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

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: Completed
• Conditions: Cholangitis
• Intervention / Treatment: Drug: cefrtriaxone, gentamicin, cefuroxim, ciprofloxin or other antibiotics according to local guideline (24 hours); Drug: cefrtriaxone, gentamicin, cefuroxim, ciprofloxin or other antibiotics according to local guideline (4 to 7 days)

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 (Actual): 410
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Flevoland
    • Almere Stad, Flevoland, Netherlands, 1315 RA
      • Flevoziekenhuis
  • Gelderland
    • Arnhem, Gelderland, Netherlands, 6815 AD
      • Rijnstate Ziekenhuis
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud UMC
    • Nijmegen, Gelderland, Netherlands, 6532 SZ
      • Canisius Wilhelmina Ziekenhuis
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Maastricht UMC+
  • North Brabant
    • 's-Hertogenbosch, North Brabant, Netherlands, 5223 GZ
      • Jeroen Bosch Ziekenhuis
    • Eindhoven, North Brabant, Netherlands, 5623 EJ
      • Catharina Ziekenhuis
    • Tilburg, North Brabant, Netherlands, 5022 GC
      • Elisabeth Tweesteden Ziekenhuis
  • North Holland
    • Amstelveen, North Holland, Netherlands, 1186 AM
      • Amstelland Ziekenhuis
    • Amsterdam, North Holland, Netherlands, 1081 HZ
      • Amsterdam UMC
    • Amsterdam, North Holland, Netherlands, 1091 AC
      • OLVG
    • Hoofddorp, North Holland, Netherlands, 2134 TM
      • Spaarne Gasthuis
    • Hoorn, North Holland, Netherlands, 1624 AR
      • Dijklander Ziekenhuis
    • Zaandam, North Holland, Netherlands, 1502 DV
      • Zaans Medisch Centrum
  • Overijssel
    • Deventer, Overijssel, Netherlands, 7416 SE
      • Deventer Ziekenhuis
    • Enschede, Overijssel, Netherlands, 7512 KZ
      • Medisch Spectrum Twente
    • Zwolle, Overijssel, Netherlands, 8025 AB
      • Isala
  • Provincie Friesland
    • Leeuwarden, Provincie Friesland, Netherlands, 8934 AD
      • Medisch Centrum Leeuwarden
  • Provincie Groningen
    • Groningen, Provincie Groningen, Netherlands, 9713 GZ
      • Universitair Medisch Centrum Groningen
    • Groningen, Provincie Groningen, Netherlands, 9728 NT
      • Martini Ziekenhuis
  • South Holland
    • Delft, South Holland, Netherlands, 2625 AD
      • Reinier de Graaf Gasthuis
    • Dordrecht, South Holland, Netherlands, 3318 AT
      • Albert Schweitzer ziekenhuis
    • Gouda, South Holland, Netherlands, 2803 HH
      • Groene Hart Ziekenhuis
    • Leiden, South Holland, Netherlands, 2333 ZA
      • Leids Universitair Medisch Centrum
    • Leiderdorp, South Holland, Netherlands, 2353 GA
      • Alrijne Ziekenhuis
    • Rotterdam, South Holland, Netherlands, 3079 DZ
      • Maasstad ziekenhuis
    • Rotterdam, South Holland, Netherlands, 3015 GD
      • Erasmus MC
    • The Hague, South Holland, Netherlands, 2512 VA
      • Haaglanden Medisch Centrum
  • Utrecht
    • Amersfoort, Utrecht, Netherlands, 3813 TZ
      • Meander MC
    • Nieuwegein, Utrecht, Netherlands, 3435 CM
      • St. Antonius Ziekenhuis
    • Utrecht, Utrecht, Netherlands, 3584 CX
      • Universitair Medisch Centrum Utrecht

Participation Criteria

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

How is the study designed?

