COBRA: Short-course Antibiotics vs Standard Course Antibiotics in Patients With Cholangitis

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05750966

Collaborator

ZonMw: The Netherlands Organisation for Health Research and Development (Other)

440

Enrollment

Location

Arms

42.1

Anticipated Duration (Months)

10.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this multicentre randomized controlled trial is to investigate if a very short-course of antibiotics (1 day) for cholangitis after adequate drainage is non-inferior with respect to clinical cure in comparison with a standard course of antibiotics (4 to 7 days). Secondary objectives include:

Will a one-day course of antibiotics for cholangitis after adequate drainage be non-inferior with respect to relapse of cholangitis and mortality in comparison with a standard course of antibiotics?
Will a one-day course of antibiotics for cholangitis after adequate drainage result in less adverse drug events in comparison with a standard course of antibiotics?
Will a one-day course of antibiotics for cholangitis after adequate drainage reduce length of hospital stay?
Will a one-day course of antibiotics for cholangitis after adequate drainage improve quality of life?
Will a one-day course of antibiotics for cholangitis after adequate drainage be cost-effective?

Condition or Disease	Intervention/Treatment	Phase
Cholangitis	Drug: very short-course of standard of care antibiotics (24 hours) Drug: standard course of standard of care antibiotics (4 to 7 days)	N/A

Detailed Description

Acute cholangitis is an infection of the biliary tract which is managed with biliary drainage and antibiotic therapy (ABT). Currently the international Tokyo Guidelines 2018 (TG18) recommend 4 to 7 days of ABT after source control. The national SWAB guideline of 2020 suggests a course of one to 3 days after biliary drainage. There are no randomized studies to guide the duration of ABT for acute cholangitis. Our recent retrospective study in the Netherlands showed that a short course of ABT seems safe and more evidence is available showing that other bacterial infections, including abdominal and bloodstream infections, can be treated with a short antibiotic course than previously assumed. Hence, the hypothesis is that a very short-course of ABT for acute cholangitis is non-inferior to a course of 4 to 7 days after adequate biliary drainage.

This study is designed as a multicenter non-inferiority randomized controlled trial. Patients will be randomly assigned to the intervention group (one day of antibiotic therapy after ERCP) or the comparator group (4 to 7 days of antibiotic therapy after ERCP).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

440 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This study is designed as an open-label multicenter non-inferiority RCT. Patients will be randomly assigned to the intervention group (one day of ABT after ERCP) or the comparator group (4 to 7 days of ABT after ERCP).This study is designed as an open-label multicenter non-inferiority RCT. Patients will be randomly assigned to the intervention group (one day of ABT after ERCP) or the comparator group (4 to 7 days of ABT after ERCP).

Masking:

None (Open Label)

Masking Description:

Patients and investigators will know in which group they are assigned.

Primary Purpose:

Treatment

Official Title:

Very Short-course Versus Standard Course Antibiotic Therapy in Patients With Acute ChOlangitis After Adequate Endoscopic BiliaRy drAinage

Anticipated Study Start Date :

Mar 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2026

Anticipated Study Completion Date :

