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| ID | Type | Description | Link |
|---|---|---|---|
| 2022-002624-12 | EudraCT Number | ||
| NL80410.029.22 | Other Identifier | NL number CCMO |
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| Name | Class |
|---|---|
| ZonMw: The Netherlands Organisation for Health Research and Development | OTHER |
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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:
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Very short-course antibiotics | Experimental | 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. |
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| Standard course antibiotics | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| cefrtriaxone, gentamicin, cefuroxim, ciprofloxin or other antibiotics according to local guideline (24 hours) | Drug | 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. |
| 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 |
| 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. |
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Inclusion Criteria:
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:
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
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Flevoziekenhuis | Almere Stad | Flevoland | 1315 RA | Netherlands | ||
| Rijnstate Ziekenhuis |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28941329 | Background | 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. | |
| 35953772 |
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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).
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Patients and investigators will know in which group they are assigned.
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|
|
| cefrtriaxone, gentamicin, cefuroxim, ciprofloxin or other antibiotics according to local guideline (4 to 7 days) | Drug | 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. |
|
|
| 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 |
| Arnhem |
| Gelderland |
| 6815 AD |
| Netherlands |
| Radboud umc | Nijmegen | Gelderland | 6525 GA | Netherlands |
| Canisius Wilhelmina Ziekenhuis | Nijmegen | Gelderland | 6532 SZ | Netherlands |
| Maastricht UMC+ | Maastricht | Limburg | 6229 HX | Netherlands |
| Jeroen Bosch Ziekenhuis | 's-Hertogenbosch | North Brabant | 5223 GZ | Netherlands |
| Catharina Ziekenhuis | Eindhoven | North Brabant | 5623 EJ | Netherlands |
| Elisabeth Tweesteden Ziekenhuis | Tilburg | North Brabant | 5022 GC | Netherlands |
| Amstelland Ziekenhuis | Amstelveen | North Holland | 1186 AM | Netherlands |
| Amsterdam UMC | Amsterdam | North Holland | 1081 HZ | Netherlands |
| OLVG | Amsterdam | North Holland | 1091 AC | Netherlands |
| Spaarne Gasthuis | Hoofddorp | North Holland | 2134 TM | Netherlands |
| Dijklander Ziekenhuis | Hoorn | North Holland | 1624 AR | Netherlands |
| Zaans Medisch Centrum | Zaandam | North Holland | 1502 DV | Netherlands |
| Deventer Ziekenhuis | Deventer | Overijssel | 7416 SE | Netherlands |
| Medisch Spectrum Twente | Enschede | Overijssel | 7512 KZ | Netherlands |
| Isala | Zwolle | Overijssel | 8025 AB | Netherlands |
| Medisch Centrum Leeuwarden | Leeuwarden | Provincie Friesland | 8934 AD | Netherlands |
| Universitair Medisch Centrum Groningen | Groningen | Provincie Groningen | 9713 GZ | Netherlands |
| Martini Ziekenhuis | Groningen | Provincie Groningen | 9728 NT | Netherlands |
| Reinier de Graaf Gasthuis | Delft | South Holland | 2625 AD | Netherlands |
| Albert Schweitzer Ziekenhuis | Dordrecht | South Holland | 3318 AT | Netherlands |
| Groene Hart Ziekenhuis | Gouda | South Holland | 2803 HH | Netherlands |
| Leids Universitair Medisch Centrum | Leiden | South Holland | 2333 ZA | Netherlands |
| Alrijne Ziekenhuis | Leiderdorp | South Holland | 2353 GA | Netherlands |
| Erasmus MC | Rotterdam | South Holland | 3015 GD | Netherlands |
| Maasstad Ziekenhuis | Rotterdam | South Holland | 3079 DZ | Netherlands |
| Haaglanden Medisch Centrum | The Hague | South Holland | 2512 VA | Netherlands |
| Meander MC | Amersfoort | Utrecht | 3813 TZ | Netherlands |
| St. Antonius Ziekenhuis | Nieuwegein | Utrecht | 3435 CM | Netherlands |
| Universitair Medisch Centrum Utrecht | Utrecht | Utrecht | 3584 CX | Netherlands |
| Background |
| 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. |
| 33462749 | Background | 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. |
| 41689066 | Derived | 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. |
| ID | Term |
|---|---|
| D002761 | Cholangitis |
| ID | Term |
|---|---|
| D001649 | Bile Duct Diseases |
| D001660 | Biliary Tract Diseases |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| D005839 | Gentamicins |
| D002444 | Cefuroxime |
| D002443 | Ceftriaxone |
| D002939 | Ciprofloxacin |
| ID | Term |
|---|---|
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D002511 | Cephalosporins |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013843 | Thiazines |
| D013457 | Sulfur Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D002439 | Cefotaxime |
| D002505 | Cephacetrile |
| D024841 | Fluoroquinolones |
| D042462 | 4-Quinolones |
| D015363 | Quinolones |
| D011804 | Quinolines |
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