with Simo˜es, MD, MB, BS, DCH,b,c Ron Dagan, MD,d Caroline B. palivizumab has been shown to reduce RSV hospitalizations by Hall, MD,e Brian Harris, MS,f Micki Hultquist, MS,f Edward ϳ50% overall compared with placebo in children at high risk for f f M. Connor, MD, and Genevieve A. Losonsky, MD, for the severe RSV disease. Motavizumab, a monoclonal antibody Motavizumab Study Group developed from palivizumab, has enhanced preclinical activity aNeonatology Service, Hospital Clínic, Agrupacio´Sanite`ria Clínic, against RSV. Hospital de Sant Joan de De´u, Barcelona, Spain; bDepartment of Pediatrics, University of Colorado School of Medicine, Denver, Colorado; cDivision of Infectious Diseases, Children’s Hospital, WHAT THIS STUDY ADDS: Motavizumab may offer an improved Denver, Colorado; dPediatric Infectious Disease Unit, Soroka alternative in prophylaxis for serious RSV disease in children at University Medical Center and Faculty of Health Sciences, Ben- high risk. Motavizumab was noninferior to palivizumab for Gurion University, Beer-Sheva, Israel; eDepartments of Pediatrics prevention of RSV hospitalization (primary end point) and and Medicine, University of Rochester Medical Center, superior to palivizumab for reduction of RSV-specific outpatient Rochester, New York; and fMedImmune, Gaithersburg, Maryland MALRI (a secondary end point). KEY WORDS clinical trial, motavizumab, palivizumab, pediatric, respiratory infection, respiratory syncytial virus ABBREVIATIONS RSV—respiratory syncytial virus CLD—chronic lung disease of prematurity abstract MALRI—medically attended lower respiratory tract infection OBJECTIVE: Palivizumab reduces respiratory syncytial virus (RSV) hospi- OM—otitis media ϳ AE—adverse event talization in children at high risk by 50% compared with placebo. We SAE—serious adverse event compared the efficacy and safety of motavizumab, an investigational ADA—anti-drug antibody monoclonal antibody with enhanced anti-RSV activity in preclinical studies, ITT—intention to treat with palivizumab. ATP—according-to-protocol METHODS: This randomized, double-blind, multinational, phase 3, noninferi- CI—confidence interval ority trial assessed safety and RSV hospitalization in 6635 preterm infants RR—relative risk aged Յ6 months at enrollment or children aged Յ24 months with chronic This trial has been registered at www.clinicaltrials.gov lung disease of prematurity who received 15 mg/kg palivizumab or motavi- (identifier NCT00129766). zumab monthly. Secondary end points included outpatient medically attended www.pediatrics.org/cgi/doi/10.1542/peds.2008-1036 lower respiratory tract infections (MALRIs), RSV-specific LRIs, otitis media, doi:10.1542/peds.2008-1036 antibiotic use, development of antimotavizumab antibodies, and motavizumab serum concentrations. Accepted for publication Jun 18, 2009 Address correspondence to Xavier Carbonell-Estrany, MD, PhD, RESULTS: Motavizumab recipients had a 26% relative reduction in RSV Hospital Clínic, Neonatology Service, C/Sabino Arana 1, 08028 hospitalization compared with palivizumab recipients, achieving nonin- Barcelona, Spain. E-mail: [email protected] feriority. Motavizumab was superior to palivizumab for reduction of RSV- specific outpatient MALRIs (50% relative reduction). Overall, adverse PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). events (AEs) were not significantly different between groups. Cutaneous Copyright © 2009 by the American Academy of Pediatrics events were reported in 2 percentage points more motavizumab recipi- FINANCIAL DISCLOSURE: Drs Carbonell-Estrany and Simo˜es ents (7.2% vs 5.1%); most were mild, but 0.3% resulted in dosing discon- have received compensation for consultation and research tinuation. Antidrug antibodies (ADA) were detected in 1.8% of motavizumab services from MedImmune and Abbott International; Drs Dagan recipients. Patients with anti-drug antibody reported 6 RSV events and 17 and Hall have received compensation for consultation and research services from MedImmune; Dr Connor was an cutaneous events. employee of MedImmune at the time of the study and was a CONCLUSIONS: Children receiving prophylaxis with motavizumab or palivi- consultant for MedImmune during the preparation of this zumab had low rates of RSV hospitalization; motavizumab recipients experi- manuscript; and Mr Harris, Ms Hultquist, and Dr Losonsky are employees of MedImmune. This study was sponsored by enced 50% fewer RSV MALRIs than palivizumab recipients. AEs were similar in MedImmune. both groups, although cutaneous AEs were higher for motavizumab recipients. Motavizumab may offer an improved alternative in prophylaxis for serious RSV disease in infants and children at high risk. Pediatrics 2010;125:e35–e51

PEDIATRICS Volume 125, Number 1, January 2010 e35 Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 Palivizumab(Synagis[MedImmune,Gai- tional Conference on Harmonisation (all sites) and RSV-specific (all patients thersburg, MD]), a humanized mono- Guidelines for Good Clinical Practice at a subset of sites) outpatient medi- clonal antibody that recognizes a and was approved by the institutional cally attended lower respiratory tract highly conserved neutralizing epitope review board or independent ethics infection (MALRI), frequency and inci- on the fusion protein of respiratory committee of each participating cen- dence of medically attended otitis me- syncytial virus (RSV),1 is recom- ter and safety was monitored by an in- dia (OM), and the frequency of pre- mended for RSV prophylaxis of chil- dependent data safety monitoring scribed antibiotics for LRI and OM. dren at high risk.2,3 Monthly palivi- board. Parents or legal guardians pro- Outpatient MALRI required medical zumab reduced RSV hospitalizations vided written informed consent for management (physician’s office, clinic, by ϳ50% compared with placebo in each child. or emergency department) with a di- 4–6 children at high risk. Recognizing the difficulty in showing agnosis of bronchiolitis or pneumonia Motavizumab (Medi-524 [MedImmune]), superiority compared with an effective or an LRI as determined by the site in- an investigational monoclonal anti- agent, this study was designed to vestigator after review of medical doc- body developed by affinity maturation evaluate whether motavizumab was umentation, on the basis of the pres- of palivizumab, has significantly higher noninferior and possibly superior ence of cough, retractions, rhonchi, affinity for RSV fusion protein than to palivizumab in the reduction of wheezing, crackles, or rales associ- 7,8 ated with coryza, fever, or apnea. palivizumab. Compared with palivi- RSV hospitalization and other RSV- Safety end points included adverse zumab, motavizumab was ϳ20-fold associated end points. Preterm chil- events (AEs) and serious AEs (SAEs) more potent in microneutralization dren were randomly assigned 1:1 (by graded for severity and causality by studies and, in the cotton rat model, using an interactive voice-response the site investigators. An AE was any reduced nasal and lung RSV titers 25- system) to receive intramuscular in- 8,9 change from the patient’s baseline sta- and 100-fold, respectively. jections of 15 mg/kg motavizumab or tus. An SAE was any event that resulted In early pediatric trials of motavi- palivizumab at ϳ30-day intervals. All in a significant disability (a substantial zumab, no dose-limiting toxicities were personnel at all sites were blind to impairment of baseline function) or found, and serum pharmacokinetics study treatment. Five doses were cho- death, required or prolonged hospital- were consistent with published data sen to maximize overlap of the RSV ization, or otherwise was considered with palivizumab.10,11 In a phase 1 season at all study sites and to provide an important medical event. study, a single dose of intravenous mo- uniform drug exposure and end point tavizumab significantly reduced culti- surveillance for all patients. Motavi- Participants vatable RSV in nasal aspirates of chil- zumab and palivizumab were provided Eligible preterm children (gestational dren who were hospitalized with RSV.11 in identical vials in coded kits. Ran- age Յ 35 weeks) either were Յ24 Significant antiviral effects were not domization was stratified by site and months of age with CLD that required seen in the upper respiratory tract in a diagnosis of protocol-defined chronic medical management within 6 months similar study conducted with palivi- lung disease of prematurity (CLD). Pa- before randomization or were Յ6 zumab.12 This noninferiority study was tients were involved during only 1 sea- months of age. Exclusion criteria were designed to test the hypothesis that son and were followed up for 150 days hospitalization at randomization (un- motavizumab was at least as good as after randomization. less discharge was anticipated within palivizumab for reduction of serious 10 days); mechanical ventilation or RSV disease. Study End Points other mechanical support; life expect- METHODS The primary efficacy end point was ancy Ͻ6 months; active RSV infection; met when a child had a positive RSV known renal, hepatic, chronic seizure, Study Design test and was hospitalized (on the basis unstable neurologic, or hemodynam- This phase 3, randomized, double-blind, of the assessment of the admitting ically significant congenital heart palivizumab-controlled study was con- physician) for respiratory symptoms disorders; immunodeficiency; use of ducted between November 2004 and or had a new onset of RSV-positive palivizumab or RSV intravenous immu- May 2006 during 2 RSV seasons in the lower respiratory illness with worsen- noglobulin Ͻ3 months before random- northern hemisphere and 1 season in ing respiratory status while already in ization or anticipated use during the the southern hemisphere.5,6 The study the hospital or when a death caused by study; receipt of RSV vaccine; and par- was conducted in accordance with the RSV occurred. Secondary efficacy end ticipation in any other investigational Declaration of Helsinki and the Interna- points included the incidence of any study.

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Laboratory Assessments sessed simultaneous with the post- be assessed. Superiority required the Respiratory secretions for RSV testing dose sample. Samples confirmed to upper bound of the 95% CI of the RR to Ͻ were collected within 2 days of or as contain ADA were tested and titered be 1. Sample size calculations as- soon as possible after a respiratory for IgE ADA. IgE ADA assays were ho- sumed an RSV hospitalization rate of 5,6,15 hospitalization or nosocomial event or mogenous assays consisting of biotin- 3% in palivizumab recipients with a an outpatient MALRI. Nasal secretions ylated drug, test sample, and rutheny- 45% reduction of RSV hospitalization (aspirates or posterior nasopharyn- lated anti-human IgE. The sensitivity of by motavizumab compared with palivi- 4–6 geal swabs) were preferred; however, the IgE screening assay was 1.46 zumab. Assuming a 5% dropout rate, Յ ϳ when intubated, tracheal secretions ng/mL and drug tolerance was 15.6 2875 patients provided 99% and ␮ Ն were permitted. Respiratory speci- ng/ml in the presence of 300 g/mL 90% power to demonstrate noninfe- drug assessed using a chimeric mens were tested by reverse tran- riority or superiority, respectively, of mouse/human IgE anti-idiotypic mono- scriptase–polymerase chain reaction motavizumab to palivizumab. For the clonal antibody to motavizumab. A pos- specific for the N gene of RSV A and RSV primary analysis, a 95% CI for the RR itive antimotavizumab titer was Ն1:30. B at a central laboratory by personnel was constructed by using the exact conditional binomial method condi- who were blind to treatment assign- Study Populations ment.13 Before the analysis of study tioning on the total number of cases The intention-to-treat (ITT) population 16 samples, the real-time reverse tran- with midprobability adjustment. The included all randomly assigned pa- scriptase–polymerase chain reaction primary analysis included a 2-level cat- tients or, for the RSV outpatient MALRI assays were validated for specificity, egorical covariate to control for CLD. end point, all randomly assigned pa- sensitivity, and accuracy. These assays Secondary end points were evaluated tients in the subset. The according-to- were not subject to potential interfer- by using a Cochran-Mantel-Haenszel protocol (ATP) population included all ence by either study drug. approach that was stratified by CLD randomly assigned patients who re- and based on an assumption of supe- Serum samples for anti-drug antibod- ceived the same treatment for all 5 riority. Sample size calculations for ies (ADA) and motavizumab concentra- doses without a major protocol viola- RSV MALRI assumed a rate of 4% tion were obtained from all study sub- tion. The safety population included all among palivizumab recipients and that jects before the first and last dose with patients who received any study medi- motavizumab was superior to palivi- an additional randomly assigned sam- cation and had any safety follow-up. zumab by 50%, providing at least 90% ple taken before 1 of the other 3 doses. Patients who were randomly as- power. Subgroups were analyzed by ADA was assessed using a new assay signed to motavizumab and received demographics and region. Exploratory that was developed after unblinding. commercial palivizumab within 3 logistic regression models investi- Tiered homogeneous, double bridging months before receiving study drug gated the effects of covariates with immunoassays were developed to were excluded from the safety, im- treatment, without adjustment for screen, confirm, and titer ADAs using munogenicity, and pharmacokinetic electrochemiluminescent technology analyses. multiple comparisons. Fisher’s exact (Meso Scale Discovery, Gaithersburg, test was used for comparison of the MD). Cut point factors (screening as- Statistical Analyses number of patients who reported at say) and cut points (confirmatory as- The analyses for RSV hospitalization least 1 AE, related AEs, SAEs, and says) were established through statis- first examined noninferiority, then su- deaths. tical evaluations.14 The tolerance for periority, because the efficacy of palivi- RESULTS the presence of motavizumab in the as- zumab was previously demonstrated say was determined using a purified for this end point.5 Noninferiority of A total of 6635 children were randomly polyclonal anti-idiotypic reagent to mo- motavizumab compared with palivi- assigned to motavizumab (n ϭ 3329) tavizumab as surrogate for ADA. The zumab required the upper bound of or palivizumab (n ϭ 3306) at 347 sites sensitivity in the absence of motavi- the 2-sided 95% confidence interval in 24 countries. A mean of 19 patients zumab was 4.69 ng/mL; Յ250 ng/mL (CI) for the relative risk (RR) to be were enrolled at each site (median: 18 ADA was detectable in the presence of Ͻ1.265 (chosen to preserve at least [range: 1–101; interquartile range: 11– 100 ␮g/mL motavizumab. Samples 50% of the benefit observed for palivi- 25]); no site contributed Ͼ1.5% of the positive for ADA were confirmed in the zumab over placebo). The study proto- study population. The ATP population presence of excess drug; an individu- col specified that, if noninferiority comprised 6367 children (motavi- al’s pre-dose (day 0) sample was as- were achieved, then superiority was to zumab, n ϭ 3183; palivizumab, n ϭ

PEDIATRICS Volume 125, Number 1, January 2010 e37 Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 Patients enrolled N = 6635

Randomization

Motavizumab Palivizumab ITT Population n = 3329 (50.2%) n = 3306 (49.8%)

Patients excluded from efficacy Patients excluded from efficacy analysis, n (%) 146 (4.4) analysis, n (%) 122 (3.7) Incomplete/incorrect dosinga 135 (4.1) Incomplete/incorrect dosinga118 (3.6) Major enrollment violation 11 (0.3) Major enrollment violation 4 (0.1)

ATP population ATP population n = 3183 (95.6%) n = 3184 (96.3%)

Patients withdrawn, n (%) 59 (1.8) Patients withdrawn, n (%) 60 (1.8) Lost to follow-up 21 (0.6) Lost to follow-up 26 (0.8) Parental request 30 (0.9) Parental request 31 (0.9) taeD h 8 (0.2) Death 3b (0.1)

Completed study Completed study n = 3270 (98.2%) n = 3246 (98.2%) Received all 5 doses Received all 5 doses n = 3211 (96.5%) n = 3198 (96.7%) FIGURE 1 Patient disposition. a The most frequent reason for a patient classified as having “incomplete/incorrect dosing” was for not having received all 5 doses; however, this category also includes patients who received an incorrect dose of study drug, who received commercial palivizumab during the trial, or who received commercial palivizumab within 3 months of randomization. b One additional patient died after meeting the primary end point and thus completed the study.

3184; Fig 1). Entry violations and drug- in RSV hospitalization compared with palivizumab recipients. In logistic re- dispensing errors were infrequent palivizumab recipients (RR: 0.74 [95% gression analyses, no treatment inter- (Ͻ1%) and balanced between the 2 CI: 0.503–1.083), meeting the noninferi- actions were found by age, gender, groups. ority criteria but not the superiority weight, gestational age, race, and re- Groups were well matched, with no criteria for the primary end point (Figs gion, indicating consistent treatment statistically significant differences for 2 and 3, Table 3). RSV hospitalization effects across baseline covariates. demographics, baseline characteris- outcomes were similar in the ATP pop- RSV-Specific Outpatient MALRI tics, or RSV risk factors (Table 1). The ulation and in analyses that accounted mean Ϯ SD gestational age was 31.1 Ϯ for premature discontinuation and The incidence of RSV MALRI was 3.1 weeks, and 1445 (21.8%) children missed samples for RSV testing. assessed in all randomly assigned children at 133 sites (motavizumab, had CLD. Baseline characteristics of Subgroup analyses of RSV hospitaliza- participants at sites that tested for n ϭ 1227; palivizumab, n ϭ 1183). Mo- tion by gestational age, CLD status, RSV MALRI were also balanced (Table tavizumab was superior to palivi- and other characteristics (Fig 2B) 2). Overall, 6516 (98.2%) children com- zumab, reducing RSV-specific outpa- were consistent with the overall nonin- pleted the study (Fig 1) and 6409 (97%) tient MALRI by 50% compared with feriority outcome. The observed rate of children received all 5 doses of study palivizumab (2.0% vs 3.9%; P ϭ .005; RSV hospitalization for North America drug. Fig 4, Table 4). These results were con- Ͼ and all children who were 32 weeks’ sistent by geographic region, gesta- RSV Hospitalization gestation was similar between groups; tional age, CLD status, and other demo- Low rates of RSV hospitalizations were the rates for preterm infants who did graphic characteristics and were observed in both groups (ITT popula- not have CLD and were Յ32 weeks’ supported by a sensitivity analysis that tion: motavizumab, 1.4%; palivizumab, gestation or Ͼ32 weeks’ gestation and accounted for children with follow-up 1.9%; Fig 2, Table 3). Motavizumab re- for other regions were lower in mota- of Ͻ150 days and patients with miss- cipients had a 26% relative reduction vizumab recipients compared with ing RSV testing. This outcome was not

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TABLE 1 Demographic Characteristics of the ITT Population that are common in this high-risk pop- Characteristic Motavizumab Palivizumab ulation and were similar in incidence (N ϭ 3329) (N ϭ 3306) and severity for both treatment groups Age, mean Ϯ SD, mo 3.99 Ϯ 3.75 3.98 Ϯ 3.78 (Tables 6 and 7). Significant differences Gestational age at birth Mean Ϯ SD, wk 31.1 Ϯ 3.1 31.1 Ϯ 3.1 were found only in 2 body systems: psy- Յ32, n (%) 1958 (58.8) 1924 (58.2) chiatric AEs (including agitation and Ͼ32, n (%) 1371 (41.2) 1382 (41.8) insomnia) were more common in palivi- Boys, n (%) 1816 (54.6) 1811 (54.8) ϭ Race/ethnicity, n (%) zumab recipients (2.9% vs 1.9%; P White/non-Hispanic 2612 (78.5) 2601 (78.7) .010), and skin AEs were more common Hispanic 289 (8.7) 280 (8.5) in motavizumab recipients (7.2% vs 5.1%, Black 250 (7.5) 271 (8.2) Ͻ Asian 41 (1.2) 44 (1.3) P .001; Table 6). Other 136 (4.1) 109 (3.3) Missing 1 (Ͻ0.1) 1 (Ͻ0.1) Skin events are summarized in Fig 5. Geographic region Skin AEs were transient, and most re- North Americaa 1229 (39.0) 1264 (38.2) solved within 7 days of onset; 80% b European Union 1224 (36.8) 1237 (37.4) were nonspecific rash events that did Rest of worldc 806 (24.2) 805 (24.3) Multiple birth, n (%) 1411 (42.4) 1328 (40.2) not result in dosing discontinuation. Weight, mean Ϯ SD, kgd 4.453 Ϯ 1.964 4.438 Ϯ 2.011 No association was found between the CLD, n (%) 722 (21.7) 723 (21.9) occurrence of skin events and the Preterm, no CLD, n (%) 2607 (78.3) 2583 (78.1) Յ32 wk gestational age 1306 (39.2) 1265 (38.3) number of doses received. More mo- Ͼ32 wk gestational age 1301 (39.1) 1318 (39.9) tavizumab recipients experienced Previous RSV hospitalization, n (%)e 17 (0.6) 28 (1.0) events consistent with possible cuta- Child in child care, n (%)f 105 (3.6) 106 (3.7) Family history of atopy, n (%) neous hypersensitivity (including ur- Any 1490 (44.8) 1469 (44.4) ticaria, allergic dermatitis, eyelid Asthma 931 (28.0) 926 (28.0) edema, and drug hypersensitivity) Hay fever 667 (20.0) 685 (20.7) Eczema 566 (17.0) 526 (15.9) within 2 days of dosing (motavi- Ն1 smoker in household, n (%) 1081 (32.5) 1108 (33.5) zumab, 22 of 3329 [0.7%]; palivizumab, Children Ͻ6 y in household, n (%) 1972 (59.2) 1907 (57.7) 8 of 3306 [0.2%]; P ϭ .016). No clear None of the differences between groups were statistically significant. distinctions were seen in the fre- a United States and Canada. b Austria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Poland, Spain, Sweden, and the United quency of cutaneous reactions by gen- Kingdom. der, gestational age (Ͻ32 weeks or c Argentina, Australia, Brazil, Bulgaria, Chile, Iceland, Israel, New Zealand, Russia, and Turkey. d n ϭ 3320 (motavizumab); n ϭ 3299 (palivizumab). Ͼ32 weeks), CLD status, race, or re- e Excludes children who had not yet been discharged from their birth hospitalization at the time of randomization. A total of gion. Skin events that were of level 3 or 434 (13.0%) were missing/excluded for motavizumab; 479 (14.5%) for palivizumab. f Excludes children who had not yet been discharged from their birth hospitalization at the time of randomization. A total of 4 severity or classified as SAEs oc- 423 (12.7%) were missing/excluded for motavizumab; 469 (14.2%) for palivizumab. curred in 14 (0.4%) motavizumab and 2 (0.1%) palivizumab recipients (P ϭ confounded by RSV hospitalization; At RSV hospitalization, patients in both .004). There were no cases of anaphy- only 1 palivizumab recipient had both groups were similar in CLD status and laxis or evidence of respiratory hyper- an RSV-specific outpatient MALRI and gestational age. In a posthoc analysis sensitivity in either treatment group. an RSV hospitalization, indicating an (Table 5), a smaller proportion of pa- One motavizumab recipient was hospi- independent effect. tients who received motavizumab than talized for observation within 2 days of palivizumab required mechanical ven- dose 5 for drug hypersensitivity. Three Other End Points tilation (2 of 3329 [0.1%] vs 11 of 3306 other AEs (angioneurotic edema [4 The rate of all-cause outpatient MALRI [0.3%], respectively; P ϭ .012) for days after dose 2], urticaria [7 days did not differ significantly between shorter periods (days per 100 pa- after dose 2], and rash [12 days after groups (motavizumab, 19.5%; palivi- tients: motavizumab, 0.5; palivizumab, dose 5]) were judged to be unrelated zumab, 21.1%; P ϭ .110). Significant 3.8; P ϭ .012). to motavizumab and occurred in hos- differences were not found in the inci- pitalized children with staphylococcal dence of medically attended OM or the Safety infection, viral illness with fever and frequency of prescribed antibiotics for Overall AEs and SAEs were consistent diarrhea, and suspected ampicillin LRI or OM. with the underlying medical conditions rash, respectively.

