Laparoscopic Peritoneal Lavage or Resection for Generalised Peritonitis for Perforated Diverticulitis (Ladies)

Laparoscopic Peritoneal Lavage or Resection for Generalised Peritonitis for Perforated Diverticulitis: a Nationwide Multicenter Randomised Trial

The first objective (LOLA) of this integrated trial is to determine whether laparoscopic lavage leads to better clinical outcomes compared to sigmoidectomy in patients with perforated diverticulitis with purulent peritonitis in terms of mortality and major morbidity. The second objective (DIVA) is to determine whether sigmoidectomy with anastomosis or sigmoidectomy with end-colostomy is the superior approach in patients with perforated diverticulitis with either purulent or faecal peritonitis in terms of stoma free survival. The study is designed as a multicenter and randomised trial.

Study Overview

• Status: Unknown
• Conditions: Perforated Diverticulitis
• Intervention / Treatment: Procedure: Laparoscopic lavage and drainage; Procedure: Sigmoidectomy with primary anastomosis; Procedure: Sigmoidectomy with end-colostomy

Detailed Description

Patients diagnosed as having perforated diverticulitis with free air on plain abdominal X-ray or CT scan fulfilling the in- and exclusion criteria are randomised during laparoscopy via a central computer. In case of purulent diverticulitis patients are randomised to three arms: (a) laparoscopic lavage, (b) sigmoidectomy with colostomy or (c) sigmoidectomy with anastomosis in ratio of 2:1:1. In case of faecal peritonitis or an overt perforation of the sigmoid, the patient will be randomised 1:1 to sigmoidectomy with colostomy or sigmoidectomy with primary anastomosis.

The first primary outcome parameter consists of a combined endpoint consisting of mortality and major morbidity (LOLA). The second primary endpoint consists of stoma-free survival one year after initial surgery (DIVA). Secondary endpoints are number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs. A sample size of 132:66:66 patients per treatment arm will be able to detect a difference in the combined endpoint of serious complications and mortality from 25% in the two sigmoidectomy groups compared to 10% in the lavage group (two-side alpha of 5% and a power of 90%. In the DIVA analysis 2x132 patients are needed to significantly demonstrate a difference of 30% in stoma-free survival between both treatment arms (log rank test two-sided alpha of 5% and power of 90%) in favour of the patients with primary anastomosis. More than 35 hospitals will participate in this study with an estimated total inclusion of 100 patients per year. Patients will be followed for one year.

The study will be executed in concordance with the protocol, the Good Clinical Practice guidelines and regulatory requirements.

After closure of the LOLA-arm due to safety concerns for laparoscopic lavage, the protocol and sample size has for the DIVA-arm been adjusted to 118 patients per study arm (faecal or purulent peritonitis).

• Study Type: Interventional
• Enrollment (Anticipated): 283
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: W.A. Bemelman, Professor; Email: w.a.bemelman@amc.uva.nl
• Study Contact Backup: Name: J.F. Lange, Professor; Email: j.f.lange@erasmusmc.nl

