- Email: [email protected]
Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease
PALIVIZUMAB PROPHYLAXIS REDUCES HOSPITALIZATION DUE TO RESPIRATORY SYNCYTIAL VIRUS IN YOUNG CHILDREN WITH HEMODYNAMICALLY SIGNIFICANT CONGENITAL HEART DISEASE TIMOTHY F. FELTES, MD, ALLISON K. CABALKA, MD, H. CODY MEISSNER, MD, FRANCO M. PIAZZA, MD, MPH, DAVID A. CARLIN, PHD, FRANKLIN H. TOP, JR, MD, EDWARD M. CONNOR, MD, AND HENRY M. SONDHEIMER, MD, FOR THE CARDIAC SYNAGIS STUDY GROUP*
Objectives To evaluate the safety, tolerance, and efficacy of palivizumab in children with hemodynamically significant congenital heart disease (CHD). Study design A randomized, double-blind, placebo-controlled trial included 1287 children with CHD randomly assigned 1:1 to receive 5 monthly intramuscular injections of 15 mg/kg palivizumab or placebo. Children were followed for 150 days. The primary efficacy end point was antigen-confirmed respiratory syncytial virus (RSV) hospitalization. Results
Palivizumab recipients had a 45% relative reduction in RSV hospitalizations (P = .003), a 56% reduction in total days of RSV hospitalization per 100 children (P = .003), and a 73% reduction in total RSV hospital days with increased supplemental oxygen per 100 children (P = .014). Adverse events were similar in the treatment groups; no child had drug discontinued for a related adverse event. Serious adverse events occurred in 55.4% of palivizumab recipients and 63.1% of placebo recipients (P < .005); none were related to palivizumab. Twenty-one children (3.3%) in the palivizumab group and 27 (4.2%) in the placebo group died; no deaths were attributed to palivizumab. The rates of cardiac surgeries performed earlier than planned were similar in the treatment groups.
Conclusions Monthly palivizumab (15 mg/kg IM) was safe, well-tolerated, and effective for prophylaxis of serious RSV disease in young children with hemodynamically significant CHD. (J Pediatr 2003;143:532-40)
ower respiratory tract disease caused by respiratory syncytial virus (RSV) accounts for more than 125,000 pediatric hospitalizations and approximately 6.3 deaths per 100,000 person-years among children up to 4 years of age in the United States.1-3 Children more likely to have increased morbidity and mortality rates as the result of complications of RSV infection include those with prematurity, chronic lung disease, or congenital heart disease (CHD).4,5 In children with cardiac abnormalities, one early study showed a 37% fatality rate for RSV-infected, hospitalized infants with CHD.6 More recent studies suggest that among infants with CHD who are hospitalized with RSV disease, 33% will require treatment in a pediatric intensive care unit (ICU), and 2.5% to 3.4% die of complications of the RSV infection.7,8 Infants with pulmonary hypertension are at greatest risk from RSV infection.6,7 In addition, nosocomial RSV infection has a particularly adverse impact on infants and children who become infected in the immediate preoperative or postoperative period for heart surgery.9,10 Two early efficacy trials with a hyperimmune RSV globulin (RSV-IGIV) to prevent RSV infection included infants and children with CHD. As part of the initial National Institutes of Health–sponsored RSV-IGIV trial, 87 infants with CHD were enrolled among 249 high-risk subjects.11 Results of this trial demonstrated an overall 63% relative reduction in RSV hospitalization compared with the control group; however, the trial was not powered for subgroup analysis of children with heart disease. A second trial conducted
L
CHD Congenital heart disease COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms
532
RSV RSV-IGIV
Respiratory syncytial virus Respiratory syncytial virus immune globulin, intravenous
From The Ohio State University and The Children’s Hospital, Columbus, Ohio; The Mayo Clinic and Mayo Eugenio Litta Children’s Hospital, Rochester, Minnesota; New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts; MedImmune, Inc, Gaithersburg, Maryland; and The University of Colorado and the Children’s Hospital, Denver, Colorado. *The members of the Cardiac Synagis Study Group appear in the Appendix. Supported by MedImmune, Inc. Submitted for publication Mar 11, 2003; revision received July 14, 2003; accepted Aug 1, 2003. Reprint requests: Timothy F. Feltes, MD, The Children’s Hospital, 700 Children’s Dr, ED622, Columbus, OH 43205. E-mail: [email protected]. Copyright ª 2003 Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1067/S0022-3476(03)00454-2
in 1992 to 1995 evaluated 416 children #4 years of age with CHD who were assigned to receive monthly RSV-IGIV or to an uninfused control group.12 Results showed only a trend toward RSV disease prevention. Interpretation of results in the second study was confounded by a disproportionately higher number of children with cyanotic CHD in the treatment group. An unexpected increase in surgically related adverse events in RSV-IGIV recipients with cyanotic CHD occurred relative to the control group. Although the precise explanation for this observation in infants with cyanotic heart disease is unclear, it may have been caused by an alteration in blood viscosity after administration of RSV-IGIV to patients with an elevated hematocrit concentration. The use of RSV-IGIV for prophylaxis of high-risk infants with prematurity and chronic lung disease has been largely replaced by a humanized murine monoclonal anti-F glycoprotein antibody preparation, palivizumab.13 Palivizumab has been studied extensively in children with prematurity with or without chronic lung disease and shown to be safe and effective at a dose of 15 mg/kg monthly, reducing the incidence of RSV-associated hospitalizations by 55%.14 Palivizumab was expected to be safe and effective in infants with cyanotic heart disease because it is administered in a 100-fold lesser volume and 50-fold smaller protein load than RSVIGIV. Nonetheless, pending the availability of data in CHD patients, palivizumab was recommended for use in children with CHD only if heart disease was hemodynamically insignificant and only if an infant qualified for prophylaxis on the basis of the presence of prematurity or chronic lung disease.15 The purpose of the current study was to address the safety, tolerance, and efficacy of palivizumab in infants and young children with hemodynamically significant CHD.
METHODS Design and Patient Population This was a multicenter, randomized, double-blind, placebo-controlled trial in children with CHD. The study was conducted during 4 consecutive RSV seasons, 1998 through 2002. Each child participated during only one season. The local institutional review board or independent ethics committee approved the study protocol, and parents or guardians gave written informed consent before participation. The study was conducted at 76 centers in the United States (n = 47), Canada (n = 6), Sweden (n = 3), Germany (n = 4), Poland (n = 6), France (n = 4), and the United Kingdom (n = 6). The primary objective of this study was to compare the safety, tolerance, and efficacy of palivizumab with placebo when given monthly for the reduction of the incidence of RSV hospitalization among children with hemodynamically significant CHD. The secondary objectives were to determine the effect of monthly palivizumab prophylaxis compared with placebo on RSV hospitalization outcomes as measured by total days of RSV hospitalization, total RSV hospital days with increased oxygen requirement, incidence and total days of
RSV-associated intensive care, and incidence and total days of RSV-associated mechanical ventilation (total days were summarized per 100 randomized children); to describe the effect of cardiac bypass on serum palivizumab concentrations; and to determine palivizumab trough concentrations before the second and fifth doses. Children were eligible if they were #24 months old at the time of random assignment, had documented hemodynamically significant CHD determined by the investigator, and had unoperated or partially corrected CHD. Children were not eligible if they had unstable cardiac or respiratory status, including cardiac defects so severe that survival was not expected or for which cardiac transplantation was planned or anticipated; were hospitalized, unless discharge was anticipated within 21 days; anticipated cardiac surgery within 2 weeks of random assignment; required mechanical ventilation, extracorporeal membrane oxygenation, continuous positive airway pressure, or other mechanical respiratory or cardiac support; had associated noncardiac anomalies or end-organ dysfunction resulting in anticipated survival of <6 months or unstable abnormalities of end-organ function. Additional exclusion criteria were known HIV infection; acute RSV or other acute infection or illness; previous receipt of palivizumab or other monoclonal antibody; receipt of investigational agents within the previous 3 months (other than investigational agents commonly used during cardiac surgery or the immediate postoperative period, ie, nitric oxide); current participation in other investigational protocols of drugs or biological agents; or receipt of intravenous immune globulin (IGIV), including RSV-IGIV (RespiGam, MedImmune, Inc, Gaithersburg, Md), within 3 months before random assignment or anticipated use of IGIV, RSV-IGIV, or open-label palivizumab during the study period. Children with uncomplicated small atrial or ventricular septal defects or patent ductus arteriosus were excluded. Random assignment was based on a computer-generated sequence and was stratified by site to reduce the effect of practice discrepancies and anatomic cardiac lesion (cyanotic or ‘‘other’’). Random assignment was performed centrally with the use of an interactive voice response system. Children with the following anatomic diagnoses were included in the cyanotic stratum: pulmonary atresia with ventricular septal defect, pulmonary atresia with intact septum, tetralogy of Fallot, single ventricle including hypoplastic left or right heart, tricuspid atresia, double-outlet right ventricle with transposed great arteries, Ebstein anomaly, or D-transposition of the great arteries with/without ventricular septal defect, with/without pulmonary stenosis. The remaining children were stratified to the ‘‘other’’ (acyanotic) stratum. Eligible children were randomly assigned (1:1) to receive either palivizumab (15 mg/kg) or an equal volume of identically appearing placebo (same formulation without antibody and with 0.02% Tween-80 added) by intramuscular injection every 30 days for a total of 5 doses. Palivizumab and placebo were supplied as lyophilized product in coded vials that were reconstituted by the pharmacist with sterile water for injection (final concentration of palivizumab is 100 mg/mL) and dispensed in a syringe that did not identify the contents.
Palivizumab Prophylaxis Reduces Hospitalization Due to Respiratory Syncytial Virus in Young Children With Hemodynamically Significant Congenital Heart Disease
533
Outcomes Children were followed for 150 days from random assignment (30 days after the last scheduled study injection) for hospitalization and for the occurrence of adverse events. All hospitalizations were identified, and in children with an acute cardiorespiratory hospitalization, RSV antigen testing of respiratory secretions was performed with the use of commercially available tests. The primary end point of the trial was the incidence of RSV hospitalization, including primary RSV hospitalizations and nosocomial RSV hospitalizations. A primary RSV hospitalization was defined as a hospitalization for an acute cardiorespiratory illness in which the RSV antigen test was positive within 48 hours before or after admission. Deaths occurring outside the hospital that could be demonstrated to be associated with RSV were also considered as primary RSV hospitalization end points. A nosocomial RSV hospitalization was one in which hospitalized patients had an objective measure of worsening cardiorespiratory status reported as a serious adverse event and the RSV antigen test was positive. RSV hospitalizations were monitored for total days, days of supplemental oxygen, days of intensive care, and days of mechanical ventilation. Decisions on hospitalization, discharge, and other aspects of therapy for RSV disease were left to the treating physician’s discretion. Any adverse change from a child’s medical condition at entry was reported as an adverse event, graded for severity, and assessed by the blinded investigator as to potential relation to study drug. Serious adverse events were those that resulted in death; were lifethreatening; resulted in hospitalization or prolonged hospitalization; resulted in significant disability; or were another important medical event that required intervention to prevent one of the above outcomes. Serum was collected before the first, second, and fifth injections of study drug, and, if cardiac bypass was used during surgery, before bypass and on the day after bypass. Palivizumab concentrations were analyzed with the use of a previously described enzyme immunosorbent assay.16 Serum RSV neutralizing antibody titers at study entry were assessed in a plaque reduction neutralization test.17
Sample Size and Statistical Analysis Assuming an RSV hospitalization rate of 12.0% in the placebo group compared with 7.2% in the palivizumab group, approximately 1280 children were to be randomly assigned (1:1) to provide 80% power of showing a 40% relative reduction in the incidence of RSV hospitalizations, using a 2-sided a-level of 0.05. After completion of the second year of the study, the Data Safety Monitoring Board undertook a planned interim analysis of the primary end point of RSV hospitalization. Six hundred ninety-eight patients representing approximately 54% of the total number of patients had completed the study at that time. The Lan-DeMets procedure, using the approximate O’Brien-Fleming boundaries, was used to determine the adjusted P value (.048) required for significance of the primary end point. All randomly assigned patients were included in the safety and efficacy analyses. Statistical comparison of groups 534
Feltes et al
was performed with the Fisher exact test for categorical variables and Wilcoxon rank sum test for continuous variables. The Kaplan-Meier analysis assessing time to first RSV hospitalization was used as a confirmatory test accounting for incomplete follow-up. The Cochran-Mantel-Haenszel test was used to evaluate the primary end point across strata. Logistic regression was performed with the use of predefined variables (age, sex, and stratum). Treatment groups were compared for adverse events (COSTART coded terms) by evaluating the number of children in each group with at least one event by body system and the distribution of severity and relatedness of these events. Patients who received at least one dose of study drug were included in the analyses of serum palivizumab concentrations, unless they were known to have received off-study palivizumab or had a documented dosing error (eg, received the incorrect study drug on at least one occasion).
