Clinical trial NCT05148702: EXTENDed Antibiotic Durations Compared to Standard Durations for Patients With Complicated Intra-abdominal Infection.
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Complicated Intra-abdominal Infection
Keywords: infection
antibiotics
antibiotic resistance
Lead sponsor: University of York
Sponsor class: OTHER
Collaborators: name: University of York
name: University of Birmingham
name: Chesterfield Royal Hospital NHS Foundation Trust
name: University of Leeds
name: The Leeds Teaching Hospitals NHS Trust
First posted: 2021-12-08
Enrollment: 1166
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A phase III multicentre, open label, two-arm, parallel group, pragmatic, randomised controlled trial with internal pilot.
Primary purpose: TREATMENT

Brief summary: 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: 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 criteria: 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.

Primary outcomes:
measure: Treatment failure within 180 days of randomisation.
timeFrame: 180 days
Secondary outcomes:
measure: Quality of life (EQ-5D-5L)
timeFrame: 180 days
measure: Cost effectiveness
timeFrame: 180 days
measure: Desirability Of Outcome Ranking (DOOR)
timeFrame: 180 days
measure: Number and type of source control procedures
timeFrame: 180 days
measure: Relapse of cIAI
timeFrame: 180 days
measure: All-cause mortality
timeFrame: 180 days
measure: Length of hospital stay
timeFrame: 180 days
measure: Re-admission
timeFrame: 180 days
measure: C. difficile infection
timeFrame: 180 days
measure: Anti-microbial resistant (AMR) infections
timeFrame: 180 days
measure: Days of antibiotic therapy (in-patient and outpatient)
timeFrame: 180 days
measure: Acute kidney injury
timeFrame: 180 days
measure: Complications
timeFrame: 180 days
measure: Number of days on ventilation and days of renal replacement therapy.
timeFrame: 180 days
measure: Time to treatment failure
timeFrame: 180 days.
Other outcomes:
Locations:
city: Abercynon
country: United Kingdom
facility: Cwm Taf Morgannwg University Health Board,
city: Aberdeen
country: United Kingdom
facility: NHS Grampian
city: Aberystwyth
country: United Kingdom
facility: Hywel Dda University Health Board
city: Aylesbury
country: United Kingdom
facility: Buckinghamshire Healthcare NHS Trust
city: Birmingham
country: United Kingdom
facility: UniversityHospitals Birmingham NHS Foundation Trust
city: Bolton
country: United Kingdom
facility: Bolton NHS Foundation Trust
city: Boston
country: United Kingdom
facility: United Lincolnshire Hospitals NHS Trust - Pilgrim Hospital Boston
city: Brighton
country: United Kingdom
facility: University Hospitals Sussex NHS Foundation Trust
city: Bristol
country: United Kingdom
facility: North Bristol NHS Trust
city: Carlisle
country: United Kingdom
facility: North Cumbria Integrated Care NHS Foundation Turst
city: Chesterfield
country: United Kingdom
facility: Chesterfield Royal Hospital NHS Foundation Trust
city: Coventry
country: United Kingdom
facility: University Hospital Coventry & Warwickshire
city: Darlington
country: United Kingdom
facility: County Durham and Darlington NHS Foundation Trust
city: Grimsby
country: United Kingdom
facility: Northern Lincolnshire and Goole NHS Foundation Trust - Grimsby
city: Hull
country: United Kingdom
facility: Hull University Teaching Hospitals NHS Trust
city: Ipswich
country: United Kingdom
facility: East Suffolk and North Essex NHS Foundation Trust
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
city: London
country: United Kingdom
facility: Chelsea and Westminster Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Guys and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: King'S College Hospital Nhs Foundation Trust
city: Macclesfield
country: United Kingdom
facility: East Cheshire NHS Trust
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust
city: Newport
country: United Kingdom
facility: Aneurin Bevan University Health Board
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital NHS Trust
city: Plymouth
country: United Kingdom
facility: University Hospitals Plymouth NHS Trust
city: Preston
country: United Kingdom
facility: Lancashire Teaching Hospitals NHS Foundation Trust
city: Romford
country: United Kingdom
facility: Barking, Havering and Redbridge University Hospitals Nhs Trust
city: Saint Leonards-on-Sea
country: United Kingdom
facility: East Sussex Hospitals NHS Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
city: Stockton-on-Tees
country: United Kingdom
facility: North Tees and Hartlepool NHS Foundation Trust
city: Sutton In Ashfield
country: United Kingdom
facility: Sherwood Forest Hospitals NHS Foundation Trust
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospitals NHS Trust
city: Worthing
country: United Kingdom
facility: University Hospitals Sussex NHS Foundation Trust
Study officials:
affiliation: University of Leeds
name: Andrew Kirby, MD
role: PRINCIPAL_INVESTIGATOR
References: