EXTENDed Antibiotic Durations Compared to Standard Durations for Patients With Complicated Intra-abdominal Infection.

Study Overview
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Brief Summary
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A multicentre, open label, two-arm, parallel group, pragmatic, randomised controlled trial with internal pilot. A total of 1166 consenting adult patients with cIAI will be recruited and randomised on a 1:1 basis between 28-days antibiotics and standard care antibiotics. Patients will be followed up for 180 days to determine cost effectiveness and the rate of treatment failure in each group.

Detailed Description
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UK data suggests that current treatment for complicated intra-abdominal infections (cIAIs) results in unacceptably high rates of cIAI relapse and extra-abdominal infection. As a guiding rule, shorter antibiotic durations are important to combat antimicrobial resistance, but this is not true when these shorter courses need repeating and result in more days in hospital. Optimal care for patients should be our primary concern. The EXTEND trial aims to find out whether a fixed extended duration of 28 days of antibiotics is superior to the current standard duration (typically 7-18 days) based on clinical outcomes and quality of life assessed over 180 days of follow up. Cost effectiveness will also be determined. A target of 1166 patients will be recruited from ICUs and hospital in-patient wards across 30 NHS trust hospitals. Only patients that provide consent (or a consultee provides consent on their behalf) can take part in the trial. They will receive antibiotics as prescribed by their treating clinician, but the duration of treatment will be determined by randomisation. Patients will have equal chance of randomisation to the standard care arm, in which the antibiotic duration will be determined by the treating clinician, or the intervention arm, a fixed duration of 28 days treatment. Patients (or a personal consultee) will complete a quality of life questionnaire at baseline and 30, 60 and 180 days after randomisation. At follow-up timepoints they will also complete questionnaires on antibiotic use and health care resource use. Hospital notes will be used to collect data on inpatient admissions, relapse and further infections.

Official Title
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The EXTEND Trial: Fixed-extended-duration Antibiotics (28 Days) Compared to Standard Care Antibiotic Durations in Adult Patients With Complicated Intra-abdominal Infection and Their Impact on Treatment Failure

Conditions
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Complicated Intra-abdominal Infection