RESULTS Starting on November 1 and ending on or before December 31 of each year between 1998 and 2001, a total of 1287 patients were randomly assigned. Study sites in the United States and Canada randomly assigned 800 (62.2%) and 133 (10.3%) children, respectively. The remaining children were randomly assigned in Poland (150, 11.6%), the United Kingdom (95, 7.4%), Germany (49, 3.8%), Sweden (33, 2.6%), and France (27, 2.1%). From 1 to 45 patients were randomly assigned per site, with an average of 17 patients per site. Six sites randomly assigned less than 5 patients, and 25 sites randomly assigned 20 or more patients. A total of 1287 children were randomly assigned: 639 to the palivizumab group and 648 to the placebo group. Overall, 93.0% of children in the palivizumab group and 91.8% in the placebo group received all five planned injections; 95.6% in the palivizumab group and 95.5% in the placebo group completed the study. The groups were balanced for demographic characteristics, RSV risk factors, and parameters of cardiovascular disease (Table I). Of the 1287 children randomly assigned in the study, 682 (53.0%) were in the cyanotic stratsum and 605 (47.0%) in the ‘‘other’’ stratum. The distribution of cardiac lesions was balanced between the two treatment groups. The cyanotic lesions, single ventricle including hypoplastic left or right heart and tetralogy of Fallot, accounted for 21.9% and 11.4%, respectively, of all children enrolled, whereas the acyanotic lesions, ventricular septal defect and atrioventricular septal defect, occurred in 18.0% and 7.2%, respectively, of those enrolled.
Incidence of RSV Hospitalization Monthly prophylaxis with palivizumab was associated with a 45% relative reduction in RSV hospitalization rate (P = .003, Table II). RSV hospitalization rates were 9.7% in the placebo group and 5.3% in the palivizumab group. Nine placebo recipients and three palivizumab recipients had nosocomial RSV hospitalizations. Five children (3 placebo The Journal of Pediatrics October 2003
Table I. Demographic characteristics, RSV risk factors, and parameters of CHD at study entry Palivizumab (n = 639)
Placebo (n = 648)
P value*
290 (45.4%)
304 (46.9%)
.615
453 77 52 57 27 6.8 6.1 38.5
459 (70.8%) 66 (10.2%) 61 (9.4%) 62 (9.6%) 23 (3.5%) 6.5 (0.2) 6.0 (0.1) 38.5 (0.1)
.639
.566 .510 .683 .741
Demographic characteristics Sex Female Race/ethnic group White Hispanic Black Other Multiple birth Mean age in months at entry (SE) Mean weight in kg at entry (SE) Mean gestational age in weeks (SE)
(70.9%) (12.1%) (8.1%) (8.9%) (4.2%) (0.2) (0.1) (0.1)
RSV risk factors Mean number of persons in home (SE) Proportion with RSV neutralizing antibody titer $1:200 at baseline Child in day care Other children in day care Smoker in household Family history of asthma
4.4 (0.1) 170 (31.4%)y
4.4 (0.1) 173 (30.5%)y
.918 .795
76 100 211 172
(11.9%) (15.6%) (33.0%) (27.7%)z
69 (10.6%) 115 (17.7%) 223 (34.4%) 191 (29.7%)z
.482 .152 .122 .456
Characteristics of CHD at study entry Cyanotic stratum Previous cardiac surgery or interventional catheterization Hypercyanotic episode Receiving cardiac medications Congestive heart failure Pulmonary hypertension Increased pulmonary blood flow
339 396 73 484 401 152 237
(53.1%) (62.0%) (11.4%) (75.7%) (62.8%) (23.8%) (37.1%)
343 (52.9%) 391 (60.3%) 84 (13.0%) 491 (75.8%) 428 (66.0%) 164 (25.3%) 253 (39.0%)
1.000 .568 .443 1.000 .333 .534 .491
*P values for categorical variables were obtained from Fisher exact test; those for continuous variables were obtained from Wilcoxon rank sum test. yn = 542 palivizumab, 567 placebo. zn = 622 palivizumab, 643 placebo.
and 2 palivizumab recipients) had more than one RSV hospitalization. The result was robust in sensitivity analyses including (1) addition of adjusted rates for those children with respiratory hospitalizations for whom an RSV antigen test was not performed (P = .004), (2) inclusion of children who did not have an RSV hospitalization documented and did not complete follow-up through day 150 (P = .005), and (3) inclusion of children (n = 3) hospitalized with virologic evidence of RSV but who did not meet the protocol defined criteria for RSV hospitalization (P = .002). Cochran-MantelHaenszel analysis of RSV hospitalization across strata was significant (P = .003), and treatment remained significant (P = .004) in logistic regression performed with predefined variables (age, sex, and cardiac strata). Reductions in RSV hospitalization were seen in both strata, although the study was not powered for subgroup analyses. In the cyanotic stratum, RSV hospitalizations were reduced by 29%, from 7.9% in the placebo group to 5.6% in the palivizumab group (P = .285). In the ‘‘other’’ stratum, RSV hospitalizations were
reduced by 58%, from 11.8% in the placebo group to 5.0% in the palivizumab group (P = .003). Cochran-Mantel-Haenszel analyses of RSV hospitalization across sex, age at entry (#6 months or >6 months), weight at entry (#6 kg or >6 kg), race (white or other), location (United States, Canada, Europe), study year (year 1, 2, 3, 4), and neutralizing antibody at entry (<1:200 or $1:200) all were highly significant (P < .01), indicating consistency of the benefit across these subgroups. RSV hospitalization rates for infants <6 months old were 12.2% placebo versus 6.0% palivizumab, with corresponding rates of 7.3% versus 6.1% for infants 6 to 12 months old and 4.3% versus 1.8% for children 1 to 2 years old. RSV hospitalization rates for the placebo and palivizumab groups, respectively, by locations were the United States (10.6% vs 5.9%), Canada (11.9% vs 7.6%), and Europe (7.0% vs 3.0%).
Secondary Efficacy End Points As shown in Table III, children randomly assigned to palivizumab had significantly fewer total days of RSV
Palivizumab Prophylaxis Reduces Hospitalization Due to Respiratory Syncytial Virus in Young Children With Hemodynamically Significant Congenital Heart Disease
535
Table II. Analysis of incidence of RSV hospitalization
Primary end point analysisy Kaplan-Meier analysisz Sensitivity analyses Inclusion of no antigen test §k Inclusion of noncompleters§{ Inclusion of nonprotocol RSV testing**
Palivizumab (n = 639)
Placebo (n = 648)
Relative reduction (95% CI)
P value*
34 (5.3%) 34 (5.3%)
63 (9.7%) 63 (9.7%)
45% (23, 67) 45% (23, 67)
.003 .003
35 (5.5%) 37 (5.8%) 35 (5.5%)
63 (9.7%) 65 (10.0%) 65 (10.0%)
43% (20, 66) 42% (19, 65) 45% (23, 67)
.004 .005 .002
*P value was obtained from Fisher exact test. yChildren with more than one RSV hospitalization were counted only once. Two children (1 in each treatment group) died in the ER from RSV bronchiolitis and, by convention, were counted as end points. zKaplan-Meier estimate of the proportion with RSV hospitalization at 150 days. Deaths before RSV hospitalization, withdrawals, and lost events were treated as censored. For the 2 children who died in the ER from RSV bronchiolitis, total days on study were used for the analysis. §Events were added to each treatment group in proportion to the number of children who would have had a RSV hospitalization if the proportion hospitalized was equal to that of the other treatment group (n 3 0.097 events added for palivizumab; n 3 0.053 events added for placebo). kProportional adjustments made for the number of children (14 palivizumab; 9 placebo) who had no endpoint and who had a hospitalization for an acute cardiorespiratory illness with evidence of respiratory infection (coryza, fever, apnea), without alternative etiology and with no RSV antigen test done (or negative test and done outside the protocol-specified window). {Proportional adjustments made for the number of children (28 palivizumab; 29 placebo) who stopped follow-up before day 150 and who had no endpoint through the last follow-up visit. **Three children (1 palivizumab, 2 placebo) who were hospitalized with virologic evidence of RSV lower respiratory tract infection but did not meet the protocol-specified case definition were added.
Table III. Summary of secondary end points related to RSV hospitalization
Days of RSV hospitalization Total days Total days/100 children RSV hospital days of increased supplemental oxygen therapy Total days Total days/100 children ICU admission No Yes Days of ICU stay Total days Total days/100 children Mechanical ventilation No Yes Days of mechanical ventilation Total days Total days/100 children
Palivizumab (n = 639)
Placebo (n = 648)
367 57.4
836 129.0
Relative reduction (%)
P value* .003
56 .014
178 27.9
658 101.5
626 (98.0%) 13 (2.0%)
624 (96.3%) 24 (3.7%)
101 15.9
461 71.2
631 (98.7%) 8 (1.3%)
634 (97.8%) 14 (2.2%)
42 6.5
354 54.7
73 .094 46 .080 78 .282 41 .224 88
*P values for total days were obtained from Wilcoxon test; P values for incidence were obtained from Fisher exact test.
hospitalization per 100 children (56% reduction; 129.0 days placebo vs 57.4 days palivizumab, P = .003) and RSV hospital days with increased oxygen requirement per 100 children (73% reduction; 101.5 days placebo vs 27.9 days palivizumab, P = .014). A similar trend favoring palivizumab was observed for incidence of RSV-associated intensive care (46% reduction, P = .094), days of RSV-associated intensive care per 536
Feltes et al
100 children (78% reduction, P = .080), incidence of RSVassociated mechanical ventilation (41% reduction, P = .282), and days of RSV-associated mechanical ventilation per 100 children (88% reduction, P = .224). Prolonged RSV hospitalization ($14 days) occurred in fewer palivizumab recipients compared with placebo recipients (16 placebo vs 5 palivizumab). The Journal of Pediatrics October 2003
Table IV. Summary of safety data Adverse event category Total No. of adverse events Total No. of children with Adverse event Adverse event coding to cardiovascular system Adverse event coding to respiratory system Adverse event requiring medical intervention Related adverse event Related adverse event resulting in permanent discontinuation Serious adverse event Related serious adverse event Fatalities
Palivizumab (n = 639)
Placebo (n = 648)
4169
4518
611 (95.6%) 286 (44.8%) 525 (82.2%) 588 (92.0%) 46 (7.2%) 0 (0.0%) 354 (55.4%) 0 (0.0%) 21 (3.3%)
625 (96.5%) 315 (48.6%) 547 (84.4%) 605 (93.4%) 45 (6.9%) 0 (0.0%) 409 (63.1%) 3 (0.5%) 27 (4.2%)
P value*
.477 .180 .296 .392 .914 — .005 .249 .463
*P values were obtained from Fisher exact test.
