APAP Hepatotoxicity After Therapeutic Doses

NCT03602274 | Unknown

• 1 other identifier: 13-265
• Study Type: observational
• Target: 96
• Locations: 1 country
• Sites: 1

Brief Summary

Paracetamol (acetaminophen, APAP) is the most commonly used antipyretic and painkiller worldwide, but also the leading cause of acute liver failure (ALF) in developed countries after supra-therapeutic doses (half overdoses being unintentional). At therapeutic doses (4g/day), up to one third of healthy volunteers develop liver test elevation and cases of ALF have been described in the presence of suggested risk factors such as malnutrition, fasting and low body weight as a result of glutathione depletion. However, no well conducted study has aimed to prospectively assess the impact of malnutrition/fasting on the toxicity to therapeutic doses of APAP. Considering the widespread use of APAP and the prevalence of malnutrition in hospitalized patients (up to 30%), it is of crucial importance to assess whether these patients are at higher risk of hepatotoxicity. It is indeed likely that cases of liver damage secondary to normal recommended dose are under-estimated in these situations as the dose is not perceived as excessive and not described as such in international guidelines for pain management. The primary objective of our project will therefore be to assess if malnutrition and fasting are risk factors for liver toxicity after therapeutic doses (4g/day) of APAP in surgery patients. The second objective will be to evaluate the pharmacokinetics of APAP and metabolites according to nutrition status in order to establish, if necessary, dose reduction guidelines. Developing and validating an early and easily accessible marker of hepatotoxicity would especially be useful in these putative higher risk and fragile populations in order to improve early detection diagnosis and allow earlier management.

Conditions

Paracetamol Toxicity; Hepatotoxicity; Malnutrition

Keywords

Paracetamol; APAP; malnutrition; biomarker; liver toxicity; NAPQI

Outcome Measures

Primary Outcomes (1)

• Measure association between MNA score and increased risk of liver toxicity

  Calculate the statistical association between MNA score and ALT elevation 2x above the patients own baseline

  though patient hospitalisation max. 14 days

Secondary Outcomes (15)

• Measure correlation between blood hemoglobin adducts and ALT elevation

  through patient hospitalisation max. 14 days

• Measure correlation between blood albumine adducts and ALT elevation

  through patient hospitalisation max. 14 days

• Compare population pharmacokinetics of APAP in function of nutritional status

  through patient hospitalisation max. 14 days

• Compare population pharmacokinetics of APAP metabolite in function of nutritional status

  through patient hospitalisation max. 14 days

• Measure association between nutritional status and increased risk of liver toxicity

  through patient hospitalisation max. 14 days

Other Outcomes (2)

• Establish a dose reduction guideline according to nutritional status

  through patient hospitalisation max. 14 days

• Calculate the prevalence of ALT elevation in study population under therapeutic doses of APAP

  through patient hospitalisation max. 14 days

Study Arms (2)

orthopedic and visceral surgery patients

patient having been subjected to an intervention from the orthopedic or visceral surgery department being prescribed 4 g paracetamol / day

Diagnostic Test: Hepatic function monitoring; Diagnostic Test: Nutritional status assesment; Other: Biomarker research sampling

Overdosed patients

Patent admitted to hospital with paracetamol overdoses

Diagnostic Test: Hepatic function monitoring; Other: Biomarker research sampling

Interventions

Hepatic function monitoring DIAGNOSTIC_TEST

AST, ALT, GGT, AP, Bilirubin

Overdosed patients; orthopedic and visceral surgery patients

Nutritional status assesment DIAGNOSTIC_TEST

PINI, MNA nutritional assessment, PG-SGA assessment, anthropometric measurements

orthopedic and visceral surgery patients

Biomarker research sampling OTHER

Blood collection for proteomic, genetic, metabolomic and microRNA transcriptomic profiling

Overdosed patients; orthopedic and visceral surgery patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Any \> 18 years-old patient (except those listed in the non-inclusion criteria) admitted to the orthopedic or visceral surgery department that will be started on an APAP 4 gram per day regimen.

You may qualify if:

• Age \> 18 years-old patient admitted to the orthopedic or visceral surgery department that will be started on an APAP 4 gram per day regimen.

You may not qualify if:

• Serum ALT, AST or bilirubin above the ULN before APAP intake
• More than 20% of the liver involved with metastases
• Primary hepatocellular carcinoma
• Known hypersensitivity to APAP
• Inability to give written informed consent
• Inability to give blood samples.

Sponsors & Collaborators

• University Hospital, Geneva: lead

Study Sites (1)

Geneva University Hospitals

Geneva, 1211, Switzerland

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Plasma, serum, heparinated and EDTA blood samples, erythrocytes

MeSH Terms

Conditions

Malnutrition

Condition Hierarchy (Ancestors)

Nutrition Disorders; Nutritional and Metabolic Diseases

Study Officials

• Jules Desmeules, Prof.

  HUG

  STUDY DIRECTOR

• Caroline Samer, MD

  HUG

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Caroline Samer, MD

CONTACT

+41223729947; Caroline.Samer@hcuge.ch

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Doctor

Study Record Dates

• First Submitted: April 9, 2018
• First Posted: July 26, 2018
• Study Start: February 10, 2015
• Primary Completion: July 1, 2018
• Study Completion: December 1, 2018
• Last Updated: July 26, 2018

Record last verified: 2018-07

Locations

CH (1)