Intervention / Treatment
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* Drug: Antibiotic - standard duration
* Drug: Antibiotic - fixed-extended-duration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (≥ 18 years) with cIAI (see cIAI definition) Being treated with antibiotics until the point of randomisation, but within 10 days of initiation of antibiotic treatment for cIAI Ability to provide informed consent by the patient or their consultee. More than 72 hours of active in-patient management for the patients cIAI is required Specific inclusions where patients require more than 72 hours of in-patient management, are Patients with diverticulitis abscess Perforated appendix with peri-appendiceal phlegmon, abscess or diffuse peritonitis (Grade 5 and 6 of the 2017 American Association for the Surgery on Trauma Grading System) Discrete pancreatic infections (abscess, infected pseudocyst) Patients will be included in the trial whether or not they undergo surgical or radiological source control procedures. cIAI is defined by the following case definition: A clinical presentation consistent with cIAI, plus Fever (temperature of ≥ 37.8°C) and/or a neutrophilia (> 7.5×109/L) and/or pathogens cultured from sterile sites (closed peritoneum or blood) with an intestinal pathogen, plus Evidence of pathologic findings on radiologic examination, or Evidence of pathologic findings at operation Exclusion Criteria: Perforated gastric ulcer or duodenal ulcer treated within 24 hours of the onset of symptoms. Traumatic injury to the bowel (including iatrogenic or intra-operative) treated within 12 hours of injury. Uncomplicated diverticulitis defined as an episode with a short history and with clinical signs of diverticulitis, with an increased body temperature and inflammatory parameters, verified by computed tomography (CT), and without any sign of complications such as abscess, free air or fistula. Non-perforated, non-gangrenous appendicitis (Grade 4 and below of the 2017 American Association for the Surgery on Trauma Grading System) or cholecystitis. Ischemic or necrotic intestine without perforation Uterine perforation following uterine surgery treated <six hours following injury. cIAIs with a low risk of complications who may receive more than 72 hours antibiotics are not intended to be included, such as those listed above. Clinician assessment on the eligibility of patients receiving more than 72 hours of in-patient surgical care and antibiotics for their cIAI may be required in patients who have clinically improved at this point and do not require active surgical care but remain in hospital and on antibiotics. Current enrolment in another trial dictating antibiotic treatment duration. Previous Clostridium difficile infection Infected necrotic pancreatitis Concomitant infection requiring ≥4 weeks antibiotic therapy including Intra-hepatic abscess/es planned to be treated with fixed-extended-duration antibiotics of 4 to 6 weeks antibiotics, osteomyelitis, and endocarditis. Peritoneal dialysis Previously recruited for the EXTEND trial cIAI with an antimicrobially resistant infection without a safe (non-toxic) and effective antibiotic treatment option Treatment with Interleukin-6 Inhibitors High likelihood of death within 72 hours of cIAI randomisation in the opinion of the local Investigator or limitations in treatment decided before inclusion Patient with persistent cIAI of more than 6 months duration Specific non-exclusions are; Placement of drains and irrigation of the abdomen do not exclude patients from the trial. Immunodeficiency/Steroids/Pregnancy/Malignancy do not exclude patients from the trial. Patients with anastomotic leak will not be excluded from the trial. Patients with infected Central Venous Catheters. Prolonged use of central venous catheter prophylaxis e.g., Tauralock Patients on long term antibiotics for prophylaxis of recurrent urinary tract infection or splenectomy. Patients with a relapse of a cIAI not previously recruited for the EXTEND trial. Patients who relapse should have not received antibiotic treatment for their cIAI in the preceding two weeks. A maximum of 20% of participants entering the trial can have a source of cIAI as the appendix. If 230 patients with appendix as the source are recruited, this will become an exclusion criteria for subsequent patients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A phase III multicentre, open label, two-arm, parallel group, pragmatic, randomised controlled trial with internal pilot.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard care<br>Clinician decided antibiotic treatment duration | Drug: Antibiotic - standard duration<br>* Clinician decided antibiotic and duration of treatment<br>|
| Experimental: Fixed-extended-duration antibiotics<br>28 day antibiotic treatment duration | Drug: Antibiotic - fixed-extended-duration<br>* Clinician decided antibiotic for a fixed duration of 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure within 180 days of randomisation. | For in-patients, treatment failure is defined when a patient meets objective criteria for both inflammation and infection within a 5 day period. Meeting of the criteria for inflammation may precede or follow the date that criteria for infection were met (the first day of an eligible antibiotic treatment course). These criteria are: Criteria for Inflammation A fever (≥ 37.8 degrees Celsius), plus A neutrophilia (>7.5 x109/L), plus A CRP over 100 mg/L PLUS, criteria for infection Initiation of a new antibiotic treatment course of ≥ 5 days, or A change in antibiotic treatment continued for ≥ 5 days, or Initiation of a new antibiotic treatment, or a change in antibiotic treatment, and death within 5 days. | 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life (EQ-5D-5L) | Participants will complete the EQ-5D-5L at baseline, and at 30, 90 and 180 days post-randomisation. | 180 days | 
| Cost effectiveness | Participants will complete health care resource use questionnaires at 30, 90 and 180 days after randomisation to record activity outside of hospital. Research teams will record data related to expenses as an inpatient. | 180 days | 
| Desirability Of Outcome Ranking (DOOR) | Patients will be categorised according to the worst outcome they experience over the 6 months follow up period using a four-level ordinal classification. The four levels will be C1 = No treatment failure, C2 = Treatment failure (as for the primary outcome), C3 = Treatment failure associated with sepsis and C4 = Treatment failure associated with death. | 180 days | 
| Number and type of source control procedures | The total number of source control procedures of different types (radiological, surgical) and source control procedures of any type occurring in each randomised group will be compared using a proportional odds model, with fixed effects for allocation, the stratification factors and other prognostic baseline covariates, and random intercepts for study recruitment site. | 180 days | 
| Relapse of cIAI | The proportion of patients that experience a relapse of cIAI during the 180 days following randomisation will be reported by randomised group. | 180 days | 
| All-cause mortality | Brief summaries of the total time at risk and number/proportion of participants who died will be presented by randomised group and overall | 180 days | 
| Length of hospital stay | Total number of nights in hospital (with death coded as the worst/highest outcome) will be compared using a proportional odds model, with fixed effects for allocation, the stratification factors and other prognostic baseline covariates, and random intercepts for study recruitment site. | 180 days | 
| Re-admission | The proportion of participants who are re-admitted to hospital during the 180 days following randomisation, and number of re-admissions per participant will be reported descriptively by randomised group and overall | 180 days | 
| C. difficile infection | The proportion of patients that experience C. difficile infection during the 180 days following randomisation will be reported by randomised group. | 180 days | 
| Anti-microbial resistant (AMR) infections | Participants will undergo passive surveillance for antimicrobial resistant infections (including MRSA, VRE, ESBL and CPE) during the 180 days following randomisation. The proportion of patients that experience each type of antimicrobial infection, number of days receiving carbapenem class antibiotics and the number of antibiotic class switches will be reported descriptively by randomised group and overall. | 180 days | 
| Days of antibiotic therapy (in-patient and outpatient) | The total number of days of anti-microbial therapy (inpatient, outpatient and overall) during the 180 days following randomisation, proportion of total follow up time on anti-microbial therapy, and mortality will be reported descriptively by randomised group and overall. | 180 days | 
| Acute kidney injury | The proportion of patients that experience acute kidney injury during the 180 days following randomisation will be reported by randomised group. | 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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infection, antibiotics, antibiotic resistance