Diverticulitis: Antibiotics or Close Observation? (DIABOLO)

DIABOLO Trial: A Multicenter Randomized Clinical Trial Investigating the Cost-effectiveness of Treatment Strategies With or Without Antibiotics for Uncomplicated Acute Diverticulitis.

Rationale

The prevalence of colonic diverticular disease is increasing in Western countries. Approximately 10 to 25% of patients with diverticular disease will eventually develop an episode of acute diverticulitis. Currently conservative treatment often includes antibiotic therapy. This advice lacks sound evidence and is merely based on experts' opinion. An old clinical dogma is being clarified with this randomized trial.

Objective

Primary objective is to evaluate whether or not using antibiotics reduces to time to full recovery of an attack of uncomplicated (mild) diverticulitis. Secondary objectives are to evaluate complications, quality of life, readmission rate, recurrence rate, medical and non-medical costs, and antibiotic resistance/sensitivity in both groups.

Hypothesis

The investigators hypothesis is that in the treatment of uncomplicated (mild) acute diverticulitis, supportive treatment without antibiotics is a more cost-effective approach than conservative treatment with antibiotics with respect to time-to-recovery as primary outcome.

Study design

A randomized, open label, multicenter clinical trial comparing treatment of acute uncomplicated diverticulitis with antibiotics to observation and supportive care alone.

Study population

Patients 18 years or older are eligible for inclusion if they have a diagnosis of acute uncomplicated diverticulitis as demonstrated by imaging. Only patients with stages 1a and 1b according to Hinchey's classification or "mild" diverticulitis according to the Ambrosetti criteria are included.

Intervention

Conservative strategy with antibiotics: supportive measures and at least 48 hours of intravenous antibiotics (and therefore admittance to the hospital) and subsequently switch to oral antibiotics if tolerated (total duration of 10 days).

Control

Liberal strategy without antibiotics: supportive measures only. Observation and oral intake as tolerated. Admittance only if discharge criteria are not met on presentation.

Main study parameters/endpoints

The primary endpoint is time-to-recovery with a 6-month follow-up period. Secondary endpoints are occurrence of complicated diverticulitis requiring surgery or percutaneous treatment, morbidity, health related quality of life, readmission rate, recurrence rate, medical and non-medical costs, and antibiotic resistance/sensitivity.

Study Overview

• Status: Unknown
• Conditions: Diverticulitis
• Intervention / Treatment: Drug: Amoxicillin-clavulanate

• Study Type: Interventional
• Enrollment (Anticipated): 533
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Almelo, Netherlands
    • Ziekenhuisgroep Twente
  • Almere, Netherlands
    • Flevo Hospital
  • Amersfoort, Netherlands
    • Meander Hospital
  • Amsterdam, Netherlands
    • Onze Lieve Vrouwe Gasthuis
  • Amsterdam, Netherlands
    • Slotervaart Hospital
  • Amsterdam, Netherlands
    • Academic Medical Center
  • Amsterdam, Netherlands
    • VU Medical Center
  • Amsterdam, Netherlands
    • BovenIJ hospital
  • Amsterdam, Netherlands
    • Sint Lucas Andreas Hospital
  • Apeldoorn, Netherlands
    • Gelre Hospitals
  • Arnhem, Netherlands
    • Rijnstate Hospital
  • Beverwijk, Netherlands
    • Rode Kruis Hospital
  • Delft, Netherlands
    • Reinier de Graaf Gasthuis
  • Dordrecht, Netherlands
    • Albert Schweitzer Hospital
  • Haarlem, Netherlands
    • Kennemer Hospital
  • Hengelo, Netherlands
    • Ziekenhuisgroep Twente
  • Hilversum, Netherlands
    • Tergooi Hospital
  • Hoofddorp, Netherlands
    • Spaarne Hospitals
  • Hoorn, Netherlands
    • Westfries Gasthuis
  • Nieuwegein, Netherlands
    • Sint Antonius Hospital
  • Rotterdam, Netherlands
    • Sint Franciscus Gasthuis
  • Rotterdam, Netherlands
    • Erasmus Medical Center
  • Rotterdam, Netherlands
    • Ikazia Hospital
  • Veldhoven, Netherlands
    • Máxima Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Only left-sided uncomplicated (mild) acute diverticulitis;
• Clinical suspicion of acute diverticulitis. For acute diagnostic work-up: ultrasound or CT proven diverticulitis. In the case of diverticulitis-negative ultrasound in clinically suspected patients an intravenous contrast-enhanced CT scan is mandatory for confirmation of diverticulitis or exclusion of other pathology. CT for Hinchey/Ambrosetti classification (which is a CT-based classification system) is needed for all patients, but can be delayed 1 day in those with ultrasound diagnosis. Staging diverticulitis is defined according the modified Hinchey/Ambrosetti staging, only stages 1a and 1b and "mild" diverticulitis (1a Confined pericolic inflammation, 1b Confined small (smaller than 5cm) pericolic abscess) are included;
• All patients with informed consent.

