Randomization was performed centrally on the basis of a block design, with stratification according to the number of crises in the preceding year (2 to 4 or 5 to 10) and concomitant hydroxyurea use (yes or no). Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial Mortality in sickle cell disease — life expectancy and risk factors for early death. Ataga KI, Reid M, Ballas SK, et al. Polanowska-Grabowska R, Wallace K, Field JJ, et al. Semaglutide, a GLP-1 analogue with an extended half-life of approximately 1 week (which permits once-weekly subcutaneous administration),4 is currently in development but not yet approved for the treatment of type 2 diabetes. S2B in the Supplementary Appendix). Charache S, Terrin ML, Moore RD, et al. Regulatory guidance specifies the need to establish the cardiovascular safety of new therapies for type 2 diabetes in order to rule out excess cardiovascular risk.5 The preapproval Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diab… Create a free account now. Marso SP, et al for the SUSTAIN-6 Investigators*: N Engl J Med, 16. High-dose crizanlizumab effectively blocked P-selectin binding to PSGL-1 throughout the treatment phase, whereas low-dose crizanlizumab was associated with only partial blockade (Fig. Reported adverse events were coded with the use of preferred terms from the Medical Dictionary for Regulatory Activities, version 16.1. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. An independent data and safety monitoring committee reviewed safety during the trial. Blood 2004;104:3378-3385, 16. Quick Take Ballas SK, Lusardi M. Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance. No significant differences were observed in markers of hemolysis (hemoglobin, lactate dehydrogenase, haptoglobin levels, number of reticulocytes, and indirect bilirubin) between patients receiving crizanlizumab and those receiving placebo (data not shown). This rate was 41.8% lower with high-dose crizanlizumab than with placebo, although the difference was not significant (P=0.45) (Table 3). Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Transgenic mice with sickle cell disease that are deficient in P-selectin and E-selectin have defective leukocyte recruitment to the vessel wall and are protected from vaso-occlusion.17 In addition, the adherence of sickle erythrocytes and leukocytes to the endothelium is substantially reduced when P-selectin is blocked in transgenic mice expressing human HbS.15,18 Furthermore, doses of heparin that are sufficient to block P-selectin increase microvascular blood flow in patients with sickle cell disease.19 These data support the concept that blockade of P-selectin could reduce the risk of vaso-occlusion, inflammation, and sickle cell–related pain crises. Lancet 2010;376:2018-2031, 7. For the follow-up evaluation phase, patients returned for an assessment 6 weeks after the end of the treatment phase (8 weeks after receipt of the last dose) (see the protocol, available at NEJM.org). We are here to help you. The log-rank test was used to compare the times to the first and second crises. DOI: 10.1056/NEJMdo005120. The first draft of the manuscript was prepared by the first author, with substantial review and comments by the other authors. Bunn HF. ATTENTION:Due to global market conditions, you may experience a delivery delay for your print issue of the New England Journal of Medicine. 1. The change from baseline in responses on the Brief Pain Inventory questionnaire was analyzed with the use of a mixed linear model with repeated measures. Overall, mean eGFR decreased from baseline to week 104 across all treatment groups and subgroups, with the largest decreases in subjects with normal renal function or mild renal impairment ([Figure][1]). The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. In addition, the median times to the first and second crises were two to three times as long in patients receiving high-dose crizanlizumab as in those receiving placebo. Matsui NM, Varki A, Embury SH. This content requires an NEJM.org account. No other clinically significant bleeding events were observed in the trial. A detectable antibody response against crizanlizumab did not develop in any patient during the trial. Pathogenesis and treatment of sickle cell disease. In this randomized, phase 2 trial, we observed that treatment with high-dose crizanlizumab resulted in an annual rate of sickle cell–related pain crises that was 45.3% lower than the rate with placebo. MUNICH — A second … S1 in the Supplementary Appendix). The median crisis rate per year in the low-dose crizanlizumab group was 2.01 (indicating a 32.6% lower rate than in the placebo group, P=0.18). Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). A total of 5 patients died during the trial, including 2 patients in the high-dose crizanlizumab group (1 patient from the acute chest syndrome, and 1 from endocarditis and sepsis), 1 in the low-dose crizanlizumab group (from the acute chest syndrome, aspiration, respiratory failure, and progressive vascular congestion), and 2 in the placebo group (1 from right ventricular failure, and 1 from vaso-occlusive crisis, ischemic stroke, coma, sepsis, and venous thrombosis of the right lower limb). S2A in the Supplementary Appendix). Free Preview, Original Article There were no significant changes from baseline in the least-squares means during the trial. The first author, in consultation with the other authors, made the decision to submit the manuscript for publication. Genotypes other than HbSS were observed in 29% of the patients who underwent randomization. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Sickle cell vasoocclusion: heterotypic, multicellular aggregations driven by leukocyte adhesion. The primary endpoint was the change in mean HbA 1c from baseline to week 30, and the confirmatory secondary endpoint was the change in mean bodyweight from baseline to week 30. Arterioscler Thromb Vasc Biol 2010;30:2392-2399, 17. The full list of eligibility criteria is provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Would an antibody that blocks binding to P-selectin reduce the frequency of pain crises? Proc Natl Acad Sci U S A 2002;99:3047-3051, 18. The median crisis rate per year among patients with genotypes other than HbSS (i.e., those with HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia, and other genotypes) was 0.99 in the high-dose crizanlizumab group, as compared with 2.00 in the placebo group (indicating a 50.5% lower rate with high-dose crizanlizumab). been industry funded trials, and all are multicentre, double- blinded, randomised, placebo- controlled trials. This estimand aims at reflecting the effect of oral semaglutide compared with placebo without the confounding effect of rescue medication. Patients received two doses of crizanlizumab or placebo 2 weeks apart (loading doses) and then received a dose every 4 weeks (maintenance dosing) through week 50 for a total of 14 doses administered. Antibodies against crizanlizumab were not detected. Sickle cell–related pain crises are the primary cause of health care encounters in patients with sickle cell disease.1 These crises result in a decrease in quality of life2 and an increase in the risk of death.3 Crises are thought to be caused by vascular occlusion in the microcirculation, increased inflammation, and alterations in nociception.4 The prevention of crises could minimize or prevent tissue and organ damage and decrease the subsequent risk of death among patients with sickle cell disease. Valuable tools for building a rewarding career in health care. The authors take responsibility for the veracity and completeness of the data reported and for adherence to the trial protocol. Increased risk of stroke associated with nonsteroidal anti-inflammatory drugs: a nationwide case-crossover study. J Lab Clin Med 1997;129:507-516, 10. Patients with type 2 diabetes at high cardiovascular risk received either … Patients who were undergoing long-term red-cell transfusion therapy were excluded. Establishing Equity in Medical Education — Supporting Clinical Trainees with Disabilities, Physician, Heal Thy Double Stigma — Doctors with Mental Illness and Structural Barriers to Disclosure, Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2, Choices in a Crisis — Individual Preferences among SARS-CoV-2 Vaccines, Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19, A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis. The serum concentrations of crizanlizumab reached steady-state levels after the loading doses, were maintained throughout the 52-week treatment period, and were dose-proportional (Fig. Lisa Nainggolan. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin and blocks its interaction with P-selectin glycoprotein ligand 1 (PSGL-1). The SCALE Trial Video Summary of Original Article Jul 02, 2015 A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management X. Pi-Sunyer and Others ), and the Hematology and Hemotherapy Center, University of Campinas, Campinas (M.P.C.) Already have an account? ), For permission requests, please contact NEJM Reprints at [email protected], February 2, 2017 Chang CH, Shau WY, Kuo CW, Chen ST, Lai MS. The trial consisted of a 30-day screening phase, a 52-week treatment phase, and a 6-week follow-up evaluation phase. Blood 2002;100:3790-3796, 15. The median crisis rate per year in the per-protocol population was 1.04 in the high-dose crizanlizumab group, as compared with 2.18 in the placebo group (indicating a 52.3% lower rate with high-dose crizanlizumab, P=0.02). This finding suggests that the observed clinical benefit derived from P-selectin inhibition did not involve a reduction in hemolysis. Questions still to be answered about these agents include optimal dosing strategies, their efficacy in combination or sequence, the role of remdesivir in ambulatory patients, and the efficacy of other steroids (methylprednisolone appeared to be ineffective in one placebo-controlled trial [NEJM JW Gen Med Oct 1 2020 and Clin Infect Dis 2020 Aug 12; (e-pub)]). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). Am J Hematol 2012;87:536-539, 20. The trial is event-driven, i.e. P values are for the comparison of the high-dose or low-dose crizanlizumab group with the placebo group and were calculated with the use of the log-rank test. The primary end-point findings were supported by a sensitivity analysis of the annual crisis rate among the 125 patients in the per-protocol population. was designed to assess the noninferiority of semaglutide as compared with placebo in terms of cardiovascular safety in patients with type 2 diabetes. The median time to the first crisis was significantly longer among patients receiving high-dose crizanlizumab than among those receiving placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02) (Table 3). NEW! These trials were designed and conducted in accordance with the 2008 US Food and Drug Administration (FDA) guidance for evaluating CV safety in new glucose-lowering therapies. For the primary end point, the analysis included all 198 patients who underwent randomization, according to the intention-to-treat principle. Blood 2012;120:3647-3656, 5. To investigate whether crizanlizumab had an effect on hemolytic variables in patients with sickle cell disease, changes in hemoglobin, lactate dehydrogenase, number of reticulocytes, haptoglobin, and indirect bilirubin were assessed during the study. Zinman B, et al for the EMPA-REG OUTCOME Investigators: N Engl J Med 2015 3. Association of short-term use of nonsteroidal anti-inflammatory drugs with stroke in patients with hypertension. Data were collected, maintained, and analyzed by the Quintiles Biostatistics division. We did the randomisation with an interactive voice or web response system. Characteristics and Baseline Values of the Patients in the Intention-to-Treat Population. No significant differences were observed in any of these variables between patients receiving crizanlizumab and those receiving placebo (data not shown). Your subscription also includes full access to the NEJM.org website. Manwani D, Frenette PS. The serious adverse events that occurred in at least 2 patients in either active-treatment group and at a higher frequency than in the placebo group were pyrexia and influenza. The annual crisis rate was 32.1% lower with high-dose crizanlizumab than with placebo among patients receiving hydroxyurea and 50.0% lower among patients who were not receiving hydroxyurea. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. All the authors had access to the data and signed confidentiality agreements with the sponsor regarding the data.