Prevention of Postoperative Endoscopic Recurrence With Endoscopy-driven Versus Systematic Biological Therapy (SOPRANO-CD)

Prevention of Postoperative Endoscopic Recurrence With Endoscopy-driven Versus Systematic Biological Therapy: a Randomized, Multicentre, Parallel Group Pragmatic Non-inferiority Trial in Crohn Disease

With this prospective, randomized, multicentre, parallel group pragmatic non-inferiority trial, the investigators will evaluate if endoscopy-driven introduction of biological therapy is not leading to more postoperative endoscopic recurrence at week 86 compared to systematic prophylactic biological therapy in patients with CD undergoing an ileocolonic resection with ileocolonic anastomosis. Secondary analyses will include influence on clinical, biological and surgical CD recurrence, serious adverse events, direct costs, work productivity, and quality of life. If the investigators can demonstrate the non-inferiority of an endoscopy-driven approach, this patient-tailored management could be advocated, while a more expensive systematic introduction of biological therapies could be limited.

Finally, endoscopic images provided through the SOPRANO CD study, will be used to develop a new scoring system evaluating postoperative endoscopic recurrence.

Study Overview

• Status: Recruiting
• Conditions: Crohn Disease
• Intervention / Treatment: Drug: Biological Drug

Detailed Description

This will be a prospective, randomized, parallel group, pragmatic trial.

Prior to study group assignment, the type of biological therapy to be (eventually) used in the postoperative phase will be selected by the treating physician after thorough discussion with the patient. The use of cheaper anti-TNF biosimilars will be encouraged, but patients who received adalimumab and/or infliximab preoperatively cannot receive the same treatment again in SOPRANO CD if the participants previously encountered immunogenicity issues to this treatment.

Systematic postoperative prophylaxis with a biological:

Biological therapy (adalimumab, infliximab, ustekinumab, vedolizumab or risankizumab) will be initiated within 14 to 40 days after ileocolonic resection or restoration of the faecal stream (day 0).

In patients with both Harvey-Bradshaw Index (HBI) based clinical recurrence (HBI >4) and endoscopic recurrence (Rutgeerts score ≥i2b) at week 30, biological therapy will be optimized (reimbursed or through the available free goods / samples programs).

Beyond week 32 optimization of this biological therapy will be allowed following daily clinical practice including proactive therapeutic drug monitoring. However, the timing, type and reason for dose optimization should be recorded.

Endoscopy-driven postoperative biological therapy:

No CD related therapy will be administered between Baseline (14 to 40 days after ileocolonic resection or restoration of the faecal stream) and the endoscopic evaluation at week 30 Patients with endoscopic recurrence (Rutgeerts score ≥i2b) at week 30 will initiate biological therapy (adalimumab, infliximab, ustekinumab, vedolizumab or risankizumab) following a classical induction and maintenance schedule. The type of biological therapy has to be decided already in the perioperative phase to allow a proper stratification.

In patients initiating biological therapy at week 30, this therapy maybe optimized from week 32 onwards following daily clinical practice including proactive therapeutic drug monitoring. However, the timing, type and reason for dose optimization should be recorded.

In patients not on biological therapy yet but developing clinical recurrence (HBI >4) with objective signs of disease recurrence (faecal calprotectin >250 µg/g, C-reactive protein >5 mg/L or endoscopic recurrence ≥i2b or clear radiological disease activity at the neo-terminal ileum) beyond week 32, biological therapy can be initiated, but this will be regarded as a study failure.

Randomization:

Eligible patients will be allocated to one of the two treatment arms (1:1) according to a computer generated randomisation list in REDCap.

Stratified randomisation will be performed to achieve approximate balance for:

• Type of selected postoperative prophylactic therapy: adalimumab, infliximab, ustekinumab, vedolizumab or risankizumab.
• Number of risk factors for postoperative recurrence: 1, 2 or >2 (out of 5 predefined factors: active smoking, penetrating disease, previous ileocolonic resection ≤10 years of index surgery, ≥2 previous ileocolonic resections, biological therapy ≤3 months of index ileocolonic resection)

• Study Type: Interventional
• Enrollment (Estimated): 292
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Marc Ferrante, Professor; Phone Number: +32 016 342845; Email: marc.ferrante@uzleuven.be
• Study Contact Backup: Name: Dorien Beeckmans, PhD; Phone Number: +32 016 348545; Email: dorien.beeckmans@uzleuven.be

