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

Complicated Intra-abdominal Infection Clinical Trial

— EXTEND  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05148702
• Other study ID #: NIHR131784
• Secondary ID: ISRCTN 72819021
• Status: Recruiting
• Phase: Phase 3
• Start date: October 10, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: June 2024
• Source: University of York
• Contact: Sarah Cockayne
• Phone: 01904 321736
• Email: ytu-extend-trial[@]york.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1166
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

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.

Related Conditions & MeSH terms

• Communicable Diseases
• Complicated Intra-abdominal Infection
• Infections
• Intraabdominal Infections

Intervention

Drug:
• Antibiotic - standard duration
Clinician decided antibiotic and duration of treatment
• Antibiotic - fixed-extended-duration
Clinician decided antibiotic for a fixed duration of 28 days.

Locations

Country	Name	City	State
United Kingdom	Buckinghamshire Healthcare NHS Trust	Aylesbury
United Kingdom	University Hospitals Sussex NHS Foundation Trust	Brighton
United Kingdom	North Bristol NHS Trust	Bristol
United Kingdom	Chesterfield Royal Hospital NHS Foundation Trust	Chesterfield
United Kingdom	University Hospital Coventry & Warwickshire	Coventry
United Kingdom	County Durham and Darlington NHS Foundation Trust	Darlington
United Kingdom	Hull University Teaching Hospitals NHS Trust	Hull
United Kingdom	Leeds Teaching Hospitals NHS Trust	Leeds
United Kingdom	University Hospitals of Leicester NHS Trust	Leicester
United Kingdom	Guys and St Thomas' NHS Foundation Trust	London
United Kingdom	East Cheshire NHS Trust	Macclesfield
United Kingdom	Manchester University NHS Foundation Trust	Manchester
United Kingdom	Aneurin Bevan University Health Board	Newport
United Kingdom	University Hospitals Plymouth NHS Trust	Plymouth
United Kingdom	Lancashire Teaching Hospitals NHS Foundation Trust	Preston
United Kingdom	East Sussex Hospitals NHS Trust	Saint Leonards-on-Sea
United Kingdom	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield
United Kingdom	Sherwood Forest Hospitals NHS Foundation Trust	Sutton In Ashfield
United Kingdom	Royal Cornwall Hospitals NHS Trust	Truro
United Kingdom	University Hospitals Sussex NHS Foundation Trust	Worthing

Sponsors (4)

Lead Sponsor	Collaborator
Sarah Cockayne	Chesterfield Royal Hospital NHS Foundation Trust, University of Birmingham, University of York

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Trial website