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

Cholangitis Clinical Trial

— COBRA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05750966
• Other study ID #: 2022.0292
• Secondary ID: 2022-002624-12NL
• Status: Recruiting
• Phase: N/A
• Start date: July 19, 2023
• Est. completion date: September 1, 2026

Study information

• Verified date: July 2023
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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?

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 440
• Est. completion date: September 1, 2026
• Est. primary completion date: March 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cholangitis

Intervention

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.
• 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.

Locations

Country	Name	City	State
Netherlands	Flevoziekenhuis	Almere	Flevoland
Netherlands	Meander MC	Amersfoort	Utrecht
Netherlands	Amstelland Ziekenhuis	Amstelveen	Noord-Holland
Netherlands	Amsterdam UMC	Amsterdam	Noord Holland
Netherlands	OLVG	Amsterdam	Noord-Holland
Netherlands	Rijnstate Ziekenhuis	Arnhem	Gelderland
Netherlands	Reinier de Graaf Gasthuis	Delft	Zuid-Holland
Netherlands	Jeroen Bosch Ziekenhuis	Den Bosch	Brabant
Netherlands	Haaglanden Medisch Centrum	Den Haag	Zuid-Holland
Netherlands	Deventer Ziekenhuis	Deventer	Overijssel
Netherlands	Albert Schweitzer Ziekenhuis	Dordrecht	Zuid-Holland
Netherlands	Catharina Ziekenhuis	Eindhoven	Brabant
Netherlands	Medisch Spectrum Twente	Enschede	Overijssel
Netherlands	Groene Hart Ziekenhuis	Gouda	Zuid-Holland
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Spaarne Gasthuis	Hoofddorp	Noord-Holland
Netherlands	Dijklander Ziekenhuis	Hoorn	Noord-Holland
Netherlands	Medisch Centrum Leeuwarden	Leeuwarden	Friesland
Netherlands	Leids Universitair Medisch Centrum	Leiden	Zuid-Holland
Netherlands	Alrijne Ziekenhuis	Leiderdorp	Zuid-Holland
Netherlands	Maastricht UMC+	Maastricht	Limburg
Netherlands	St. Antonius Ziekenhuis	Nieuwegein	Utrecht
Netherlands	Canisius Wilhelmina Ziekenhuis	Nijmegen	Gelderland
Netherlands	Radboud umc	Nijmegen	Gelderland
Netherlands	Erasmus MC	Rotterdam	Zuid-Holland
Netherlands	Maasstad Ziekenhuis	Rotterdam	Zuid-Holland
Netherlands	Elisabeth Tweesteden Ziekenhuis	Tilburg	Brabant
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Netherlands	Zaans Medisch Centrum	Zaandam	Noord-Holland
Netherlands	Isala	Zwolle	Overijssel

Sponsors (2)

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

Country where clinical trial is conducted

Netherlands, 

References & Publications (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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	All-cause 90-day mortality.	Mortality, which includes all causes.	90 days
Secondary	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
Secondary	Rate of any other subsequent infection requiring antibiotic therapy within 90 days.	Subsequent infections excluding recurrent cholangitis.	90 days
Secondary	Rate of subsequent infections with MDR bacteria or Clostridioides difficile within 90 days.	Subsequent infections, in particular due to resistant bacteria.	90 days
Secondary	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
Secondary	Length of intensive care and hospital stay for the initial episode of cholangitis.	Length of IC and hospital stay defined in days.	30 days
Secondary	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
Secondary	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