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • Recruiting
    • OLV Aalst
    • Contact: Stijn Vanden Branden, MD; Phone Number: +3253724428; Email: Stijn.Vanden.branden@olvz-aalst.be
  • Bonheiden, Belgium, 2820
    • Recruiting
    • Imeldaziekenhuis
    • Contact: Lieven Pouillon, MD; Phone Number: +3215504969; Email: lieven.pouillon@imelda.be
  • Brasschaat, Belgium, 2930
    • Recruiting
    • AZ Klina
    • Contact: Evi Van Dyck, MD; Phone Number: +3236505227; Email: evi.van.dyck@klina.be
  • Bruges, Belgium, 8000
    • Recruiting
    • AZ Sint-Jan
    • Contact: Barbara Willandt, MD; Phone Number: +3250452180; Email: barbara.willandt@azsintjan.be
  • Ghent, Belgium, 9000
    • Recruiting
    • AZ Sint Lucas
    • Contact: Harald Peeters, MD; Phone Number: 092245170; Email: harald.peeters@azstlucas.be
  • Hasselt, Belgium, 3500
    • Recruiting
    • Jessa Ziekenhuis
    • Contact: Liesbeth Thijs, MD; Phone Number: +3211337619; Email: liesbeth.thijs@jessazh.be
  • Mechelen, Belgium, 2800
    • Withdrawn
    • Az Sint Maarten
  • Roeselare, Belgium, 8800
    • Recruiting
    • AZ Delta
    • Contact: Filip Baert, MD; Phone Number: +3251237215; Email: filip.baert@azdelta.be
  • Sint-Niklaas, Belgium, 9100
    • Recruiting
    • Vitaz
    • Contact: Tom Holvoet, MD; Phone Number: +32474926904; Email: tom.holvoet@aznikolaas.be
  • Antwerpen
    • Antwerp, Antwerpen, Belgium, 2018
      • Recruiting
      • ZAS
      • Contact: Filip Couturier, MD; Phone Number: +3232852815; Email: filip.couturier@gza.be
    • Edegem, Antwerpen, Belgium, 2650
      • Recruiting
      • UZA
      • Contact: Michaël Somers, MD; Phone Number: +3238215584; Email: michael.somers@uza.be
  • Brussels Capital
    • Brussels, Brussels Capital, Belgium, 1070
      • Recruiting
      • Erasmus ziekenhuis
      • Contact: Denis Franchimont, MD; Phone Number: +3225558307; Email: denis.franchimont@erasme.ulb.ac.be
    • Brussels, Brussels Capital, Belgium, 1200
      • Recruiting
      • Cliniques Universitaires Saint Luc
      • Contact: Olivier Dewit, MD; Phone Number: +3227642871; Email: Olivier.Dewit@uclouvain.be
    • Jette, Brussels Capital, Belgium, 1090
      • Recruiting
      • UZ Brussel
      • Contact: Liv Vandermeulen, MD; Phone Number: +3224776812; Email: Liv.Vandermeulen@uzbrussel.be
  • Henegouwen
    • Tournai, Henegouwen, Belgium, 7500
      • Recruiting
      • CHWAPI
      • Contact: Maxence Lefebvre, MD; Phone Number: +3269331650; Email: maxence.lefebvre@chwapi.be
  • Limburg
    • Genk, Limburg, Belgium, 3600
      • Recruiting
      • ZOL GENK
      • Contact: Evelien Humblet, MD; Phone Number: +3289326515; Email: evelien.humblet@zol.be
  • Liège
    • Liège, Liège, Belgium, 4000
      • Recruiting
      • CHC MontLegia
      • Contact: Arnaud Colard, MD; Phone Number: +3243554211; Email: arnaud.colard@chc.be
    • Liège, Liège, Belgium, 4000
      • Recruiting
      • CHU de Liège
      • Contact: Edouard Louis, MD; Phone Number: +3243667256; Email: edouard.louis@uliege.be
  • Namur
    • Yvoir, Namur, Belgium, 5530
      • Not yet recruiting
      • CHU UCL Namur Site Godinne
      • Contact: Jean-Francois rahier, prof; Email: jfrahier@gmail.com
  • Oost-Vlaanderen
    • Ghent, Oost-Vlaanderen, Belgium, 9000
      • Recruiting
      • Uz Gent
      • Contact: Triana Lobaton Ortega, MD; Phone Number: +3293322371; Email: triana.lobatonortega@uzgent.be
    • Ghent, Oost-Vlaanderen, Belgium, 9000
      • Recruiting
      • AZ Maria Middelares
      • Contact: Didier Baert, MD; Phone Number: +3292467100; Email: didier.baert@azmmsj.be
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • Recruiting
      • UZ Leuven
      • Contact: Marc Ferrante, MD; Phone Number: +3216348856; Email: marc.ferrante@uzleuven.be
      • Contact: Dorien Beeckmans, PhD; Phone Number: +32474474817; Email: dorien.beeckmans@uzleuven.be
  • West-Vlaanderen
    • Bruges, West-Vlaanderen, Belgium, 8310
      • Not yet recruiting
      • Sint lucas Brugge
      • Contact: Julie Busschaert, MD; Phone Number: 050365165; Email: Julie.Busschaert@stlucas.be
    • Ostend, West-Vlaanderen, Belgium, 8400
      • Recruiting
      • AZ Damiaan
      • Contact: Guy Lambrecht, MD; Phone Number: +3259416334; Email: glambrecht@azdamiaan.be
• Italy
  • Castellana Grotte, Italy, 70013
    • Recruiting
    • IRCCS De Bellis Castellana Grotte
    • Contact: Mauro Mastronardi; Email: mauro21mastronardi@gmail.com
  • Florence, Italy, 50134
    • Recruiting
    • Careggi University Hospital
    • Contact: Gabriele Dragoni, MD; Email: gabriele.dragoni@unifi.it
  • Milan, Italy, 20132
    • Recruiting
    • IRCCS San Raffael Hospital
    • Contact: Silvio Danese, MD; Phone Number: +31226432069; Email: DANESE.SILVIO@HSR.IT
  • Rozzano MI
    • Milan, Rozzano MI, Italy, 20089
      • Not yet recruiting
      • Humanitas Research Hospital
      • Contact: Alessandro Armuzzi, Prof; Phone Number: 0282247714; Email: alessandro.armuzzi@hunimed.eu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures.
2. Patients with a diagnosis of Crohn's disease based on radiology, endoscopy and/or histology
3. Males and females 18-80 years old.