PEDIATRICS Volume 125, Number 1, January 2010 e39 Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 TABLE 2 Demographic Characteristics of the ITT RSV-Specific MALRI Population ered related to study medication or Characteristic Motavizumab (N ϭ 1227) Palivizumab (N ϭ 1183) RSV. The rates of sudden infant death Mean (SD) age, mo 4.10 (4.10) 4.20 (4.31) syndrome/sudden unexplained death Gestational age at birth were also similar (motavizumab, 4 of Mean (SD), wk 31.4 (3.0) 31.3 (3.0) Յ32 wk, n (%) 699 (57.0) 671 (56.7) 3315 [0.1%]; palivizumab, 2 of 3298 Ͼ32 wk, n (%) 528 (43.0) 512 (43.3) [0.1%]). Boys, n (%) 655 (53.4) 636 (53.8) Race/ethnicity, n (%) Antimotavizumab Antibodies and White/non-Hispanic 940 (76.6) 897 (75.8) Hispanic 80 (6.5) 72 (6.1) Motavizumab Serum Black 117 (9.5) 135 (11.4) Concentrations Asian 25 (2.0) 25 (2.1) Other 65 (5.3) 54 (4.6) Fifty-eight (1.8%) motavizumab recipi- Geographic region ents had detectable ADA with titers North Americaa 588 (47.9) 555 (46.9) from 1:30 to 1:122 880. No specific IgE European Unionb 181 (14.8) 179 (15.1) Rest of worldc 458 (37.3) 449 (38.0) was detected. More subjects with ADA Multiple birth, n (%) 535 (43.6) 472 (39.9) compared with those without ADA had Weight, mean (SD), kgd 4.533 (2.083) 4.568 (2.195) reports of skin AEs (17 of 58 [29.3%] vs CLD of prematurity, n (%) 259 (21.1) 263 (22.2) Ͻ Preterm, no CLD, n (%) 968 (78.9) 920 (77.8) 217 of 3173 [6.8%]; P .001) or Level 3 Յ32 wk gestational age 491 (40.0) 446 (37.7) or serious skin AEs (6 of 58 [10.3%] vs 8 Ͼ32 wk gestational age 477 (38.9) 474 (40.1) of 3173 [0.3%]; P Ͻ .001). Among the 17 Previous RSV hospitalization, n (%)e 6 (0.6) 15 (1.4) Child in day care, n (%)f 43 (4.0) 48 (4.6) subjects with ADA with skin events, 5 Family history of atopy, n (%) had potential alternative etiologies Any 519 (42.3) 499 (42.2) and 14 were given subsequent doses Asthma 357 (29.1) 343 (29.0) (including 3 subjects with more severe Hay fever 225 (18.3) 218 (18.4) Eczema 189 (15.4) 181 (15.3) or serious events): 9 had no recur- Ն1 smoker in household, n (%) 400 (32.6) 392 (33.2) rences (including 1 subject with an ini- Children Ͻ6 y in household, n (%) 747 (60.9) 691 (58.4) tial level 3 urticaria), 3 had level 1 or 2 None of the differences between groups were statistically significant. a United States and Canada. recurrences (including 2 subjects with b Austria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Poland, Spain, Sweden, and the United King- initial serious or level 3 events), and 2 dom. had dissimilar skin events after subse- c Argentina, Australia, Brazil, Bulgaria, Chile, Iceland, Israel, New Zealand, Russia, and Turkey. d n ϭ 1224 (motavizumab); n ϭ 1181 (palivizumab). quent doses (1 patient with a sebor- e Excludes children who had not yet been discharged from their birth hospitalization at the time of randomization. One rhea rash after dose 2 reported ery- hundred forty-eight (11.5%) were missing/excluded for motavizumab; 136 (14.5%) for palivizumab. f Excludes children who had not yet been discharged from their birth hospitalization at the time of randomization. One thema multiforme minor concurrent hundred forty (11.4%) were missing/excluded for motavizumab; 132 (11.1%) for palivizumab. with DPT vaccination after dose 4 and 1 patient with a rash thought to be due to amoxicillin [level 1 urticaria 7 days af- Overall, drug discontinuations as a re- recurrences of the same or lower se- ter dose 2] experienced level 1 hives at sult of any AE were not significantly dif- verity after subsequent doses. the motavizumab injection site within 1 ferent between groups: 13 (0.4%) mo- The incidence of injection-site reactions day of dose 3). tavizumab and 10 (0.3%) palivizumab was similar between groups (motavi- Mean trough serum concentrations of recipients. Discontinuation as a result zumab, 106 of 3315 [3.2%]; palivizumab, of skin AEs was infrequent (motavi- motavizumab were 64.59, 80.24, and 88 of 3298 [2.7%]; P ϭ .216). The inci- ␮ zumab, 9 [0.3%] of 3315; palivizumab, 0 88.52 g/mL at 30 days after doses 2, 3, dence of alanine and/or aspartate ami- of 3298; P ϭ .004). Motavizumab was and 4, respectively. Children with ADA notransferase increases reported as not discontinued because of any initial had lower observed mean trough serum AEs was also similar (motavizumab, 59 of skin AE with onset Ͼ2 days after a motavizumab concentrations, although 3315 [1.8%]; palivizumab, 63 of 3298 dose. Approximately half of motavi- individual trough motavizumab concen- ϭ zumab recipients (9 of 22; 0.7% of all [1.9%]; P .715; Table 8). trations were within the ranges of motavizumab recipients) with events Mortality rates were not significantly trough serum concentrations reported consistent with possible hypersensi- different between the 2 groups (mo- in children without detectable ADA. tivity within 2 days after a dose had tavizumab, 8 [0.2%]; palivizumab, 4 While few patients had ADA, an in- drug discontinued; 2 of 10 children had [0.1%]; P ϭ .387); none was consid- crease was observed in the incidence

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A Motavizumab Palivizumab

2.0 Patients, n 3329 3306 Patients with events, n (%) 46 (1.4) 62 (1.9) Patients censored, n (%) 3283 (98.6) 3244 (98.1) Rates of RSV hospitalization at day 150, % 1.4 1.9

1.5

1.0

0.5 Incidence of RSV hospitalization, %

0.0 0 30 60 90 120 150 Study day 10.0 4.0 B Motavizumab Palivizumab

3.0

8.0 2.0

1.0 6.0 Patients with RSV hospitalization, %

0.0 ≤32 wk >32 wk ≤32 wk >32 wk North European Rest of No CLD No CLD America Union world 4.0

2.0 3.9 3.0 Patients with RSV hospitalization, % 1.9 1.9 1.4 1.4 1.3 0.9 0.0 ITT ATP CLD No CLD FIGURE 2 A, Kaplan-Meier curves for time to RSV hospitalization. B, Incidence of RSV hospitalization. The subgroup analyses (inset) are consistent with the noninfe- riority outcome of RSV hospitalization in motavizumab recipients compared with palivizumab recipients. North America includes United States and Canada; European Union, Austria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Poland, Spain, Sweden, and the United Kingdom; Rest of world, Argentina, Australia, Brazil, Bulgaria, Chile, Iceland, Israel, New Zealand, Russia, and Turkey.

PEDIATRICS Volume 125, Number 1, January 2010 e41 Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 TABLE 3 Incidence of RSV Hospitalization Population Motavizumab Palivizumab RRb 95% CIb Na n % Na n % Overall ITT population 3329 46 1.4 3306 62 1.9 0.740 (0.503–1.083) ATP population 3183 43 1.4 3184 59 1.9 0.730 (0.490–1.081) By geographic region (ITT population) North Americac 1299 22 1.7 1264 21 1.7 1.017 (0.555–1.866) European Uniond 1224 13 1.1 1237 24 1.9 0.553 (0.273–1.078) Rest of worlde 806 11 1.4 805 17 2.1 0.649 (0.294–1.387) By baseline characteristics (ITT population) Gender Boys 1816 30 1.7 1811 40 2.2 0.748 (0.462–1.200) Girls 1513 16 1.1 1495 22 1.5 0.737 (0.380–1.406) Gestational age Յ32 wk 1958 31 1.6 1924 47 2.4 0.656 (0.413–1.031) Ͼ32 wk 1371 15 1.1 1382 15 1.1 1.002 (0.483–2.077) Race White/non-Hispanic 2612 29 1.1 2601 41 1.6 0.713 (0.439–1.146) Other 716 17 2.4 704 21 3.0 0.781 (0.406–1.487) Weight at entry Յ5 kg 2187 33 1.5 2156 41 1.9 0.791 (0.497–1.251) Ͼ5 kg 1133 13 1.1 1143 21 1.8 0.630 (0.307–1.256) By CLD status (ITT population) CLD of prematurity 722 22 3.0 723 28 3.9 0.789 (0.447–1.382) Premature, no CLD 2607 24 0.9 2583 34 1.3 0.700 (0.410–1.180) Յ32 wk 1306 13 1.0 1265 19 1.5 0.664 (0.320–1.347) Ͼ32 wk 1301 11 0.8 1318 15 1.1 0.742 (0.331–1.625) Sensitivity analysis RSV hospitalization ratef adjusted for 3329 47 1.4 3306 63 1.9 0.740 (0.503–1.083) patients with follow-up of Ͻ150 d RSV hospitalization rateg adjusted for 3329 46.3 1.4 3306 62.3 1.9 0.740 (0.503–1.083) patients with missed RSV sample for hospitalizationh a N indicates the total number of patients in each subpopulation for each treatment group; n indicates the number affected by RSV hospitalization. b 95% CI and RR were adjusted for stratification according to the presence or absence of CLD of prematurity. c United States and Canada. d Austria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Poland, Spain, Sweden, and the United Kingdom. e Argentina, Australia, Brazil, Bulgaria, Chile, Iceland, Israel, New Zealand, Russia, and Turkey. f Motavizumab RSV hospitalization rate was equivalent to palivizumab RSV hospitalization rate (ie, 1.9%). g Adjusted for the number of children who did not reach a primary end point and had no end-point assessment (at 150 days from randomization) and would have been hospitalized for RSV if the proportion of children hospitalized was equal to that of the other treatment group. h A patient was counted as having a missed sample if the patient did not have a sample within the specified window and the patient did not otherwise meet the end point. of RSV hospitalization and RSV MALRI in motavizumab has greater neutralization able population size; therefore, an patients with motavizumab ADA (4 of activity against RSV in preclinical stud- active-controlled trial to assess nonin- 58 [6.9%] and 2 of 23 [9.7%], respec- ies, it was unclear whether this would feriority to the standard of care (ie, tively) compared with patients without translate into improved clinical effica- motavizumab is not worse than palivi- ADA (40 of 3173 [1.3%] and 22 of 1169 cy.7–9 zumab), as well as superiority, was [1.9%], respectively). Some of these This pivotal study assessed the effi- used. RSV events occurred before ADA detec- cacy and safety of motavizumab in Treatment with motavizumab met tion or had appropriate serum drug high-risk infants. A placebo-controlled the noninferiority criteria for RSV levels before or after the event, making design was not possible because the hospitalization, with a 26% relative it difficult to determine causality. efficacy of palivizumab has been well reduction in RSV hospitalization. The DISCUSSION established.5,6 A low rate of hospitaliza- rate of RSV hospitalization among Palivizumab has been used since 1998 in tion among palivizumab recipients palivizumab recipients was low (1.9%), the United States and 61 other countries was anticipated to make the hypothe- which represented a challenge for for passive prevention of serious RSV in sized superior efficacy of motavizumab the superiority test. The study, how- children at high risk.5,15,17–19 Although difficult to demonstrate with a reason- ever, included an RSV-specific second-

