Study of the application of the 12-hour N-Acetylcysteine protocol in the emergency service for paracetamol overdose: a multicentre, non-inferiority, randomized, open label, controlled clinical trial

Abstract

Background Paracetamol is commonly used worldwide. It is the first step on the World Health Organization (WHO) pain ladder and is currently recommended as first-line pharmacological therapy for acute and chronic painful conditions. Paracetamol is the main drug causing acute liver failure in countries as in United Kingdom (UK) and United States (US), the incidence is 70% and 46% respectively. In Spain, the incidence is lower than in the aforementioned countries, at 2,2% of cases of paracetamol overdose. The paracetamol overdose can be acute (single dose greater than 7.5 to 10 grams) or chronic (repeated dose). The hepatotoxicity per paracetamol is caused by an accumulation of metabolite toxic NAPQI and glutathione stores depleted. The clinical course of hepatotoxicity it can be asymptomatic to a hepatic encephalopathy caused by hepatitis fulminant. The treatment of paracetamol is an N-acetylcysteine (antidote) for 21 hours. Objectives The main purpose of this study is to compare the incidence of hepatotoxicity in patients with paracetamol overdose between NAC protocol 12 hours vs. NAC protocol 21 hours. In addition, this study will compare the incidence of adverse effects and hospital length of stay in both groups. Design

This study is designed as a non-inferiority, randomized, parallel group controlled, open- label clinical trial will be performed among different hospitals of Catalonia, Madrid and

Andalusia. Method Patients enrolled in this study will be randomized in two groups (A and B). The group A (n= 235) will receive therapy A which consist a standard protocol of NAC for 21 hours, while the group B (n=235) will receive therapy B which consist a modified protocol of NAC for 12 hours. Main outcome will be the hepatotoxicity caused by paracetamol, which will measure with parameters of laboratory (include ATL, INR, PT). This outcome is defined as a 50% increase in ALT after 21 h post-treatment compared with the admission value overall; ALT > 1000, INR > 1.5 and Quick time >20% at 21 h vs 12h post-treatment. The follow-up will be done the hospital length of stay in the emergency service of patient, according to her/his clinical situation (includes symptoms and the laboratory tests) and her/his response to treatment