4. Patients undergoing an ileocolonic resection with ileocolonic anastomosis (with or without temporary ileostomy) within 3 and 40 days prior to the Screening visit.

   Patients who underwent an ileocolonic resection with ileocolonic anastomosis with a temporary ileostomy are also eligible if the ileocolonic resection was performed within eight months prior to the Screening visit, and the restoration of the faecal stream was performed within 3 and 40 days prior to the Screening visit.

5. Patients having an increased risk for postoperative recurrence for any of the following reasons:

   1. Penetrating disease as reason for ileocolonic resection
   2. Previous ileocolonic resection within ten years of index surgery
   3. Two or more previous ileocolonic resections
   4. Active smoking
   5. Biological therapy for Crohn's disease within 3 months of index ileocolonic resection
6. Curative ileocolonic resection. All inflamed colon segments should have been removed. Strictureplasties in the small bowel not involving the anastomotic region are allowed.
7. Patients previously failing at least three months of steroids and/or three months of immunosuppressive therapy, or showing intolerance or a real contraindication for any of these therapies.
8. Patients able and willing to start and continue biological therapy, and this at the timepoint indicated through study randomization

Exclusion Criteria:

1. Participant has a history of primary non response or secondary loss of response to all five biological therapies of interest, namely adalimumab, infliximab, ustekinumab, vedolizumab and risankizumab..
2. Any disorder, which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol.
3. Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the Trial.
4. Participation in an interventional Trial with an Investigational Medicinal Product (IMP) or device.
5. Patients initiating biological therapy for CD as part of another clinical trial or a medical need program.
6. Patients not understanding Dutch, French, German or English.
7. Patients with ulcerative colitis or inflammatory bowel disease type unclassified.
8. Patients with an ileorectal anastomosis, or an ileal pouch-anal anastomosis.
9. Patients with active perianal disease.
10. Patients with a colorectal stenosis.
11. Patients with an ostomy.
12. Patients with sepsis or other postoperative complications necessitating the use of antibiotics for more than ten days after ileocolonic resection or restoration of the faecal stream.
13. Patients with (an imminent risk) of a short bowel syndrome.
14. Patients who had qualifying ileocolonic resection for dysplasia or cancer without ongoing inflammation.
15. Patients with liver test abnormalities (aspartate transaminase, alanine transaminase, alkaline phosphatases, or bilirubin > 2 upper limit of normal), leukopenia (<3000 white blood cells 109/L, <1500 neutrophils 109/L ), thrombocytopenia (platelets < 50.000/mm3).
16. Patients with severe renal, pulmonary or cardiac disease.
17. Ongoing alcohol or substance abuse.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Endoscopy-driven postoperative biological therapy; Endoscopic recurrence at week 30 Adalimumab: 160 mg SC at week 32, 80 mg SC at week 34, 40 mg SC at week 36 and every two weeks thereafter. Infliximab: Induction with 5 mg/kg IV at week 32, and 5 mg/kg IV at week 34; maintenance with 5 mg/kg IV at week 38, week 42 or week 46 and every eight weeks thereafter or with 120 mg SC at week 38 and every two weeks thereafter. Ustekinumab: 260 mg (body weight ≤55kg) or 390 mg (55-85kg) or 520 mg (>85kg) IV at week 32, 90 mg SC at week 40, and every eight weeks thereafter. Vedolizumab: Induction with 300 mg IV at week 32, and 300 mg IV at week 34; maintenance with 300 mg IV at week 38 and every eight weeks thereafter or with 108 mg SC at week 38, week 42 or week 46 and every two weeks thereafter. Risankizumab: Induction with 600 mg IV at week 32, week 36 and week 40; maintenance with 360 mg SC at week 44 and every eight weeks thereafter.	Drug: Biological Drug; Biological therapy used in daily clinical practice in patients with Crohn's disease to prevent disease recurrence; Other Names: Vedolizumab; Adalimumab; Infliximab; Ustekinumab; Risankizumab
