ASEPTIC: primary antibiotic prophylaxis using co-trimoxazole to prevent SpontanEous bacterial PeritoniTIs in Cirrhosis-study protocol for an interventional randomised controlled trial

Dominic Crocombe, Norin Ahmed, Indran Balakrishnan, Ekaterina Bordea, Marisa Chau, Louise China, Lynsey Corless, Victoria Danquah, Hakim-Moulay Dehbi, John F. Dillon, Ewan H. Forrest, Nick Freemantle, David Peter Gear, Coral Hollywood, Rachael Hunter, Tasheeka Jeyapalan, Yiannis Kallis, Stuart McPherson, Iulia Munteanu, Jim PortalPaul Richardson, Stephen D. Ryder, Amandeep Virk, Gavin Wright, Alastair O'Brien (Lead / Corresponding author)

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Abstract

Background: Bacterial infection is a major cause of mortality in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is a serious and common infection in patients with cirrhosis and ascites. Secondary prophylactic antibiotic therapy has been shown to improve outcomes after an episode of SBP but primary prophylaxis to prevent the first episode of SBP remains contentious. The aim of this trial is to assess whether primary antibiotic prophylaxis with co-trimoxazole improves overall survival compared to placebo in adults with cirrhosis and ascites.

Methods: The ASEPTIC trial is a multicentre, placebo-controlled, double-blinded, randomised controlled trial (RCT) in England, Scotland, and Wales. Patients aged 18 years and older with cirrhosis and ascites requiring diuretic treatment or paracentesis, and no current or previous episodes of SBP, are eligible, subject to exclusion criteria. The trial aims to recruit 432 patients from at least 30 sites. Patients will be randomised in a 1:1 ratio to receive either oral co-trimoxazole 960 mg or an identical placebo once daily for 18 months, with 6 monthly follow-up visits thereafter (with a maximum possible follow-up period of 48 months, and a minimum of 18 months). The primary outcome is overall survival. Secondary outcomes include the time to the first incidence of SBP, hospital admission rates, incidence of other infections (including Clostridium difficile) and antimicrobial resistance, patients' health-related quality of life, health and social care resource use, incidence of cirrhosis-related decompensation events, liver transplantation, and treatment-related serious adverse events.

Discussion: This trial will investigate the efficacy, safety, and cost-effectiveness of co-trimoxazole for patients with liver cirrhosis and ascites to determine whether this strategy improves clinical outcomes. Given there are no treatments that improve survival in decompensated cirrhosis outside of liver transplant, if the trial has a positive outcome, we anticipate widespread adoption of primary antibiotic prophylaxis.

Trial registration: ClinicalTrials.gov NCT043955365 . Registered on 18 April 2020. Research ethical approval was granted by the Research Ethics Committee (South Central - Oxford B; REC 19/SC/0311) and the Medicines and Healthcare products Regulatory Agency (MHRA).

Original languageEnglish
Article number812
Number of pages14
JournalTrials
Volume23
DOIs
Publication statusPublished - 27 Sep 2022

Keywords

  • Adult
  • Anti-Bacterial Agents/adverse effects
  • Antibiotic Prophylaxis/adverse effects
  • Ascites/drug therapy
  • Bacterial Infections/drug therapy
  • Diuretics/therapeutic use
  • Humans
  • Liver Cirrhosis/complications
  • Multicenter Studies as Topic
  • Peritonitis/diagnosis
  • Randomized Controlled Trials as Topic
  • Trimethoprim, Sulfamethoxazole Drug Combination/adverse effects
  • Primary prophylaxis
  • Spontaneous bacterial peritonitis
  • Co-trimoxazole
  • Infection
  • Antimicrobial resistance
  • Ascites
  • Liver cirrhosis

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