Leflunomide treatment for patients hospitalised with COVID-19: DEFEAT-COVID randomised controlled trial.

OBJECTIVE: To evaluate the clinical efficacy and safety of leflunomide (L) added to the standard-of-care (SOC) treatment in COVID-19 patients hospitalised with moderate/critical clinical symptoms. DESIGN: Prospective, open-label, multicentre, stratified, randomised clinical trial. SETTING: Five hospitals in UK and India, from September 2020 to May 2021. PARTICIPANTS: Adults with PCR confirmed COVID-19 infection with moderate/critical symptoms within 15 days of onset. INTERVENTION: Leflunomide 100 mg/day (3 days) followed by 10-20 mg/day (7 days) added to standard care. PRIMARY OUTCOMES: The time to clinical improvement (TTCI) defined as two-point reduction on a clinical status scale or live discharge prior to 28 days; safety profile measured by the incidence of adverse events (AEs) within 28 days. RESULTS: Eligible patients (n=214; age 56.3±14.9 years; 33% female) were randomised to SOC+L (n=104) and SOC group (n=110), stratified according to their clinical risk profile. TTCI was 7 vs 8 days in SOC+L vs SOC group (HR 1.317; 95% CI 0.980 to 1.768; p=0.070). Incidence of serious AEs was similar between the groups and none was attributed to leflunomide. In sensitivity analyses, excluding 10 patients not fulfilling the inclusion criteria and 3 who withdrew consent before leflunomide treatment, TTCI was 7 vs 8 days (HR 1.416, 95% CI 1.041 to 1.935; p=0.028), indicating a trend in favour of the intervention group. All-cause mortality rate was similar between groups, 9/104 vs 10/110. Duration of oxygen dependence was shorter in the SOC+L group being a median 6 days (IQR 4-8) compared with 7 days (IQR 5-10) in SOC group (p=0.047). CONCLUSION: Leflunomide, added to the SOC treatment for COVID-19, was safe and well tolerated but had no major impact on clinical outcomes. It may shorten the time of oxygen dependence by 1 day and thereby improve TTCI/hospital discharge in moderately affected COVID-19 patients. TRIAL REGISTRATION NUMBERS: EudraCT Number: 2020-002952-18, NCT05007678.

International randomised controlled trial evaluating metabolic syndrome in type 2 diabetic cigarette smokers following switching to combustion-free nicotine delivery systems: the DIASMOKE protocol.

INTRODUCTION: Reducing exposure to cigarette smoke is an imperative for public health and for patients with diabetes. Increasingly, combustion-free nicotine delivery systems (C-F NDS) such as e-cigarettes and heated tobacco products are substituting conventional cigarettes and accelerating the downward trends in smoking prevalence. However, there is limited information about the long-term health impact in patients with diabetes who use C-F NDS. This randomised trial of type 2 diabetic cigarette smokers will test the hypothesis that following a switch from conventional cigarettes to C-F NDS a measurable improvement in metabolic syndrome (MetS) factors will be shown over the course of 2 years. METHODS AND ANALYSIS: The study is multicentre and thus will take place in five locations in four countries in an ambulatory setting. A total of 576 patients with diabetes will be randomised (1:2 ratio) to either a control arm (Study Arm A), in which they will be offered referral to smoking cessation programmes or to an intervention arm (Study Arm B) assigned to C-F NDS use. Participants will be at least 23 years old and of any gender. Patient recruitment will start in February 2021 and is expected to be completed by December 2021. Primary outcome measures include fasting plasma glucose, blood pressure, triglycerides, high-density lipoprotein and waist circumference, while secondary feature absolute change in the sum of the individual factors of MetS and change in each individual factor of MetS measured at each study time point. ETHICS AND DISSEMINATION: The approval of research ethics committee (REC) regarding the trial protocol, informed consent forms and other relevant documents is required to commence the study. Substantial amendments to the study protocol cannot be implemented until the REC grants a favourable opinion. The results of the study are intended to be published as articles in high quality peer-reviewed journals and disseminated through conference papers. TRIAL REGISTRATION NUMBER: NCT04231838. Pre-results stage.

Effect of dopexamine infusion on mortality following major surgery: individual patient data meta-regression analysis of published clinical trials.

OBJECTIVES: To establish whether perioperative low-dose dopexamine infusion (< or = 1 microg/kg/min) is associated with a reduction in mortality and duration of hospital stay following major surgery. DATA SOURCE: Medline, EMBASE, CINAHL, Cochrane Library, Google Scholar, and reference lists. STUDY SELECTION: Two reviewers independently screened studies for inclusion, assessed trial quality, and extracted data. Eligible trials were randomized controlled trials comparing dopexamine infusion to control treatment. Data are reported as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals. DATA EXTRACTION: Systematic review and meta-regression analysis of individual patient data. DATA SYNTHESIS: Five studies fulfilled the inclusion criteria. Analysis of pooled data from high- and low-dose dopexamine groups identified a reduction in duration of hospital stay (median 14 vs. 15 days; HR 0.85 [0.73-0.91]; p = .03) but no improvement in mortality (9.1% vs. 12.3%; OR 0.78 [0.31-1.99]; p = .61). However, low-dose dopexamine was associated with a 50% reduction in 28-day mortality (6.3% vs. 12.3%; OR 0.50 [0.28-0.88]; p = .016) as well as a reduced duration of stay (median 13 vs. 15 days; HR 0.75 [0.64-0.88]; p = .0005). When high-dose dopexamine groups were compared with controls, there was no difference in either mortality (OR 1.06 [0.60-1.87]; p = .85) or duration of stay (HR 1.04 [0.94-1.16]; p = .36). CONCLUSIONS: For pooled data describing perioperative dopexamine infusion at all doses, there was an improvement in duration of hospital stay but no survival benefit. However, at low doses, dopexamine was associated with improved survival and reduced duration of stay. Further clinical trials are warranted to confirm this observation.

Cost effectiveness of oral triptan therapy: a trans-national comparison based on a meta-analysis of randomised controlled trials.

OBJECTIVE: The objective of this study was to appraise the relative cost effectiveness of oral triptan therapy in the management of acute migraine, comparing the results obtained using drug cost data from six different countries, USA, UK, Canada, Germany, Italy and The Netherlands. METHOD: A meta-analysis of randomised placebo controlled trials of single dose oral triptans was carried out in order to calculate aggregate Numbers Needed to Treat (NNT) for each triptan and dose. Cost effectiveness ratios were then derived for each treatment by applying mean drug acquisition costs for each country to these NNTs. Using a graphical plot for each country, incremental cost effectiveness comparisons were then made versus sumatriptan 100 mg, the most commonly used oral triptan. RESULTS: When analysed in terms of 2-h pain one country to another. When compared to free outcomes, rizatriptan 10 mg and eletriptan 40 and 80 mg were the most effective oral triptans. Rizatriptan 10mg has the most advantageous absolute cost effectiveness ratio in all six countries studied, although levels of statistical significance compared to other agents varied from sumatriptan 100mg, rizatriptan 10 mg and eletriptan 40 mg are most consistently the cost effective treatment choices, both being cost dominant in five out of six countries studied. CONCLUSIONS: There are systematic differences in triptan efficacy that have an impact on treatment choice. Differences in pricing structure between countries mean that hierarchies of cost effectiveness will vary. Country-specific data should therefore be examined before defining treatment strategies.