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Noninferiority transient and did not result in discontin- Upper bound of 95% CI < 1.265 uation of study drug. Although nearly half of the patients who experienced events that were consistent with cuta- Superiority neous hypersensitivity and were tem- Upper bound of 95% CI < 1 porally associated with receipt of mota- vizumab discontinued treatment, these This study events were not observed in 80% of Upper bound of 95% CI = 1.083 the children who received subsequent 1 1.265 ∞ doses, suggesting that they were not consistent with immediate hypersensi- Equal efficacy tivity reactions. Skin reactions (and se- FIGURE 3 vere reactions) were also significantly RR of motavizumab versus palivizumab for RSV hospitalization. Criteria used to define noninferiority and superiority are shown in relation to the results of RSV hospitalization, the primary end point. The increased in motavizumab recipients 26% relative reduction in RSV hospitalization in recipients who received motavizumab compared with with ADA compared with those without those who received palivizumab (RR: 0.74 [95% CI: 0.503–1.083]) met the noninferiority criteria but not ADA. However, because few patients de- the superiority criteria for the primary end point. veloped ADA (1.8%), the overall effect was small. The inability to detect IgE and the lack of recurrences or increase in ary end point (RSV outpatient MALRI) with the overall noninferiority out- the severity of skin reactions after sub- that was expected to occur more fre- come), the RR for RSV outpatient MALRI sequent doses in the majority of pati- quently than RSV hospitalization.8,11 If in these subgroups was substantively ents with ADA with skin reactions (9 of motavizumab had a clinical advantage Ͻ1 (0.577 and 0.424, respectively); this 14 patients) is reassuring and similar to over palivizumab, then differences in result was consistent with the superi- the overall experience for all patients outpatient RSV MALRI should be appar- ority outcome seen overall. Logistic re- without ADA who had skin reactions in ent. Here, motavizumab was shown to gression analyses of RSV hospitaliza- this study. be superior to palivizumab for RSV tions and outpatient MALRI indicated MALRI, with a 50% relative reduction in consistent treatment effects across Motavizumab recipients with ADA ac- motavizumab recipients (P ϭ .005). No baseline characteristics. counted for a minority (Ͻ10%) of sub- jects with RSV events in this study statistical differences were observed Because palivizumab has an excellent and, overall, improved efficacy was in non–RSV-specific secondary end record of safety in clinical trials and in observed among motavizumab recipi- points. postmarketing experience,4,5,20 the safety ents compared with palivizumab recip- Relevant subgroups were assessed to profile of motavizumab is an important ients. Even among patients with ADA, a evaluate the consistency of the efficacy consideration in assessing the risk/ causal link between ADA and those results. Because the rates of RSV hos- benefit ratio of the drug. Overall, the events was not certain. pitalization and RSV outpatient MALRI rates of AEs and SAEs in motavizumab were lower than expected in both recipients were similar to those in palivi- The serum trough concentrations of mo- treatment groups, the differences be- zumab recipients. For both treatment tavizumab that were seen in this study tween treatments must be interpreted groups, the overall death rate was well are consistent with previous observa- with caution. The rates for RSV hospi- below the postneonatal rate of 0.9% re- tions.10 The similarities in the serum talization and RSV outpatient MALRI cently reported in the United States for trough concentrations of motavizumab were lower in children with CLD and in preterm infants, as was the 0.1% rate of compared with those reported for palivi- preterm infants who did not have sudden infant death syndrome/sudden zumab suggest that the realization of the protocol-defined CLD (Յ32 weeks’ or unexplained death.21,22 Events that coded efficacy benefits of motavizumab require Ͼ32 weeks’ gestation) and received to the skin and subcutaneous category maintaining the dose and frequency cur- motavizumab than in comparable chil- were significantly higher in motavizu- rently recommended for palivizumab. dren who received palivizumab. Al- mab recipients. These included nonspe- though the RR for RSV hospitalization cific reports of rash as well as events CONCLUSIONS in children in North America and in that were consistent with cutaneous hy- In this large, multinational, well- children of Ͼ32 weeks’ gestation (re- persensitivity (eg, urticaria, edema) and controlled trial, motavizumab was gardless of CLD) was ϳ1 (consistent were generally mild or moderate and shown to be noninferior to palivizumab

PEDIATRICS Volume 125, Number 1, January 2010 e43 Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 A Motavizumab Palivizumab

4.0 Patients, n 1227 1183 Patients with events, n (%) 24 (2.0) 46 (3.9) Patients censored, n (%) 1203 (98.0) 1137 (96.1) 3.5 Rates of RSV MALRI % ,051 yad ta yad ,051 % 0.2 9.3

3.0

2.5

2.0

1.5

1.0 Incidence of RSV MALRI, %

0.5

0.0 0 30 60 90 120 150 Study day

8.0 B Motavizumab 10.0 7.0 Palivizumab

6.0

5.0

8.0 4.0 3.0

2.0 Probability of RSV MALRI, % RSV MALRI, of Probability

1.0

6.0 0.0 ≤32 wk >32 wk ≤32 wk >32 wk North European Rest of No CLD No CLD America Union world

4.0 9.3 4.0 9.4 6.3

Patients with RSV MALRI, % 2.0 0.2 2.0 3.2 9.1

0.0 ITT ATP CLD No CLD FIGURE 4 A, Kaplan-Meier curves for time to RSV-specific outpatient MALRI. B, Incidence of RSV-specific outpatient MALRI. The subgroup analyses (inset) are consistent with the superiority outcome of RSV outpatient MALRI in those who received motavizumab compared with those who received palivizumab. North America includes United States and Canada; European Union, Austria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Poland, Spain, Sweden, and the United Kingdom; Rest of world, Argentina, Australia, Brazil, Bulgaria, Chile, Iceland, Israel, New Zealand, Russia, and Turkey.

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TABLE 4 Incidence of RSV-Specific Outpatient MALRI zonal General de Agudos “Dr Diego Population Motavizumab Palivizumab RRb Pc Paroissien,” Isidro Casanova; N. Vain, Na n % Na n % Sanatorio de la Trinidad, Capital Fed- Overall eral. Australia: A. Carmichael, Royal ITT population 1227 24 2.0 1183 46 3.9 0.503 .005 Hobart Hospital, Hobart; M. Cole, West- ATP population 1160 23 2.0 1123 45 4.0 0.497 .005 mead Hospital, Westmead; P. Gray, Ma- By geographic region (ITT population) North Americad 588 11 1.9 555 18 3.2 0.575 .142 ter Mothers’ Hospital, South Brisbane; European Unione 181 4 2.2 179 10 5.6 0.405 .112 J. McCreanor, Peninsula Clinical Re- Rest of worldf 458 9 2.0 449 18 4.0 0.489 .069 search Centre, Kippa-Ring; M. Nissen, By baseline characteristics (ITT population) Gender Royal Children’s Hospital (Brisbane), Boys 655 13 2.0 636 28 4.4 0.452 .013 Herston; G. Reynolds, Canberra Hospi- Girls 572 11 1.9 547 18 3.3 0.590 .167 tal, Garran; D. Roberton, Women’s and Gestational age Յ32 wk 699 17 2.4 671 30 4.5 0.545 .041 Children’s Hospital, North Adelaide; C. Ͼ32 wk 528 7 1.3 512 16 3.1 0.422 .048 Robertson, Royal Children’s Hospital Race (Melbourne), Parkville; C. Wake, John White/non-Hispanic 940 19 2.0 897 36 4.0 0.505 .013 Hunter Children’s Hospital, New Lamb- Other 287 5 1.7 286 10 3.5 0.493 .189 Weight at entry ton; A. Wilson, Princess Margaret Chil- Յ5 kg 782 12 1.5 755 21 2.8 0.545 .088 dren’s Hospital, Subiaco. Austria: A. Ͼ5 kg 442 12 2.7 426 25 5.9 0.452 .018 Berger, Allgemenes Krankenhaus Uni- By CLD status (ITT population) CLD of prematurity 259 6 2.3 263 13 4.9 0.469 .109 versita¨tskliniken Wien, Wien; B. Resch, Premature, no CLD 968 18 1.9 920 33 3.6 0.516 .021 Universita¨tskilinken fu¨r Kinder und Ju- Յ32 wk 491 11 2.2 446 19 4.3 0.526 .080 genheilkinde Graz, Graz; H. Salzer, Ͼ32 wk 477 7 1.5 474 14 3.0 0.497 .119 Sensitivity analysis Landeskrankenhaus Tulln, Kinderabte- MALRI rate adjusted for patients with 1227 24.8 2.0 1183 47.1 4.0 0.503 .005 ilung, Tulln; W. Sterniste, SMZ-Ost follow-up of Ͻ150 dg Donauspital Wien, Wien. Brazil: O. Araujo, MALRI rateh adjusted for patients with 1227 26.3 2.1 1183 47.2 4.0 0.503 .009 Hospital e Maternidade Santa Marina, E. missed RSV samplei Berezin, Santa Casa de Misericordia de a N indicates the total number of patients in each subpopulation for each treatment group; n indicates the number affected by RSV-specific outpatient MALRI. Sa˜o Paulo, Sa˜o Paulo; O. Cintra, Hospi- b Prespecified analysis was Cochran-Mantel-Haenszel; however, RR (adjusted for the stratification factor of presence or tal das Clinicas da Faculdade de Medi- absence of CLD of prematurity) is presented for comparison with the primary end point. c The Cochran-Mantel-Haenszel test was stratified according to the presence or absence of CLD of prematurity. cina de Ribeirao Preto da Universidade d United States and Canada. de Sa˜o Paulo, Ribeirao Preto; C. da e Austria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Poland, Spain, Sweden, and the United King- dom. Cunha, Mernidade Nossa Senhora de f Argentina, Australia, Brazil, Bulgaria, Chile, Iceland, Israel, New Zealand, Russia, and Turkey. Fatima, Curitiba; N. Filho, Hospital de g Motavizumab RSV-specific outpatient MALRI rate was equivalent to the palivizumab rate. h Adjusted for the number of children who did not reach a primary end point and had no end-point assessment (at 150 days Clinicas da UFPR, Curitiba; N. Hein, from randomization) and would have been characterized as having RSV-specific MALRI if the proportion of children with Hospital Universitario da Univer- MALRI was equal to that of the other treatment group. sidade Sa˜o Paulo, Sa˜o Paulo; M. Lima, i A patient was counted as having a missed sample if the patient did not have a sample within the specified window and the patient did not otherwise meet the end point. Hospital e Maternidade Celso Pierro- PUCCAMP, Campinas; Sa˜o Paulo; R. Stein, Hospital Sa˜o Lucas da PUC-RS, for prevention of RSV hospitalization significant reduction in outpatient Porto Alegre. Bulgaria: S. Dachev, Re- (primary end point) and was superior MALRI compared with palivizumab. As gional Hospital of Pulmonary Diseases, to palivizumab for reduction of RSV- such, motavizumab may offer an im- Rousse; I. Galabov, MHAT “St Marina,” specific outpatient MALRI (a secondary proved alternative for preventing seri- Varna; A. Georgieva, MHAT–Plovdiv, Plo- end point). Overall, the safety profile ous RSV disease in high-risk infants vdiv; E. Ghenev, UMHAT “St George” (rates and severity of AEs) of motavi- and children. Clinic of Pediatrics, Plovdiv; E. Hristova, zumab seemed similar to palivizumab. Specialized Hospital for Active Treat- However, cutaneous reactions were The Motavizumab Study Group ment of Pediatric Diseases, Sofia; V. Il- higher in motavizumab recipients. Al- Argentina: F. Ferrero, Hospital General ieva, Specialized Hospital for Active though not better than palivizumab in de Ninos “Pedro de Elizalde,” Buenos Treatment of Cardiovascular Diseases, reducing RSV-associated hospitaliza- Aires; M. Gran˜a, Hospital Materno Neo- Sofia; M. Krasteva, UMHAT “St George” tions, motavizumab did demonstrate a natal, Cordoba; E. Szyld, Hospital Inter- Neonatology Clinic, Plovdiv; V. Nedkova,

PEDIATRICS Volume 125, Number 1, January 2010 e45 Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 TABLE 5 Severity of RSV Hospitalization Clinico San Borja Arriaran, Santiago; Parameter Motavizumab Palivizumab Pa G. Vivanco, Hospital Dr Felix Bulnes (N ϭ 3329) (N ϭ 3306) Cerda, Santiago. Czech Republic: J. Bi- Duration of RSV hospitalization, db olek, Nemocnice s poliklinikou v Moste, Total d per 100 patients 9.1 18.1 .112 During RSV hospitalization Most; M. Cihar, Fakultni Nemocnice Mo- Patients with Ն1 instance of supplemental 26 (0.8) 40 (1.2) .080 tol, Praha; J. Dort, Fakultni Nemocnice oxygen, n (%) Plzen, Plzen; M. Hanzl, Nemocnice Duration of supplemental oxygen, total d 4.1 9.5 .077 Ceske Budejovice, Ceske Budejovice; H. per 100 patients Patients admitted to the ICU,c n (%) 10 (0.3) 19 (0.6) .092 Honomichlova, Fakultni Nemocnice Pl- Duration of ICU stay, total d per 100 patients 2.0 6.3 .091 zen, Plzen; J. Janota, Fakultni Thomay- Patients on mechanical ventilation, n (%) 2 (0.1) 11 (0.3) .012 erova Nemocnice s poliklinikou, Praha; Duration of mechanical ventilation, total d 0.5 3.8 .012 per 100 patients L. Kantor, Fakultni Nemocnice Olo- a The Cochran-Mantel-Haenszel test was stratified according to the presence or absence of CLD. mouc, Olomouc Neonatologicke; Z. Kok- b Duration within the time period from study day 0 through study completion or discontinuation; if a patient had multiple stein, Fakultni Nemocnice Hradec events, the durations for each event were summed for this analysis. c ICU admissions for a respiratory reason. Kralove Detska klinika, Hradec Kralove; J. Macko, Batova krajska Nemocnice Zlin, Zlin; H. Podesvova, FNsP Ostrava,

TABLE 6 Overview of AEs Ostrava; R. Plavka, Vseobecna Fakultni Nemocnice 1.LF UK, Praha; Z. Stranak, Parameter Motavizumab Palivizumab (N ϭ 3315), (N ϭ 3298), Ustav pro peci o matku a dite, Praha; J. n (%) n (%) Zach, Fakultni Thomayerova Nemoc- AEsa 12 467 12 640 nice s poliklinikou, Praha. Denmark: P. Patients reporting Albertsen, Hillerød Sygehus, Hillerød; Ն1 AE 2839 (85.6) 2837 (86.0) Psychiatric disordersb 64 (1.9) 96 (2.9)c M. Dirdal, Paediatrisk Afdeling Herning Skin and subcutaneous tissue disorders 687 (20.7)d 609 (18.5) Centralsygehus, Herning; K. Nørgaard- Ն1 level 3 AE as the highest severity 271 (8.2) 292 (8.9) Hansen, Sygehus Viborg, Viborg; N. Ն1 level 4 AE 54 (1.6) 61 (1.8) Ն1 SAE 485 (14.6) 506 (15.3) Valerius, Hvidovre Hospital, Hvidovre. Ն1 AE resulting in discontinuation of study drug 13 (0.4) 10 (0.3) France: A. de la Pintiere, CHU Rennes a The differences between groups were not statistically significant except as indicated. Hoˆpital Sud, Rennes; B. Escande, CH b Terms mapping to “psychiatric disorders” include restlessness, sleepiness, unsettled, and irritability. Hautepierre Service de Pe´diatrie II, c P ϭ .010. d P Ͻ .001. Strasbourg; C. Gire, CHU Nord, Mar- seille; I. Glorieux, CHU Toulouse–Hoˆpi- tal des Enfants, Toulouse; C. Guiller- MHAT–“Pleven” Clinic of Pediatrics, University Health Centre, Montreal; I. met, CHU de Besanc¸on–Hoˆpital Saint- Pleven; R. Rosmanova, MHAT-“Pleven” Mitchell, Alberta Children’s Hospital, Jacques, Besanc¸on; N. Kacet, Hoˆpital Neonatology Clinic; B. Slancheva, Spe- Calgary; B. Paes, McMaster Children’s Jeanne de Flandre, Lille; S. Le Bouedec, cialized Hospital for Active Treatment Hospital, Hamilton; J. Robinson, Univer- CHU Angers, Angers; A. Leke, CHU d’ of Obstetrics and Gynaecology–“Mai- sity of Alberta Stollery Children’s Hos- Amiens, Amiens; R. Lenclen, CHI chin Dom,” Sofia. Canada: G. Bacheyie, pital, Edmonton; A. Singh, Children and Poissy/St Germain en Laye, Poissy; J. Windsor Regional Hospital, Windsor; Women’s Hospital of British Columbia, Picaud, CHU Montpellier, Montpellier; K. Bigsby, Queen Elizabeth Hospital, Vancouver, and Victoria General Hospi- D. Pinquier, CHU Rouen, Rouen; J.-C. Charlottetown; M. Blayney, Children’s tal, Victoria; B. Tan, Royal University Roze, CHU de Nantes Hoˆpital Me`re- Hospital of Eastern Ontario, Ottawa, Hospital, Saskatoon. Chile: K. Abarca, Enfant, Nantes; E. Saliba, Centre Pe´di- F. Boucher, Centre Hospitalier de Hospital Clínico Pontificia Universidad atrique Gatien de Clocheville, Tours; J. L’Universite Laval, Quebec City; A. Chiu, Cato´lica de Chile, Santiago, Santiago; P. Sarlangue, CHU Bordeaux Hoˆpital des Manitoba Institute of Child Health Uni- Fernandez, Hospital Clínico Univer- enfants, Bordeaux; D. Semama, CHU Di- versity of Manitoba, Winnipeg; C. Hui, sidad de Chile, Santiago; C. Lindemann, jon, Dijon; M. Walther, CH Chambery, Children’s Hospital of Eastern Ontario, Hospital San Jose, Independencia; P. Chambery. Germany: R. Berner, Zen- Ottawa; J. Langley, Dalhousie Univer- Mena, Hospital Dr Sotero del Rio, trum Klinische Studien Universita¨- sity, Halifax; M. Lebel, Sainte Justine Santiago; J. Novoa, Hospital Padre tsklinikum Freiburg, Freiburg; K. Hospital, Montreal; J. McDonald, McGill Hurtado, Santiago; V. Pen˜a, Hospital Harms, Universita¨tsklinikum Go¨ttin-

