ICF: POC-DILI-2 Point-of-care diagnostic-guided randomised trial comparing early treatment vs standard care in high-risk paracetamol overdose patients
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Cardiovascular Science
Abstract
Paracetamol overdose (POD) is common, with approximately 100,000 cases attending hospital emergency departments in the UK each year (same as heart attacks). Of these patients around half (50,000) need urgent treatment yet, despite an effective antidote being available, around 5,000 patients every year still develop drug-induced liver injury (DILI). The prompt administration of the antidote acetylcysteine (NAC) to patients at risk of DILI is crucial to prevent potentially life-threatening liver failure. Treatment efficacy decreases substantially as the delay between POD and starting NAC increases. NAC is almost 100% effective if started within 8 hours of overdose but offers only modest benefits if started after around 20 hours.
There are no specific symptoms or clinical signs of early liver damage therefore healthcare workers rely on blood tests measured in a central hospital laboratory to pick up liver injury after POD. At hospital presentation, prior to blood results being available, the current method for early risk stratification after POD uses the patient-reported time of overdose to estimate the delay between POD and NAC. This approach is inherently subjective, cannot be used in staggered overdoses and accidental therapeutic excess ingestions (around one third of cases) and has sub-optimal accuracy even when applicable. There is a pressing need for a rapid, cost-effective, point-of-care assay to identify high-risk patients at hospital presentation with sufficient sensitivity and specificity for targeted early treatment.
The standard serum biomarker for DILI diagnosis, alanine aminotransferase (ALT), increases too slowly post-POD to accurately diagnose DILI within the NAC optimal therapeutic window. Multiple studies have repeatedly demonstrated that a circulating biomarker called cytokeratin-18 (K18) can be used to accurately detect DILI within 8 hours of overdose (the optimal time window for effective NAC treatment). Using DPFS funding, our multi-disciplinary team have developed a point-of-care (POC) assay called the POC-DILI Diagnostic, which combines a K18 Lateral Flow Assay (K18 LFA) with a bespoke Handheld Raman Reader (HRR). The K18 LFA uses antibodies and gold nanoparticles (AuNP) to create a sandwich assay with K18. The AuNPs are functionalised with a Raman reporter to produce a quantitative Surface Enhanced Raman Scattering (SERS) assay, read out by the HRR from the K18 LFA strip.
In banked samples, the POC-DILI Diagnostic has achieved its target product profile, with high sensitivity and specificity in identifying DILI and time-to-result within 20 minutes (milestone 1 achieved). A prospective performance evaluation study has now commenced (POC-DILI study).
There are no specific symptoms or clinical signs of early liver damage therefore healthcare workers rely on blood tests measured in a central hospital laboratory to pick up liver injury after POD. At hospital presentation, prior to blood results being available, the current method for early risk stratification after POD uses the patient-reported time of overdose to estimate the delay between POD and NAC. This approach is inherently subjective, cannot be used in staggered overdoses and accidental therapeutic excess ingestions (around one third of cases) and has sub-optimal accuracy even when applicable. There is a pressing need for a rapid, cost-effective, point-of-care assay to identify high-risk patients at hospital presentation with sufficient sensitivity and specificity for targeted early treatment.
The standard serum biomarker for DILI diagnosis, alanine aminotransferase (ALT), increases too slowly post-POD to accurately diagnose DILI within the NAC optimal therapeutic window. Multiple studies have repeatedly demonstrated that a circulating biomarker called cytokeratin-18 (K18) can be used to accurately detect DILI within 8 hours of overdose (the optimal time window for effective NAC treatment). Using DPFS funding, our multi-disciplinary team have developed a point-of-care (POC) assay called the POC-DILI Diagnostic, which combines a K18 Lateral Flow Assay (K18 LFA) with a bespoke Handheld Raman Reader (HRR). The K18 LFA uses antibodies and gold nanoparticles (AuNP) to create a sandwich assay with K18. The AuNPs are functionalised with a Raman reporter to produce a quantitative Surface Enhanced Raman Scattering (SERS) assay, read out by the HRR from the K18 LFA strip.
In banked samples, the POC-DILI Diagnostic has achieved its target product profile, with high sensitivity and specificity in identifying DILI and time-to-result within 20 minutes (milestone 1 achieved). A prospective performance evaluation study has now commenced (POC-DILI study).