An 11.8% reduction in the incidence of hospitalization for any cause was observed in the palivizumab group (62.3% placebo vs 54.9% palivizumab, P = .008). Differences in the relative rates of RSV hospitalization were major contributions to this difference; when RSV hospitalizations were removed from the analysis, the reduction in hospitalization rate was 9.3% (59.0% placebo vs 53.5% palivizumab, P = .056). The proportion of children with a cardiorespiratory hospitalization was 55.4% in the placebo group and 50.2% in the palivizumab group (P = .066).
Safety and Tolerability As shown in Table IV, the proportion of children with adverse events, adverse events that required medical intervention, and adverse events judged by the blinded investigator to be related to the study drug was similar between the two groups. No child had study drug discontinued for a related adverse event. Few adverse events were reported at an absolute incidence $1% higher in the palivizumab group compared with the placebo group. Those adverse events were limited to fever (27.1% palivizumab vs 23.9% placebo), infection (5.6% vs 2.9%), study drug injection site reaction (3.4% vs 2.2%), URI (47.4% vs 46.1%), conjunctivitis (11.3% vs 9.3%), arrhythmia (3.1% vs 1.7%), and cyanosis (9.1% vs 6.9%). None of the events reported as arrhythmia and one reported as cyanosis (placebo recipient) were judged related to the study drug. The most common injection site reactions were redness, swelling and bruising; none was serious. The incidence of serious adverse events was significantly lower in the palivizumab group compared with the placebo group (55.4% vs 63.1%, P = .005, Table IV). This trend was observed in both the cyanotic stratum (59.9% vs 67.1%, P = .056) and the ‘‘other’’ stratum (50.3% vs 58.7%, P = .041). When serious adverse events reported during all RSV hospitalizations were removed from the analysis, the P value was .043. Arrhythmia was reported as a serious adverse event in 0.2% and 0.3% of the palivizumab and placebo groups,
Table V. Summary of cardiac surgery/interventional catheterization Palivizumab (n = 639) No. of children with proceduresy None Planned Earlier than planned Urgent
Placebo (n = 648)
P value* .665
421 (65.9%) 164 (25.7%) 34 (5.3%) 20 (3.1%)
410 (63.3%) 186 (28.7%) 34 (5.2%) 18 (2.8%)
*P value obtained from Fisher exact test assessing independence of treatment assignments and cardiac procedures. yChildren having multiple procedures were counted only once by the most urgent procedure.
respectively. Cyanosis was reported as a serious adverse event in 3.6% of the palivizumab group (23 patients) and 2.2% of the placebo group (14 patients); these included 20 and 14 patients, respectively, in the cyanotic stratum and 3 and 0, respectively, in the ‘‘other’’ stratum. Within 30 days after onset of the cyanotic serious adverse event, equal proportions of the palivizumab group (14 patients, 2.2%) and placebo group (12 patients, 1.9%) had earlier-than-planned or urgent surgery or died (1 in each group). No serious adverse events related to palivizumab were reported. The incidence rates of cardiac surgeries classified as planned, earlier than planned, or urgent were balanced between treatment groups (Table V). A total of 48 children died during the study: 21 (3.3%) in the palivizumab group and 27 (4.2%) in the placebo group (Table IV). No deaths were attributed to study drug. Six children (4 cyanotic and 2 ‘‘other’’ strata) in the palivizumab group and 5 children (2 cyanotic and 3 ‘‘other’’ strata) in the placebo group had surgery-associated deaths. Deaths associated with RSV infection occurred in 2 patients in the palivizumab group and 4 patients in the placebo group.
Palivizumab Prophylaxis Reduces Hospitalization Due to Respiratory Syncytial Virus in Young Children With Hemodynamically Significant Congenital Heart Disease
537
Serum Palivizumab Levels Mean (±SD) serum palivizumab concentrations before the second and fifth doses were 55.5 (±19) lg/mL and 90.8 (±35) lg/mL in the palivizumab group and 0.4 (±5) lg/mL and 0.1 (±2) lg/mL in the placebo group. Only 7.9% of the palivizumab group tested had concentrations before the second dose <30 lg/mL, the concentration found to reduce mean pulmonary RSV titers by 2 log10 in the cotton rat model.13 Paired serum was available before and after cardiac bypass for 139 palivizumab recipients. Before and after cardiopulmonary bypass, the mean (±SD) serum palivizumab concentrations were 98.0 (±52) lg/mL and 41.4 (±33) lg/mL, respectively. This represents a reduction of 58% (P = .0001) in serum palivizumab concentration after bypass.
DISCUSSION This large, placebo-controlled trial demonstrates the benefit of palivizumab prophylaxis in children with CHD. Children receiving prophylaxis had a 45% (95% CI: 23, 67) relative reduction in RSV hospitalization. These results are consistent with the IMpact-RSV trial in children with prematurity with or without chronic lung disease, in which a 55% (95% CI: 38, 72) relative reduction was observed.14 The reduction in RSV hospitalization rate was evident in both the cyanotic (7.9% placebo vs 5.6% palivizumab, P = .285) and the ‘‘other’’ or acyanotic strata (11.8% vs 5.0%, P = .003), although reduction was statistically significant only in the acyanotic stratum. Using the predicted 12.0% placebo RSV hospitalization rate, the power to show a statistically significant reduction of 40% in the cyanotic stratum was 51%. Using the low placebo RSV hospitalization rate of 7.9% observed in the cyanotic stratum, the post hoc power estimation is 34%. When RSV hospitalization was assessed across strata through the use of the Cochran-Mantel-Haenszel method, the P value was .003, consistent with benefit in both strata. This trend was consistent in patients from all geographic areas (United States, Canada, and Europe) and was evident in male and female subjects, in children #6 months and >6 months of age at entry, in children #6 kg and >6 kg at entry, and in children of either white race or all other races combined. The reduction in RSV hospitalization was accompanied by a significant reduction in days of RSV hospitalization per 100 children randomly assigned (129.0 days placebo vs 57.4 days palivizumab, P = .003) and RSV hospital days with increased oxygen requirement per 100 children (101.5 days vs 27.9 days, P = .014). Prolonged RSV hospitalization ($14 days) occurred in fewer palivizumab recipients compared with placebo recipients (16 placebo vs 5 palivizumab). The incidence and days of RSV-associated intensive care and the incidence and days of RSV-associated mechanical ventilation appeared lower in the palivizumab group; the study was not powered to show statistical significance for these outcomes. Deaths associated with RSV infection occurred in 2 patients in the palivizumab group and 4 patients in the placebo group, a trend similar to that seen in a previous RSV-IGIV study in 538
Feltes et al
patients with CHD (1 patient in the RSV-IGIV group and 3 patients in the control group).12 In the current study, the safety profile of palivizumab in patients with CHD was similar to that observed in other pediatric populations. Children receiving palivizumab prophylaxis had a slightly higher rate of fever (3.2% difference between groups) and reactions at the injection site (1.2% difference) compared with control subjects. These events were generally of low severity and did not result in alteration of the prophylaxis regimen. The incidence of adverse events was similar between groups, whereas there was significantly lower incidence of serious adverse events among palivizumab recipients relative to control subjects. Serious adverse events coding to cyanosis were somewhat more frequent in the palivizumab group (23 children, 3.6%) than the placebo group (14 children, 2.2%). However, cyanotic serious adverse events leading to earlier-than-planned or urgent surgery or death (1 child in each group) were balanced between treatment groups. Rates of earlier-than-planned and urgent cardiac surgeries were carefully and prospectively monitored throughout the course of the study. There were no differences observed in the rates of these events between palivizumab and placebo recipients. Previous studies suggested a potential problem in RSVIGIV recipients with regard to deaths associated with surgery.11,12 A total of 48 children died during the current study: 21 (3.3%) in the palivizumab group and 27 (4.2%) in the placebo group. Deaths associated with cardiac surgery were similar between treatment groups. No deaths were attributed to study drug. Thus the results from this study demonstrate the safety of monthly palivizumab prophylaxis in children with CHD. Patients with CHD receiving palivizumab prophylaxis may undergo cardiopulmonary bypass during surgical procedures. Data obtained during this study demonstrate that serum palivizumab concentrations in children undergoing open heart surgery were reduced by >50% after the cardiopulmonary bypass procedure. Because serum concentrations may fall below a protective level, it is appropriate to administer another dose of palivizumab (15 mg/kg) after surgery. The results of this trial demonstrate that palivizumab can be administered safely to infants and young children with hemodynamically significant CHD. Monthly prophylaxis results in a 45% reduction in RSV hospitalization in this high-risk population. Guidelines for the use of palivizumab in patients with CHD have been issued by the American Academy of Pediatrics,18 and evaluation by the United States Food and Drug Administration is pending. We thank W. Ripley Ballou, MD, James F. Balsley, MD, PhD, Bernard Landry, MPH, Judith Scott, MPH, Peggy McDonald, RN, Lori Ovington, Ray Hsieh, Rong Ye, and Kevin Crawford of MedImmune, Inc, for their contributions to this study; Barbara Shepherd, PhD, of MedImmune, Inc, for assistance in preparation of the manuscript; Virginia Capps, Randi Gower, Patricia Keegan, and the clinical monitoring and data management/biostatistics staff at PPD Development, Inc; the clinical research staff at all the participating sites; and all of the children and families who The Journal of Pediatrics October 2003
participated in this study. We also thank the members of the Data Safety and Monitoring Board, Catherine Wilfert, MD, David DeMets, PhD, and Maryanne Kichuk-Chrisant, MD, for their time and effort.
REFERENCES 1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children. JAMA 1999;282:1440-6. 2. Shay DK, Holman RC, Roosevelt GE, Clarke MJ, Anderson LJ. Bronchiolitis-associated mortality and estimates of respiratory syncytial virusassociated deaths among US children, 1979-1997. J Infect Dis 2001;183: 16-22. 3. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-86. 4. Aujard Y, Fauroux B. Risk factors for severe respiratory syncytial virus infection in infants. Respir Med 2002;96:S9-14. 5. Boyce TG, Mellen BG, Mitchel EF, Wright PF, Griffen MR. Rates of hospitalization for respiratory syncytial virus among children in Medicaid. J Pediatr 2000;137:865-70. 6. MacDonald NE, Hall CB, Suffin SC, Alexson C, Harris PJ, Manning JA. Respiratory syncytial viral infection in infants with congenital heart disease. N Engl J Med 1982;307:397-400. 7. Navas L, Wang E, de Carvalho V, Robinson J. Pediatric Investigators Collaborative Network on Infections in Canada: improved outcome of respiratory syncytial virus infection in a high-risk hospitalized population of Canadian children. J Pediatr 1992;121:348-54. 8. Moler FW, Khan AS, Meliones JN, Custer JR, Palmisano J, Shope TC. Respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience. Crit Care Med 1992;20:1406-13. 9. Khongphatthanayothin A, Wong PC, Samara Y, Newth CJL, Wells WJ, Starnes VA, et al. Impact of respiratory syncytial virus infection on surgery for congenital heart disease; postoperative course and outcome. Crit Care Med 1999;27:1974-81. 10. Altman CA, Englund JA, Demmler G, Drescher KL, Alexander MA, Watrin C, et al. Respiratory syncytial virus in patients with congenital heart disease: a contemporary look at epidemiology and success of preoperative screening. Pediatr Cardiol 2000;21:433-8. 11. Groothuis JR, Simoes EAF, Levin MJ, Hall CB, Long CE, Rodriguez WJ, et al. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 1993;329:1524-30. 12. Simoes EAF, Sondheimer HM, Top FH Jr, Meissner HC, Welliver RC, Kramer AA, et al. Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. J Pediatr 1998;133:492-9. 13. Johnson S, Oliver C, Prince GA, Hemming VG, Pfarr DS, Wang SC, et al. Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis 1997;176:1215-24. 14. IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102:531-7. 15. American Academy of Pediatrics. Respiratory Syncytial Virus. In: Pickering LK, editor. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th edition. Elk Grove Village, Ill: American Academy of Pediatrics; 2000. p. 483-7. 16. Saez-Llorens X, Castano E, Null D, Steichen J, Sanchez PJ, Ramilo O, et al. Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. Pediatr Infect Dis J 1998;17:787-91. 17. Coates HV, Alling DW, Chanock RM. An antigenic analysis of respiratory syncytial virus isolates by a plaque reduction neutralization test. Am J Epidemiol 1966;83:299-313. 18. American Academy of Pediatrics. Respiratory Syncytial Virus. In: Pickering LK, editor. 2003 Red Book: Report of the Committee on Infectious
Diseases. 26th edition. Elk Grove Village, Ill: American Academy of Pediatrics; 2003. p. 523-8.
APPENDIX Members of the Cardiac Synagis Study Group (yadvisory/ writing committee; zlead statistician): Timothy F. Feltes, MDy, Beth Kossmann, RN, Children’s Hospital, Columbus, OH, and Jennifer Clifton, RN, Linda Drake, RN, Angelia Turner, RN, Texas Children’s Hospital, Houston, TX; Allison K. Cabalka, MDy, Patrick W. O’Leary, MD, Cindy M. Woltman, RN, Mayo Clinic, Rochester, MN; H. Cody Meissner, MDy, Ziyad M. Hijazi, MD, Sharon E. O’Brien, MD, Jonathan Rhodes, MD, New England Medical Center, Boston, MA; Henry M. Sondheimer, MDy, Rosa Owens, RN, Barbara Carillo, Children’s Hospital and University of Colorado HSC, Denver, CO; Scott D. Gullquist, MD, Richard M. Schieken, MD, Ellen B. Swoope, RN, Medical College of Virginia and VCU Health System, Richmond, VA; Charles S. Kleinman, MD, Alan H. Friedman, MD, Cindy Guandalini, APRN, BC, Yale University School of Medicine, New Haven, CT; Lorry G. Rubin, MD, Steven Ritz, MD, Nancy Stellato, RN, The Schneider Children’s Hospital of the North Shore, Long Island Jewish Health System, New Hyde Park, NY; Arno R. Hohn, MD, Children’s Hospital of Los Angeles and University of Southern California’s Keck School of Medicine, Los Angeles, CA; Angela Sharkey MD, Mary Boyle, RN, St Louis Children’s Hospital, St Louis, Mo; Michael S. Epstein, MD, Vijaya Joshi, MD, Children’s Hospital of Michigan and Wayne State University, Detroit, MI; Dennis Crowley, MD, C. S. Mott Children’s Hospital and University of Michigan, Ann Arbor, MI; Susan A. Miller, MD, Pamela Bowman, RN, Children’s Hospital of Pittsburgh, Pittsburgh, PA; Ira H. Gessner, MD, Connie Nixon, RN, University of Florida College of Medicine, Gainesville, FL; Kenneth J. Dooley, MD, Sibley Heart Center-Cardiology, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA; Sam Gidding, MD, Ram Yogev, MD, Children’s Memorial Hospital, Chicago, IL; Thomas P. Graham, MD, Judy Burger, RN, Vanderbilt University Medical Center, Nashville, TN; Christian Hardy, MD, Julie Simon, Children’s Hospital Oakland, Oakland, CA; Frank F. Ing, MD, Children’s Hospital and Health Center, San Diego, CA; Craig R. Cohen, MD, Sharon Pfeiffel, RN, MS, CPNP, Arizona Pediatric Cardiology Consultants, Phoenix, AZ; Marc H. Lebel, MD, FRCPC, Sainte Justine Hospital, University of Montreal, Quebec, Canada; Stephen Paridon, MD, Alena Hogerty, MD, Children’s Hospital of Philadelphia, Philadelphia, PA; Mark D. Reller, MD, Oregon Health and Science Center, Portland, OR; David A. Roberson, MD, Anne Freter, RN, The Heart Institute for Children, Oaklawn, IL; Kerry L. Rosen, MD, Sarah Sturgis, CRNP, Deb Dilworth, RN, CCRC, The Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA; Geoffrey Rosenthal, MD, PhD, Collette Fearneyhough, MSN, PNP, Children’s Hospital and Regional Medical Center, Seattle, WA; Patricia A. Hughes, DO, Martha L.
Palivizumab Prophylaxis Reduces Hospitalization Due to Respiratory Syncytial Virus in Young Children With Hemodynamically Significant Congenital Heart Disease
539
Lepow, MD, Mary Terese Evans, RN, Albany Medical College, Albany, NY; Denise Bratcher, DO, Judith Theriot, MD, Alice Gittings, RN, CCRC, University of Louisville, Louisville, KY; Robert C. Welliver, MD, Cynthia Shuff, Kathy Alessi, Children’s Hospital of Buffalo, Buffalo, NY; Luby Abdurrahman, MD, Shirah Shore, Khaled Salaymeh, Children’s Hospital Medical Center, Cincinnati, OH; Raymond T. Fedderly, MD, Children’s Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee, WI; David E. Fixler, MD, Fiker Zeray, PNP, Children’s Medical Center and University of Texas Southwestern Medical Center, Dallas, TX; Joanne M. Langley, MD, Andrew Warren, IWK Health Center and Dalhousie University, Halifax, Nova Scotia, Canada; Jay M. Lieberman, MD, Robin Doroshow, MD, Nan O’Donnell, MS, RN, Miller Children’s Hospital, Long Beach, CA; Jane McDonald, MD, Charles Rohlicek, MD, Lorraine Piche-Walker, RN, Montreal Children’s Hospital, Quebec, Canada; David W. Kimberlin, MD, Kelly Smitherman, RN, The University of Alabama at Birmingham, Birmingham, AL; Leonard R. Krilov, MD, Carlos Montoya, MD, Kathy Usmani, NP, Winthrop University Hospital, Mineola, NY; Elaine Wang, MD, David Nykanen, MD, Kyong-Jin Lee, MD, The Hospital for Sick Children, Toronto, Ontario, Canada; Michael Tosi, MD, Mount Sinai Medical Center, New York, NY; Anne Thomson, MD, Joanna Sidey, John Radcliffe Hospital, Oxford, United Kingdom; Andrzej Sysa, MD, Pawet Dryzek, Katarzyna Ostrowska, Department of Pediatric Cardiology, Mother and Child Health Center-Research Institute, Lodz, Poland; Maria Popczynska-Marek, MD, Leslaw Szydlowski, MD, Maciej Pitak, Department of Pediatric Cardiology, Polish-American Children’s Hospital, Jagiellonian University, Crakow, Poland; Michael Blackburn, MD, Pediatric Cardiology, Leeds General Infirmary, Leeds, United Kingdom; Marc P. Blayney, MB, BCh, FRCPC, Jane Lougheed, MD, FRCPC, Nancy Dean-Melanson, RN, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Joel Brenner, MD, Glenda Roberts, RN, Johns Hopkins Hospital, Baltimore, MD; Michael M. Brook, MD, Elizabeth Tong, RN, University of California, San Francisco, CA; Francis Casey, MD, FRCP, Isabel Hannigan, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland, United Kingdom; Alan Chantepie, MD, Hopital Clocheville, University of Tours, Tours Cedex, France; Piers Daubeney, MD, Dominic Abrams, MD, Elizabeth Cashin, Royal Brompton Hospital, London, United Kingdom; Patrick Finnigan, MD, Lori Davis, RN, Children’s Cardiology Associates, Austin, TX; Therese M. Giglia, MD, Russell Cross, MD, Susan Young, RN, Children’s National Medical Center, Washington, DC; Gerd Hausdorf, MD, Universitatsklinikum Gottingen, Gottingen, Germany; Matthias Peuster, MD, Julia Recuers, MD, Iranziska Cohnen, Heart
540
Feltes et al
Center Nordrhein-Westfalen, Gottingen, Germany; Isabelle Denjoy, MD, Jean-Marc Lupoglazoff, MD, Hopital Robert Debre, Paris, France; Francois Marcon, MD, Lucron Hugues, MD, Centre Hospitalier Universitaire De Nancy, Vandoeuvre Les Nancy, France; Michael J. Marsh, MD, Sarah L. Marsh, Elspeth Brown, Southampton General Hospital, Southampton, United Kingdom; Patrice Morville, MD, Pediatric Cardiology at American Memorial Hospital, Reims Cedex, France; Steven Neish, MD, Jayme Frank, RN, PNP, University of Wisconsin Children’s Hospital, Madison, WI; Mark Parrish, MD, Celia Buckley, RN, University of California, Davis, Sacramento, CA; Erkki Pesonen, MD, Gylfi Oskarsson, Laura Darcy, Lund University Hospital, Lund, Sweden; Gautam K. Singh, MD, Mary Pat Spillane, Colleen Puer, Cardinal Glennon Children’s Hospital and St Louis University, St Louis, MO; Athos Colon, MD, Charlie J. Sang, Jr, MD, Joon Park, MD, Sharon Welsh, RN, Barbara Levijoki, RN, Andrea Thomas, Texas Tech University Health Sciences Center, Lubbock, TX; Koravangattu Sankaran, MD, Ashok Kakadekar, MD, Michael Tyrrell, MD, University of Saskatchewan and Royal University Hospital, Saskatoon, Saskatchewan, Canada; Achim A. Schmaltz, MD, Ulrich E. Neudorf, MD, Frank Hentrich, MD, University Children’s Hospital, Essen, Germany; Hans-Heiner Kramer, MD, Angela Uebing, MD, Ulrike Hoffmann, MD, Department of Pediatric Cardiology, Christian Albrechts University, Kiel, Germany; Jan Sunnegardh, MD, Anders Nygren, MD, The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden; Debra Tristram, MD, East Carolina School of Medicine, Greenville, NC; Robert M. R. Tulloh, MD, Guys Hospital and St Thomas NHS Trust, London, United Kingdom; Henry B. Wiles, MD, Andrew M. Atz, MD, Medical University of South Carolina, Charleston, SC; Per Winberg, MD, Bo Sahlgren, Gunilla Malmquist, Astrid Lindgrens Children’s Hospital, Stockholm, Sweden; Fred P. Zepp, MD, P. Habermehl, MD, C. Kampmann, MD, Children’s Hospital, University of Mainz, Mainz, Germany; Jan Pellar, MD, Ewa Maskowska, MD, PhD, Elzbieta Wojcik, MD, PhD, First Department of Pediatrics, Allergology and Cardiology, Medical University of Wroclaw, Wroclaw, Poland; Grazyna Dawid, MD, PhD, Wojciech Wnuk, MD, PhD, Anita Horodnicka-Jozwa, MD, PhD, Pediatric Cardiology Department, Pomeranian Academy of Medicine, Szczecin, Poland; Krystyna Mackowska, MD, Wojewodzki Sziptal Dzieciecy Oddzial Pediatrii i Kardiologii, Bydgoszcz, Poland; Aleksander A. Wagner, MD, Barbara Antoniak, First Department of Cardiac and General Pediatric Surgery, Warszaw, Poland; Martin Ottolini, MD, Sally Henson, Uniformed Services University of the Health Sciences, Bethesda, MD; Franco M. Piazza, MD, MPHy, David A. Carlin, PhDz, Franklin H. Top, Jr, MDy, Edward M. Connor, MDy, MedImmune, Inc, Gaithersburg, MD.
