ASEPTIC

This is a National Institute for Health Research funded trial to examine the efficacy of primary antibiotic prophylaxis using Co-Trimoxazole in patients with cirrhosis and ascites. Aims: Patients who have advanced liver disease are at high risk of suffering infection, hospital admission and death and our aim is to prevent infection in the first place. We are targeting a specific infection that affects fluid that builds up in the abdomen (known as ascites) of advanced liver disease patients, called Spontaneous Bacterial Peritonitis or SBP for short.

Preventing SBP could help people with liver disease live longer, healthier lives. Background: Liver disease is a common cause of death and the three major causes are excessive alcohol drinking, obesity or infection with viral hepatitis. It develops over 15-30 years and causes irreversible liver scarring, cirrhosis. Some patients develop features of advanced liver disease - a yellow skin, vomiting of blood or fluid in their abdomen and this affects 6000 people a year in Britain.

They are very vulnerable to infection with bacteria because of their weak immune systems. These infections almost always require hospital admission and worsen their liver disease. A strategy of prevention of infection may be better than cure. We will look at whether giving these people antibiotics when they do not have an infection for 18 months improves overall survival and prevents development of SBP.

This is called prophylaxis and has been shown to work but only in small numbers of people and for short time frames. We do not know if this would work across a wider population in the longer term. Antibiotic prophylaxis may cause harm, during antibiotic treatment bugs can find ways to stop antibiotics from killing them, antimicrobial resistance. These resistant bugs are even more dangerous as we have fewer antibiotics that work against them.

We therefore need to test our approach in a clinical trial. Design: We will recruit 432 people with cirrhosis and ascites but no SBP from 30 hospitals. Each will be given a pill once a day. These pills will look identical but half will be an antibiotic and half an inactive tablet, a placebo. The antibiotic is co-trimoxazole, commonly used for urine infections. Neither patients nor doctors will know which is which, a double-blind trial, as if patients or investigators know which pill they are taking this can affect results even with an inactive drug, the placebo effect.

Participants will take the medication for 18 months and meet research nurses every 3 months to check if they have developed SBP or required admission to hospital. Information on liver function and quality of life will be collected and participants tested for antimicrobial resistance. Co-trimoxazole causes significant side effects in 1 of every 100 patients, usually skin rash. Very rarely (1-7 cases per million people per year) a severe dangerous skin rash develops, Stevens-Johnson, which people will be taught to look out for.

High blood potassium levels can also occur and will be monitored by 3 monthly blood testing. Information will be stored securely so that participants cannot be identified and analysed by statisticians to inform us if co-trimoxazole prophylaxis prevents SBP effectively and safely. Patient and public involvement: An infection in cirrhosis patient group has been set up to inform about concerns e.g. safety or adverse effects.

We will meet before the trial to design the protocol, consent forms, patient information sheets and a lay FAQ sheet for patients. Dissemination: The results will be spread to patients, the public and health care workers via medical publications, meetings, British Liver Trust, social and conventional media.