SAFETY AND TOLERANCE OF PALIVIZUMAB ADMINISTRATION IN A LARGE NORTHERN HEMISPHERE TRIAL

An Expanded Access Study was conducted to collect additional safety data on palivizumab. Preterm infants with or without bronchopulmonary dysplasia received palivizumab every 30 days during the respiratory syncytial virus season. Adverse events were low (6.9%) in the 565 subjects. Serious adverse events included hospitalization and 1 case of respiratory syncytial virus bronchiolitis not requiring hospitalization. This study reaffirms the safety and tolerability of palivizumab. Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract illness in infants and children worldwide. 1 Infants born prematurely are at particular risk for severe RSV lower respiratory tract infection. 2, 3 In the absence of effective treatment modalities, prevention becomes the most desirable approach in the management of RSV disease. The need for a safe and easily administered prophylaxis led to the development of palivizumab (Synagis). The safety and efficacy of palivizumab were first demonstrated in the IMpact-RSV trial, a large, Phase III, multicenter, double blind, placebo control trial. 4 This trial, conducted in the United States, Canada and the United Kingdom, included preterm infants with and without bronchopulmonary dysplasia (BPD). On the basis of the results of this pivotal trial, the United States Food and Drug Administration granted regulatory approval for palivizumab in June, 1998, and the European Agency for the Evaluation of Medicinal Products followed in August, 1999. In October, 1998, Abbott Laboratories initiated an Expanded Access trial, designed to collect additional safety data on palivizumab-treated infants from countries in which palivizumab was not yet readily available. Methods. The Expanded Access trial was a Phase III and IV, multicenter, single arm, open label study. Inclusion criteria for the study were: preterm children ≤6 months of age at enrollment, born at ≤35 weeks of gestation; or children with BPD ≤24 months of age at enrollment, who required medical intervention within 6 months of enrollment. 5 The study protocol was approved by Human Subject Review boards of all institutions. Informed consent was obtained from the parent or legal guardian of patients who met the enrollment criteria and who were interested in participating in the study. Subjects received 15 mg/kg palivizumab intramuscularly approximately every 30 days throughout the RSV season (November, 1998, through March, 1999), for a maximum of five doses. Demographic data collected at enrollment included gender, race, birth weight, gestational age, age at enrollment in months, multiple birth and prior treatment with RespiGam. The child’s weight was determined at each visit and was used to calculate the correct palivizumab dose to be administered. Concomitant medications were recorded before each injection of palivizumab. Children were closely monitored for acute allergic reactions during palivizumab administration and for 30 min after the injection. Adverse events were reported in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice. 6 Study subjects were evaluated for adverse events for a maximum period of 150 days; 120 days of dosing period (five injections, 30 days apart) and for 30 days after the final dose. Study investigators collected information on adverse events, including all hospitalizations. The criteria for hospitalization were defined by the individual treating physician and participating medical facility. RSV testing was not required; when performed local routine testing methods were used. Parents of patients were also instructed to call in any adverse events. Medical records were reviewed monthly to capture any additional reportable events. Adverse events were summarized by occurrence rate, relationship to study drug and severity. RSV hospitalization rate was calculated by applying the percent of RSV-positive cases in patients tested to all respiratory hospitalizations. 7 Results. Five hundred sixty-five patients were enrolled from 80 centers in 15 countries in the Northern Hemisphere. The patient population was closely balanced with respect to gender: 297 male (52.6%); 268 female (47.4%). Subject demographics and baseline characteristics at study entry were: mean (±sd) age in weeks, 18.3 (16.1); gestational age at birth (weeks), 29.6 (3.1); birth weight (kg), 1.3 (0.5); weight (kg), 3.9 (1.8). The race distribution was: White, 500 (88.5%); Black, 16 (2.8%); Asian, 11 (1.9%); Hispanic, 27 (4.8%); other, 11 (1.9%). The multiple birth status was 386 (68.3%) single, 141 (25.0%) twin and 38 (6.7%) triplet or greater. Of the 565 children enrolled 530 (93.8%) completed the study. Discontinuation was because of personal reasons in 14 (2.5%) cases, adverse events in 11 (1.9%) cases, loss to follow-up in 5 (0.9%) cases, noncompliance in 2 (0.4%) cases and other in 3 (0.5%) cases. In the 11 cases discontinued because of adverse events, only 3 were considered to be possibly or probably related to palivizumab: 1 case of oxygen desaturation immediately after the third injection; 1 case of gastroenteritis; and 1 case of abdominal and peripheral edema. Of the children completing the study 70.9% (376 of 530) received 5 doses and 90.0% (477 of 530) received at least 4 doses. The number of patients reporting at least 1 adverse event (either related or nonrelated) during the study was 254 of 565 (45.0%). Only 39 patients (6.9%) reported 40 adverse events that, in the opinion of the investigator, were considered related to palivizumab. Of these none were severe, 7 were moderate and 33 were mild. The more common related adverse events are depicted in Table 1.Table 1: Comparison of related adverse events between the Expanded Access Study and the IMpact-RSV StudyThere were 78 hospitalizations during the study, 27 because of nonrespiratory causes. RSV testing was performed in 29; 7 tested positive for RSV (24%), 22 tested negative and 22 were not tested. If the positivity rate is applied to the untested cases (24% of 22, or 5), the RSV hospitalization rate in this population would be estimated to be 2.1% (12 of 565). One child, diagnosed with RSV bronchiolitis, did not require hospitalization. Two deaths were reported during the study. Neither death was judged by the study investigator to be related to palivizumab or to RSV-associated illness. Discussion. Respiratory syncytial virus presents a large public health burden worldwide. Recent technologic advances in genetic engineering enabled the development of palivizumab, a humanized monoclonal IgG antibody, which binds the RSV fusion protein and thus provides passive protection against RSV lower respiratory tract infection. The Expanded Access study reported here was conducted to collect additional safety data from geographic regions in the Northern Hemisphere in which palivizumab was not yet available, to supplement that collected in the IMpact-RSV trial. The dosing regimen was completed by 93.8% of the children enrolled, with 90.0% of the children enrolled early enough in the season to have received at least four doses. The level of compliance was excellent and illustrates that parents of high risk children are both willing and able to adhere to the recommended dosing schedule to protect their infants. The proportion of children with one or more palivizumab-related adverse events was very low. The majority of these events (33 of 40) were classified as mild and were comparable with those observed in the IMpact-RSV trial (Table 1). The similarity between the rates in the palivizumab-treated groups provides a reference for comparison and reaffirms the safety profile of palivizumab. Serious adverse events were primarily limited to events leading to hospitalization. Of the total hospitalizations 65% (51 of 78) were the result of respiratory causes. RSV testing was not required and therefore was not performed consistently in this study. Therefore we used a method described by Carbonell et al. 7 to calculate the probable RSV hospitalization rate based on the available RSV testing information. Hospitalization was caused by RSV in 24% (7 of 29) of the RSV-tested cases. If this rate were applied to the untested cases (24% of 22, or 5), a total of 12 respiratory hospitalizations would have been anticipated to be caused by RSV in these 565 children (2.1%). The Expanded Access study reaffirms and broadens the safety profile of palivizumab to additional Northern Hemisphere populations. It was well-tolerated by the study participants, with fewer than 2% of the patients discontinuing the study because of adverse events. Currently palivizumab is the only licensed, safe and effective intramuscular drug available to prevent serious RSV lower respiratory tract disease in the high risk preterm infant. Acknowledgment. This study was supported by a grant from Abbott Laboratories.

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