The Journal of Pediatrics October 2003
Objectives To evaluate the safety, tolerance, and efficacy of palivizumab in children with hemodynamically significant congenital heart disease (CHD). Study design A randomized, double-blind, placebo-controlled trial included 1287 children with CHD randomly assigned 1:1 to receive 5 monthly intramuscular injections of 15 mg/kg palivizumab or placebo. Children were followed for 150 days. The primary efficacy end point was antigen-confirmed respiratory syncytial virus (RSV) hospitalization. Results
Palivizumab recipients had a 45% relative reduction in RSV hospitalizations (P = .003), a 56% reduction in total days of RSV hospitalization per 100 children (P = .003), and a 73% reduction in total RSV hospital days with increased supplemental oxygen per 100 children (P = .014). Adverse events were similar in the treatment groups; no child had drug discontinued for a related adverse event. Serious adverse events occurred in 55.4% of palivizumab recipients and 63.1% of placebo recipients (P < .005); none were related to palivizumab. Twenty-one children (3.3%) in the palivizumab group and 27 (4.2%) in the placebo group died; no deaths were attributed to palivizumab. The rates of cardiac surgeries performed earlier than planned were similar in the treatment groups.
Conclusions Monthly palivizumab (15 mg/kg IM) was safe, well-tolerated, and effective for prophylaxis of serious RSV disease in young children with hemodynamically significant CHD. (J Pediatr 2003;143:532-40)
ower respiratory tract disease caused by respiratory syncytial virus (RSV) accounts for more than 125,000 pediatric hospitalizations and approximately 6.3 deaths per 100,000 person-years among children up to 4 years of age in the United States.1-3 Children more likely to have increased morbidity and mortality rates as the result of complications of RSV infection include those with prematurity, chronic lung disease, or congenital heart disease (CHD).4,5 In children with cardiac abnormalities, one early study showed a 37% fatality rate for RSV-infected, hospitalized infants with CHD.6 More recent studies suggest that among infants with CHD who are hospitalized with RSV disease, 33% will require treatment in a pediatric intensive care unit (ICU), and 2.5% to 3.4% die of complications of the RSV infection.7,8 Infants with pulmonary hypertension are at greatest risk from RSV infection.6,7 In addition, nosocomial RSV infection has a particularly adverse impact on infants and children who become infected in the immediate preoperative or postoperative period for heart surgery.9,10 Two early efficacy trials with a hyperimmune RSV globulin (RSV-IGIV) to prevent RSV infection included infants and children with CHD. As part of the initial National Institutes of Health–sponsored RSV-IGIV trial, 87 infants with CHD were enrolled among 249 high-risk subjects.11 Results of this trial demonstrated an overall 63% relative reduction in RSV hospitalization compared with the control group; however, the trial was not powered for subgroup analysis of children with heart disease. A second trial conducted
L
CHD Congenital heart disease COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms
532
RSV RSV-IGIV
Respiratory syncytial virus Respiratory syncytial virus immune globulin, intravenous
From The Ohio State University and The Children’s Hospital, Columbus, Ohio; The Mayo Clinic and Mayo Eugenio Litta Children’s Hospital, Rochester, Minnesota; New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts; MedImmune, Inc, Gaithersburg, Maryland; and The University of Colorado and the Children’s Hospital, Denver, Colorado. *The members of the Cardiac Synagis Study Group appear in the Appendix. Supported by MedImmune, Inc. Submitted for publication Mar 11, 2003; revision received July 14, 2003; accepted Aug 1, 2003. Reprint requests: Timothy F. Feltes, MD, The Children’s Hospital, 700 Children’s Dr, ED622, Columbus, OH 43205. E-mail: [email protected]. Copyright ª 2003 Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1067/S0022-3476(03)00454-2
in 1992 to 1995 evaluated 416 children #4 years of age with CHD who were assigned to receive monthly RSV-IGIV or to an uninfused control group.12 Results showed only a trend toward RSV disease prevention. Interpretation of results in the second study was confounded by a disproportionately higher number of children with cyanotic CHD in the treatment group. An unexpected increase in surgically related adverse events in RSV-IGIV recipients with cyanotic CHD occurred relative to the control group. Although the precise explanation for this observation in infants with cyanotic heart disease is unclear, it may have been caused by an alteration in blood viscosity after administration of RSV-IGIV to patients with an elevated hematocrit concentration. The use of RSV-IGIV for prophylaxis of high-risk infants with prematurity and chronic lung disease has been largely replaced by a humanized murine monoclonal anti-F glycoprotein antibody preparation, palivizumab.13 Palivizumab has been studied extensively in children with prematurity with or without chronic lung disease and shown to be safe and effective at a dose of 15 mg/kg monthly, reducing the incidence of RSV-associated hospitalizations by 55%.14 Palivizumab was expected to be safe and effective in infants with cyanotic heart disease because it is administered in a 100-fold lesser volume and 50-fold smaller protein load than RSVIGIV. Nonetheless, pending the availability of data in CHD patients, palivizumab was recommended for use in children with CHD only if heart disease was hemodynamically insignificant and only if an infant qualified for prophylaxis on the basis of the presence of prematurity or chronic lung disease.15 The purpose of the current study was to address the safety, tolerance, and efficacy of palivizumab in infants and young children with hemodynamically significant CHD.
METHODS Design and Patient Population This was a multicenter, randomized, double-blind, placebo-controlled trial in children with CHD. The study was conducted during 4 consecutive RSV seasons, 1998 through 2002. Each child participated during only one season. The local institutional review board or independent ethics committee approved the study protocol, and parents or guardians gave written informed consent before participation. The study was conducted at 76 centers in the United States (n = 47), Canada (n = 6), Sweden (n = 3), Germany (n = 4), Poland (n = 6), France (n = 4), and the United Kingdom (n = 6). The primary objective of this study was to compare the safety, tolerance, and efficacy of palivizumab with placebo when given monthly for the reduction of the incidence of RSV hospitalization among children with hemodynamically significant CHD. The secondary objectives were to determine the effect of monthly palivizumab prophylaxis compared with placebo on RSV hospitalization outcomes as measured by total days of RSV hospitalization, total RSV hospital days with increased oxygen requirement, incidence and total days of
RSV-associated intensive care, and incidence and total days of RSV-associated mechanical ventilation (total days were summarized per 100 randomized children); to describe the effect of cardiac bypass on serum palivizumab concentrations; and to determine palivizumab trough concentrations before the second and fifth doses. Children were eligible if they were #24 months old at the time of random assignment, had documented hemodynamically significant CHD determined by the investigator, and had unoperated or partially corrected CHD. Children were not eligible if they had unstable cardiac or respiratory status, including cardiac defects so severe that survival was not expected or for which cardiac transplantation was planned or anticipated; were hospitalized, unless discharge was anticipated within 21 days; anticipated cardiac surgery within 2 weeks of random assignment; required mechanical ventilation, extracorporeal membrane oxygenation, continuous positive airway pressure, or other mechanical respiratory or cardiac support; had associated noncardiac anomalies or end-organ dysfunction resulting in anticipated survival of <6 months or unstable abnormalities of end-organ function. Additional exclusion criteria were known HIV infection; acute RSV or other acute infection or illness; previous receipt of palivizumab or other monoclonal antibody; receipt of investigational agents within the previous 3 months (other than investigational agents commonly used during cardiac surgery or the immediate postoperative period, ie, nitric oxide); current participation in other investigational protocols of drugs or biological agents; or receipt of intravenous immune globulin (IGIV), including RSV-IGIV (RespiGam, MedImmune, Inc, Gaithersburg, Md), within 3 months before random assignment or anticipated use of IGIV, RSV-IGIV, or open-label palivizumab during the study period. Children with uncomplicated small atrial or ventricular septal defects or patent ductus arteriosus were excluded. Random assignment was based on a computer-generated sequence and was stratified by site to reduce the effect of practice discrepancies and anatomic cardiac lesion (cyanotic or ‘‘other’’). Random assignment was performed centrally with the use of an interactive voice response system. Children with the following anatomic diagnoses were included in the cyanotic stratum: pulmonary atresia with ventricular septal defect, pulmonary atresia with intact septum, tetralogy of Fallot, single ventricle including hypoplastic left or right heart, tricuspid atresia, double-outlet right ventricle with transposed great arteries, Ebstein anomaly, or D-transposition of the great arteries with/without ventricular septal defect, with/without pulmonary stenosis. The remaining children were stratified to the ‘‘other’’ (acyanotic) stratum. Eligible children were randomly assigned (1:1) to receive either palivizumab (15 mg/kg) or an equal volume of identically appearing placebo (same formulation without antibody and with 0.02% Tween-80 added) by intramuscular injection every 30 days for a total of 5 doses. Palivizumab and placebo were supplied as lyophilized product in coded vials that were reconstituted by the pharmacist with sterile water for injection (final concentration of palivizumab is 100 mg/mL) and dispensed in a syringe that did not identify the contents.
Palivizumab Prophylaxis Reduces Hospitalization Due to Respiratory Syncytial Virus in Young Children With Hemodynamically Significant Congenital Heart Disease
533
Outcomes Children were followed for 150 days from random assignment (30 days after the last scheduled study injection) for hospitalization and for the occurrence of adverse events. All hospitalizations were identified, and in children with an acute cardiorespiratory hospitalization, RSV antigen testing of respiratory secretions was performed with the use of commercially available tests. The primary end point of the trial was the incidence of RSV hospitalization, including primary RSV hospitalizations and nosocomial RSV hospitalizations. A primary RSV hospitalization was defined as a hospitalization for an acute cardiorespiratory illness in which the RSV antigen test was positive within 48 hours before or after admission. Deaths occurring outside the hospital that could be demonstrated to be associated with RSV were also considered as primary RSV hospitalization end points. A nosocomial RSV hospitalization was one in which hospitalized patients had an objective measure of worsening cardiorespiratory status reported as a serious adverse event and the RSV antigen test was positive. RSV hospitalizations were monitored for total days, days of supplemental oxygen, days of intensive care, and days of mechanical ventilation. Decisions on hospitalization, discharge, and other aspects of therapy for RSV disease were left to the treating physician’s discretion. Any adverse change from a child’s medical condition at entry was reported as an adverse event, graded for severity, and assessed by the blinded investigator as to potential relation to study drug. Serious adverse events were those that resulted in death; were lifethreatening; resulted in hospitalization or prolonged hospitalization; resulted in significant disability; or were another important medical event that required intervention to prevent one of the above outcomes. Serum was collected before the first, second, and fifth injections of study drug, and, if cardiac bypass was used during surgery, before bypass and on the day after bypass. Palivizumab concentrations were analyzed with the use of a previously described enzyme immunosorbent assay.16 Serum RSV neutralizing antibody titers at study entry were assessed in a plaque reduction neutralization test.17
Sample Size and Statistical Analysis Assuming an RSV hospitalization rate of 12.0% in the placebo group compared with 7.2% in the palivizumab group, approximately 1280 children were to be randomly assigned (1:1) to provide 80% power of showing a 40% relative reduction in the incidence of RSV hospitalizations, using a 2-sided a-level of 0.05. After completion of the second year of the study, the Data Safety Monitoring Board undertook a planned interim analysis of the primary end point of RSV hospitalization. Six hundred ninety-eight patients representing approximately 54% of the total number of patients had completed the study at that time. The Lan-DeMets procedure, using the approximate O’Brien-Fleming boundaries, was used to determine the adjusted P value (.048) required for significance of the primary end point. All randomly assigned patients were included in the safety and efficacy analyses. Statistical comparison of groups 534
Feltes et al
was performed with the Fisher exact test for categorical variables and Wilcoxon rank sum test for continuous variables. The Kaplan-Meier analysis assessing time to first RSV hospitalization was used as a confirmatory test accounting for incomplete follow-up. The Cochran-Mantel-Haenszel test was used to evaluate the primary end point across strata. Logistic regression was performed with the use of predefined variables (age, sex, and stratum). Treatment groups were compared for adverse events (COSTART coded terms) by evaluating the number of children in each group with at least one event by body system and the distribution of severity and relatedness of these events. Patients who received at least one dose of study drug were included in the analyses of serum palivizumab concentrations, unless they were known to have received off-study palivizumab or had a documented dosing error (eg, received the incorrect study drug on at least one occasion).