Design Details

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

Number of Arms

2

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	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.	Mortality, which includes all causes.	90 days
Relapse of cholangitis within 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.	Subsequent infections excluding recurrent cholangitis.	90 days
Rate of subsequent infections with MDR bacteria or Clostridioides difficile within 90 days.	Subsequent infections, in particular due to resistant bacteria.	90 days
Rate of other adverse drug events within 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.	Length of IC and hospital stay defined in days.	30 days
Quality of life and health utility.	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	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

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development

Publications and helpful links

General Publications

• Miura F, Okamoto K, Takada T, Strasberg SM, Asbun HJ, Pitt HA, Gomi H, Solomkin JS, Schlossberg D, Han HS, Kim MH, Hwang TL, Chen MF, Huang WS, Kiriyama S, Itoi T, Garden OJ, Liau KH, Horiguchi A, Liu KH, Su CH, Gouma DJ, Belli G, Dervenis C, Jagannath P, Chan ACW, Lau WY, Endo I, Suzuki K, Yoon YS, de Santibanes E, Gimenez ME, Jonas E, Singh H, Honda G, Asai K, Mori Y, Wada K, Higuchi R, Watanabe M, Rikiyama T, Sata N, Kano N, Umezawa A, Mukai S, Tokumura H, Hata J, Kozaka K, Iwashita Y, Hibi T, Yokoe M, Kimura T, Kitano S, Inomata M, Hirata K, Sumiyama Y, Inui K, Yamamoto M. Tokyo Guidelines 2018: initial management of acute biliary infection and flowchart for acute cholangitis. J Hepatobiliary Pancreat Sci. 2018 Jan;25(1):31-40. doi: 10.1002/jhbp.509. Epub 2018 Jan 8.
• Sieswerda E, Bax HI, Hoogerwerf JJ, de Boer MGJ, Boermeester M, Bonten MJM, Dekker D, van Wijk RG, Juffermans NP, Kuindersma M, van der Linden PD, Melles DC, Pickkers P, Schouten JA, Rebel JR, van Zanten ARH, Prins JM, Wiersinga WJ. The 2021 Dutch Working Party on Antibiotic Policy (SWAB) guidelines for empirical antibacterial therapy of sepsis in adults. BMC Infect Dis. 2022 Aug 11;22(1):687. doi: 10.1186/s12879-022-07653-3.
• Haal S, Wielenga MCB, Fockens P, Leseman CA, Ponsioen CY, van Soest EJ, van Wanrooij RLJ, Sieswerda E, Voermans RP. Antibiotic Therapy of 3 Days May Be Sufficient After Biliary Drainage for Acute Cholangitis: A Systematic Review. Dig Dis Sci. 2021 Dec;66(12):4128-4139. doi: 10.1007/s10620-020-06820-3. Epub 2021 Jan 19.
• Overdevest AG, Sieswerda E, Haal S, Bogaards JA, Baven-Pronk MAMC, Bogte A, Boparai KS, Ter Borg F, Brink MA, van Delft F, Dik VK, Fockens P, Gilissen LPL, Hadithi M, Hazen WL, van der Heide F, den Hollander WJ, Inderson A, de Jonge PJF, Kuiken SD, Munneke JM, Perk LE, Poen AC, Poley JW, Quispel R, Scheffer RCH, Scholvinck DW, van Soest EJ, Tan ACITL, Thijs WJ, Venneman NG, Verdonk RC, van de Vrie W, Vrolijk JM, van Wanrooij RLJ, Weijenborg PW, Dijkgraaf MGW, Prins JM, Voermans RP. Antibiotic treatment for 1 day versus 4-7 days in patients with acute cholangitis after adequate endoscopic biliary drainage (COBRA): study protocol for a randomized controlled trial. Trials. 2026 Feb 14;27(1):222. doi: 10.1186/s13063-026-09524-7.

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2023
• Primary Completion (Actual): April 1, 2026
• Study Completion (Actual): June 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): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 10, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: randomized controlled trial; antibiotics
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholangitis; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Carbohydrates; Glycosides; Amides; Aminoglycosides; beta-Lactams; Lactams; Cephalosporins; Thiazines; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Cefotaxime; Cephacetrile; Ceftriaxone; Ciprofloxacin; Cefuroxime; Gentamicins
• 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
• product manufactured in and exported from the U.S.: No