Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): a prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease

Background: A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance.<p></p> Trial Design: CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance–guided care, single-photon emission computed tomography–guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines–based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed.<p></p> Conclusions: The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation

Rationale and design of the LIBERATES trial: Protocol for a randomised controlled trial of flash glucose monitoring for optimisation of glycaemia in individuals with type 2 diabetes and recent myocardial infarction.

Hyperglycaemia in individuals with type 2 diabetes (T2D) and myocardial infarction (MI) is associated with guarded clinical prognosis. Studies improving glucose levels in T2D following MI relied on HbA1c as the main glycaemic marker, failing to address potential adverse effects of hypoglycaemia and glucose variability. We describe the design of the LIBERATES trial that investigates the role of flash glucose monitoring in optimising glycaemic markers in high vascular risk individuals with T2D. This multicentre trial is designed to recruit up to 150 insulin and/or sulphonylurea-treated T2D patients, within 5 days of a proven MI. Individuals will be randomised 1:1 into intervention and control groups using flash glucose monitoring sensors and traditional self-monitoring of blood glucose, respectively. The control group will also wear a blinded continuous glucose monitoring sensor. The primary outcome is the difference in time spent in euglycaemia (defined as glucose levels between 3.9-10.0 mmol/l), comparing study groups 3 months following recruitment, assessed daily for 14 days and as an average. Secondary and exploratory end points include time spent in hypoglycaemia and hyperglycaemia, HbA1c, quality of life measures, major adverse cardiac events and cost-effectiveness of the intervention. This study will establish the role of flash glucose monitoring in glycaemic management of individuals with T2D sustaining a cardiac event.(Trial Registration: ISRCTN14974233, registered 12th June 2017)

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren’s syndrome: results of the TRACTISS randomised double-blind multicentre substudy

Objectives To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren’s syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. Methods Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0–11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. Results 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were −1.2 (95% CI −2.1 to −0.3; P=0.0099) and −1.2 (95% CI −2.0 to −0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. Conclusions We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker

Visualising harms in publications of randomised controlled trials: consensus and recommendations

OBJECTIVE: To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes. DESIGN: Consensus study. SETTING: 15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ. PARTICIPANTS: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians. MAIN OUTCOME: measures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached. RESULTS: 28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation. CONCLUSIONS: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles

Individual component analysis of the multi-parametric cardiovascular magnetic resonance protocol in the CE-MARC trial

Background: The CE-MARC study assessed the diagnostic performance investigated the use of cardiovascular magnetic resonance (CMR) in patients with suspected coronary artery disease (CAD). The study used a multi-parametric CMR protocol assessing 4 components: i) left ventricular function; ii) myocardial perfusion; iii) viability (late gadolinium enhancement (LGE)) and iv) coronary magnetic resonance angiography (MRA). In this pre-specified CE-MARC sub-study we assessed the diagnostic accuracy of the individual CMR components and their combinations. Methods: All patients from the CE-MARC population (n = 752) were included using data from the original blinded-read. The four individual core components of the CMR protocol was determined separately and then in paired and triplet combinations. Results were then compared to the full multi-parametric protocol. Results: CMR and X-ray angiography results were available in 676 patients. The maximum sensitivity for the detection of significant CAD by CMR was achieved when all four components were used (86.5 %). Specificity of perfusion (91.8 %), function (93.7 %) and LGE (95.8 %) on its own was significantly better than specificity of the multi-parametric protocol (83.4 %) (all P < 0.0001) but with the penalty of decreased sensitivity (86.5 % vs. 76.9 %, 47.4 % and 40.8 % respectively). The full multi-parametric protocol was the optimum to rule-out significant CAD (Likelihood Ratio negative (LR-) 0.16) and the LGE component alone was the best to rue-in CAD (LR+ 9.81). Overall diagnostic accuracy was similar with the full multi-parametric protocol (85.9 %) compared to paired and triplet combinations. The use of coronary MRA within the full multi-parametric protocol had no additional diagnostic benefit compared to the perfusion/function/LGE combination (overall accuracy 84.6 % vs. 84.2 % (P = 0.5316); LR- 0.16 vs. 0.21; LR+ 5.21 vs. 5.77). Conclusions: From this pre-specified sub-analysis of the CE-MARC study, the full multi-parametric protocol had the highest sensitivity and was the optimal approach to rule-out significant CAD. The LGE component alone was the optimal rule-in strategy. Finally the inclusion of coronary MRA provided no additional benefit when compared to the combination of perfusion/function/LGE. Trial registration: Current Controlled Trials ISRCTN77246133