Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Proactive multifactorial intervention strategy reduces the risk of cardiovascular disease estimated with region-specific risk assessment models in Pacific Asian patients participating in the CRUCIAL trial.

Despite race, ethnic, and regional differences in cardiovascular disease risk, many worldwide hypertension management guidelines recommend the use of the Framingham coronary heart disease (CHD) risk equation to guide treatment decisions. This subanalysis of the recently published CRUCIAL trial compared the treatment-related reductions in calculated CHD and stroke risk among Pacific Asian (PA) patients using a variety of region-specific risk assessment models. As a result, greater reductions in systolic and diastolic blood pressure, low-density lipoprotein cholesterol, and triglycerides were observed in the proactive multifactorial intervention (PMI) arm compared with the usual care arm at Week 52 for PA patients. The relative percentage change in 10-yr CHD risk between baseline and Week 52 in the PMI versus usual care arms was greatest using the NIPPON DATA80 fatal CHD model (LS [least square] mean difference -42.6%), and similar in the SCORE fatal CHD and Framingham total CHD models (LS mean difference -29.4% and -30.8%, respectively). The single-pill based PMI approach is consistently effective in reducing cardiovascular disease risk, evaluated using a variety of risk assessment models. (ClinicalTrials.gov registration number: NCT00407537).

Proactive cardiovascular risk management versus usual care in patients with and without diabetes mellitus: CRUCIAL trial subanalysis.

UNLABELLED: Patients with diabetes mellitus (DM) and additional cardiovascular (CV) risk factors are at very high risk for future CV events. This study investigated the efficacy and safety of a proactive, multifactorial CV risk factor-management strategy based on single-pill amlodipine/atorvastatin (SPAA) versus continuing physicians' usual care (UC) over 52 weeks in patients with and without DM. Patients with hypertension and ≥ 3 additional CV risk factors from the Cluster Randomized Usual Care vs Caduet Investigation Assessing Long-Term-Risk (CRUCIAL) trial--an open-label, cluster-randomized trial conducted in 19 countries--were enrolled and randomized to receive proactive intervention (based on SPAA 5/10 to 10/20 mg) or UC (based on investigators' best clinical judgment). Patients were analyzed according to baseline DM status. Six hundred patients had DM. Patients with DM in the SPAA and UC arms had mean ages of 61.8 and 61.5 years, respectively, and an absolute coronary heart disease (CHD) risk of 25.2% and 21.5%, respectively. Among non-DM patients, mean ages were 58.6 and 59.5 years, respectively, and CHD risk was 16.0% vs 15.7%, respectively. Least-squares mean treatment differences in percentage change from baseline in calculated 10-year Framingham CHD risk were -26.3% vs -27.3% among DM and non-DM patients (adjusted for respective baseline values) (both P < 0.0001). Among DM and non-DM patients, adverse events were reported in 52.8% versus 45.6% in the SPAA and 49.6% versus 41.6% in the UC arms, respectively. This global risk-management approach, simultaneously targeting blood pressure and lipids, was more effective for reducing calculated 10-year Framingham CHD risk than UC in patients with DM. While blood pressure changes were of smaller magnitude among patients with DM, this strategy reduced overall risk to an extent comparable with that observed in non-DM patients. Further studies are thus warranted to study this proactive risk factor intervention on CV or mortality endpoints in patients with and without DM. TRIAL REGISTRATION: www.ClinicalTrials.gov identifier NCT00407537.

Specific barriers to the conduct of randomized trials.

Large randomized trials are required to provide reliable evidence of the typically moderate benefit of most interventions. To be affordable, such trials need to be simple; to be widely applicable, they need to be close to normal clinical practice. However, current regulations and guidelines have hugely increased trial complexity, effectively becoming barriers to their design and conduct. Key barriers include inadequate funding, overly complex regulations producing needlessly complex trial procedures, excessive monitoring, over restrictive interpretation of privacy laws without evidence of subject benefit, and inadequate understanding of methodology. Complex regulations result in multiple ethics approvals for a multi-center study, unnecessary complexity in the study protocol, delays in securing regulatory approval, and cumbersome regulatory procedures, even for drugs widely used in clinical practice. The type of detailed safety monitoring currently needed in trials of new drugs is being applied indiscriminately to all studies including a simpler and basic level of monitoring that constitutes good practice in most trials could be agreed on, with that level being exceeded only in specific instances. More evidence about the pros and cons of alternative approaches to data quality monitoring would help inform this process. Complex procedures in the form of multiple-page consent forms, overzealous monitoring of side effects and adverse events, source data verification, and over-restrictive approaches to protocol amendments, can impede, rather than facilitate, trial objectives. Finally, further education on the nuances and functions of randomisation would facilitate trial conduct, and reduce the need for burdensome complexity. A radical re-evaluation of existing trial guidelines is needed, based on a clear understanding of the important principles of randomized trials, with the objective of eliminating unnecessary documentation and reporting without sacrificing validity or safety. Researchers should encourage public debate about how best to strike the balance between regulation and cost.