David Carlin

Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease

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.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial

BACKGROUND Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. METHODS In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. FINDINGS 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). INTERPRETATION Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. FUNDING MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Reduction of Respiratory Syncytial Virus (RSV) in Tracheal Aspirates in Intubated Infants by Use of Humanized Monoclonal Antibody to RSV F Protein

Thirty-five children <2 years of age mechanically ventilated for respiratory syncytial virus (RSV) infection were randomized to receive an intravenous infusion of 15 mg/kg MEDI-493 or placebo. RSV concentration was measured in tracheal secretions by plaque assay before and at 24-h intervals after treatment. The reduction in tracheal RSV concentration from day 0 to day 1 (-1.7+/-0.28 vs. -0. 6+/-0.21 log10 pfu/mL; P=.004) and from day 0 to day 2 (-2.5+/-0.26 vs. -1.0+/-0.41 log10 pfu/mL; P=.012) was significantly greater in the MEDI-493 group than in the placebo group. RSV concentration in nasal aspirates did not differ significantly between the groups. No significant differences were observed in the tracheal aspirate white blood cell count, or myeloperoxidase or eosinophilic cationic protein concentration, or in measures of disease severity between the groups. Thus, treatment with 15 mg/kg MEDI-493 intravenously was well-tolerated and significantly reduced RSV concentration in tracheal aspirates of children with respiratory failure due to RSV.

Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia

BACKGROUND Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. OBJECTIVE To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. DESIGN Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. PATIENT POPULATION Infants born prematurely (< or = 35 weeks of gestation) who were < or = 6 months of age and infants with bronchopulmonary dysplasia who were < or = 24 months of age were eligible for study participation. STUDY AGENTS: Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. RESULTS MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after Infusion 1 were 6.8, 36.1 and 60.6 microg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 microg/ml. After subsequent doses the mean trough values ranged from 14 to 18 microg/ml in those given 3 mg/kg and were > 40 microg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 microg/ml and 88 to 96 microg/ml, respectively). CONCLUSIONS MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of > 40 microg/ml for the majority of patients.

A Direct Comparison of the Activities of Two Humanized Respiratory Syncytial Virus Monoclonal Antibodies: MEDI-493 and RSHZl9

Two humanized monoclonal antibodies, MEDI-493 and RSHZ19, were developed independently as potential improvements over RSV-IGIV for prevention of respiratory syncytial virus (RSV) infection. RSV-IGIV is a polyclonal human antibody preparation for intravenous infusion enriched for RSV neutralizing activity. A phase III clinical trial showed that MEDI-493 significantly reduced hospitalizations due to RSV infection. In a separate trial, RSHZ19 failed to show significant efficacy. In new studies, the in vitro and in vivo activities of MEDI-493 and RSHZ19 were compared to determine whether the different clinical results are related to differences in biologic activity. MEDI-493 was consistently 4- to 5-fold more potent than RSHZ19 in antigen binding, RSV neutralization, and fusion inhibition assays. Although both MEDI-493 and RSHZ19 were effective against A and B subtypes of RSV in the cotton rat model of RSV infection, 2- to 4-fold higher doses of RSHZ19 were required for similar protection. The enhanced activity of MEDI-493 compared with RSHZ19 may, in part, explain its better clinical effect.

Teplizumab Preserves C-Peptide in Recent-Onset Type 1 Diabetes Two-Year Results From the Randomized, Placebo-Controlled Protégé Trial

Protégé was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized ≤6 weeks after diagnosis, HbA1c <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8–17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose.

Safety and immunogenicity of palivizumab (Synagis) administered for two seasons.

To evaluate the safety and immunogenicity of palivizumab, 55 children who received palivizumab in the IMpact-RSV trial received 5 monthly doses of 15 mg/kg palivizumab (Synagis) during the subsequent year. The single child with an antipalivizumab titer of >1/40 had no associated serious adverse events and had expected serum palivizumab trough concentrations. Second year palivizumab prophylaxis was safe and well-tolerated.

ROC SURFACE: A GENERALIZATION OF ROC CURVE ANALYSIS

Receiver operating characteristic (ROC) curve analysis is widely used in biomedical research to assess the performance of diagnostic tests. Much of the work has been directed at developing accurate indices to describe ROC curves and appropriate statistics to test differences between them. The analysis, however, is largely built on the assumption that the test results are dichotomous. We generalize the ROC curve analysis to allow for tests to have more than two outcomes. The generalized ROC curve constitutes a surface. We propose to use the volume under the surface to measure the accuracy of a diagnostic test.

Evaluation of Reconstituted Lyophilized Palivizumab (Synagis(TM)) Given Intravenously at 15 and 30 mg/kg

Evaluation of Reconstituted Lyophilized Palivizumab (Synagis(TM)) Given Intravenously at 15 and 30 mg/kg

Prophylaxis against respiratory syncytial virus in premature infants. IMpact-RSV Study Group.

demographic data, diagnosis, reason for admission, APACHE II score, exposure to invasive devices, microbial culture results, antimicrobial use, and other relevant clinical data. ICUacquired infection was defined as an infection which began at least 48 h after admission. Definitions were based on the recommendations of the Centres for Disease Control and Prevention. Pneumonia was considered definite if the chest radiograph revealed new and persistent infiltrates and identification of micro-organisms by tracheobronchial aspirates, broncho-alveolar lavage, or protected specimen brush with bacterial growth above the defined thresholds. Pneumonia was excluded when other causes could explain the abnormalities, recovery occurred without antimicrobial therapy, or in the absence of positive sputum cultures. From April, 1999, to June, 1999, 140 patients (mean age 55·9 years, 54 men and 86 women, mean APACHE II score 15·7) were admitted for medical, trauma, and surgical reasons. Mean ICU stay was 7·4 (range 1–62) days. ICU mortality was 23%. 87 (62%) patients were endotracheally intubated and ventilated in the supine position for a mean of 7·6 (range 1–53) days. Selective digestive decontamination was not administered to any patient. Stress-ulcer prophylaxis was continued if used in 25 patients. Nasogastric or orogastric tube was present in all ventilated patients. One patient received parenteral feeding. Nine men and five women developed nosocomial infections. Five central venous catheter colonisations and 13 urinary tract infections were recorded. Two patients developed paranasal sinusitis. In one patient we diagnosed pneumonia occurring within 36 h of intubation therefore not meeting the pre-set criteria for VAP. Pathogens causing VAP are derived either from endogenous or exogenous sources. Drakulovic and colleagues showed a striking reduction in VAP in the semirecumbent position, which illustrates the potential role of the abnormal oropharyngeal colonisation as a reservoir for microaspiration. The frequency of VAP varies widely between hospitals and ICUs as our data indicate. Why these differences arise is unclear but they may reflect the efficacy of various preventive and therapeutic measures and other local factors. The main limitation of our investigation is its short observational period. The results of the study by Drakulovic and colleagues show the benefit of easily available methods for prevention of VAP. This is important if VAP is the main nosocomial infection in an ICU.