Prevention of Postoperative Endoscopic Recurrence with Endoscopy-driven Versus Systematic Biological Therapy

Phase 4

Recruiting

• Conditions: Crohn Disease
• Interventions: Drug: Biological Drug

• Registration Number: NCT05169593
• Lead Sponsor: Universitaire Ziekenhuizen KU Leuven

Brief Summary

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.

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 Timeline

• Study First Submitted: 2021-11-08
• Study First Submitted QC: 2021-12-07
• Study First Posted: 2021-12-27
• Study Start: 2022-09-08
• Status Verified: 2024-05
• Last Update Submitted: 2024-12-05
• Last Update Posted: 2024-12-11
• Primary Completion: 2027-10
• Study Completion: 2030-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 292

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Systematic postoperative prophylaxis with a biological	Biological Drug	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.
Endoscopy-driven postoperative biological therapy	Biological Drug	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.

Primary Outcome Measures

Name	Time	Method
need for unscheduled treatment adaptation prior to week 86	86 weeks	When, due to clinical symptoms, therapy needs to be started or switched prior to week 86
postoperative endoscopic recurrence (Rutgeerts score ≥i2b)	86 weeks	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

Secondary Outcome Measures

Name	Time	Method
Severe adverse reactions	86 weeks	Severe adverse reactions to biological therapy prior to week 86
Direct costs	86 weeks	Direct costs from Baseline to week 86
new ileocolonic resection	86 weeks	Need for a new ileocolonic resection prior to week 86
Serious adverse events	86 weeks	Serious adverse events prior to week 86
European Quality of Live Five Dimension Five Level Scale	86 weeks	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)
Harvey Bradshaw Index (HBI) based clinical recurrence	86 weeks	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.

Trial Locations

Locations (28)

ZOL Genk; 🇧🇪 Genk, Limburg, Belgium

CHU UCL Namur site Godinne; 🇧🇪 Yvoir, Namur, Belgium

AZ Maria Middelares; 🇧🇪 Gent, Oost-Vlaanderen, Belgium

UZA; 🇧🇪 Edegem, Antwerpen, Belgium

UZ Brussel; 🇧🇪 Jette, Brussel, Belgium

CHwapi; 🇧🇪 Tournai, Henegouwen, Belgium

UZ Gent; 🇧🇪 Gent, Oost-Vlaanderen, Belgium

UZ Leuven; 🇧🇪 Leuven, Vlaams-Brabant, Belgium

Sint lucas Brugge; 🇧🇪 Brugge, West-Vlaanderen, Belgium

OLV Aalst; 🇧🇪 Aalst, Belgium

AZ Damiaan; 🇧🇪 Oostende, West-Vlaanderen, Belgium

GZA; 🇧🇪 Antwerpen, Belgium

Imeldaziekenhuis; 🇧🇪 Bonheiden, Belgium

AZ Klina; 🇧🇪 Brasschaat, Belgium

Jessa ziekenhuis; 🇧🇪 Hasselt, Belgium

CHC Montlégia; 🇧🇪 Liège, Belgium

AZ Sint-Jan; 🇧🇪 Brugge, Belgium

Erasmus ziekenhuis; 🇧🇪 Brussel, Belgium

Cliniques Universitaires Saint Luc; 🇧🇪 Brussel, Belgium

AZ Sint Lucas; 🇧🇪 Gent, Belgium

AZ Sint Maarten; 🇧🇪 Mechelen, Belgium

CHU de Liège; 🇧🇪 Liège, Belgium

AZ Delta; 🇧🇪 Roeselare, Belgium

Vitaz; 🇧🇪 Sint-Niklaas, Belgium

Humanitas research hospital; 🇮🇹 Milano, Rozzano Mi, Italy

IRCCS De Bellis Castellana Grotte; 🇮🇹 Castellana Grotte, Italy

Careggi University Hospital; 🇮🇹 Firenze, Italy

IRCCS San Raffael Hospital; 🇮🇹 Milano, Italy