A plain language summary of what clinical studies can tell us about the safety of evobrutinib – a potential treatment for multiple sclerosis

Immunology; Rheumatology; Systemic lupus erythematosusInmunología; Reumatología; Lupus eritematoso sistémicoImmunologia; Reumatologia; Lupus eritematós sistèmicWhat is this summary about?: This summary explains the findings from a recent investigation that combined the results of over 1000 people from three clinical studies to understand the safety of evobrutinib. Evobrutinib is an oral medication (taken by mouth), being researched as a potential treatment for multiple sclerosis (MS). This medication was also investigated in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Over 1000 people have taken evobrutinib as part of three separate phase 2 clinical studies. These studies looked at how much of the drug should be taken, how safe the drug is, and how well it might work for treating a certain medical condition. What were the results?: Evobrutinib was well-tolerated by participants in all three studies. The number of side effects reported by participants taking the medication was very similar to those reported by participants taking the placebo (a 'dummy' treatment without a real drug). The most common side effects in clinical studies were urinary tract infections, headache, swelling of the nose and throat, diarrhoea and blood markers of potential liver damage (these returned to normal once the treatment was stopped). What do the results mean?: The safety data from all three clinical studies are encouraging and can be used to inform further research into using evobrutinib in MS.X Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS. D Wallace has received consultant fees from Amgen, Celgene, Eli Lilly, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (an affiliate of Merck KGaA), Janssen and Merck. MC Genovese is an employee of and has financial interests in Gilead. D Tomic is an employee of Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, and received stock or an ownership interest from Novartis. D Parsons-Rich was an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, at the time of the study, and is currently an employee of and has received stock from Pfizer. C Le Bolay and H Guehring are employees of Merck Healthcare KGaA, Darmstadt, Germany. A Kao is an employee of and received stock or an ownership interest from EMD Serono Inc., Billerica, MA, USA, a healthcare business of Merck KGaA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was supported by Merck (CrossRef Funder ID: 10.13039/100009945). This summary was prepared by Lumanity on behalf of, and funded by, Merck KGaA, Darmstadt, Germany

212 Phase 2, randomized, double-blind, placebo-controlled, dose-finding study, evaluating the Bruton's tyrosine kinase inhibitor evobrutinib in patients with systemic lupus erythematosus: study design

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Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis

Immunology; Multiple sclerosis; RheumatologyInmunología; Esclerosis múltiple; ReumatologíaImmunologia; Esclerosi múltiple; ReumatologiaObjective Analyse the integrated safety profile of evobrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), using pooled data from multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) trials. Methods Phase II, randomised, double-blind, placebo-controlled trial data were analysed (N=1083; MS: n=213, 48 weeks (W); RA: n=390, 12W; SLE: n=480, 52W). The analysis included all patients who received ≥1 dose of evobrutinib (25 mg or 75 mg once daily, or 50 mg or 75 mgtwice daily) or placebo. Descriptive statistics and exposure-adjusted incidence rates (EAIR) were used to report treatment-emergent adverse events (TEAEs). Results Data from 1083 patients were pooled: evobrutinib, n=861; placebo, n=271 (sum >1083 due to MS trial design: n=49 received both placebo (W0–24) and evobrutinib 25 mg (W25–48)); median follow-up time (pt-years): evobrutinib, 0.501; placebo, 0.463. Across indications, the proportion of patients with TEAEs and the EAIR were similar for evobrutinib and placebo (66.2% (247.6 events/100 pt-years) vs 62.4% (261.4 events/100 pt-years)). By indication, the EAIR (events/100 pt-years) of TEAEs for evobrutinib versus placebo were: MS: 119.7 vs 148.3; RA: 331.8 vs 306.8; SLE: 343.0 vs 302.1. Two fatal events occurred (in SLE). The serious infections EAIR was 2.7 and 2.1 events/100 pt-years for evobrutinib and placebo. For previously reported BTKi-class effects, the EAIR of transient elevated alanine aminotransferase/aspartate aminotransferase TEAEs (events/100 pt-years) with evobrutinib versus placebo was 4.8 vs 2.8/3.5 vs 0.7, respectively. IgG levels were similar in evobrutinib/placebo-treated patients. Conclusions This is the first BTKi-integrated safety analysis that includes patients with MS. Overall, evobrutinib treatment (all doses) was generally well tolerated across indications.The trial was sponsored by Merck Healthcare KGaA (CrossRef Funder ID: 10.13039/100009945)

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London