Clinical trial NCT05169593: Prevention of Postoperative Endoscopic Recurrence with Endoscopy-driven Versus Systematic Biological Therapy
Official title: Prevention of Postoperative Endoscopic Recurrence with Endoscopy-driven Versus Systematic Biological Therapy: a Randomized, Multicentre, Parallel Group Pragmatic Non-inferiority Trial in Crohn Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Crohn Disease
Keywords: biological therapy
ileocolonoscopy
ileocolonic resection
ileocolonic anastomosis
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2021-12-27
Enrollment: 292
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, multicentre, parallel group pragmatic non-inferiority trial
Primary purpose: PREVENTION

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)

Eligibility criteria: 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.

Primary outcomes:
measure: postoperative endoscopic recurrence (Rutgeerts score ≥i2b)
timeFrame: 86 weeks
measure: need for unscheduled treatment adaptation prior to week 86
timeFrame: 86 weeks
Secondary outcomes:
measure: Harvey Bradshaw Index (HBI) based clinical recurrence
timeFrame: 86 weeks
measure: Direct costs
timeFrame: 86 weeks
measure: new ileocolonic resection
timeFrame: 86 weeks
measure: Severe adverse reactions
timeFrame: 86 weeks
measure: Serious adverse events
timeFrame: 86 weeks
measure: European Quality of Live Five Dimension Five Level Scale
timeFrame: 86 weeks
Other outcomes:
measure: Crohn's disease activity index (CDAI) based clinical recurrence
timeFrame: 86 weeks
measure: Harvey Bradshaw Index (HBI score higher than 4) based clinical recurrence
timeFrame: 86 weeks
measure: Two-component Patient Reported Outcome (PRO-2) based clinical recurrence
timeFrame: 86 weeks
measure: Endoscopic disease activity
timeFrame: 86 weeks
measure: Endoscopic recurrence
timeFrame: 30 weeks
measure: Endoscopic disease activity
timeFrame: 30 weeks
measure: Persistent endoscopic recurrence
timeFrame: 86 weeks
measure: a new ileocolonic resection, a balloon dilation or a strictureplasty
timeFrame: 86 weeks
measure: Work Productivity and Activity Impairment in Crohn's Disease questionnaire
timeFrame: 86 weeks
measure: Change in medical therapy
timeFrame: 86 weeks
measure: Change in C-reactive protein
timeFrame: 86 weeks
measure: Change in faecal calprotectin
timeFrame: 86 weeks
measure: unscheduled visits
timeFrame: 86 weeks
measure: Suspected unexpected serious adverse reactions
timeFrame: 86 weeks
measure: Two-component Patient Reported Outcome (PRO-2) based clinical recurrence in longterm follow-up
timeFrame: 242 weeks
measure: European Quality of Live Five Dimension Five Level Scale in longterm follow-up
timeFrame: 242 weeks
measure: Work Productivity and Activity Impairment in Crohn's Disease questionnaire in longterm follow-up
timeFrame: 242 weeks
measure: Change in C-reactive protein in longterm follow-up
timeFrame: 242 weeks
measure: Change in faecal calprotectin in longterm follow-up
timeFrame: 242 weeks
measure: Change in medical therapy in longterm follow-up
timeFrame: 242 weeks
measure: a new ileocolonic resection, a balloon dilation or a strictureplasty in longterm follow-up
timeFrame: 242 weeks
measure: Severe adverse reactions in longterm follow-up
timeFrame: 242 weeks
measure: Serious adverse events in longterm follow-up
timeFrame: 242 weeks
measure: Suspected unexpected serious adverse reactions in longterm follow-up
timeFrame: 242 weeks
Locations:
city: Edegem
country: Belgium
facility: UZA
state: Antwerpen
city: Jette
country: Belgium
facility: UZ Brussel
state: Brussel
city: Tournai
country: Belgium
facility: CHwapi
state: Henegouwen
city: Genk
country: Belgium
facility: ZOL Genk
state: Limburg
city: Yvoir
country: Belgium
facility: CHU UCL Namur site Godinne
state: Namur
city: Gent
country: Belgium
facility: AZ Maria Middelares
state: Oost-Vlaanderen
city: Gent
country: Belgium
facility: UZ Gent
state: Oost-Vlaanderen
city: Leuven
country: Belgium
facility: UZ Leuven
state: Vlaams-Brabant
city: Brugge
country: Belgium
facility: Sint lucas Brugge
state: West-Vlaanderen
city: Oostende
country: Belgium
facility: AZ Damiaan
state: West-Vlaanderen
city: Aalst
country: Belgium
facility: OLV Aalst
city: Antwerpen
country: Belgium
facility: GZA
city: Bonheiden
country: Belgium
facility: Imeldaziekenhuis
city: Brasschaat
country: Belgium
facility: AZ Klina
city: Brugge
country: Belgium
facility: AZ Sint-Jan
city: Brussel
country: Belgium
facility: Erasmus ziekenhuis
city: Brussel
country: Belgium
facility: Cliniques Universitaires Saint Luc
city: Gent
country: Belgium
facility: AZ Sint Lucas
city: Hasselt
country: Belgium
facility: Jessa ziekenhuis
city: Liège
country: Belgium
facility: CHC Montlégia
city: Liège
country: Belgium
facility: CHU de Liège
city: Mechelen
country: Belgium
facility: AZ Sint Maarten
city: Roeselare
country: Belgium
facility: AZ Delta
city: Sint-Niklaas
country: Belgium
facility: Vitaz
city: Milano
country: Italy
facility: Humanitas research hospital
state: Rozzano Mi
city: Castellana Grotte
country: Italy
facility: IRCCS De Bellis Castellana Grotte
city: Firenze
country: Italy
facility: Careggi University Hospital
city: Milano
country: Italy
facility: IRCCS San Raffael Hospital
Study officials:
affiliation: IG/MAAG-DARM-LEVER, UZ Leuven, campus Gasthuisberg, Herestraat 49 3000 Leuven
name: Marc Ferrante, Professor
role: PRINCIPAL_INVESTIGATOR
References: