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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - RADIcAL (Non-invasive rapid assessment of chronic liver disease using Magnetic Resonance Imaging with LiverMultiScan)

Teaser

Summary

Liver disease is a rapidly developing epidemic that poses a huge medical and socio-economic burden on society. Chronic liver diseases are called \'silent killers\', as clinical symptoms only surface at late stages of the disease when it is not treatable. Non-alcoholic fatty liver disease (NAFLD), a condition defined by fat accumulation in the liver, and its sub-type non-alcoholic steatohepatitis (NASH), are the major forms of liver disease. Untreated NAFLD/NASH can lead to cirrhosis and liver failure. The economic burden of NAFLD and associated co-morbidities in Europe continues to grow. In Germany, France, Italy and the UK the annual cost of NAFLD is around â‚¬35 billion, equating to â‚¬354 to â‚¬1,163 per patient (Younossi et al,2016). Furthermore, annual healthcare costs related to liver disease are 86% higher in those with advanced liver disease than without. Procedures for those with severe liver disease, such as liver transplant surgery, is estimated to total â‚¬55,677 per patient annually (Petta et al,2019). NAFLD/NASH, is primarily a consequence of obesity and metabolic syndromes such as diabetes, insulin resistance, hyperlipidaemia and hypertension. Thus, treating NAFLD/NASH patients at an early stage, when the disease is still curable, could benefit these patients and society as a whole.

At present, the gold standard for diagnosing and staging liver disease is liver biopsy, which is costly, invasive, and carries risk for the patient. For these reasons, clinicians are reluctant to use it for people suspected of having NAFLD/NASH. In addition, invasive biopsy is not optimal for serial assessment (e.g. monitoring transplant population for signs of liver rejection). Perspectum Diagnostics Ltd (PD) has developed LiverMultiScanâ„¢, a novel, non-invasive, quantitative Magnetic Resonance Imaging (MRI) post-processing software tool that has demonstrated high diagnostic accuracy for the early assessment of liver disease (Banerjee et al,2014; Pavlides et al,2016; Pavlides et al,2017). This technology has the potential to improve the care pathway for patients with suspected NAFLD, by reducing the number of visits and unnecessary liver biopsies, if the cost benefits can be realised. PD was awarded a Horizon 2020 grant by the European Commission, Executive Agency for Small and Medium-sized Enterprises (EASME) to develop the health economic case for LiverMultiScanâ„¢ as part of the diagnostic pathway in European healthcare settings. This project is known as RADIcAL.

RADIcAL comprises two clinical studies RADIcAL1 (R1) (1072 patients) and RADIcAL2 (R2) (200 patients).
The specific objectives are:
â€¢ To validate the cost-effectiveness and added value of LiverMultiScanâ„¢ compared to the standard care pathway for assessing chronic liver disease;
â€¢ To demonstrate the sensitivity and specificity of LiverMultiScanâ„¢ as a medical support tool for stratifying patients that have high risk of liver transplant rejection;
â€¢ Share and disseminate evidence of benefits of LiverMultiScanâ„¢ as a novel non-invasive, radiation-free, one-step solution that provides fast detection of liver disease at early stage, providing accurate diagnosis for all types of patients (including obese people and those with high iron levels in the liver), and capable of assessing the entire liver volume.

Work performed

Both R1 and R2 studies are running and actively recruiting subjects. Ulm, Leiden, Coimbra, Liverpool, Southampton and Dundee are recruiting patients for the R1 study. Leiden, Coimbra, and Kingâ€™s College are recruiting patients to the R2 study. All individuals who will be acquiring and uploading LiverMultiScanâ„¢ data at the sites have received training on PDâ€™s secure cloud-based data transfer portal, Edison. Research teams at all recruiting sites have also been trained to use the ProMISe database, the online eCRF managed by Leiden CTU. During this reporting period, PD\'s Data Protection Officer has improved the process for the secure handling of study data to meet GDPR requirements. Both R1 and R2 are registered on clinicaltrials.gov NCT03289897, NCT03165201 respectively.

406 subjects have been enrolled into R1 and 106 to R2 (up to 30th June 2019). To increase the recruitment rate for R1, 10 additional sites in the UK are being added. In RP3, 5 of these sites were activated with a 6th site being activated between the end of RP3 and this report being submitted. We are in discussion with the final 4 sites, 2 of which have already passed the feasibility assessment.

The R1 study protocol has been updated to reflect the recent grant amendment e.g. new study end date, new sites and reduced sample size. Between the end of RP3 and the time this report was submitted, the R1 study amendment was submitted and approved by the Research Ethics Committee (REC) and Health Research Authority (HRA). A substantial study amendment to R2 to change the biomarker for fibroinflammation (LIF to cT1) is currently under REC and HRA review.

Regular communication with all RADIcAL sites has been maintained via frequent teleconferences and email communication that has focused on site-set up processes, eCRF and Edison troubleshooting, study amendments, general trial updates and progression. We recently issued the 1st RADIcAL study newsletter and disseminated to all study sites via email. Dissemination to the wider community took place at key liver conferences - AASLD 2017, EASL 2018 and 2019 - and through the dedicated study website. The RADIcAL team will also be attending AASLD 2019 to present an abstract focussing on preliminary R1 results.

With regards to the health economics work package (WP3), HERC have completed deliverables 3.1-3.3 with D3.4 onwards being assigned to a new Health Economist at PD with support from an economics intern. Preliminary internal analysis has shown promising results that suggest the implementation of LiverMultiScanâ„¢ in the clinical care pathway could reduce the number of medical appointments for patients with suspected NAFLD.

Final results

An abstract looking at R1 preliminary data has been accepted for presentation at The Liver Meeting (AASLD 2019). At the conference, PD will be represented with a booth and provide interested parties with information about LiverMultiScanâ„¢ and RADIcAL project progress.

The methodology will be submitted for peer-review to an Open Access journal. Following completion of R1 and R2 studies, we will publish our results on clinical validation in a high impact Open Access journal for optimal knowledge distribution. We will further promote our results through publication in national and international magazines and journals, specifically aimed at radiologists and liver specialists.

The RADIcAL study continues to progress and a positive outcome is predicted with potential to lead to earlier detection of liver disease. Good quality imaging, economic and clinical data has been collected from all active sites, and preliminary analysis has shown clinical utility of the new technology, adding to the argument for state-of-the-art. Consequently, this will have considerable impact on changing the course of illness, better treatment management, reducing early morbidity and mortality from end-stage liver disease and reducing healthcare costs.

PD aims to transform the current care pathway for liver disease through the establishment of LiverMultiScanâ„¢ as a cost-effective diagnostic tool to detect change and early signs of rejection in patients who have had a previous liver transplant.