Sep 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Very short-course antibiotics The antibiotic regimens will be according to the local hospital's antibiotic guideline for cholangitis (e.g. dosage form, dosage, frequency)and/or the national SWAB guideline in the Netherlands. In the experimental group, duration of ABT after adequate drainage will be 1 day. The duration will be 4 days and can be extended to 7 days in case of gram-negative bacteraemia, according to the national SWAB guideline regarding gram-negative sepsis.	Drug: very short-course of standard of care antibiotics (24 hours) The duration of antibiotics is 24 hours after adequate biliary drainage. The choice of antibiotics will be according to local protocol and/or national Dutch SWAB guidelines. The most common antibiotics are described above, but this can differ based on allergies, local protocol or previous cultures. Drug classes may include: aminoglycosides, carbapenems, cefalosporins, fluorquinolones, sulfonamides, penicillines. Other Names: ceftriaxone gentamicin cefuroxim ciprofloxacin
Active Comparator: Standard course antibiotics The antibiotic regimens will be according to the local hospital's antibiotic guideline for cholangitis, which are based on the previously mentioned national SWAB guideline. This means that the type of ABT, dosage and frequency will be comparable to the experimental group. In the comparator group treatment duration with ABT after ERCP will be according to the international well known and widely used TG18. The duration will be 4 days and can be extended to 7 days in case of gram-negative bacteraemia, according to the national SWAB guideline regarding gram-negative sepsis.	Drug: standard course of standard of care antibiotics (4 to 7 days) The duration of antibiotics is 4 to 7 days after adequate biliary drainage. The choice of antibiotics will be according to local protocol and/or national Dutch SWAB guidelines. The most common antibiotics are described above, but this can differ based on allergies, local protocol or previous cultures. Drug classes may include: aminoglycosides, carbapenems, cefalosporins, fluorquinolones, sulfonamides, penicillines. Other Names: ceftriaxone gentamicin cefuroxim ciprofloxacin

Arm

Intervention/Treatment

Experimental: Very short-course antibiotics

The antibiotic regimens will be according to the local hospital's antibiotic guideline for cholangitis (e.g. dosage form, dosage, frequency)and/or the national SWAB guideline in the Netherlands. In the experimental group, duration of ABT after adequate drainage will be 1 day. The duration will be 4 days and can be extended to 7 days in case of gram-negative bacteraemia, according to the national SWAB guideline regarding gram-negative sepsis.

Drug: very short-course of standard of care antibiotics (24 hours)

The duration of antibiotics is 24 hours after adequate biliary drainage. The choice of antibiotics will be according to local protocol and/or national Dutch SWAB guidelines. The most common antibiotics are described above, but this can differ based on allergies, local protocol or previous cultures. Drug classes may include: aminoglycosides, carbapenems, cefalosporins, fluorquinolones, sulfonamides, penicillines.

Other Names:

ceftriaxone

gentamicin

cefuroxim

ciprofloxacin

Active Comparator: Standard course antibiotics

The antibiotic regimens will be according to the local hospital's antibiotic guideline for cholangitis, which are based on the previously mentioned national SWAB guideline. This means that the type of ABT, dosage and frequency will be comparable to the experimental group. In the comparator group treatment duration with ABT after ERCP will be according to the international well known and widely used TG18. The duration will be 4 days and can be extended to 7 days in case of gram-negative bacteraemia, according to the national SWAB guideline regarding gram-negative sepsis.

Drug: standard course of standard of care antibiotics (4 to 7 days)

The duration of antibiotics is 4 to 7 days after adequate biliary drainage. The choice of antibiotics will be according to local protocol and/or national Dutch SWAB guidelines. The most common antibiotics are described above, but this can differ based on allergies, local protocol or previous cultures. Drug classes may include: aminoglycosides, carbapenems, cefalosporins, fluorquinolones, sulfonamides, penicillines.

Other Names:

ceftriaxone

gentamicin

cefuroxim

ciprofloxacin

Outcome Measures

Primary Outcome Measures

clinical cure rate by day 14 after ERCP without relapse by day 30 [30 days]
Clinical cure is defined as the absence of both fever (>38°C) and/or shaking chills, and initial presenting symptoms. Relapse is defined as the initiation of new antibiotic therapy for recurrent cholangitis, subsequent infection in the hepatic-pancreatic-biliary region, or any other subsequent infection possibly related to the initial episode of cholangitis.

