Title: Primary Antibiotic Prophylaxis using Cotrimoxazole to Prevent Spontaneous Bacterial Peritonitis in Cirrhosis_x000D_ _x000D_ ACRONYM: ASEPTIC - Antibiotic SpontanEous PeritoniTIs Cirrhosis
Funder: Department of Health and Social Care

Abstract: Aims _x000D_ 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. _x000D_ Background_x000D_ 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 24 months 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. Also 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._x000D_ Design_x000D_ We will recruit 548 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 cotrimoxazole, 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 24 months and meet research nurses every 3 months to check if they have developed SBP. Information on liver function and quality of life will be collected and participants tested for antimicrobial resistance. Cotrimoxazole 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 2 monthly blood testing. Information will be stored securely so that participants cannot be identified and analysed by statisticians to inform us if cotrimoxazole prophylaxis prevents SBP effectively and safely._x000D_ Patient and public involvement_x000D_ 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._x000D_ Dissemination_x000D_ The results will be spread to patients, the public and health care workers via medical publications, meetings, British Liver Trust, social and conventional media.

Lay abstract: Research question: We will determine the efficacy of antibiotic prophylaxis for adults with cirrhosis & ascites but no previous spontaneous bacterial peritonitis (SBP) to prevent development of SBP, “primary prophylaxis”._x000D_ _x000D_ Background: Bacterial infections are a leading cause of death in cirrhosis and SBP is the most common cause. A strategy of prevention with antibiotic prophylaxis may be beneficial. This is established for those with prior SBP but not for primary prophylaxis yet importantly >90% of SBPs have no previous episode. Antibiotic prophylaxis appears to prevent infection but there is a risk of anti-microbial resistance (AMR) and Clostridium difficile associated diarrhoea (CDAD). With liver disease set to overtake heart disease as the leading cause of lost working life years, there is huge necessity for this trial._x000D_ The choices are quinolones, cotrimoxazole or rifaximin. In view of likely equivalent efficacy, low cost and less concern of CDAD & AMR compared to quinolones, we will use cotrimoxazole. As rifaximin may be beneficial and is prescribed for encephalopathy, participants will be stratified according to its use. _x000D_ _x000D_ Method: We plan a multicentre placebo controlled randomised doubled blind trial to assess efficacy, cost-effectiveness and safety of cotrimoxazole for 2 years to prevent SBP in 548 participants with cirrhosis, ascites and a low ascitic fluid (AF) protein count (<1.5g/dl) from 30 NHS sites. This has been adopted by the UCL CCTU and we have good experience of managing a cirrhosis multicentre trial. The primary outcome will be event free survival with time to first incidence of SBP compared between arms. Sample size calculation used 90% power and 2-sided 5% significance level with 20% loss-to-follow-up. Secondary outcomes include mortality, AMR & CDAD incidence and cost effectiveness. Patients will be stratified by liver disease severity and active alcohol use._x000D_ Patients >18 years with cirrhosis, ascites and low AF protein count will be eligible and if life expectancy <8 weeks excluded. They will have 2 monthly follow-up visits to collect medication, bloods and sampling for AMR. A case report form (CRF) will document SBP admissions. Patients will stop treatment if ascites resolves, undergo transplant or complete 2 years follow-up._x000D_ A detailed statistical analysis plan will be approved before analysis of unblinded data, including health economics, quality of life & serious adverse events. _x000D_ _x000D_ Timelines for delivery: We anticipate 6 month setup for protocol development, CRFs and organising contracts with sites. Recruitment will be 24 months with anticipated recruitment rate of 1 patient per site per month with a staggered initiation of 30 sites over 12 months. A 9 month GO/NO GO internal pilot will demonstrate deliverability based on anticipated recruitment. We estimate recruiting 320 patients from first 15 sites & 230 from the next 15 giving 548 participants required to demonstrate a 55% relative reduction in cumulative event probabilities of SBP. Treatment duration is 24 months. Close out, cleaning & analysis will be 6 months_x000D_ _x000D_ Anticipated impact and dissemination: This will be the largest study of SBP prophylaxis ever and if successful we will update international guidance. Our findings will be communicated to NICE, journals, policy/academic meetings & (social) media. We will work with public engagement and patient involvement networks established in the trial to spread findings to patients & the public.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL