Search

Summary: Background: Baricitinib, an oral selective Janus kinase (JAK)1 and JAK 2 inhibitor, was shown to improve the signs and symptoms of moderate‐to‐severe atopic dermatitis (AD). Objectives: To evaluate the efficacy and safety of baricitinib with background topical corticosteroids (TCS) in patients with moderate‐to‐severe AD and inadequate response, intolerance or contraindication to ciclosporin A (CA). Methods: In this double‐blind, randomized, placebo‐controlled, phase III study, patients were randomized 1: 1: 2: 1 to placebo (N = 93), baricitinib 1 mg (N = 93), 2 mg (N = 185) or 4 mg (N = 92) with background TCS. The primary endpoint was the proportion of patients receiving baricitinib 4 mg or 2 mg (+ TCS) vs. placebo + TCS who achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index (EASI 75) at week 16. Results: Baricitinib 4 mg + TCS was superior to placebo + TCS for EASI 75 (4 mg: 32%, placebo: 17%, P = 0·031) at week 16 and for improvements in itch, skin pain and number of night‐time awakenings owing to itch. Improvements were maintained through 52 weeks of treatment. Treatment‐emergent adverse events (TEAEs) were more common with baricitinib than placebo (+ TCS); most were mild or moderate. The most frequent TEAEs with baricitinib 4 mg + TCS were nasopharyngitis, herpes simplex, influenza and headache. No deaths or deep vein thromboses were reported. Conclusions: Baricitinib 4 mg + TCS improved the signs and symptoms of moderate‐to‐severe AD through 52 weeks of treatment in patients with inadequate response, intolerance or contraindication to CA. The safety profile was consistent with previous studies of baricitinib in moderate‐to‐severe AD. What is already known about this topic?Ciclosporin A is indicated for the treatment of atopic dermatitis that is refractory to topical therapies. However, its use is limited by safety concerns and it may not provide adequate response for some patients.Baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor, has been shown to improve the signs and symptoms of moderate‐to‐severe atopic dermatitis as a monotherapy or in combination with topical corticosteroids. What does this study add?Baricitinib combined with background low‐ or moderate‐potency topical corticosteroids provided improvements in the signs and symptoms of moderate‐to‐severe atopic dermatitis through 1 year of treatment in patients with a contraindication, intolerance or failure to respond to ciclosporin A.The most common treatment‐emergent adverse events with baricitinib 4 mg were nasopharyngitis, herpes simplex, influenza and headache.The safety profile was consistent with previous studies in patients with moderate‐to‐severe atopic dermatitis. [ABSTRACT FROM AUTHOR]