Study Locations

• Belgium
  • Brussels, Belgium
    • Not yet recruiting
    • University Clinic St. Luc
    • Contact: A. Kartheuser
    • Sub-Investigator: C. Remue
  • Leuven, Belgium
    • Recruiting
    • University Hospital Leuven
    • Contact: A. d'Hoore
• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Recruiting
    • Jeroen Bosch Hospital
    • Contact: H. Prins
  • Almere, Netherlands
    • Recruiting
    • Flevo Hospital
    • Contact: M. Boom
  • Alphen aan de Rijn and Leiderdorp, Netherlands
    • Not yet recruiting
    • Rijnland Hospital
    • Contact: P.A. Neijenhuis
  • Amersfoort, Netherlands
    • Recruiting
    • Meander Medical Centre
    • Contact: E.C.J. Consten
  • Amsterdam, Netherlands
    • Recruiting
    • Academic Medical Centre
    • Contact: W.A. Bemelman
  • Amsterdam, Netherlands
    • Recruiting
    • Free University Medical Centre
    • Contact: D.L. van der Peet
  • Amsterdam, Netherlands
    • Recruiting
    • Onze Lieve Vrouwe Hospital
    • Contact: M.F. Gerhards
  • Amsterdam, Netherlands
    • Recruiting
    • Slotervaart Hospital
    • Contact: S.C. Bruin
  • Amsterdam, Netherlands
    • Recruiting
    • St. Lucas Andreas Hospital
    • Contact: B.A. van Wagensveld
  • Arnhem, Netherlands
    • Recruiting
    • Alysis Medical Centre
    • Contact: C.F.J.M. Blanken-Peeters
  • Beverwijk, Netherlands
    • Recruiting
    • Rode Kruis Hospital
    • Contact: H.A. Cense
  • Breda, Netherlands
    • Recruiting
    • Amphia Hospital
    • Contact: R.M.P.M. Crolla
  • Capelle aan de IJssel, Netherlands
    • Recruiting
    • Ijsselland Hospital
    • Contact: E.J.R. de Graaf
  • Delft, Netherlands
    • Recruiting
    • Reinier de Graaf Hospital
    • Contact: T.M. Karsten
  • Deventer, Netherlands
    • Not yet recruiting
    • Deventer Hospital
    • Contact: R.J.I. Bosker
  • Dordrecht and Zwijndrecht, Netherlands
    • Recruiting
    • Albert Schweitzer Hospital
    • Contact: J.A.B. van der Hoeven
  • Ede, Netherlands
    • Recruiting
    • Gelderse Vallei Hospital
    • Contact: Ph.M. Kruyt
  • Eindhoven, Netherlands
    • Recruiting
    • Catharina Hospital
    • Contact: S.W. Nienhuijs
  • Enschede, Netherlands
    • Recruiting
    • Medical spectrum Twente
    • Contact: E.B. van Duyn
  • Gouda, Netherlands
    • Recruiting
    • Groene Hart Hospital
    • Contact: D.J. Swank
  • Haarlem, Netherlands
    • Recruiting
    • Kennemer Hospital
  • Heerlen and Brunssum, Netherlands
    • Recruiting
    • Atrium Medical Centre
    • Contact: M.N. Sosef
  • Hilversum and Blaricum, Netherlands
    • Recruiting
    • Tergooi Hospitals
    • Contact: A.A.W. van Geloven
  • Hoofddorp, Netherlands
    • Recruiting
    • Spaarne Hospital
    • Contact: Q.A.J. Eijsbouts
  • Hoorn, Netherlands
    • Recruiting
    • Westfries Hospital
    • Contact: M.J.P.M. Govaert
  • Leiden, Netherlands
    • Not yet recruiting
    • Leiden University Medical Centre
    • Contact: R.A.E.M. Tollenaar
  • Maastricht, Netherlands
    • Recruiting
    • Maastricht University Medical Centre
    • Contact: L.P.S. Stassen
  • Nieuwegein, Netherlands
    • Recruiting
    • St. Antonius Hospital
    • Contact: M.J. Wiezer
  • Rotterdam, Netherlands
    • Recruiting
    • Maasstad Hospital
    • Contact: P.P.L.O. Coene
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Centre
    • Contact: J.F. Lange
  • Rotterdam, Netherlands
    • Recruiting
    • Ikazia Hospital
    • Contact: W.F. Weidema
  • Rotterdam, Netherlands
    • Recruiting
    • St. Franciscus Hospital
    • Contact: G.H.H. Mannaerts
  • Sittard, Netherlands
    • Recruiting
    • Orbis Medical Centre
    • Contact: A.G.M. Hoofwijk
  • The Hague, Netherlands
    • Recruiting
    • Haga Hospital
    • Contact: W.H. Steup
  • Tilburg and Waalwijk, Netherlands
    • Recruiting
    • Twee Steden Hospital
    • Contact: J.K. Maring
  • Utrecht, Netherlands
    • Recruiting
    • University Medical Centre Utrecht
    • Contact: W.M.U. van Grevenstein
  • Veldhoven, Netherlands
    • Recruiting
    • Maxima Medical Centre
    • Contact: G.D. Slooter
  • Zaandam, Netherlands
    • Recruiting
    • Zaans Medical Centre
    • Contact: A.F. Engel
  • Zwolle, Netherlands
    • Recruiting
    • Isala Hospitals
    • Contact: E.G.J.M. Pierik