RESULTS Starting on November 1 and ending on or before December 31 of each year between 1998 and 2001, a total of 1287 patients were randomly assigned. Study sites in the United States and Canada randomly assigned 800 (62.2%) and 133 (10.3%) children, respectively. The remaining children were randomly assigned in Poland (150, 11.6%), the United Kingdom (95, 7.4%), Germany (49, 3.8%), Sweden (33, 2.6%), and France (27, 2.1%). From 1 to 45 patients were randomly assigned per site, with an average of 17 patients per site. Six sites randomly assigned less than 5 patients, and 25 sites randomly assigned 20 or more patients. A total of 1287 children were randomly assigned: 639 to the palivizumab group and 648 to the placebo group. Overall, 93.0% of children in the palivizumab group and 91.8% in the placebo group received all five planned injections; 95.6% in the palivizumab group and 95.5% in the placebo group completed the study. The groups were balanced for demographic characteristics, RSV risk factors, and parameters of cardiovascular disease (Table I). Of the 1287 children randomly assigned in the study, 682 (53.0%) were in the cyanotic stratsum and 605 (47.0%) in the ‘‘other’’ stratum. The distribution of cardiac lesions was balanced between the two treatment groups. The cyanotic lesions, single ventricle including hypoplastic left or right heart and tetralogy of Fallot, accounted for 21.9% and 11.4%, respectively, of all children enrolled, whereas the acyanotic lesions, ventricular septal defect and atrioventricular septal defect, occurred in 18.0% and 7.2%, respectively, of those enrolled.
Incidence of RSV Hospitalization Monthly prophylaxis with palivizumab was associated with a 45% relative reduction in RSV hospitalization rate (P = .003, Table II). RSV hospitalization rates were 9.7% in the placebo group and 5.3% in the palivizumab group. Nine placebo recipients and three palivizumab recipients had nosocomial RSV hospitalizations. Five children (3 placebo The Journal of Pediatrics October 2003
Table I. Demographic characteristics, RSV risk factors, and parameters of CHD at study entry Palivizumab (n = 639)
Placebo (n = 648)
P value*
290 (45.4%)
304 (46.9%)
.615
453 77 52 57 27 6.8 6.1 38.5
459 (70.8%) 66 (10.2%) 61 (9.4%) 62 (9.6%) 23 (3.5%) 6.5 (0.2) 6.0 (0.1) 38.5 (0.1)
.639
.566 .510 .683 .741
Demographic characteristics Sex Female Race/ethnic group White Hispanic Black Other Multiple birth Mean age in months at entry (SE) Mean weight in kg at entry (SE) Mean gestational age in weeks (SE)
(70.9%) (12.1%) (8.1%) (8.9%) (4.2%) (0.2) (0.1) (0.1)
RSV risk factors Mean number of persons in home (SE) Proportion with RSV neutralizing antibody titer $1:200 at baseline Child in day care Other children in day care Smoker in household Family history of asthma
4.4 (0.1) 170 (31.4%)y
4.4 (0.1) 173 (30.5%)y
.918 .795
76 100 211 172
(11.9%) (15.6%) (33.0%) (27.7%)z
69 (10.6%) 115 (17.7%) 223 (34.4%) 191 (29.7%)z
.482 .152 .122 .456
Characteristics of CHD at study entry Cyanotic stratum Previous cardiac surgery or interventional catheterization Hypercyanotic episode Receiving cardiac medications Congestive heart failure Pulmonary hypertension Increased pulmonary blood flow
339 396 73 484 401 152 237
(53.1%) (62.0%) (11.4%) (75.7%) (62.8%) (23.8%) (37.1%)
343 (52.9%) 391 (60.3%) 84 (13.0%) 491 (75.8%) 428 (66.0%) 164 (25.3%) 253 (39.0%)
1.000 .568 .443 1.000 .333 .534 .491
*P values for categorical variables were obtained from Fisher exact test; those for continuous variables were obtained from Wilcoxon rank sum test. yn = 542 palivizumab, 567 placebo. zn = 622 palivizumab, 643 placebo.
and 2 palivizumab recipients) had more than one RSV hospitalization. The result was robust in sensitivity analyses including (1) addition of adjusted rates for those children with respiratory hospitalizations for whom an RSV antigen test was not performed (P = .004), (2) inclusion of children who did not have an RSV hospitalization documented and did not complete follow-up through day 150 (P = .005), and (3) inclusion of children (n = 3) hospitalized with virologic evidence of RSV but who did not meet the protocol defined criteria for RSV hospitalization (P = .002). Cochran-MantelHaenszel analysis of RSV hospitalization across strata was significant (P = .003), and treatment remained significant (P = .004) in logistic regression performed with predefined variables (age, sex, and cardiac strata). Reductions in RSV hospitalization were seen in both strata, although the study was not powered for subgroup analyses. In the cyanotic stratum, RSV hospitalizations were reduced by 29%, from 7.9% in the placebo group to 5.6% in the palivizumab group (P = .285). In the ‘‘other’’ stratum, RSV hospitalizations were
reduced by 58%, from 11.8% in the placebo group to 5.0% in the palivizumab group (P = .003). Cochran-Mantel-Haenszel analyses of RSV hospitalization across sex, age at entry (#6 months or >6 months), weight at entry (#6 kg or >6 kg), race (white or other), location (United States, Canada, Europe), study year (year 1, 2, 3, 4), and neutralizing antibody at entry (<1:200 or $1:200) all were highly significant (P < .01), indicating consistency of the benefit across these subgroups. RSV hospitalization rates for infants <6 months old were 12.2% placebo versus 6.0% palivizumab, with corresponding rates of 7.3% versus 6.1% for infants 6 to 12 months old and 4.3% versus 1.8% for children 1 to 2 years old. RSV hospitalization rates for the placebo and palivizumab groups, respectively, by locations were the United States (10.6% vs 5.9%), Canada (11.9% vs 7.6%), and Europe (7.0% vs 3.0%).
Secondary Efficacy End Points As shown in Table III, children randomly assigned to palivizumab had significantly fewer total days of RSV
Palivizumab Prophylaxis Reduces Hospitalization Due to Respiratory Syncytial Virus in Young Children With Hemodynamically Significant Congenital Heart Disease
535
Table II. Analysis of incidence of RSV hospitalization
Primary end point analysisy Kaplan-Meier analysisz Sensitivity analyses Inclusion of no antigen test §k Inclusion of noncompleters§{ Inclusion of nonprotocol RSV testing**
Palivizumab (n = 639)
Placebo (n = 648)
Relative reduction (95% CI)
P value*
34 (5.3%) 34 (5.3%)
63 (9.7%) 63 (9.7%)
45% (23, 67) 45% (23, 67)
.003 .003
35 (5.5%) 37 (5.8%) 35 (5.5%)
63 (9.7%) 65 (10.0%) 65 (10.0%)
43% (20, 66) 42% (19, 65) 45% (23, 67)
.004 .005 .002
*P value was obtained from Fisher exact test. yChildren with more than one RSV hospitalization were counted only once. Two children (1 in each treatment group) died in the ER from RSV bronchiolitis and, by convention, were counted as end points. zKaplan-Meier estimate of the proportion with RSV hospitalization at 150 days. Deaths before RSV hospitalization, withdrawals, and lost events were treated as censored. For the 2 children who died in the ER from RSV bronchiolitis, total days on study were used for the analysis. §Events were added to each treatment group in proportion to the number of children who would have had a RSV hospitalization if the proportion hospitalized was equal to that of the other treatment group (n 3 0.097 events added for palivizumab; n 3 0.053 events added for placebo). kProportional adjustments made for the number of children (14 palivizumab; 9 placebo) who had no endpoint and who had a hospitalization for an acute cardiorespiratory illness with evidence of respiratory infection (coryza, fever, apnea), without alternative etiology and with no RSV antigen test done (or negative test and done outside the protocol-specified window). {Proportional adjustments made for the number of children (28 palivizumab; 29 placebo) who stopped follow-up before day 150 and who had no endpoint through the last follow-up visit. **Three children (1 palivizumab, 2 placebo) who were hospitalized with virologic evidence of RSV lower respiratory tract infection but did not meet the protocol-specified case definition were added.
Table III. Summary of secondary end points related to RSV hospitalization
Days of RSV hospitalization Total days Total days/100 children RSV hospital days of increased supplemental oxygen therapy Total days Total days/100 children ICU admission No Yes Days of ICU stay Total days Total days/100 children Mechanical ventilation No Yes Days of mechanical ventilation Total days Total days/100 children
Palivizumab (n = 639)
Placebo (n = 648)
367 57.4
836 129.0
Relative reduction (%)
P value* .003
56 .014
178 27.9
658 101.5
626 (98.0%) 13 (2.0%)
624 (96.3%) 24 (3.7%)
101 15.9
461 71.2
631 (98.7%) 8 (1.3%)
634 (97.8%) 14 (2.2%)
42 6.5
354 54.7
73 .094 46 .080 78 .282 41 .224 88
*P values for total days were obtained from Wilcoxon test; P values for incidence were obtained from Fisher exact test.
hospitalization per 100 children (56% reduction; 129.0 days placebo vs 57.4 days palivizumab, P = .003) and RSV hospital days with increased oxygen requirement per 100 children (73% reduction; 101.5 days placebo vs 27.9 days palivizumab, P = .014). A similar trend favoring palivizumab was observed for incidence of RSV-associated intensive care (46% reduction, P = .094), days of RSV-associated intensive care per 536
Feltes et al
100 children (78% reduction, P = .080), incidence of RSVassociated mechanical ventilation (41% reduction, P = .282), and days of RSV-associated mechanical ventilation per 100 children (88% reduction, P = .224). Prolonged RSV hospitalization ($14 days) occurred in fewer palivizumab recipients compared with placebo recipients (16 placebo vs 5 palivizumab). The Journal of Pediatrics October 2003
Table IV. Summary of safety data Adverse event category Total No. of adverse events Total No. of children with Adverse event Adverse event coding to cardiovascular system Adverse event coding to respiratory system Adverse event requiring medical intervention Related adverse event Related adverse event resulting in permanent discontinuation Serious adverse event Related serious adverse event Fatalities
Palivizumab (n = 639)
Placebo (n = 648)
4169
4518
611 (95.6%) 286 (44.8%) 525 (82.2%) 588 (92.0%) 46 (7.2%) 0 (0.0%) 354 (55.4%) 0 (0.0%) 21 (3.3%)
625 (96.5%) 315 (48.6%) 547 (84.4%) 605 (93.4%) 45 (6.9%) 0 (0.0%) 409 (63.1%) 3 (0.5%) 27 (4.2%)
P value*
.477 .180 .296 .392 .914 — .005 .249 .463
*P values were obtained from Fisher exact test.