Active Comparator: Systematic postoperative prophylaxis with a biological; Adalimumab: 160 mg subcutaneous (SC) at day 0, 80 mg SC at week 2, 40 mg SC at week 4 and every two weeks thereafter. Infliximab: Induction with 5 mg/kg intravenous (IV) at day 0, and 5 mg/kg IV at week 2; maintenance with 5 mg/kg IV at week 6, week 10 or week 14 and every eight weeks thereafter or with 120 mg SC at week 6 and every two weeks thereafter. Ustekinumab: 260 mg (body weight ≤55kg), 390 mg (55-85kg) or 520 mg (>85kg) IV at day 0, 90 mg SC at week 8 and every eight weeks thereafter. Vedolizumab: Induction with 300 mg IV at day 0, and 300 mg IV at week 2; maintenance with 300 mg IV at week 6 and every eight weeks thereafter or with 108 mg SC at week 6, week 10 or week 14 and every two weeks thereafter. Risankizumab: Induction with 600 mg IV at day 0, week 4 and week 8; maintenance with 360 mg SC at week 12 and every eight weeks thereafter.	Drug: Biological Drug; Biological therapy used in daily clinical practice in patients with Crohn's disease to prevent disease recurrence; Other Names: Vedolizumab; Adalimumab; Infliximab; Ustekinumab; Risankizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
postoperative endoscopic recurrence (Rutgeerts score ≥i2b)	To compare the postoperative endoscopic recurrence rate in patients with Crohn's disease undergoing an ileocolonic resection with ileocolonic anastomosis randomized to systematic biological therapy or endoscopy-driven biological therapy	86 weeks
need for unscheduled treatment adaptation prior to week 86	When, due to clinical symptoms, therapy needs to be started or switched prior to week 86	86 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Harvey Bradshaw Index (HBI) based clinical recurrence	HBI based clinical recurrence (score higher than 4) prior to week 86. HBI based clinical recurrence is defined as HBI >4; AND objective signs of disease recurrence, namely faecal calprotectin >250 µg/g, CRP >5 mg/L, or endoscopic recurrence Rutgeerts score ≥i2b, or clear radiological disease activity at the neo-terminal ileum.	86 weeks
Direct costs	Direct costs from Baseline to week 86	86 weeks
new ileocolonic resection	Need for a new ileocolonic resection prior to week 86	86 weeks
Severe adverse reactions	Severe adverse reactions to biological therapy prior to week 86	86 weeks
Serious adverse events	Serious adverse events prior to week 86	86 weeks
European Quality of Live Five Dimension Five Level Scale	Quality of life at week 30, week 62 and week 86 in comparison to Baseline (score between 0 and 100; higher score, better quality of life)	86 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Crohn's disease activity index (CDAI) based clinical recurrence	CDAI based clinical recurrence prior and at week 86 and time to CDAI based clinical recurrence	86 weeks
Harvey Bradshaw Index (HBI score higher than 4) based clinical recurrence	HBI based clinical recurrence at week 86 and time to HBI based clinical recurrence. HBI based clinical recurrence is defined as HBI >4; AND objective signs of disease recurrence, namely faecal calprotectin >250 µg/g, CRP >5 mg/L, or endoscopic recurrence ≥i2b, or clear radiological disease activity at the neo-terminal ileum.	86 weeks
Two-component Patient Reported Outcome (PRO-2) based clinical recurrence	PRO-2 based clinical recurrence prior and at week 86 and time to PRO-2 clinical recurrence. PRO-2 based clinical recurrence is defined as average liquid or very soft stool frequency of >2.8 and/or abdominal pain score >1.0	86 weeks
Endoscopic disease activity	Endoscopic disease activity (Rutgeerts score ≥i3, ≥i2a, or ≥i1) at week 86	86 weeks