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TABLE 7 Incidence of AEs Reported in Ն1% of Patients gen, Go¨ttingen; G. Horneff, Wittenberg AE Motavizumab Palivizumab Zentrum fu¨r Kinderheilkunde Universi- (N ϭ 3315), (N ϭ 3298), ta¨tsklinik und Poliklinik fu¨r Kinder und n (%) n (%) Jugendmedizin, Halle; E. Kattner, Stif- Upper respiratory tract infection 964 (29.1) 993 (30.1) Pyrexia 544 (16.4) 559 (16.9) tung Hannoversche Kinderheilan- Rhinitis 441 (13.3) 446 (13.5) stalt, Hannover; J. Liese, Kinderklinik OM 435 (13.1) 421 (12.8) und Kinderpoliklinik Kinderspital, Teething 299 (9.0) 282 (8.6) Mu¨nchen; U. Lieser, Wittenberg Zen- Respiratory disorder 296 (8.9) 276 (8.4) Bronchiolitisa 275 (8.3) 327 (9.9) trum fu¨r Kinderheilkunde Universita¨- Nasal congestion 269 (8.1) 265 (8.0) tsklinik und Poliklinik fu¨r Kinder und Diarrhea 256 (7.7) 279 (8.5) Jugendmedizin, Halle, Halle; O. Mo¨ller, Conjunctivitis 246 (7.4) 251 (7.6) Nasopharyngitis 241 (7.3) 264 (8.0) Universita¨tsklinikum Go¨ttingen, Go¨ttin- Constipation 236 (7.1) 227 (6.9) gen; H. Pirmin, Universita¨tskinderk- Gastroenteritis 223 (6.7) 234 (7.1) linik Zentrum fu¨r klinische Studien, Cough 221 (6.7) 216 (6.5) Gastroesophageal reflux disease 205 (6.2) 209 (6.3) Mainz J. Poeschl, Universita¨tsklinikum Bronchitis 202 (6.1) 227 (6.9) Heidelberg, Heidelberg; W. Rascher, Irritability 193 (5.8) 164 (5.0) Klinik fu¨r Kinder und Jugendliche, Er- Diaper dermatitis 174 (5.2) 192 (5.8) langen; A. Rech, Klinikum Duisburg, Vomiting 164 (4.9) 170 (5.2) LRI 136 (4.1) 139 (4.2) Wedau Kliniken, Klinik f. Kinderhei- Eczemaa, b 132 (4.0) 96 (2.9) lkunde und Jugendmedizin, Duis- Rash 131 (4.0) 103 (3.1) burg; C. Rieger, Ruhr-Uni St Josef Flatulence 126 (3.8) 121 (3.7) Oral candidiasis 102 (3.1) 106 (3.2) Hospital, Klinik f. Kinder- und Jugend Immunization reaction 102 (3.1) 99 (3.0) Medizin, Bochum; R. Roos, Sta¨dtisches Rhinorrhea 99 (3.0) 92 (2.8) Krankenhaus Mu¨nchen-Harlaching Abt. Viral infection 90 (2.7) 105 (3.2) Inguinal hernia 80 (2.4) 76 (2.3) fu¨r Kinderheilkunde u. Jugendmedizin, Umbilical hernia 78 (2.4) 64 (1.9) Mu¨nchen; H.-J. Schmitt, Universita¨ts- Anemia 71 (2.1) 76 (2.3) kinderklinik Zentrum fu¨r klinische Pharyngitis 70 (2.1) 92 (2.8) Studien, Mainz; H. Schroten, Uni- Acute OM 65 (2.0) 54 (1.6) Viral upper respiratory tract infection 61 (1.8) 62 (1.9) Kinderklinik, Du¨sseldorf; J. Seiden- Seborrheic dermatitis 57 (1.7) 54 (1.6) berg, Klinikum Oldenburg Zentrum fu¨r Abdominal pain 56 (1.7) 73 (2.2) Kinder-u. Jugendmedizin Elisabeth- Wheezing 55 (1.7) 72 (2.2) Candidiasis 53 (1.6) 72 (2.2) Kinderkrankenhaus, Oldenburg; V.-H. Ta, Bronchitis acute 50 (1.5) 60 (1.8) Evangelischisches Krankenhaus Klinik Bronchial hyperactivity 49 (1.5) 60 (1.8) fu¨r Kinder u. Jugendliche, Oberhausen; Injection site pain 45 (1.4) 49 (1.5) Dermatitis atopic 44 (1.3) 53 (1.6) A. Trotter, Klinikum Duisburg, Wedau Pneumoniaa 42 (1.3) 65 (2.0) Kliniken, Klinik f. Kinderheilkunde Gastroenteritis viral 42 (1.3) 38 (1.2) und Jugendmedizin, Duisburg; T. Uhlig, Injection site erythema 41 (1.2) 28 (0.8) Klinikum Rosenheim Klinik fu¨r Asthma 39 (1.2) 40 (1.2) Agitation 35 (1.1) 46 (1.4) Kinderheilkunde und Jugendmedizin, Dacryostenosis acquired 35 (1.1) 34 (1.0) Rosenheim; C. Vogtmann, Klinik und Blood urea increased 35 (1.1) 25 (0.8) Poliklinik und Jugendliche der Univer- Dry skin 35 (1.1) 25 (0.8) Plagiocephaly 34 (1.0) 29 (0.9) sita¨t Leipzig, Leipzig. Greece: S. Arvani- Urinary tract infection 33 (1.0) 36 (1.1) takis, General Hospital “Papageorgiou,” Hemangioma 31 (0.9) 41 (1.2) Thessaloniki; A. Constantopoulos, 2nd Bronchopulmonary dysplasia 31 (0.9) 32 (1.0) Croup infectious 28 (0.8) 33 (1.0) Clinic for Pediatrics “P. & A. Kyriakou” Gastroenteritis rotavirusa 18 (0.5) 33 (1.0) Children’s Hospital, Athens; M. Empori- a P Ͻ .05; other comparisons were not statistically significant. adou, B Pediatric Clinic of Aristotele b In addition to eczema, other preferred terms considered to be synonyms for eczema were combined for analysis: University of Thessaloniki General “AX- dermatitis atopic, dermatitis contact, diaper dermatitis, eczema infantile, prurigo, seborrhea, and seborrheic dermatitis. Overall, the incidence of these AEs was comparable between treatment groups (motavizumab: 403 ͓12.2%͔; palivizumab: 384 EPA” Hospital, Thessaloniki; I. Tsana- ͓11.6%)͔); the difference was not statistically significant. kas, Hippokration Hospital, University of Thessaloniki, Thessaloniki; M. Xan-

PEDIATRICS Volume 125, Number 1, January 2010 e47 Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 10 Medical Center, Kfar-Saba; M. Efrat, Car- Motavizumab mel Medical Center, Haifa; D. Engelhard, 9 Palivizumab Hadassah Ein-Kerem Medical Center, 8 Jerusalem; I. Kassis, Rambam Medical 7.2 Center, Haifa; F. Mimouni, Sourasky Med- 7 6.9 ical Center (Ichilov), Tel-Aviv; D. Miron, 5.9 6 HaEmek Medical Center, Afula and Poria 5.1 5.3 5.1 Medical Center, Tiberia; Y. Schlesinger, 5 4.6 Shaare Zedek Medical Center, Jerusa- 4.1 4

Patients, % Patients, lem; E. Shinwell, Kaplan Medical Center, Rehovot; E. Somekh, Wolfson Medical 3 2.1 Center, Holon; S. Zangen, Barzilai Medical 2 Center, Ashkelon. Italy: I. Barbieri, 1.4 1.2 Azienda Ospedaliera Universitaria Poli- 1 0.5 0.4 0.1 clinico Gaetano Martino Universita`di 0 Messina, Messina; R. Bellu, Ospedale Skin Non- Within Mild or Severe Alessandro Manzoni Lecco–Presidio Specific events specific >2 d 2 d moderate or SAE dell’Azienda, Lecco; G. Bevilacqua, Type Timing Severity Azienda Ospedaliera di Parma, Parma; FIGURE 5 A. Boldrini, Azienda Ospedaliera Uni- Incidence of hypersensitivity events. Nonspecific skin events consistent with rash were erythema, versitaria Pisana–Ospedale S. Chiara, exanthema, flushing, pruritus, rash, erythematous rash, macular rash, maculopapular rash, and pruritic rash. Skin events consistent with possible cutaneous hypersensitivity were anaphylactoid Pisa; V. Carnielli, Presio Ospedaliero di reaction, angioedema, angioneurotic edema, allergic dermatitis, drug eruption, drug hypersensitivity, Alta Specializzazione “G. Salesi”–Azienda erythema annulare, erythema marginatum, erythema multiforme, eye swelling, eyelid edema, face Ospedaliera Universitaria–Ospedali Riuniti edema, hypersensitivity, injection-site erythema (an event with localized urticaria), laryngeal edema, lip swelling, edema, periorbital edema, generalized rash, swelling, facial swelling, tracheal edema, “Umberto I–G. M. Lancisi–G. Salesi,” An- urticaria, generalized urticaria, and papular urticaria. cona; G. Chirico, Spedali Civili di Brescia, Brescia; A. Colombo, Ospedali Riuniti TABLE 8 Changes in Serum Chemistry Results Recorded as AEs di Bergamo–Azienda Ospedaliera, Ber- gamo; C. Fabris, Azienda Sanitaria Os- Event Motavizumab Palivizumab (N ϭ 3315), (N ϭ 3298), pedaliera O.I.R.M.-S. Anna, Torino; G. n (%) n (%) Faldella, Azienda Ospedaliera di Bo- Ն1 event 59 (1.8) 63 (1.9) logna–Policlinico S. Orsola–Malpighi, Alanine aminotransferase increased 26 (0.8) 26 (0.8) Bologna; G. Gancia, Azienda Osped- Aspartate aminotransferase increased 23 (0.7) 31 (0.9) Hepatic enzyme increased 11 (0.3) 14 (0.4) aliera S. Croce e Carle, Cuneo; M. La- Liver function tests abnormal 4 (0.1) 4 (0.1) nari, Azienda USL di Imola–Ospedale di Transaminase increased 2 (0.1) 3 (0.1) Imola, Imola; F. Macagno, Azienda Os- Aspartate aminotransferase abnormal 1 (Ͻ0.1) 0 (0.0) Alanine aminotransferase abnormal 0 1 (Ͻ0.1) pedaliera S. Maria della Misericordia, Udine; H. Messner, Ospedale Generale di Bolzano, Bolzano; G. Rinaldi, Azienda thou, Aghia Sofia Children’s Hospital, pest; A. Nagy, DEOEC, Debrecen; E. Szabo, Ospedaliera Universitaria, Foggia; P. Athens. Hungary: K. Adamovich, Univer- Csolnoky Ferenc Hospital; G. Szonyi, Tagliabue, Azienda Ospedaliera San sity of Pecs, Pecs; G. Balla, DEOEC, Deb- Schopf-Merei Agost Hospital, Budapest. Gerardo, Monza; R. Zanini, Ospedale recen; M. Alexy, Petz Aladar Teaching Iceland: S. Kristjansson, Children’s Hos- Alessandro Manzoni Lecco–Presidio Hospital, Gyor; F. Dicso, Josa Andras pital Landspitali University Hospital, dell’Azienda Ospedaliera “Ospedale di Hospital, Nyíregyha´za; T. Ertl, Univer- Reykjavik. Israel: S. Ashkenazi, Schneider Lecco,” Lecco. New Zealand: P. Brown, sity of Pecs, Pecs; M. Fejes, Borsod- Medical Center, Petah Tikva; D. Bader, Palmerston North Hospital, Palmers- Abau´j-Zemple´n Megyei O¨ nkorma´nyzat Bnei Zion Medical Center, Haifa; A. Bar- ton North; P. Jackson, Dunedin Hospi- Ko´rha´za, Miskolc; G. Fekete, Semmel- zilai, Chaim Sheba Medical Center, Tel- tal, Dunedin; A. Trenholme, Middlemore weis University, Budapest; J. Hajdu, Hashomer; Y. Bental, Laniado Medical Hospital, Auckland; P. Weston, Waikato Semmelweis University, Budapest; T. Center, Natanya; R. Dagan, Soroka Medi- Hospital, Hamilton. Poland: G. Dawid, II Machay, Semmelweis University, Buda- cal Center, Beer-Sheva; T. Dolfin, Sapir Klinika Choro´b Dzieci PAM, Samod-

