Title: The EXTEND trial: EXTENDed antibiotic durations compared to standard antibiotic durations for patients with complicated intra-abdominal infection
Funder: Department of Health and Social Care

Abstract: Bacteria living in the intestine (guts, or bowels) help people digest food. Sometimes the intestine is damaged by an operation or disease such as cancer. When this happens bacteria leak into the space surrounding the intestine. This space is called the abdominal cavity. When bacteria reach the abdominal cavity they cause serious abdominal cavity infections._x000D_ _x000D_ The care of patients with serious abdominal cavity infections is a big problem for doctors. Over thirty thousand patients per year suffer from this type of infection. Patients with the infection may need an operation to remove damaged intestine to help them get better. They also need antibiotics to cure the infection by killing bacteria left in the abdominal cavity. The treatment does not seem to be working as well as doctors would hope. In up to half of patients the original infection may come back or patients may develop another infection such as pneumonia. This means patients with abdominal cavity infections may need a second round of treatment to cure the infection. This treatment could include antibiotics and surgery._x000D_ _x000D_ We asked 30 UK hospitals how they use antibiotics to treat abdominal cavity infections. We found that patients usually receive antibiotics for 7 to 18 days. We wondered if giving patients a longer antibiotic treatment of four weeks (28-days) might cure and prevent more infections than the usual length of treatment. Research from other studies shows longer courses of antibiotics may help patients with serious abdominal infections. We talked to patients to find out how they would feel about taking longer courses of antibiotics. We also ran a test study looking at 28-day antibiotics in 2017 to 2018. Half the thirty patients in the study took a longer course of antibiotics of 28-days. This study showed patients and doctors were happy to take part in a study using 28-days of antibiotics, and the results were consistent with 28-days antibiotics helping more patients recover._x000D_ _x000D_ We think it is important to find out if 28-days of antibiotic treatment work better in patients with serious abdominal infections. We want to know if 28-days antibiotics are better at curing the infection first time and at stopping other infections developing. We will also find out if taking antibiotics for 28-days keeps more patients out of hospital and reduces the number of antibiotic resistant infections. The Public and Patient Involvement (PPI) groups we talked to thought the issue of antibiotic treatment was important to patients. The PPI groups helped us design the test study and will be involved in our new study, the EXTEND Trial. There will be two groups of patients in the EXTEND trial. Patients in one group will take antibiotics as normal, between 7 to 18 days. The exact duration will be decided by their own doctor. The other group will take antibiotics for 28-days. Patients will receive all other care as usual. The choice of group that patients are put in is decided by chance. We will follow both groups for the next six months to see which treatment worked the best._x000D_ _x000D_ Finding the best treatment for patients with serious abdominal cavity infections is an important challenge. The results of this study will help patients and doctors decide if 28-days antibiotics are better than shorter treatments. The results of the research will be shared with the NHS and patient groups. We will also write a summary of the results for patients, families and carers.

Lay abstract: Research question: Does the use of fixed-extended-duration antibiotics improve patient outcomes compared to standard antibiotic durations in patients with complicated intra-abdominal infection._x000D_ _x000D_ Background: Complicated intra-abdominal infections (cIAIs) are the second most common source of sepsis on Intensive Care Units, and a major challenge on surgical wards with between 33,000-215,000 cases per year. Complications including death, cIAI relapse after antibiotic therapy and extra-abdominal infections are common in this at risk patient group. Complications require more antibiotic treatment and additional surgical interventions. Trial data shows longer antibiotic durations delay time to relapse, reduce the need for radiological drainage and may reduce extra-abdominal infections. Randomised controlled trial (RCT) data from the UK is needed to evaluate fixed-extended-durations of antibiotics for patients with cIAI before implementation in the NHS._x000D_ _x000D_ Aim: To investigate the clinical and cost effectiveness of a fixed-extended-duration of 28-days antibiotic treatment compared to standard care for patients with cIAIs._x000D_ _x000D_ Objectives: To complete a randomised parallel group comparison to determine if a fixed-extended-duration of 28-days antibiotic treatment is superior to standard care based on treatment failure assessed over 180 days from diagnosis. To conduct an economic evaluation to assess the cost-effectiveness of these comparisons and further modelling for long term effects._x000D_ _x000D_ Methods: A multicentre, open label, 2-arm, parallel group, pragmatic, randomised controlled superiority trial with internal pilot and cost-effectiveness study. Eligible patients are adults with cIAI requiring >72 hours in-patient surgical care with or without a source control procedure. Intervention treatment will be a fixed-extended-duration of 28-days antibiotics for the treatment of cIAI and the comparator will be standard care antibiotic duration. The primary outcome will be treatment failure within 180 days of diagnosis. Secondary outcomes include Desirability of Outcome Ranking analysis, EQ-5D-5L, mortality, number/type of source control procedures, relapse of cIAI, length of hospital stay, re-admission, C. difficile infection, anti-microbial resistant infections and days of antibiotics within 180 days of diagnosis. The sample size will be 1166 based on an effect size of 10% assuming an event rate of 50% or more in the standard treatment arm. Participants will be randomised 1:1 between 28-days antibiotics and a standard care antibiotic duration stratified by post-operative cIAI vs non post-operative cIAI, surgical source control procedure vs no surgical source control procedure and ICU stay vs no ICU stay._x000D_ _x000D_ Timelines for delivery: Six months is required for protocol development, ethical/HRA approval and trial/site set-up. Recruitment will take 36 months including a 12 month pilot, with a six month follow up period followed by a six month analysis phase._x000D_ _x000D_ Anticipated impact and dissemination: This will be the first RCT to provide evidence for the use of fixed-extended-duration antibiotic durations in the treatment of cIAI, providing evidence required for adoption into clinical practice. Patients will potentially benefit from less treatment failure after cIAI treatment and long term improvements in quality of life. The trial will be disseminated via conference presentations, publications and to the public/patients supported by the EXTEND PPI group.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION