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

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