Byline: Jean-Francois Dhainaut (1), Pierre-Francois Laterre (2), Jonathan M. Janes (3), Gordon R. Bernard (4), Antonio Artigas (5), Jan Bakker (6), Hanno Riess (7), Bruce R. Basson (8), Julien Charpentier (1), Barbara G. Utterback (8), Jean-Louis Vincent (9) Keywords: Drotrecogin alfa (activated) Activated protein C Xigris Recombinant proteins Sepsis Septic shock Abstract: Objective. Based on the results of the PROWESS trial the European Agency for the Evaluation of Medicinal Products has recently approved drotrecogin alfa (activated) for treatment of adult patients with severe sepsis and multiple-organ failure. We report study's data on efficacy and safety in patients with multiple-organ dysfunction. Design and setting. Randomized, double-blind, placebo-controlled, multicenter trial in 164 medical centers. Patients. 1271 patients (75.2% of the intention-to-treat population, n=1690) with multiple-organ dysfunction at study entry. Interventions. Drotrecogin alfa (activated) n=634, 24 Aug/kg per hour for 96 h or placebo (n=637). Results. Observed 28-day mortality was significantly lower with drug treatment than with placebo (26.5%vs. 33.9%), cardiovascular and respiratory organ dysfunction resolved more rapidly over the first 7 days, and serious bleeding events were more frequent (2.4% vs. 1.3%). Conclusions. Treatment with drotrecogin alfa (activated) significantly reduced 28-day mortality and more quickly resolved cardiovascular and respiratory organ dysfunction. The difference in serious bleeding event rates may be clinically significant however, the overall benefit-risk profile appears favorable. Author Affiliation: (1) Department of Intensive Care, Cochin Hospital AP-HP, Cochin Institute, Cochin Port-Royal Medical School, Paris V University, 27 rue due Faubourg Saint Jacques, 75679, Paris cedex 14, France (2) Department of Critical Care and Emergency Medicine, Cliniques Universitaires St. Luc, Brussels, Belgium (3) Lilly Research Centre, Eli Lilly & Co. Ltd., Erl Wood Manor, Surrey, UK (4) Divisions of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn., USA (5) Critical Care Center, Sabadell Hospital, University Institute parc Tauli, Autonomous University of Barcelona, Sabadell, Spain (6) , Isala Klinieken, Zwolle, The Netherlands (7) Universitatsklinikum Charite,Medizinische Klinik fur Haematologie und Onkologie, Humbolt Universitat, Berlin, Germany (8) Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Ind., USA (9) Department of Intensive Care, Erasme University Hospital, Free University of Brussels, Brussels, Belgium Article History: Received Date: 29/07/2002 Accepted Date: 25/02/2003 Article note: Electronic Publication

Introduction: We report data from adult and pediatric patients with severe sepsis from studies evaluating drotrecogin alfa (activated) (DrotAA) and presenting with purpura fulminans (PF), meningitis (MEN), or meningococcal disease (MD) (PF/MEN/MD). Such conditions may be associated with an increased bleeding risk but occur in a relatively small proportion of patients presenting with severe sepsis; pooling data across clinical trials provides an opportunity for improving the characterization of outcomes., Methods: A retrospective analysis of placebo-controlled, open-label, and compassionate-use trials was conducted. Adult patients received infusions of either DrotAA or placebo. All pediatric patients (<18 years old) received DrotAA. 189 adult and 121 pediatric patients presented with PF/MEN/MD., Results: Fewer adult patients with PF/MEN/MD met cardiovascular (68.3% versus 78.8%) or respiratory (57.8% versus 80.5%) organ dysfunction entry criteria than those without. DrotAA-treated adult patients with PF/MEN/MD (n = 163) had an observed 28-day mortality rate of 19.0%, a 28-day serious bleeding event (SBE) rate of 6.1%, and an intracranial hemorrhage (ICH) rate of 4.3%. Six of the seven ICHs occurred in patients with MEN (three of whom were more than 65 years old with a history of hypertension). DrotAA-treated adult patients without PF/MEN/MD (n = 3,088) had an observed 28-day mortality rate of 25.5%, a 28-day SBE rate of 5.8%, and an ICH rate of 1.0%. In contrast, a greater number of pediatric patients with PF/MEN/MD met the cardiovascular organ dysfunction entry criterion (93.5% versus 82.5%) than those without. DrotAA-treated PF/MEN/MD pediatric patients (n = 119) had a 14-day mortality rate of 10.1%, an SBE rate of 5.9%, and an ICH rate of 2.5%. DrotAA-treated pediatric patients without PF/MEN/MD (n = 142) had a 14-day mortality rate of 14.1%, an SBE rate of 9.2%, and an ICH rate of 3.5%., Conclusion: DrotAA-treated adult patients with severe sepsis presenting with PF/MEN/MD had a similar SBE rate, a lower observed 28-day mortality rate, and a higher observed rate of ICH than DrotAA-treated patients without PF/MEN/MD. DrotAA-treated pediatric patients with severe sepsis with PF/MEN/MD may differ from adults, because all three outcome rates (SBE, mortality, and ICH) were lower in pediatric patients with PF/MEN/MD.