e48 CARBONELL-ESTRANY et al Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 ARTICLES zielny Publiczny Szpital Kliniczny nr 1, Szc- terno Infantil de Canarias, Las Palmas de lands Hospital, Birmingham; D. Schapira, zecin; M. Borszewska-Kornacka, Klinika Gran Canaria; X. Krauel, Hospital Sant Royal Hampshire County Hospital, Win- Neonatologii AM w Warszawie, Szpital Joan de De´u, Barcelona; A. Losada, Hos- chester; S. Sinha, James Cook University Kliniczny im. Ksie˛z˙nej Anny Mazowieckiej, pital Maternal Virgen del Rocío, Sevilla; Hospital, Middlesborough; H. Vyas, Warszawa; J. Gadzinowski, Katedra i L. Milla´n, Hospital Materno Infantil de Queen’s Medical Centre Nottingham Klinika Neonatologii AM w Poznaniu, Jae´n, Jae´n; L. Molto, Hospital Materno University Hospital, Nottingham. United Poznan´, and Instytut Centrum Zdrowia Infantil Virgen de las Nieves, Granada; States: S. Abbasi, Pennsylvania Hospital, Matki Polki, Ło´dz´; G. Go´rnicka, Choro´b M. Moro, Hospital Clínico San Carlos, Ma- Philadelphia, PA; N. Abughali, Metro Płuc i Reumatologii, Lublin; B. Kassur- drid; J. Ortíz, Hospital General de Jerez, Health Medical Center, Cleveland, OH; A. Siemienska, Klinika Niemowle˛ca, Insty- Jerez; L. Paisa´n, Hospital de Donostia Ahmed, Carolinas Medical Center, Char- tut Pomnik–Centrum Zdrowia Wars- (San Sebastian), Guipuzcoa; C. Parades, lotte, NC; M. Aouthmany, St Vincent Med- zawa; A. Kojro-Wojcieszonek, Wojewo´dzki Hospital Clinico Universitario de Valen- ical Center, Toledo, OH; B. Asmar, Chil- Szpital Dziecie˛cy w Bydgoszczy, Byd- cia, Valencia; C. Pedraz, Hospital Clinico dren’s Hospital of Michigan, Detroit, MI; goszcz; P. Korball, Samodzielny Publiczny de Salamanca, Salamanca; G. Pe´rez, Hos- A. Atz, Medical University of South Caro- Zakład Opieki Zdrowotnej Wojewo´dzki, pital Virgen Macarena, Sevilla; J. Pe´rez lina Hospital, Charleston, SC; P. Azimi, Bydgoszcz; R. Lauterbach, Szpitala Uni- Frías, Hospital Materno Infantil, Malaga; Children’s Hospital of Oakland, Oakland, wersyteckiego w Krakowie, Krako´w; W. C. Planell, Hospital Josep Trueta, Giriona; CA; V. Balaraman, Kapiolani Medical Cen- Lewanowicz, Wojewo´dzki Szpital Specjal- J. Quero, Hospital Universario Infantil La ter for Women and Children, Honolulu, HI; istyczny, Cze˛stochowa; K. Mackowska, Paz, Madrid; V. Roque´s, Hospital Univer- B. Barnett, Toledo Children’s Hospital, To- Wojewo´dzki Szpital Dziecie˛cy w Byd- sitario La Fe Maternidad, Valencia; M. ledo, OH; L. Bernard, Children’s Hospital goszczy, Bydgoszcz; A. Piotrowski, Szpital Santos, Hospital Severo Ochoa, Madrid; San Diego, San Diego, CA; J. Bernbaum, Kliniczny nr 4 im.M.Konopnickiej, Ło´dz´; L. Sastre, Hospital Central de Asturias, Children’s Hospital of Philadelphia, Phil- H. Swiatkowska, Szpital Morski im. PCK, Oviedo; M. Taboada, Hospital Juan Ca- adelphia, PA; J. Berstein, Raleigh Pediat- Gdynia; J. Szczapa, Samodzielny Public- nalejo; La Corun˜a; A. Valls, Hospital de ric Associates, Raleigh, NC; J. Bhatia, zny Szpital Kliniczny nr 1, Gdan´sk; M. Szc- Cruces, Barakaldo; M. Zapatero, Hos- Medical College of Georgia, Augusta, GA; zepanski, Samodzielny Publiczny Szpital pital Reina Sophia, Cordoba. Sweden: E. Bifano, Crouse Hospital, Syracuse, NY; Kliniczny AM-Klinika Neonatologii, Białys- E. Bergen Brostro¨m, Karolinska Univer- A. Bonner, Scott and White Memorial tok; B. Tetiurka, Niepubliczny Zakład sity Hospital, Stockholm; M. Ericksson, Hospital, Temple, TX; D. Bratcher, Chil- Opieki Zdrowotnej Salmed s.c., Łe˛czna. Karolinska Hospital, Astrid Lindgren Chil- dren’s Mercy Hospital, Kansas City, MO; Russia: S. Avrusin, Saint-Petersburg drens Hospital, Stockholm; U. Ewald, K. Bromberg, Brooklyn Hospital Center, State Pediatric Medical Academy, St Pe- Karolinska Hospital, Astrid Lindgren Chil- Brooklyn, NY; K. Bryant, University of tersburg; N. Baltserovich, St Petersburg drens Hospital, Stockholm; T. Hertzberg, Louisville, Louisville, KY; D. Burchfield, City Outpatient Hospital #45, St Peters- Karolinska Institute Hospital Solna, Shands Hospital at the University of burg; A. Galustyan, Saint-Petersburg Stockholm; S. Swanstro¨m, Department Florida, Gainesville, FL; H. Chaney, Chil- State Pediatric Medical Academy, St Pe- of Pediatrics, Eskilstuna; I. Tessin, Queen dren’s National Medical Center, Wash- tersburg; L. Iljenko, Pediatric City Hospi- Silvia Childrens Hospital, Go¨teborg. Tur- ington, DC; G. Chang, Bryn Mawr Hospital, tal #13, Moscow; L. Kozlova, Smolensk key: S. Arsan, Ankara U¨niversitesi Tıp Bryn Mawr, PA; M. Collins, Advocate Hope State Medical Academy, Smolensk; L. Faku¨ltesi, Ankara; N. Ku¨ltu¨rsay, Ege U¨ni- Children’s Hospital, Cook, IL; J. Connor, Strachounski, Smolensk State Medical versitesi Tıp Faku¨ltesi, Izmir; H. Ozkan, University of California San Diego, San Academy, Smolensk; O. Solovieva, Pediat- Dokuz Eylu¨l U¨niversitesi Tıp Faku¨ltesi, Diego, CA; E. Cooper, Boston Medical Cen- ric City Hospital #1, St Petersburg; V. Izmir; M. Yurdako¨k, Hacettepe U¨niversi- ter, Boston, MA; C. Cotten, Duke Univer- Uchaikin, Russian State Medical Univer- tesi, Ankara. United Kingdom: P. Chetcuti, sity Medical Center, Durham, NC; E. Cox, sity, Moscow. Spain: J. Antelo, Complejo Leeds General Infirmary, Leeds; M. Ever- DeVos Children’s Hospital, Grand Rapids, Hospitalario Univeristario de Vigo, Vigo; ard, Sheffield Children’s Hospital, Shef- MI; Penelope Dennehy, Rhode Island X. Carbonell, Hopital Clinic I Provinical, field; M. Hall, Princess Anne Hospital, Hospital, Providence, RI; J. DeVincenzo, Barcelona; R. Closa, Hospital Joan XXIII, Hants; B. Jani, Medway Maritime Hospi- Lebonheur Children’s Medical Center, Tarragona; E. Domenech, Hospital Uni- tal, Gillingham; L. Miall, St James Univer- Memphis, TN; R. Diaz, Children’s Lung versitario de Canarias, Santa Cruz de sity Hospital, Leeds; A. Mitra, Dumfries Specialist, Ltd, Las Vegas, NV; J. Doma- Tenerife; J. Fraga, Hospital Clinico Uni- and Galloway Royal Infirmary, Dumfries; chowske, SUNY Upstate Medical Univer- versitario de Santiago, Santiago de Com- S. Mukhopadhyay, Ninewells Hospital, sity, Syracuse, NY; S. Donn, University of postela; F. García Mun˜oz, Hospital Ma- Dundee; S. Rose, Birmingham Heart- Michigan Mott Children’s Hospital, Ann

PEDIATRICS Volume 125, Number 1, January 2010 e49 Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 Arbor, MI; R. Dorand, Alabama Neonatal Children’s Medical Group, Poughkeepsie, University of Miami Medical Center Medicine OC, Pike Road, AL; M. Duenas, NY; J. Lieberman, Miller Children’s Hospi- Batchelor Children’s Institute, Miami, FL; St John Hospital and Medical Center, De- tal, Long Beach, CA; M. Mammel, Chil- G. Shay, Kaiser Permanente Health Care troit, MI; S. Eppes, A. I. Dupont Hospital for dren’s Healthcare D.B.A. Hospitals and Plan, Oakland, CA; S. Shipman, Oregon Children, Wilmington, DE; H. Farrag, Bay- Clinics, St Paul, MN; W. McNett, Jefferson- Health Sciences University, Portland, OR; state Medical Center, Springfield, MA; J. duPont Children’s Health Program, Phil- P. Shurin, Montefiore Medical Center, Fergie, Driscoll Children’s Hospital, Cor- adelphia, PA; C. Meissner, Tufts-New En- Bronx, NY; E. Simoes, Children’s Hospital, pus Christi, TX; R. Fink, Children’s Medical gland Medical Center, Boston, MA; L. Denver, CO; Y. Smith, Georgetown Univer- Center, Dayton, OH; R. Fox, University of Meloy, VCU Medical Center, Richmond, sity Medical Center, Washington, DC; J. Maryland School of Medicine, Baltimore, VA; S. Midani, Nemours Children’s Clinic, Sneed, Children’s Clinic of Jonesboro, MD; D. Freeman, Arkansas Pediatric Jacksonville, FL; C. Morabito, Lehigh Val- Jonesboro, AR; M. Speer, Texas Chil- Clinic, Little Rock, AR; M. Gaglani, Scott ley Hospital, Allentown, PA; M. Mufson, dren’s Hospital, Houston, TX; J. Steichen, and White Memorial Hospital, Temple, TX; University Physicians, Huntington, WV; L. University of Cincinnati College of Medi- J. Garland, St Joseph’s Hospital, Milwau- Muskovitz, St Mary’s Medical Center, Du- cine, Cincinnati, OH; E. Steinberg, Kaiser kee, WI; L. Givner, Wake Forest University luth, MN; S. Nachman, Stony Brook Uni- Permanente Los Angeles, Los Angeles, School of Medicine, Winston-Salem, NC; versity Hospital, Stony Brook, NY; D. Null, CA; J. Stevens, James Whitcomb Riley M. Gomez, Saint Francis Hospital, Tulsa, Primary Children’s Medical Center, Salt Hospital for Children, Indianapolis, IN; OK; G. Goodman, Children’s Hospital of Lake City, UT; M. Odom, University of T. Stewart, Little Rock Children’s Clinic Orange County, Orange CA; S. Grant, Lou- Texas Health Science Center, San Anto- P.A., Little Rock, AR; S. Sun, Saint Bar- isiana State University MidCity Clinic, nio, TX; J. Park, Texas Tech Health Science nabas Medical Center, Livingston, NJ; Baton Rouge, LA; M. Green, Children’s Center, Lubbock, TX; L. Park, University of M. Suterwala, Baylor University Medical Hospital of Pittsburgh, Pittsburgh, PA; Illinois at Chicago, Chicago, IL; B. Patel, Center Tiny Tots Clinic, Dallas, TX; B. J. Gross, Marshfield Clinic, Marshfield, Geisinger Medical Center–JW Children’s Thomas, Arkansas Children’s Hospital WI; R. Guthrie, Allegheny General Hospi- Hospital, Danville, PA; G. Piedimonte, Uni- Research Institute, Little Rock, AR; C. Ti- tal, Pittsburgh, PA; C. Hall, University of versity of Miami Medical Center Batch- man, Pediatric Clinical Trials Interna- Rochester Medical Center, Rochester, elor Children’s Institute, Miami, FL; M. Po- tional Inc, Columbus, OH; W. Topper, Re- NY; K. Hardy, California Pacific Medical lak, West Virginia University Hospital, search Medical Center, Kansas City, MO; Center, San Francisco, CA; D. Hargunani, Morgantown, WV; B. Pollara, University of D. Tristram, East Carolina School of Oregon Health Sciences University, Port- South Florida Pediatrics Ambulatory Medicine, Greenville, NC; R. Van Dyke, Tu- land, OR; F. Henderson, University of Care Center, Tampa, FL; S. Ponthenkan- lane Hospital for Children, New Orleans, North Carolina, Chapel Hill, NC; A. Holmes, dath, Children’s Corporate Center, Wau- LA; E. Wachtel, Jacobi Medical Center, Central Arkansas Pediatric Clinic, Ben- watosa, WI, and Waukesha Memorial Bronx, NY; E. Wald, Children’s Hospital of ton, AR; P. Hughes, Albany Medical Cen- Hospital, Inc, Waukesha, WI; B. Puppala, Pittsburgh, Pittsburgh, PA; J. Wallace, ter, Albany, NY; S. Imaizumi, Children’s Lutheran General Children’s Hospital, Sioux Valley Hospital University of South Regional Hospital, Camden, NJ; E. Jung, Park Ridge, IL; M. Purswani, Bronx- Dakota Medical Center, Sioux Falls, SD; Pediatrix Medical Group, St John’s Mercy Lebanon Hospital Center, Bronx, NY; T. R. Welliver, Women & Children’s Hos- Medical Center, St Louis, MO; A. Kantak, Rhodes, Dartmouth Medical School, Leb- pital of Buffalo, Buffalo, NY; R. White, Children’s Hospital Medical Center of anon, NH; M. Riaz, St Luke’s Hospital, Memorial Hospital of South Bend, South Akron, Akron, OH; D. Kaufman, University Bethlehem, PA; J. Romero, University of Bend, IN; L. Wolkoff, Connecticut Chil- of Virginia Hospital, Charlottesville, VA; Nebraska Medical Center, Omaha, NE; dren’s Medical Center, Hartford, CT; P. R. Keisari, Santa Clara Valley Medical L. Rubin, Schneider Children’s Hospital, Wright, Vanderbilt University Medical Center, San Jose, CA; J. Kelly, Maricopa New Hyde Park, NY; H. Sadeghi, Pediatric Center, Nashville, TN; R. Yetman, Univer- Medical Center, Phoenix, AZ; H. Keyser- Pulmonology LLC, Stamford, CT; F. Saker, sity of Texas Houston Medical School, ling, Emory University School of Medi- Beehly Medical Park Women’s and Chil- Houston, TX; R. Yogev, Children’s Memo- cine, Atlanta, GA; L. Krilov, Winthrop Uni- dren’s Pavilion, Boardman, OH; V. San rial Hospital, Chicago, IL. versity Hospital, Mineola, NY; C. Joaquin, Children’s Hospital of Okla- Lamprecht, Nemours Children’s Clinic homa, Oklahoma City, OK; P. Sanchez, ACKNOWLEDGMENTS Biomedical Research, Orlando, FL; H. Lee, University of Texas Southwest Medical We thank the participating children New Jersey Medical School, Newark, NJ; Center at Dallas, Dallas, TX; Robert Sche- and their parents, the study nurses B. Lesnick, Georgia Pediatric Pulmonol- lonka, University of Alabama at Bir- and coordinators, and the clinical ogy Associates, Atlanta, GA; H. Lessin, mingham, Birmingham, AL; S. Shahzeidi, testing laboratory staff. In particu-