Endoscopic recurrence	Endoscopic recurrence (Rutgeerts score ≥i2b) at week 30	30 weeks
Endoscopic disease activity	Endoscopic disease activity (Rutgeerts score ≥i3, ≥i2a, or ≥i1) at week 30	30 weeks
Persistent endoscopic recurrence	Persistent endoscopic recurrence at week 86 after development of endoscopic recurrence at week 30	86 weeks
a new ileocolonic resection, a balloon dilation or a strictureplasty	Need for a new ileocolonic resection, a balloon dilation or a strictureplasty at the site of the ileocolonic anastomosis prior to week 86	86 weeks
Work Productivity and Activity Impairment in Crohn's Disease questionnaire	Work productivity and activity impairment at week 30, week 62 and week 86 in comparison to Baseline (score between 0 and 20; lower score, better outcome)	86 weeks
Change in medical therapy	Change in medical therapy for Crohn's disease prior to week 86	86 weeks
Change in C-reactive protein	Change CRP at week 14, week 30, week 46, week 62 and week 86 in comparison to baseline	86 weeks
Change in faecal calprotectin	Change in faecal calprotectin at week 14, week 30, week 46, week 62 and week 86 in comparison to baseline	86 weeks
unscheduled visits	Number of unscheduled visits related to CD (clinical visit, endoscopic or radiological evaluation)	86 weeks
Suspected unexpected serious adverse reactions	Suspected unexpected serious adverse reactions prior to week 86	86 weeks
Two-component Patient Reported Outcome (PRO-2) based clinical recurrence in longterm follow-up	Evolution of PRO-2 at week 138, 190 and 242 in comparison to Baseline and Week 86	242 weeks
European Quality of Live Five Dimension Five Level Scale in longterm follow-up	Evolution of EQ-5D 5L at week 138, 190 and 242 in comparison to Baseline and Week 86	242 weeks
Work Productivity and Activity Impairment in Crohn's Disease questionnaire in longterm follow-up	Evolution of WPAI:CD at week 138, 190 and 242 in comparison to Baseline and Week 86	242 weeks
Change in C-reactive protein in longterm follow-up	Evolution of CRP at week 138, 190 and 242 in comparison to Baseline and Week 86	242 weeks
Change in faecal calprotectin in longterm follow-up	Evolution of faecal calprotectin at week 138, 190 and 242 in comparison to Baseline and Week 86	242 weeks
Change in medical therapy in longterm follow-up	Change in medical therapy for Crohn's disease prior to week 138, 190 and 242	242 weeks
a new ileocolonic resection, a balloon dilation or a strictureplasty in longterm follow-up	Need for a new ileocolonic resection, a balloon dilation or a strictureplasty at the site of the ileocolonic anastomosis prior to week 138, 190 and 242	242 weeks
Severe adverse reactions in longterm follow-up	Severe adverse reactions to biological therapy prior to week 138, 190 and 242	242 weeks
Serious adverse events in longterm follow-up	Serious adverse events prior to week 138, 190 and 242	242 weeks
Suspected unexpected serious adverse reactions in longterm follow-up	Suspected unexpected serious adverse reactions prior to week 138, 190 and 242	242 weeks

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Marc Ferrante, Professor, IG/MAAG-DARM-LEVER, UZ Leuven, campus Gasthuisberg, Herestraat 49 3000 Leuven

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2022
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2030

Study Registration Dates

• First Submitted: November 8, 2021
• First Submitted That Met QC Criteria: December 7, 2021
• First Posted (Actual): December 27, 2021

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: biological therapy; ileocolonoscopy; ileocolonic resection; ileocolonic anastomosis
• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Crohn Disease; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Complex Mixtures; Adalimumab; Infliximab; Ustekinumab; risankizumab; vedolizumab; Biological Products
• Other Study ID Numbers: s62015

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