Exclusion Criteria:

• Previous radiological (ultrasound and/or CT) proven episode of diverticulitis;
• Colonic cancer;
• Inflammatory bowel disease (ulcerative colitis, Crohn's disease);
• Hinchey stages 2, 3 and 4 or "severe" diverticulitis according to the Ambrosetti criteria, which require surgical or percutaneous treatment;
• Disease with expected survival of less than 6 months;
• Contraindication for the use of the study medication (e.g. patients with advanced renal failure or allergy to antibiotics used in this study);
• Pregnancy, breastfeeding;
• ASA (American Society of Anaesthesiologists) classification > III;
• Immunocompromised patients;
• Clinical suspicion of bacteraemia (i.e. sepsis);
• The inability of reading/understanding and filling in the questionnaires;
• Antibiotic use in the 4 weeks before admittance.

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
Active Comparator: Conservative strategy with antibiotics; Hospital admission; Intravenous fluids and at least 48 hours of intravenous antibiotics and subsequently switch to oral antibiotics if tolerated (otherwise continuation i.v.) to complete a full 10-day treatment duration; Adequate pain relief; Oral intake as tolerated; Daily monitoring	Drug: Amoxicillin-clavulanate; Amoxicillin-clavulanate: 4 times a day 1200 mg and switch to oral administration 3 times a day 625 mg after two days, for a total duration of 10 days. In case of allergy to Amoxicillin-clavulanate: intravenous administration ciprofloxacin 2 times a day 400 mg and metronidazole 3 times a day 500 mg. In case of oral administration ciprofloxacin 2 times a day 500 mg and metronidazole 3 times a day 500 mg. For a total duration of 10 days.; Other Names: Augmentin.
No Intervention: Liberal strategy without antibiotics; Admission only if discharge criteria are not met; No initial antibiotics; Intravenous fluids only for those not tolerating oral liquids; Adequate pain relief; Oral intake as tolerated; Daily monitoring when admitted to the hospital; Self-monitoring at home (Patient diary with temperature and VAS pain score until full recovery)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time-to-full-recovery	6 months follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Direct medical costs		6 months follow-up
Occurrence of complicated diverticulitis defined as abscess, perforation, stricture and/or fistula and need for percutaneous drainage and/or operation		24 months follow-up
Predefined side-effects of initial antibiotic treatment	e.g. antibiotic resistance/sensitivity pattern, allergy	24 months follow-up
Morbidity, like urinary tract infection, pneumonia, etc		24 months follow-up
Mortality		24 months follow-up
Readmission rate		6 months follow-up
Indirect medical costs		6 months follow-up
Acute diverticulitis recurrence rate		12 months follow-up
Acute diverticulitis recurrence rate		24 months follow-up
Health status	Changes and valuation over time (compared to t=0) will be measured using generic and disease specific quality of life questionnaires (Euro-Qol 5D, Short Form 36 (SF-36) and the Gastro-intestinal Quality of Life Index (Giqli))	3 months follow-up
Health status	Changes and valuation over time (compared to t=0 and 3 months) will be measured using generic and disease specific quality of life questionnaires (Euro-Qol 5D, Short Form 36 (SF-36) and the Gastro-intestinal Quality of Life Index (Giqli))	6 months follow-up
Health status	Changes and valuation over time (compared to t=0, 3 and 6 months) will be measured using generic and disease specific quality of life questionnaires (Euro-Qol 5D, Short Form 36 (SF-36) and the Gastro-intestinal Quality of Life Index (Giqli))	12 months follow-up
Health status	Changes and valuation over time (compared to t=0, 3, 6 and 12 months) will be measured using generic and disease specific quality of life questionnaires (Euro-Qol 5D, Short Form 36 (SF-36) and the Gastro-intestinal Quality of Life Index (Giqli))	24 months follow-up