e50 CARBONELL-ESTRANY et al Downloaded from pediatrics.aappublications.org at University of Manitoba Libraries on June 20, 2015 ARTICLES lar, we thank Guisela Torres who led ity testing. We also thank Beverley John E. Fincke, PhD, and Gerard P. clinical operations for this study and Trotman for administrative assis- Johnson, PhD, for medical writing Wendy White, PhD, for immunogenic- tance and Jeannie M. Fiber, PhD, and editorial assistance. REFERENCES

1. Johnson S, Oliver C, Prince GA, et al. De- ing valence on viral neutralization. J Mol 16. Guess HA, Lydick EG, Small RD, Miller LP. Ep- velopment of a humanized monoclonal Biol. 2005;350(1):126–144 idemiologic programs for computers and antibody (MEDI-493) with potent in vitro 9. Wu H, Pfarr DS, Johnson S, et al. Develop- calculators. Exact binomial confidence in- and in vivo activity against respiratory ment of motavizumab, an ultra-potent anti- tervals for the relative risk in follow-up syncytial virus. J Infect Dis. 1997;176(5): body for the prevention of respiratory syn- studies with sparsely stratified incidence 1215–1224 cytial virus infection in the upper and lower density data. Am J Epidemiol. 1987;125(2): 2. American Academy of Pediatrics, Commit- respiratory tract. J Mol Biol. 2007;368(3): 340–347 tee on Infectious Diseases and Committee 652–665 17. Romero JR. Palivizumab prophylaxis of re- on Fetus and Newborn. Revised indications 10. Abarca K, Jung E, Fernandez P, et al. Safety, spiratory syncytial virus disease from 1998 for the use of palivizumab and respiratory tolerability, pharmacokinetics, and immu- to 2002: results from four years of palivi- syncytial virus immune globulin intrave- nogenicity of motavizumab, a humanized, zumab usage. Pediatr Infect Dis J. 2003;22(2 nous for the prevention of respiratory syn- enhanced-potency monoclonal antibody for suppl):S46–S54 cytial virus infections. Pediatrics. 2003; the prevention of respiratory syncytial virus 18. Sa´ez-Llorens X, Castano E, Null D, et al. 112(6 pt 1):1442–1446 infection in at-risk children. Pediatr Infect Safety and pharmacokinetics of an intra- 3. Synagis (palivizumab) [package insert]. Dis J. 2009;28(4):267–272 muscular humanized monoclonal antibody Gaithersburg, MD: MedImmune; 2008 11. Lagos R, DeVincenzo J, Mun˜oz A, Hultquist M, to respiratory syncytial virus in premature infants and infants with bronchopulmonary 4. Feltes TF, Cabalka AK, Meissner HC, et al. Sugich J, Connor EM, Losonsky GA. Safety and antiviral activity of motavizumab, a re- dysplasia. The MEDI-493 Study Group. Pedi- Palivizumab prophylaxis reduces hospital- spiratory syncytial virus (RSV)-specific hu- atr Infect Dis J. 1998;17(9):787–791 ization due to respiratory syncytial virus in manized monoclonal antibody, when admin- young children with hemodynamically sig- 19. Subramanian KN, Weisman LE, Rhodes T, et istered to RSV-infected children. Pediatr nificant congenital heart disease. J Pediatr. al. Safety, tolerance and pharmacokinetics Infect Dis J. 2009;28(9):835–837 of a humanized monoclonal antibody to re- 2003;143(4):532–540 12. Malley R, DeVincenzo J, Ramilo O, et al. Re- spiratory syncytial virus in premature in- 5. Palivizumab, a humanized respiratory syn- duction of respiratory syncytial virus (RSV) fants and infants with bronchopulmonary cytial virus monoclonal antibody, reduces in tracheal aspirates in intubated infants by dysplasia. MEDI-493 Study Group. Pediatr In- hospitalization from respiratory syncytial use of humanized monoclonal antibody to fect Dis J. 1998;17(2):110–115 virus infection in high-risk infants. The RSV F protein. J Infect Dis. 1998;178(6): 20. Groothuis JR. Safety and tolerance of palivi- IMpact-RSV Study Group. Pediatrics. 1998; 1555–1561 zumab administration in a large northern 102(3 pt 1):531–537 13. Hu A, Colella M, Tam JS, Rappaport R, Cheng hemisphere trial. Northern Hemisphere Ex- 6. Pedraz C, Carbonell-Estrany X, Figueras- SM. Simultaneous detection, subgrouping, panded Access Study Group. Pediatr Infect Aloy J, Quero J. Effect of palivizumab pro- and quantitation of respiratory syncytial vi- Dis J. 2001;20(6):628–630 phylaxis in decreasing respiratory syncytial rus A and B by real-time PCR. J Clin Micro- 21. Mathews TJ, MacDorman MF. Infant mortal- virus hospitalizations in premature infants. biol. 2003;41(1):149–154 ity statistics from the 2004 period linked Pediatr Infect Dis J. 2003;22(9):823–827 14. Shankar G, Devanarayan V, Amaravadi L, et birth/infant death data set. Natl Vital Stat 7. Mejías A, Chavez-Bueno S, Rios AM, et al. al. Recommendations for the validation of Rep. 2007;55(14):1–32 Comparative effects of two neutralizing immunoassays used for detection of host 22. American Academy of Pediatrics, Task anti-respiratory syncytial virus (RSV) antibodies against biotechnology products. Force on Sudden Infant Death Syndrome. monoclonal antibodies in the RSV murine J Pharm Biomed Anal. 2008;48(5):1267–1281 The changing concept of sudden infant model: time versus potency. Antimicrob 15. Parnes C, Guillermin J, Habersang R, et al. death syndrome: diagnostic coding shifts, Agents Chemother. 2005;49(11):4700–4707 Palivizumab prophylaxis of respiratory syn- controversies regarding the sleeping envi- 8. Wu H, Pfarr DS, Tang Y, et al. Ultra-potent cytial virus disease in 2000–2001: results ronment, and new variables to consider in antibodies against respiratory syncytial from the Palivizumab Outcomes Registry. reducing risk. Pediatrics. 2005;116(5): virus: effects of binding kinetics and bind- Pediatr Pulmonol. 2003;35(6):484–489 1245–1255

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Motavizumab for Prophylaxis of Respiratory Syncytial Virus in High-Risk Children: A Noninferiority Trial Xavier Carbonell-Estrany, Eric A.F. Simões, Ron Dagan, Caroline B. Hall, Brian Harris, Micki Hultquist, Edward M. Connor and Genevieve A. Losonsky Pediatrics 2010;125;e35; originally published online December 14, 2009; DOI: 10.1542/peds.2008-1036 Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/125/1/e35.full.ht ml References This article cites 21 articles, 8 of which can be accessed free at: http://pediatrics.aappublications.org/content/125/1/e35.full.ht ml#ref-list-1 Citations This article has been cited by 16 HighWire-hosted articles: http://pediatrics.aappublications.org/content/125/1/e35.full.ht ml#related-urls Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Diseases http://pediatrics.aappublications.org/cgi/collection/infectious_ diseases_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Reprints Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Motavizumab for Prophylaxis of Respiratory Syncytial Virus in High-Risk Children: A Noninferiority Trial Xavier Carbonell-Estrany, Eric A.F. Simões, Ron Dagan, Caroline B. Hall, Brian Harris, Micki Hultquist, Edward M. Connor and Genevieve A. Losonsky Pediatrics 2010;125;e35; originally published online December 14, 2009; DOI: 10.1542/peds.2008-1036

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/125/1/e35.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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