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

patients suspected of diverticulitis

• age in between 18 and 85 years old
• with written informed consent
• with free air on plain abdominal or thoracic X-ray or CT-scan OR with peritonitis and diffuse gas or fluid on CT-scan

Exclusion Criteria:

• dementia
• prior sigmoidectomy
• steroid treatment > 20 mg daily
• prior pelvic irradiation
• preoperative shock: requirement of inotropics due to circulatory insufficiency

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: Purulent peritonitis; Patients with purulent peritonitis are randomised at a 2:1:1 ratio between; Laparoscopic lavage and drainage; Sigmoidectomy with primary anastomosis; Sigmoidectomy with end-colostomy	Procedure: Laparoscopic lavage and drainage; [CLOSED] The abdominal cavity is irrigated with six litres of warm saline in all four quadrants. At the end of the procedure a Douglas drain is inserted via the right lateral port. ***This part of the study was closed in 2013 on advice of the data and safety monitoring board due to safety issues; Procedure: Sigmoidectomy with primary anastomosis; [OPEN] Sigmoidectomy is done according to the guidelines of the American Society of Colon and Rectal Surgeons. The distal transsection margin has to be on the proximal rectum, the proximal margin is determined by the absence of wall thickening due to diverticulitis. The type of anastomosis is done according to the preference of the operating surgeon. A loop ileostomy can be fashioned in order to ensure faecal deviation to the discretion of the surgeon.; Other Names: Sigmoid resection; Procedure: Sigmoidectomy with end-colostomy; [OPEN] This is a two-stage procedure with the intention to close the colostomy in a second stage. During the primary surgery, only the perforated diseased part must be resected. There is no need of having the distal transsection line on the proximal rectum.; Other Names: Hartmann procedure
Experimental: Fecal peritonitis or overt perforation; Patients with fecal peritonitis or an overt perforation are randomised between; Sigmoidectomy with primary anastomosis; Sigmoidectomy with end-colostomy	Procedure: Sigmoidectomy with primary anastomosis; [OPEN] Sigmoidectomy is done according to the guidelines of the American Society of Colon and Rectal Surgeons. The distal transsection margin has to be on the proximal rectum, the proximal margin is determined by the absence of wall thickening due to diverticulitis. The type of anastomosis is done according to the preference of the operating surgeon. A loop ileostomy can be fashioned in order to ensure faecal deviation to the discretion of the surgeon.; Other Names: Sigmoid resection; Procedure: Sigmoidectomy with end-colostomy; [OPEN] This is a two-stage procedure with the intention to close the colostomy in a second stage. During the primary surgery, only the perforated diseased part must be resected. There is no need of having the distal transsection line on the proximal rectum.; Other Names: Hartmann procedure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality and major morbidity (combined)	The primary outcome in the lavage vs. resectional intervention comparison (LOLA), will be poor clinical outcome, defined as a combined endpoint consisting of mortality and major morbidity one year after initial surgery. Major morbidity includes any of the following events or conditions: reintervention, wound dehiscence, incisional hernia, abscess needing percutaneous drainage, urosepsis, myocardial infarction, renal failure and respiratory insufficiency.	One-year
Stoma-free survival	Stoma-free survival one year after initial surgery, is the primary outcome for the comparison of the resectional strategies (DIVA).	One year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Operating time		- (day 1)
Hospital stay		- (day one until discharge from hospital)
Number of days alive and outside the hospital		One year
Incisional hernia		One year
Reinterventions	All reinterventions within a one year time frame, including percutaneous abscess drainage.	One year
Health related quality of life	SF-36, EQ-5D, GIQLI measured at 2, 4, 13 and 26 weeks after primary surgery.	One year
Health care utilisation and associated costs	SF-HLQ measured at 4, 13, 26, 39 and 52 weeks after primary surgery	One year

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: J.F. Lange, Professor, Erasmus Medical Centre, Rotterdam; Principal Investigator: W.A. Bemelman, Professor, Academic Medical Centre, Amsterdam

