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

July 19, 2023 updated by: Rogier P. Voermans, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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

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?

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

440

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9713 GZ
        • Recruiting
        • Universitair Medisch Centrum Groningen
        • Contact:
        • Principal Investigator:
          • Frans Heide, van der, MD PhD
      • Groningen, Netherlands, 9728 NT
        • Not yet recruiting
        • Martini Ziekenhuis
        • Contact:
          • Willem J. Thijs, MD
          • Phone Number: 0505245940
          • Email: ThijsW@MZH.nl
        • Principal Investigator:
          • Willem J. Thijs, MD
      • Utrecht, Netherlands, 3584 CX
        • Not yet recruiting
        • Universitair Medisch Centrum Utrecht
        • Contact:
        • Principal Investigator:
          • Auke Bogte, MD
    • Brabant
      • Den Bosch, Brabant, Netherlands, 5223 GZ
        • Not yet recruiting
        • Jeroen Bosch ziekenhuis
        • Contact:
        • Principal Investigator:
          • Bob CH Scheffer, MD PhD
      • Eindhoven, Brabant, Netherlands, 5623 EJ
      • Tilburg, Brabant, Netherlands, 5022 GC
        • Recruiting
        • Elisabeth TweeSteden Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Wouter L. Hazen, MD PhD
    • Flevoland
      • Almere, Flevoland, Netherlands, 1315 RA
        • Not yet recruiting
        • Flevoziekenhuis
        • Contact:
        • Principal Investigator:
          • Marius Munneke, MD PhD
    • Friesland
      • Leeuwarden, Friesland, Netherlands, 8934 AD
        • Not yet recruiting
        • Medisch Centrum Leeuwarden
        • Contact:
        • Principal Investigator:
          • Klaas Linde, van der, MD PhD
    • Gelderland
      • Arnhem, Gelderland, Netherlands, 6815 AD
        • Not yet recruiting
        • Rijnstate Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Jan Maarten Vrolijk, MD
      • Nijmegen, Gelderland, Netherlands, 6532 SZ
        • Recruiting
        • Canisius Wilhelmina Ziekenhuis
        • Contact:
          • Adriaan Tan, MD PhD
          • Phone Number: 0243658070
          • Email: a.tan@cwz.nl
        • Principal Investigator:
          • Adriaan Tan, MD PhD
      • Nijmegen, Gelderland, Netherlands, 6525 GA
        • Recruiting
        • Radboud UMC
        • Contact:
        • Principal Investigator:
          • Foke Delft, van, MD
    • Limburg
      • Maastricht, Limburg, Netherlands, 6229 HX
        • Not yet recruiting
        • Maastricht UMC+
        • Contact:
        • Principal Investigator:
          • Jan-Werner Poley, MD PhD
    • Noord Holland
      • Amsterdam, Noord Holland, Netherlands, 1081 HZ
        • Recruiting
        • Amsterdam UMC
        • Contact:
        • Principal Investigator:
          • Rogier P. Voermans, MD PhD
    • Noord-Holland
      • Amstelveen, Noord-Holland, Netherlands, 1186 AM
        • Not yet recruiting
        • Amstelland Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Karam Boparai, MD PhD
      • Amsterdam, Noord-Holland, Netherlands, 1091 AC
        • Not yet recruiting
        • OLVG
        • Contact:
        • Principal Investigator:
          • Sjoerd D. Kuiken, MD PhD
      • Hoofddorp, Noord-Holland, Netherlands, 2134 TM
        • Not yet recruiting
        • Spaarne Gasthuis
        • Contact:
        • Principal Investigator:
          • Ellert J. Soest, van, MD PhD
      • Hoorn, Noord-Holland, Netherlands, 1624 AR
        • Recruiting
        • Dijklander ziekenhuis
        • Contact:
        • Principal Investigator:
          • Pim W. Weijenborg, MD PhD
      • Zaandam, Noord-Holland, Netherlands, 1502 DV
        • Not yet recruiting
        • Zaans Medisch Centrum
        • Contact:
        • Principal Investigator:
          • Dirk Schölvinck, MD
    • Overijssel
      • Deventer, Overijssel, Netherlands, 7416 SE
        • Not yet recruiting
        • Deventer Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Frank Borg, ten, MD PhD
      • Enschede, Overijssel, Netherlands, 7512 KZ
        • Not yet recruiting
        • Medisch Spectrum Twente
        • Contact:
        • Principal Investigator:
          • Niels Venneman, MD PhD
      • Zwolle, Overijssel, Netherlands, 8025 AB
        • Recruiting
        • Isala
        • Contact:
        • Principal Investigator:
          • Alexander C. Poen, MD PhD
    • Utrecht
      • Amersfoort, Utrecht, Netherlands, 3813 TZ
        • Not yet recruiting
        • Meander MC
        • Contact:
        • Principal Investigator:
          • Menno A. Brink, MD Phd
      • Nieuwegein, Utrecht, Netherlands, 3435 CM
        • Recruiting
        • St. Antonius Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Robert C. Verdonk, MD PhD
    • Zuid-Holland
      • Delft, Zuid-Holland, Netherlands, 2625 AD
        • Not yet recruiting
        • Reinier de Graaf Gasthuis
        • Contact:
        • Principal Investigator:
          • Rutger Quispel, MD PhD
      • Den Haag, Zuid-Holland, Netherlands, 2512 VA
        • Not yet recruiting
        • Haaglanden Medisch Centrum
        • Contact:
        • Principal Investigator:
          • Lars E. Perk, MD
      • Dordrecht, Zuid-Holland, Netherlands, 3318 AT
        • Recruiting
        • Albert Schweitzer Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Wim Vrie, van de, MD PhD
      • Gouda, Zuid-Holland, Netherlands, 2803 HH
        • Not yet recruiting
        • Groene Hart Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Bart Opsteeg, MD
      • Leiden, Zuid-Holland, Netherlands, 2333 ZA
        • Not yet recruiting
        • Leids Universitair Medisch Centrum
        • Contact:
        • Principal Investigator:
          • Akin Inderson, MD
      • Leiderdorp, Zuid-Holland, Netherlands, 2353 GA
        • Not yet recruiting
        • Alrijne Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Wouter Hollander, den, MD PhD
      • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
        • Not yet recruiting
        • Erasmus MC
        • Contact:
        • Principal Investigator:
          • Pieter Jan Jonge, de, MD PhD
      • Rotterdam, Zuid-Holland, Netherlands, 3079 DZ
        • Recruiting
        • Maasstad Ziekenhuis
        • Contact:
        • Principal Investigator:
          • Muhammed Hadithi, MD PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

A. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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: cefrtriaxone, gentamicin, cefuroxim, ciprofloxin or other antibiotics according to local guideline (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:
  • ciprofloxacin
  • ceftriaxone
  • gentamicin
  • cefuroxim
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: cefrtriaxone, gentamicin, cefuroxim, ciprofloxin or other antibiotics according to local guideline (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:
  • ciprofloxacin
  • ceftriaxone
  • gentamicin
  • cefuroxim

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
clinical cure rate by day 14 after ERCP without relapse by day 30
Time Frame: 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.
30 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-cause 90-day mortality.
Time Frame: 90 days
Mortality, which includes all causes.
90 days
Relapse of cholangitis within 90 days
Time Frame: 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.
90 days
Rate of any other subsequent infection requiring antibiotic therapy within 90 days.
Time Frame: 90 days
Subsequent infections excluding recurrent cholangitis.
90 days
Rate of subsequent infections with MDR bacteria or Clostridioides difficile within 90 days.
Time Frame: 90 days
Subsequent infections, in particular due to resistant bacteria.
90 days
Rate of other adverse drug events within 14 days
Time Frame: 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).
14 days
Length of intensive care and hospital stay for the initial episode of cholangitis.
Time Frame: 30 days
Length of IC and hospital stay defined in days.
30 days
Quality of life and health utility.
Time Frame: 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.
90 days
Societal costs and cost-effectiveness/-utility
Time Frame: 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.
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Collaborators

ZonMw: The Netherlands Organisation for Health Research and Development

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 19, 2023

Primary Completion (Estimated)

March 1, 2026

Study Completion (Estimated)

September 1, 2026

Study Registration Dates

First Submitted

February 3, 2023

First Submitted That Met QC Criteria

February 28, 2023

First Posted (Actual)

March 2, 2023

Study Record Updates

Last Update Posted (Actual)

July 20, 2023

Last Update Submitted That Met QC Criteria

July 19, 2023

Last Verified

July 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2022.0292
  • 2022-002624-12 (EudraCT Number)
  • NL80410.029.22 (Other Identifier: NL number CCMO)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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