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

Crohn Disease Clinical Trial

— SOPRANO-CD  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05169593
• Other study ID #: s62015
• Status: Recruiting
• Phase: Phase 4
• Start date: September 8, 2022
• Est. completion date: October 2030

Study information

• Verified date: May 2024
• Source: Universitaire Ziekenhuizen KU Leuven
• Contact: Marc Ferrante, Professor
• Phone: 016 342845
• Email: marc.ferrante[@]uzleuven.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 292
• Est. completion date: October 2030
• Est. primary completion date: October 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Crohn Disease
• Recurrence

Intervention

Drug:
• Biological Drug
Biological therapy used in daily clinical practice in patients with Crohn's disease to prevent disease recurrence

Locations

Country	Name	City	State
Belgium	OLV Aalst	Aalst
Belgium	GZA	Antwerpen
Belgium	Imeldaziekenhuis	Bonheiden
Belgium	AZ Klina	Brasschaat
Belgium	AZ Sint-Jan	Brugge
Belgium	Sint lucas Brugge	Brugge	West-Vlaanderen
Belgium	Cliniques Universitaires Saint Luc	Brussel
Belgium	Erasmus ziekenhuis	Brussel
Belgium	UZA	Edegem	Antwerpen
Belgium	ZOL Genk	Genk	Limburg
Belgium	AZ Maria Middelares	Gent	Oost-Vlaanderen
Belgium	AZ Sint Lucas	Gent
Belgium	UZ Gent	Gent	Oost-Vlaanderen
Belgium	Jessa ziekenhuis	Hasselt
Belgium	UZ Brussel	Jette	Brussel
Belgium	UZ Leuven	Leuven	Vlaams-Brabant
Belgium	CHC Montlégia	Liège
Belgium	CHU de Liège	Liège
Belgium	AZ Sint Maarten	Mechelen
Belgium	AZ Damiaan	Oostende	West-Vlaanderen
Belgium	AZ Delta	Roeselare
Belgium	Vitaz	Sint-Niklaas
Belgium	CHwapi	Tournai	Henegouwen
Belgium	CHU UCL Namur site Godinne	Yvoir	Namur
Italy	IRCCS De Bellis Castellana Grotte	Castellana Grotte
Italy	Careggi University Hospital	Firenze
Italy	Humanitas research hospital	Milano	Rozzano MI
Italy	IRCCS San Raffael Hospital	Milano

Sponsors (1)

Lead Sponsor	Collaborator
Universitaire Ziekenhuizen KU Leuven

Countries where clinical trial is conducted

Belgium,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	Endoscopic disease activity	Endoscopic disease activity (Rutgeerts score =i3, =i2a, or =i1) at week 86	86 weeks
Other	Endoscopic recurrence	Endoscopic recurrence (Rutgeerts score =i2b) at week 30	30 weeks
Other	Endoscopic disease activity	Endoscopic disease activity (Rutgeerts score =i3, =i2a, or =i1) at week 30	30 weeks
Other	Persistent endoscopic recurrence	Persistent endoscopic recurrence at week 86 after development of endoscopic recurrence at week 30	86 weeks
Other	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
Other	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
Other	Change in medical therapy	Change in medical therapy for Crohn's disease prior to week 86	86 weeks
Other	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
Other	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
Other	unscheduled visits	Number of unscheduled visits related to CD (clinical visit, endoscopic or radiological evaluation)	86 weeks
Other	Suspected unexpected serious adverse reactions	Suspected unexpected serious adverse reactions prior to week 86	86 weeks
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	Severe adverse reactions in longterm follow-up	Severe adverse reactions to biological therapy prior to week 138, 190 and 242	242 weeks
Other	Serious adverse events in longterm follow-up	Serious adverse events prior to week 138, 190 and 242	242 weeks
Other	Suspected unexpected serious adverse reactions in longterm follow-up	Suspected unexpected serious adverse reactions prior to week 138, 190 and 242	242 weeks
Primary	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
Primary	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	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
Secondary	Direct costs	Direct costs from Baseline to week 86	86 weeks
Secondary	new ileocolonic resection	Need for a new ileocolonic resection prior to week 86	86 weeks
Secondary	Severe adverse reactions	Severe adverse reactions to biological therapy prior to week 86	86 weeks
Secondary	Serious adverse events	Serious adverse events prior to week 86	86 weeks
Secondary	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