Secondary Outcome Measures

All-cause 90-day mortality. [90 days]
Mortality, which includes all causes.
Relapse of cholangitis within 90 days [90 days]
Relapse is defined as the initiation of new antibiotic therapy for recurrent cholangitis, subsequent infection in the hepatic-pancreatic-biliary region, or any other subsequent infection possibly related to the initial episode of cholangitis.
Rate of any other subsequent infection requiring antibiotic therapy within 90 days. [90 days]
Subsequent infections excluding recurrent cholangitis.
Rate of subsequent infections with MDR bacteria or Clostridioides difficile within 90 days. [90 days]
Subsequent infections, in particular due to resistant bacteria.
Rate of other adverse drug events within 14 days [14 days]
Includes: rash, diarrhoea (defined as ≥3 x loose stools per day), liver function abnormalities (defined as ≥5 x upper limit of normal (ULN) elevation in alanine aminotransferase (ALT) or ≥2 x ULN elevation in alkaline phosphatase (ALP) or ≥3 x ULN elevation in ALT and simultaneous elevation of total bilirubin concentration exceeding 2 x ULN (according to European association for the Study of the Liver Clinical Practice Guidelines: Drug-induced liver injury) AND without evidence of persistent obstruction on imaging OR elevation of liver enzymes after initial decrease. Lastly, other adverse drug events includes acute kidney injury, defined as increase in serum creatinine by ≥26.5 micromol/L within 48 hours or increase in serum creatinine to ≥1.5 times baseline (according to Kidney Disease: Improving Global Outcomes guidelines).
Length of intensive care and hospital stay for the initial episode of cholangitis. [30 days]
Length of IC and hospital stay defined in days.
Quality of life and health utility. [90 days]
This will be evaluated using the RAND-36 and EQ-5D-5L at day 7, day 30 and day 90. Scale title (RAND-36): Research and Devevelopment-36 Minimum raw score: 45 Maximum raw score : 198 Higher scores mean a better outcome. Scale title (EQ-5D-5L): European Quality of Life-5 Dimensions-5 Levels score Minimum score: 11111 Maximum score: 55555 Higher scores mean a worse outcome.
Societal costs and cost-effectiveness/-utility [90 days]
The costs per cured patient without relapse and the costs per quality adjusted life year (QALY) Scale Title: Quality Adjusted Life Year. One quality-adjusted life year (QALY) is equal to 1 year of life in perfect health.QALYs are calculated by estimating the years of life remaining for a patient following a particular treatment or intervention and weighting each year with a quality-of-life score (on a 0 to 1 scale). Minimum score: 0 Maximum score: 1 Higher scores mean a better outcome.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with acute cholangitis due to common bile duct stones, benign or malignant distal biliary obstruction or distal biliary stent dysfunction (only stents in situ for a minimum of 30 days)
ERCP with adequate biliary drainage (all common bile duct stones are removed and/or there is adequate flow of clear bile with or without a biliary stent(s))
Absence of fever (temperature <38.5°C) or a decrease of body temperature of at least 1°C has occurred within 24 hours after ERCP
Age ≥ 18 years
Written informed consent (IC)

Exclusion Criteria:

Other aetiologies of acute cholangitis (e.g. primary sclerosing cholangitis, (sub)hilar and/or intrahepatic strictures or hilar stents)
A recurrent cholangitis (within 3 months)
Patients with surgically altered anatomy (leading to biliary-enteric anastomosis)
Concomitant pancreatitis, according to International Association of Pancreatology/American Pancreatic Association guidelines.[18] Acute pancreatitis is diagnosed in case of fulfilment of 2 out of 3 of the following criteria:
Upper abdominal pain
Serum amylase or lipase >3x ULN
Signs of acute pancreatitis on imaging
Concomitant cholecystitis, according to TG18 criteria.[19] Acute cholecystitis is suspected in case one item in A is met and one item in B and C.

Local signs of inflammation

A1: Murphy's sign
A2: Right upper quadrant mass/pain/tenderness B. Systemic signs of inflammation
B1: Fever
B2: Elevated C-reactive protein
B3: Elevated WBC count C. Imaging findings characteristic of acute cholecystitis
Concomitant liver abscess
Another additional infectious diagnosis
Admission on an Intensive Care Unit (ICU) at time of randomisation
Use of maintenance antimicrobial therapy
Use of immunosuppressants
Neutropenia