Showing papers by "N. Franklin Adkinson published in 2016"
Durham University1, University of Virginia2, Cleveland Clinic3, Icahn School of Medicine at Mount Sinai4, University of Alberta5, Imperial College London6, Paris Diderot University7, University of Freiburg8, University of Cincinnati Academic Health Center9, Johns Hopkins University10, University of Pennsylvania11
TL;DR: Pegnivacogin should undergo additional definitive testing incorporating a risk mitigation and action plan in a phase III trial to Determine the Efficacy and Safety of the REG1 Anticoagulation System Compared to Bivalirudin in Patients Undergoing Percutaneous Coronary Intervention.
Abstract: To the Editor: PEGylation is commonly used to extend half-life and limit volume of distribution of an increasing number of nucleic acid, peptide, and small molecule therapeutics. Pegnivacogin is a modified 31-nucleotide RNA aptamer that binds to and inhibits factor IXa conjugated to an inert 40-kD branched methoxypolyethylene glycol polymer. Although early clinical testing did not identify any safety concerns, the phase IIb Randomized, Partially Blinded, Multicenter, Active-Controlled, Dose-Ranging Study Assessing the Safety, Efficacy, and Pharmacodynamics of the REG1 Anticoagulation System in Patients with Acute Coronary Syndromes (RADAR) trial was stopped after 3 allergic reactions. An extensive investigation demonstrated elevated levels of IgG anti-PEG antibodies in the 3 patients with allergic events, suggesting that the PEG moiety, and not the oligonucleotide, was the causative allergic agent. On the basis of previous safety record of PEGylated products, investigators and regulatory authorities agreed that pegnivacogin should undergo additional definitive testing incorporating a risk mitigation and action plan in a phase III trial (Randomized, Open-label, Multi-Center, Active-Controlled, Parallel Group Study to Determine the Efficacy and Safety of the REG1 Anticoagulation System Compared to Bivalirudin in Patients Undergoing Percutaneous Coronary Intervention [REGULATE-PCI]) in which subjects undergoing percutaneous coronary intervention were randomized to pegnivacogin or bivalirudin.Methodology of the trial, planned biochemical analyses, statistical analyses, and allergy definitions are available in the first and second sections in this article’s Online Repository at www.jacionline.org. REGULATE-PCI was ultimately terminated after enrollment of 3,232 of a planned 13,200 patients after an excess of allergic reactions in pegnivacogin-treated patients. The incidence and timing of allergic reactions are summarized in Table I. Descriptions of allergies meeting reporting criteria, as judged by the investigators, are provided in the third section in this article’s Online Repository at www.jacionline. org. Assignment to pegnivacogin was associated with a statistically significant increase in allergic reactions. Of the clinical variables assessed, female sex, allergic reactions in the past year, current smoking, and previous percutaneous coronary
140 citations
Harvard University1, Johns Hopkins University2, University of Colorado Denver3, Boston Children's Hospital4, Nanyang Technological University5, University of Massachusetts Medical School6, University of Washington7, Kaiser Permanente8, University of California, San Diego9, University of New Mexico10, University of Toronto11, University of Groningen12, Washington University in St. Louis13
TL;DR: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups.
Abstract: Rationale: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease (COPD). Objectives: To determine the genetic underpinnings of lung function patterns in childhood asthmatics. Methods: We performed a genome-wide association study of 581 non-Hispanic white asthmatics that were previously classified by patterns of lung function growth and decline, (Normal Growth, Normal Growth with Early Decline, Reduced Growth, and Reduced Growth with Early Decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large COPD meta-analysis cohort. Interaction between the genomic region encompassing the most strongly associated single nucleotide polymorphism (SNP) and nearby genes was assessed by two chromosomal conformation capture assays. Measurements and Main Results: An intergenic SNP (rs...
22 citations