Publications and helpful links

General Publications

• Toorenvliet BR, Swank H, Schoones JW, Hamming JF, Bemelman WA. Laparoscopic peritoneal lavage for perforated colonic diverticulitis: a systematic review. Colorectal Dis. 2010 Sep;12(9):862-7. doi: 10.1111/j.1463-1318.2009.02052.x. Epub 2009 Sep 26.
• Salem L, Flum DR. Primary anastomosis or Hartmann's procedure for patients with diverticular peritonitis? A systematic review. Dis Colon Rectum. 2004 Nov;47(11):1953-64. doi: 10.1007/s10350-004-0701-1.
• Constantinides VA, Tekkis PP, Athanasiou T, Aziz O, Purkayastha S, Remzi FH, Fazio VW, Aydin N, Darzi A, Senapati A. Primary resection with anastomosis vs. Hartmann's procedure in nonelective surgery for acute colonic diverticulitis: a systematic review. Dis Colon Rectum. 2006 Jul;49(7):966-81. doi: 10.1007/s10350-006-0547-9.
• Hoek VT, Edomskis PP, Stark PW, Lambrichts DPV, Draaisma WA, Consten ECJ, Lange JF, Bemelman WA; LADIES trial collaborators. Laparoscopic peritoneal lavage versus sigmoidectomy for perforated diverticulitis with purulent peritonitis: three-year follow-up of the randomised LOLA trial. Surg Endosc. 2022 Oct;36(10):7764-7774. doi: 10.1007/s00464-022-09326-3. Epub 2022 May 23.
• Lambrichts DPV, Vennix S, Musters GD, Mulder IM, Swank HA, Hoofwijk AGM, Belgers EHJ, Stockmann HBAC, Eijsbouts QAJ, Gerhards MF, van Wagensveld BA, van Geloven AAW, Crolla RMPH, Nienhuijs SW, Govaert MJPM, di Saverio S, D'Hoore AJL, Consten ECJ, van Grevenstein WMU, Pierik REGJM, Kruyt PM, van der Hoeven JAB, Steup WH, Catena F, Konsten JLM, Vermeulen J, van Dieren S, Bemelman WA, Lange JF; LADIES trial collaborators. Hartmann's procedure versus sigmoidectomy with primary anastomosis for perforated diverticulitis with purulent or faecal peritonitis (LADIES): a multicentre, parallel-group, randomised, open-label, superiority trial. Lancet Gastroenterol Hepatol. 2019 Aug;4(8):599-610. doi: 10.1016/S2468-1253(19)30174-8. Epub 2019 Jun 6.
• Vennix S, Musters GD, Mulder IM, Swank HA, Consten EC, Belgers EH, van Geloven AA, Gerhards MF, Govaert MJ, van Grevenstein WM, Hoofwijk AG, Kruyt PM, Nienhuijs SW, Boermeester MA, Vermeulen J, van Dieren S, Lange JF, Bemelman WA; Ladies trial colloborators. Laparoscopic peritoneal lavage or sigmoidectomy for perforated diverticulitis with purulent peritonitis: a multicentre, parallel-group, randomised, open-label trial. Lancet. 2015 Sep 26;386(10000):1269-1277. doi: 10.1016/S0140-6736(15)61168-0. Epub 2015 Jul 22. Erratum In: Lancet. 2019 Jun 1;393(10187):2200.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Anticipated): March 1, 2017
• Study Completion (Anticipated): March 1, 2017

Study Registration Dates

• First Submitted: March 16, 2011
• First Submitted That Met QC Criteria: March 16, 2011
• First Posted (Estimate): March 17, 2011

Study Record Updates

• Last Update Posted (Estimate): March 21, 2014
• Last Update Submitted That Met QC Criteria: March 20, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: lavage; laparoscopic; diverticulitis; hartmann; perforation; primary anastomosis; sigmoidectomy; sigmoid resection; wash-out; rinsing; end-colostomy
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Peritoneal Diseases; Gastrointestinal Diseases; Gastroenteritis; Diverticular Diseases; Intraabdominal Infections; Peritonitis; Diverticulitis
• Other Study ID Numbers: NTR2037