The Markers and Paracetamol Poisoning Study 2 (MAPP2)

The Markers and Paracetamol Poisoning Study 2 - Early Diagnosis of Drug-induced Liver Injury Using Point of Care Detection of microRNA

Paracetamol overdose is one of the most common medical emergencies. Annually in the UK, 100,000 people seek medical attention and 50,000 need hospital admission. Treatment is with the antidote acetylcysteine (NAC), which is effective but takes 21 hours to administer intravenously and frequently produces adverse reactions.

Current tools that are used to decide who needs treatment are inadequate. this trial team have identified and validated new blood tests that accurately identify those patients at risk of liver injury by quantifying the fundamental in vivo toxicity mechanisms.

This study aim to gain further samples in order to develop a new point-of-care test specifically for the detection of liver damage.

Study Overview

• Status: Completed
• Conditions: Paracetamol Overdose
• Intervention / Treatment: Other: Surplus blood tests

Detailed Description

Paracetamol overdose is one of the most common medical emergencies. Annually in the UK, 100,000 people seek medical attention and 50,000 need hospital admission. Treatment is with the antidote acetylcysteine (NAC), which is effective but takes 21 hours to administer intravenously and frequently produces adverse reactions. Paracetamol is the commonest cause of acute liver failure and directly kills around 200 people/year in the UK. Management of paracetamol overdose is estimated to cost around £48 million/year to the NHS.

Current tools that are used to decide who needs treatment are inadequate. This trial team have identified and validated new blood tests that accurately identify those patients at risk of liver injury by quantifying the fundamental in vivo toxicity mechanisms. Over the last 4 years the team have published data in leading journals such as The Lancet, Lancet Gastroenterology (the MAPP Trial), Hepatology and Clinical Pharmacology & Therapeutics. The current gold standard marker, serum Alanine Aminotransferase Test (ALT) activity, lacks both sensitivity and specificity for early liver injury. This has resulted in being able to qualify 3 new liver biomarkers in over 1,200 patients (microRNA-122 (miR-122), High Mobility Group Box protein 1 (HMGB1) and keratin-18 (K18)) and demonstrated they predict liver injury at first presentation to hospital with high accuracy at a time when ALT is still normal.

This project develops a new point-of-care (POC) test for circulating microRNA specifically for the detection of liver damage after paracetamol overdose. The team have developed the microRNA biomarker (miR-122) to the point where it has received formal regulatory support from the USA Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The proposed assay has backing from worldwide clinical opinion leaders and pharma partners such as AstraZeneca, GSK and Novartis. The engineering solution for POC microRNA detection is underpinned by robust pilot data and field-leading expertise. The current assay for miR-122 is PCR following extensive sample preparation which is too slow for acute clinical decision making and for dose-escalation decisions. To address this key roadblock (as identified by the FDA) the team will use electrochemical impedance spectroscopy (EIS). the trial team have over 10 years of experience in EIS-based POC test development. Pilot data demonstrate that EIS can detect miR-122 spiked into buffer and distinguish patients with DILI (high miR-122) from healthy subjects (low miR-122).

• Study Type: Observational
• Enrollment (Actual): 464

Contacts and Locations

• Study Contact: Name: Rachel O'Brien, BA BN; Phone Number: 23867 0131 242 3867; Email: rachel.o'brien@nhslothian.scot.nhs.uk
• Study Contact Backup: Name: Caroline Blackstock, BSc; Phone Number: 0131 242 1284; Email: caroline.blackstock@nhslothian.scot.nhs.uk

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom
    • NHS Lothian

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients presenting to Emergency Department or Acute Medical Unit with paracetamol overdose

Description

Inclusion Criteria:

1. Age 16 years and over.
2. Hospital attendance with paracetamol overdose alone or as part of a mixed overdose
3. Patient is able to give informed consent

Exclusion Criteria:

1. Patient detained under the Mental Health Act
2. Inability to provide informed consent
3. Unreliable history of overdose
4. Prisoners

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To establish a biobank of human serum samples from patients with paracetamol overdose to develop and test the performance of our POC Test	3 years

Collaborators and Investigators

• Sponsor: NHS Lothian
• Investigators: Principal Investigator: James Dear, University of Edinburgh

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Actual): May 31, 2023
• Study Completion (Actual): May 31, 2023

Study Registration Dates

• First Submitted: April 5, 2018
• First Submitted That Met QC Criteria: April 5, 2018
• First Posted (Actual): April 13, 2018

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Poisoning
• Other Study ID Numbers: 244423

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No