An 11.8% reduction in the incidence of hospitalization for any cause was observed in the palivizumab group (62.3% placebo vs 54.9% palivizumab, P = .008). Differences in the relative rates of RSV hospitalization were major contributions to this difference; when RSV hospitalizations were removed from the analysis, the reduction in hospitalization rate was 9.3% (59.0% placebo vs 53.5% palivizumab, P = .056). The proportion of children with a cardiorespiratory hospitalization was 55.4% in the placebo group and 50.2% in the palivizumab group (P = .066).
Safety and Tolerability As shown in Table IV, the proportion of children with adverse events, adverse events that required medical intervention, and adverse events judged by the blinded investigator to be related to the study drug was similar between the two groups. No child had study drug discontinued for a related adverse event. Few adverse events were reported at an absolute incidence $1% higher in the palivizumab group compared with the placebo group. Those adverse events were limited to fever (27.1% palivizumab vs 23.9% placebo), infection (5.6% vs 2.9%), study drug injection site reaction (3.4% vs 2.2%), URI (47.4% vs 46.1%), conjunctivitis (11.3% vs 9.3%), arrhythmia (3.1% vs 1.7%), and cyanosis (9.1% vs 6.9%). None of the events reported as arrhythmia and one reported as cyanosis (placebo recipient) were judged related to the study drug. The most common injection site reactions were redness, swelling and bruising; none was serious. The incidence of serious adverse events was significantly lower in the palivizumab group compared with the placebo group (55.4% vs 63.1%, P = .005, Table IV). This trend was observed in both the cyanotic stratum (59.9% vs 67.1%, P = .056) and the ‘‘other’’ stratum (50.3% vs 58.7%, P = .041). When serious adverse events reported during all RSV hospitalizations were removed from the analysis, the P value was .043. Arrhythmia was reported as a serious adverse event in 0.2% and 0.3% of the palivizumab and placebo groups,
Table V. Summary of cardiac surgery/interventional catheterization Palivizumab (n = 639) No. of children with proceduresy None Planned Earlier than planned Urgent
Placebo (n = 648)
P value* .665
421 (65.9%) 164 (25.7%) 34 (5.3%) 20 (3.1%)
410 (63.3%) 186 (28.7%) 34 (5.2%) 18 (2.8%)
*P value obtained from Fisher exact test assessing independence of treatment assignments and cardiac procedures. yChildren having multiple procedures were counted only once by the most urgent procedure.
respectively. Cyanosis was reported as a serious adverse event in 3.6% of the palivizumab group (23 patients) and 2.2% of the placebo group (14 patients); these included 20 and 14 patients, respectively, in the cyanotic stratum and 3 and 0, respectively, in the ‘‘other’’ stratum. Within 30 days after onset of the cyanotic serious adverse event, equal proportions of the palivizumab group (14 patients, 2.2%) and placebo group (12 patients, 1.9%) had earlier-than-planned or urgent surgery or died (1 in each group). No serious adverse events related to palivizumab were reported. The incidence rates of cardiac surgeries classified as planned, earlier than planned, or urgent were balanced between treatment groups (Table V). A total of 48 children died during the study: 21 (3.3%) in the palivizumab group and 27 (4.2%) in the placebo group (Table IV). No deaths were attributed to study drug. Six children (4 cyanotic and 2 ‘‘other’’ strata) in the palivizumab group and 5 children (2 cyanotic and 3 ‘‘other’’ strata) in the placebo group had surgery-associated deaths. Deaths associated with RSV infection occurred in 2 patients in the palivizumab group and 4 patients in the placebo group.
Palivizumab Prophylaxis Reduces Hospitalization Due to Respiratory Syncytial Virus in Young Children With Hemodynamically Significant Congenital Heart Disease
537
Serum Palivizumab Levels Mean (±SD) serum palivizumab concentrations before the second and fifth doses were 55.5 (±19) lg/mL and 90.8 (±35) lg/mL in the palivizumab group and 0.4 (±5) lg/mL and 0.1 (±2) lg/mL in the placebo group. Only 7.9% of the palivizumab group tested had concentrations before the second dose <30 lg/mL, the concentration found to reduce mean pulmonary RSV titers by 2 log10 in the cotton rat model.13 Paired serum was available before and after cardiac bypass for 139 palivizumab recipients. Before and after cardiopulmonary bypass, the mean (±SD) serum palivizumab concentrations were 98.0 (±52) lg/mL and 41.4 (±33) lg/mL, respectively. This represents a reduction of 58% (P = .0001) in serum palivizumab concentration after bypass.
DISCUSSION This large, placebo-controlled trial demonstrates the benefit of palivizumab prophylaxis in children with CHD. Children receiving prophylaxis had a 45% (95% CI: 23, 67) relative reduction in RSV hospitalization. These results are consistent with the IMpact-RSV trial in children with prematurity with or without chronic lung disease, in which a 55% (95% CI: 38, 72) relative reduction was observed.14 The reduction in RSV hospitalization rate was evident in both the cyanotic (7.9% placebo vs 5.6% palivizumab, P = .285) and the ‘‘other’’ or acyanotic strata (11.8% vs 5.0%, P = .003), although reduction was statistically significant only in the acyanotic stratum. Using the predicted 12.0% placebo RSV hospitalization rate, the power to show a statistically significant reduction of 40% in the cyanotic stratum was 51%. Using the low placebo RSV hospitalization rate of 7.9% observed in the cyanotic stratum, the post hoc power estimation is 34%. When RSV hospitalization was assessed across strata through the use of the Cochran-Mantel-Haenszel method, the P value was .003, consistent with benefit in both strata. This trend was consistent in patients from all geographic areas (United States, Canada, and Europe) and was evident in male and female subjects, in children #6 months and >6 months of age at entry, in children #6 kg and >6 kg at entry, and in children of either white race or all other races combined. The reduction in RSV hospitalization was accompanied by a significant reduction in days of RSV hospitalization per 100 children randomly assigned (129.0 days placebo vs 57.4 days palivizumab, P = .003) and RSV hospital days with increased oxygen requirement per 100 children (101.5 days vs 27.9 days, P = .014). Prolonged RSV hospitalization ($14 days) occurred in fewer palivizumab recipients compared with placebo recipients (16 placebo vs 5 palivizumab). The incidence and days of RSV-associated intensive care and the incidence and days of RSV-associated mechanical ventilation appeared lower in the palivizumab group; the study was not powered to show statistical significance for these outcomes. Deaths associated with RSV infection occurred in 2 patients in the palivizumab group and 4 patients in the placebo group, a trend similar to that seen in a previous RSV-IGIV study in 538
Feltes et al
patients with CHD (1 patient in the RSV-IGIV group and 3 patients in the control group).12 In the current study, the safety profile of palivizumab in patients with CHD was similar to that observed in other pediatric populations. Children receiving palivizumab prophylaxis had a slightly higher rate of fever (3.2% difference between groups) and reactions at the injection site (1.2% difference) compared with control subjects. These events were generally of low severity and did not result in alteration of the prophylaxis regimen. The incidence of adverse events was similar between groups, whereas there was significantly lower incidence of serious adverse events among palivizumab recipients relative to control subjects. Serious adverse events coding to cyanosis were somewhat more frequent in the palivizumab group (23 children, 3.6%) than the placebo group (14 children, 2.2%). However, cyanotic serious adverse events leading to earlier-than-planned or urgent surgery or death (1 child in each group) were balanced between treatment groups. Rates of earlier-than-planned and urgent cardiac surgeries were carefully and prospectively monitored throughout the course of the study. There were no differences observed in the rates of these events between palivizumab and placebo recipients. Previous studies suggested a potential problem in RSVIGIV recipients with regard to deaths associated with surgery.11,12 A total of 48 children died during the current study: 21 (3.3%) in the palivizumab group and 27 (4.2%) in the placebo group. Deaths associated with cardiac surgery were similar between treatment groups. No deaths were attributed to study drug. Thus the results from this study demonstrate the safety of monthly palivizumab prophylaxis in children with CHD. Patients with CHD receiving palivizumab prophylaxis may undergo cardiopulmonary bypass during surgical procedures. Data obtained during this study demonstrate that serum palivizumab concentrations in children undergoing open heart surgery were reduced by >50% after the cardiopulmonary bypass procedure. Because serum concentrations may fall below a protective level, it is appropriate to administer another dose of palivizumab (15 mg/kg) after surgery. The results of this trial demonstrate that palivizumab can be administered safely to infants and young children with hemodynamically significant CHD. Monthly prophylaxis results in a 45% reduction in RSV hospitalization in this high-risk population. Guidelines for the use of palivizumab in patients with CHD have been issued by the American Academy of Pediatrics,18 and evaluation by the United States Food and Drug Administration is pending. We thank W. Ripley Ballou, MD, James F. Balsley, MD, PhD, Bernard Landry, MPH, Judith Scott, MPH, Peggy McDonald, RN, Lori Ovington, Ray Hsieh, Rong Ye, and Kevin Crawford of MedImmune, Inc, for their contributions to this study; Barbara Shepherd, PhD, of MedImmune, Inc, for assistance in preparation of the manuscript; Virginia Capps, Randi Gower, Patricia Keegan, and the clinical monitoring and data management/biostatistics staff at PPD Development, Inc; the clinical research staff at all the participating sites; and all of the children and families who The Journal of Pediatrics October 2003
participated in this study. We also thank the members of the Data Safety and Monitoring Board, Catherine Wilfert, MD, David DeMets, PhD, and Maryanne Kichuk-Chrisant, MD, for their time and effort.
REFERENCES 1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children. JAMA 1999;282:1440-6. 2. Shay DK, Holman RC, Roosevelt GE, Clarke MJ, Anderson LJ. Bronchiolitis-associated mortality and estimates of respiratory syncytial virusassociated deaths among US children, 1979-1997. J Infect Dis 2001;183: 16-22. 3. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-86. 4. Aujard Y, Fauroux B. Risk factors for severe respiratory syncytial virus infection in infants. Respir Med 2002;96:S9-14. 5. Boyce TG, Mellen BG, Mitchel EF, Wright PF, Griffen MR. Rates of hospitalization for respiratory syncytial virus among children in Medicaid. J Pediatr 2000;137:865-70. 6. MacDonald NE, Hall CB, Suffin SC, Alexson C, Harris PJ, Manning JA. Respiratory syncytial viral infection in infants with congenital heart disease. N Engl J Med 1982;307:397-400. 7. Navas L, Wang E, de Carvalho V, Robinson J. Pediatric Investigators Collaborative Network on Infections in Canada: improved outcome of respiratory syncytial virus infection in a high-risk hospitalized population of Canadian children. J Pediatr 1992;121:348-54. 8. Moler FW, Khan AS, Meliones JN, Custer JR, Palmisano J, Shope TC. Respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience. Crit Care Med 1992;20:1406-13. 9. Khongphatthanayothin A, Wong PC, Samara Y, Newth CJL, Wells WJ, Starnes VA, et al. Impact of respiratory syncytial virus infection on surgery for congenital heart disease; postoperative course and outcome. Crit Care Med 1999;27:1974-81. 10. Altman CA, Englund JA, Demmler G, Drescher KL, Alexander MA, Watrin C, et al. Respiratory syncytial virus in patients with congenital heart disease: a contemporary look at epidemiology and success of preoperative screening. Pediatr Cardiol 2000;21:433-8. 11. Groothuis JR, Simoes EAF, Levin MJ, Hall CB, Long CE, Rodriguez WJ, et al. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 1993;329:1524-30. 12. Simoes EAF, Sondheimer HM, Top FH Jr, Meissner HC, Welliver RC, Kramer AA, et al. Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. J Pediatr 1998;133:492-9. 13. Johnson S, Oliver C, Prince GA, Hemming VG, Pfarr DS, Wang SC, et al. Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis 1997;176:1215-24. 14. IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102:531-7. 15. American Academy of Pediatrics. Respiratory Syncytial Virus. In: Pickering LK, editor. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th edition. Elk Grove Village, Ill: American Academy of Pediatrics; 2000. p. 483-7. 16. Saez-Llorens X, Castano E, Null D, Steichen J, Sanchez PJ, Ramilo O, et al. Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. Pediatr Infect Dis J 1998;17:787-91. 17. Coates HV, Alling DW, Chanock RM. An antigenic analysis of respiratory syncytial virus isolates by a plaque reduction neutralization test. Am J Epidemiol 1966;83:299-313. 18. American Academy of Pediatrics. Respiratory Syncytial Virus. In: Pickering LK, editor. 2003 Red Book: Report of the Committee on Infectious
Diseases. 26th edition. Elk Grove Village, Ill: American Academy of Pediatrics; 2003. p. 523-8.