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Dutch Digestive Diseases Foundation
• Investigators: Principal Investigator: Marie A Boermeester, MD, PhD, MSc, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General Publications

• Unlu C, de Korte N, Daniels L, Consten EC, Cuesta MA, Gerhards MF, van Geloven AA, van der Zaag ES, van der Hoeven JA, Klicks R, Cense HA, Roumen RM, Eijsbouts QA, Lange JF, Fockens P, de Borgie CA, Bemelman WA, Reitsma JB, Stockmann HB, Vrouenraets BC, Boermeester MA; Dutch Diverticular Disease 3D Collaborative Study Group. A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial). BMC Surg. 2010 Jul 20;10:23. doi: 10.1186/1471-2482-10-23.
• de Korte N, Unlu C, Boermeester MA, Cuesta MA, Vrouenreats BC, Stockmann HB. Use of antibiotics in uncomplicated diverticulitis. Br J Surg. 2011 Jun;98(6):761-7. doi: 10.1002/bjs.7376. Epub 2011 Jan 6.
• de Korte N, Kuyvenhoven JP, van der Peet DL, Felt-Bersma RJ, Cuesta MA, Stockmann HB. Mild colonic diverticulitis can be treated without antibiotics. A case-control study. Colorectal Dis. 2012 Mar;14(3):325-30. doi: 10.1111/j.1463-1318.2011.02609.x.
• de Korte N, Klarenbeek BR, Kuyvenhoven JP, Roumen RM, Cuesta MA, Stockmann HB. Management of diverticulitis: results of a survey among gastroenterologists and surgeons. Colorectal Dis. 2011 Dec;13(12):e411-7. doi: 10.1111/j.1463-1318.2011.02744.x.
• Draaisma WA, van de Wall BJ, Vermeulen J, Unlu C, de Korte N, Swank HA. [Treatment for diverticulitis not thoroughly researched]. Ned Tijdschr Geneeskd. 2009;153:A648. Dutch.
• Unlu C, Daniels L, Vrouenraets BC, Boermeester MA. A systematic review of high-fibre dietary therapy in diverticular disease. Int J Colorectal Dis. 2012 Apr;27(4):419-27. doi: 10.1007/s00384-011-1308-3. Epub 2011 Sep 16.
• Daniels L, Unlu C, de Korte N, van Dieren S, Stockmann HB, Vrouenraets BC, Consten EC, van der Hoeven JA, Eijsbouts QA, Faneyte IF, Bemelman WA, Dijkgraaf MG, Boermeester MA; Dutch Diverticular Disease (3D) Collaborative Study Group. Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis. Br J Surg. 2017 Jan;104(1):52-61. doi: 10.1002/bjs.10309. Epub 2016 Sep 30.

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Anticipated): April 1, 2013
• Study Completion (Anticipated): October 1, 2014

Study Registration Dates

• First Submitted: April 22, 2010
• First Submitted That Met QC Criteria: April 26, 2010
• First Posted (Estimate): April 27, 2010

Study Record Updates

• Last Update Posted (Estimate): October 29, 2012
• Last Update Submitted That Met QC Criteria: October 26, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: antibiotics; cost analysis; economic evaluation; multicenter randomized, open label, clinical trial; acute uncomplicated (mild) diverticulitis; treatment strategies; management of diverticulitis; observation and supportive care
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Diverticular Diseases; Diverticulitis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: 09/233; 2009-015004-26 (EudraCT Number); NL29615.018.09 (Registry Identifier: Nederlands Trial Register (=Dutch Trial Registry)); ABR 29615 (Other Identifier: CCMO Registry); 80-82310-97-10039 (Other Grant/Funding Number: ZonMW (Organisation for Health Research and Development)); WO 08-54 (Other Grant/Funding Number: MLDS)