Overview
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.
Description
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 approximately 30 NHS trust hospitals. Only patients that are able provide consent (or those with a consultee able to confirm whether the patient would wish to be included in the study) 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.
The study is Sponsored by the University of Leeds
Eligibility
Inclusion Criteria:
- Adults (≥ 16 years) with cIAI* (see cIAI definition)
- Being treated with antibiotics until the point of randomisation, but within 10 days of initiation of effective 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
- In the event that the patient is re-admitted to hospital during the trial period, they are likely to be admitted to a hospital participating in the EXTEND trial.
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
neutropaenia (<1.8 x 109 /L) and/or intestinal pathogens cultured from sterile sites
(closed peritoneum or blood) around the time of cIAI diagnosis, plus
- Evidence of pathologic findings on radiologic examination, or
- Evidence of pathologic findings at operation
** The first day of effective antibiotic treatment will be determined by the patient's
clinical team or clinical research team. Antibiotics that do not count towards these
10 days of effective treatment are:
- Antibiotic prophylaxis e.g., penicillin for splenectomy, elective surgery antibiotic
prophylaxis, UTI prophylaxis
- Treatment for other infections that is not effective for cIAI e.g., cystitis.
Antibiotics that re often used for cystitis and aren't effective for cIAI include
Cephalexin, Fosfomycin Trimethoprim, Nitrofurantoin, and Pivmecillinam.
- Oral antibiotics prescribed to treat infection prior to hospitalisation
- Previous courses of treatment antibiotics: A previous course is one stopped for 48
hours or more
- The further 72 hours starts from the first day of effective antibiotic treatment
i.e., for a patient admitted to hospital with a cIAI, 3 days of admission are
needed. Where a patient is already in hospital e.g., a post operative patient, a
further 3 days of admission are required starting from the point of the first day
of effective antibiotic treatment.
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.
- Grade 1 to 3 appendicitis. To be eligible patient must have Grade 4 or 5 appendicitis
defined by the 2017 American Association for the Surgery Trauma Grading System with
either generalised peritonitis at surgery, or no or partial source control e.g.
radiological drainage
- Non-perforated 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. Traumatic injury to the
bowel (including iatrogenic or intra-operative) treated within 12 hours of injury,
Uterine perforation following uterine surgery treated within six hours of injury,
Perforated gastric ulcer or duodenal ulcer treated within 24 hours of the onset of
symptoms). 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
- Treatment with Interleukin-6 Inhibitors
- High likelihood of death within 72 hours of cIAI randomisation in the opinion of the
local Investigator
- Limitations in treatment decided before inclusion. Limitations in treatment that
exclude patients from the EXTEND trial are those clinical decisions linked to an
expectation the patient will die during this episode of infection.
- Patient with persistent cIAI of more than 6 months duration
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.
Note: There are absolute exclusions that preclude trial participation. These include: C.
difficile infection, Infected necrotic pancreatitis, Concomitant infection requiring ≥4
weeks antibiotic therapy, Treatment with Interleukin-6 Inhibitors, High likelihood of death
within 72 hours of randomisation, Limitations in treatment decided before inclusion,
Peritoneal dialysis, Previously recruited for the EXTEND trial, Patient with persistent
cIAI of more than 6 months duration and a patient with persistent cIAI of more than 6
months duration. If a patient has two intraabdominal infections, the presence of one of the
following ineligible infections does not make a patient ineligible if the other cIAI is
eligible: 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, Ineligible cases of
appendicitis (see exclusion criteria above), Uncomplicated cholecystitis, Ischemic or
necrotic intestine without perforation, Uterine perforation following uterine surgery
treated within six hours of injury or cIAI with a low risk of complications.