APPENDIX Members of the Cardiac Synagis Study Group (yadvisory/ writing committee; zlead statistician): Timothy F. Feltes, MDy, Beth Kossmann, RN, Children’s Hospital, Columbus, OH, and Jennifer Clifton, RN, Linda Drake, RN, Angelia Turner, RN, Texas Children’s Hospital, Houston, TX; Allison K. Cabalka, MDy, Patrick W. O’Leary, MD, Cindy M. Woltman, RN, Mayo Clinic, Rochester, MN; H. Cody Meissner, MDy, Ziyad M. Hijazi, MD, Sharon E. O’Brien, MD, Jonathan Rhodes, MD, New England Medical Center, Boston, MA; Henry M. Sondheimer, MDy, Rosa Owens, RN, Barbara Carillo, Children’s Hospital and University of Colorado HSC, Denver, CO; Scott D. Gullquist, MD, Richard M. Schieken, MD, Ellen B. Swoope, RN, Medical College of Virginia and VCU Health System, Richmond, VA; Charles S. Kleinman, MD, Alan H. Friedman, MD, Cindy Guandalini, APRN, BC, Yale University School of Medicine, New Haven, CT; Lorry G. Rubin, MD, Steven Ritz, MD, Nancy Stellato, RN, The Schneider Children’s Hospital of the North Shore, Long Island Jewish Health System, New Hyde Park, NY; Arno R. Hohn, MD, Children’s Hospital of Los Angeles and University of Southern California’s Keck School of Medicine, Los Angeles, CA; Angela Sharkey MD, Mary Boyle, RN, St Louis Children’s Hospital, St Louis, Mo; Michael S. Epstein, MD, Vijaya Joshi, MD, Children’s Hospital of Michigan and Wayne State University, Detroit, MI; Dennis Crowley, MD, C. S. Mott Children’s Hospital and University of Michigan, Ann Arbor, MI; Susan A. Miller, MD, Pamela Bowman, RN, Children’s Hospital of Pittsburgh, Pittsburgh, PA; Ira H. Gessner, MD, Connie Nixon, RN, University of Florida College of Medicine, Gainesville, FL; Kenneth J. Dooley, MD, Sibley Heart Center-Cardiology, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA; Sam Gidding, MD, Ram Yogev, MD, Children’s Memorial Hospital, Chicago, IL; Thomas P. Graham, MD, Judy Burger, RN, Vanderbilt University Medical Center, Nashville, TN; Christian Hardy, MD, Julie Simon, Children’s Hospital Oakland, Oakland, CA; Frank F. Ing, MD, Children’s Hospital and Health Center, San Diego, CA; Craig R. Cohen, MD, Sharon Pfeiffel, RN, MS, CPNP, Arizona Pediatric Cardiology Consultants, Phoenix, AZ; Marc H. Lebel, MD, FRCPC, Sainte Justine Hospital, University of Montreal, Quebec, Canada; Stephen Paridon, MD, Alena Hogerty, MD, Children’s Hospital of Philadelphia, Philadelphia, PA; Mark D. Reller, MD, Oregon Health and Science Center, Portland, OR; David A. Roberson, MD, Anne Freter, RN, The Heart Institute for Children, Oaklawn, IL; Kerry L. Rosen, MD, Sarah Sturgis, CRNP, Deb Dilworth, RN, CCRC, The Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, PA; Geoffrey Rosenthal, MD, PhD, Collette Fearneyhough, MSN, PNP, Children’s Hospital and Regional Medical Center, Seattle, WA; Patricia A. Hughes, DO, Martha L.
Palivizumab Prophylaxis Reduces Hospitalization Due to Respiratory Syncytial Virus in Young Children With Hemodynamically Significant Congenital Heart Disease
539
Lepow, MD, Mary Terese Evans, RN, Albany Medical College, Albany, NY; Denise Bratcher, DO, Judith Theriot, MD, Alice Gittings, RN, CCRC, University of Louisville, Louisville, KY; Robert C. Welliver, MD, Cynthia Shuff, Kathy Alessi, Children’s Hospital of Buffalo, Buffalo, NY; Luby Abdurrahman, MD, Shirah Shore, Khaled Salaymeh, Children’s Hospital Medical Center, Cincinnati, OH; Raymond T. Fedderly, MD, Children’s Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee, WI; David E. Fixler, MD, Fiker Zeray, PNP, Children’s Medical Center and University of Texas Southwestern Medical Center, Dallas, TX; Joanne M. Langley, MD, Andrew Warren, IWK Health Center and Dalhousie University, Halifax, Nova Scotia, Canada; Jay M. Lieberman, MD, Robin Doroshow, MD, Nan O’Donnell, MS, RN, Miller Children’s Hospital, Long Beach, CA; Jane McDonald, MD, Charles Rohlicek, MD, Lorraine Piche-Walker, RN, Montreal Children’s Hospital, Quebec, Canada; David W. Kimberlin, MD, Kelly Smitherman, RN, The University of Alabama at Birmingham, Birmingham, AL; Leonard R. Krilov, MD, Carlos Montoya, MD, Kathy Usmani, NP, Winthrop University Hospital, Mineola, NY; Elaine Wang, MD, David Nykanen, MD, Kyong-Jin Lee, MD, The Hospital for Sick Children, Toronto, Ontario, Canada; Michael Tosi, MD, Mount Sinai Medical Center, New York, NY; Anne Thomson, MD, Joanna Sidey, John Radcliffe Hospital, Oxford, United Kingdom; Andrzej Sysa, MD, Pawet Dryzek, Katarzyna Ostrowska, Department of Pediatric Cardiology, Mother and Child Health Center-Research Institute, Lodz, Poland; Maria Popczynska-Marek, MD, Leslaw Szydlowski, MD, Maciej Pitak, Department of Pediatric Cardiology, Polish-American Children’s Hospital, Jagiellonian University, Crakow, Poland; Michael Blackburn, MD, Pediatric Cardiology, Leeds General Infirmary, Leeds, United Kingdom; Marc P. Blayney, MB, BCh, FRCPC, Jane Lougheed, MD, FRCPC, Nancy Dean-Melanson, RN, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Joel Brenner, MD, Glenda Roberts, RN, Johns Hopkins Hospital, Baltimore, MD; Michael M. Brook, MD, Elizabeth Tong, RN, University of California, San Francisco, CA; Francis Casey, MD, FRCP, Isabel Hannigan, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland, United Kingdom; Alan Chantepie, MD, Hopital Clocheville, University of Tours, Tours Cedex, France; Piers Daubeney, MD, Dominic Abrams, MD, Elizabeth Cashin, Royal Brompton Hospital, London, United Kingdom; Patrick Finnigan, MD, Lori Davis, RN, Children’s Cardiology Associates, Austin, TX; Therese M. Giglia, MD, Russell Cross, MD, Susan Young, RN, Children’s National Medical Center, Washington, DC; Gerd Hausdorf, MD, Universitatsklinikum Gottingen, Gottingen, Germany; Matthias Peuster, MD, Julia Recuers, MD, Iranziska Cohnen, Heart
540
Feltes et al
Center Nordrhein-Westfalen, Gottingen, Germany; Isabelle Denjoy, MD, Jean-Marc Lupoglazoff, MD, Hopital Robert Debre, Paris, France; Francois Marcon, MD, Lucron Hugues, MD, Centre Hospitalier Universitaire De Nancy, Vandoeuvre Les Nancy, France; Michael J. Marsh, MD, Sarah L. Marsh, Elspeth Brown, Southampton General Hospital, Southampton, United Kingdom; Patrice Morville, MD, Pediatric Cardiology at American Memorial Hospital, Reims Cedex, France; Steven Neish, MD, Jayme Frank, RN, PNP, University of Wisconsin Children’s Hospital, Madison, WI; Mark Parrish, MD, Celia Buckley, RN, University of California, Davis, Sacramento, CA; Erkki Pesonen, MD, Gylfi Oskarsson, Laura Darcy, Lund University Hospital, Lund, Sweden; Gautam K. Singh, MD, Mary Pat Spillane, Colleen Puer, Cardinal Glennon Children’s Hospital and St Louis University, St Louis, MO; Athos Colon, MD, Charlie J. Sang, Jr, MD, Joon Park, MD, Sharon Welsh, RN, Barbara Levijoki, RN, Andrea Thomas, Texas Tech University Health Sciences Center, Lubbock, TX; Koravangattu Sankaran, MD, Ashok Kakadekar, MD, Michael Tyrrell, MD, University of Saskatchewan and Royal University Hospital, Saskatoon, Saskatchewan, Canada; Achim A. Schmaltz, MD, Ulrich E. Neudorf, MD, Frank Hentrich, MD, University Children’s Hospital, Essen, Germany; Hans-Heiner Kramer, MD, Angela Uebing, MD, Ulrike Hoffmann, MD, Department of Pediatric Cardiology, Christian Albrechts University, Kiel, Germany; Jan Sunnegardh, MD, Anders Nygren, MD, The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden; Debra Tristram, MD, East Carolina School of Medicine, Greenville, NC; Robert M. R. Tulloh, MD, Guys Hospital and St Thomas NHS Trust, London, United Kingdom; Henry B. Wiles, MD, Andrew M. Atz, MD, Medical University of South Carolina, Charleston, SC; Per Winberg, MD, Bo Sahlgren, Gunilla Malmquist, Astrid Lindgrens Children’s Hospital, Stockholm, Sweden; Fred P. Zepp, MD, P. Habermehl, MD, C. Kampmann, MD, Children’s Hospital, University of Mainz, Mainz, Germany; Jan Pellar, MD, Ewa Maskowska, MD, PhD, Elzbieta Wojcik, MD, PhD, First Department of Pediatrics, Allergology and Cardiology, Medical University of Wroclaw, Wroclaw, Poland; Grazyna Dawid, MD, PhD, Wojciech Wnuk, MD, PhD, Anita Horodnicka-Jozwa, MD, PhD, Pediatric Cardiology Department, Pomeranian Academy of Medicine, Szczecin, Poland; Krystyna Mackowska, MD, Wojewodzki Sziptal Dzieciecy Oddzial Pediatrii i Kardiologii, Bydgoszcz, Poland; Aleksander A. Wagner, MD, Barbara Antoniak, First Department of Cardiac and General Pediatric Surgery, Warszaw, Poland; Martin Ottolini, MD, Sally Henson, Uniformed Services University of the Health Sciences, Bethesda, MD; Franco M. Piazza, MD, MPHy, David A. Carlin, PhDz, Franklin H. Top, Jr, MDy, Edward M. Connor, MDy, MedImmune, Inc, Gaithersburg, MD.
The Journal of Pediatrics October 2003