Control Crohn Safe Trial (CoCroS)

Control Crohn Safe With Episodic Adalimumab Monotherapy as First Line Treatment Study.

Crohn's disease (CD) is a chronic disease with a heterogeneous clinical presentation, relapse rate and treatment response. Insufficient control of mucosal inflammation results in irreversible bowel damage and complications and at present no markers are available to predict such a complicated disease course at diagnosis. Therefore, to prevent overtreatment of low risk patients, step-up treatment with subsequent introduction of corticosteroids, thiopurines maintenance and TNF-blockers if a previous category fails is standard care. Combination treatment with thiopurines and a TNF-blocker is more effective than monotherapy but associated with a higher risk for infectious complications. Landmark studies convincingly showed an improved long-term outcome if the TNF-blocker infliximab is introduced early after diagnosis. The standard step-care approach thus prolongs steroid exposure and delays start of disease modifying biologicals in high risks patients. Given the higher efficacy of combination therapy with a thiopurine of infliximab and potential allergic reactions and lower response rates after re-initiation of this chimeric biological, temporary monotherapy with this TNF-blocker has not been studied as first line treatment before. Adalimumab is a humanised monoclonal antibody and subsequently, combination therapy of adalimumab + thiopurines has only a marginal effect on anti-drug anti-body formation. Furthermore, combination therapy with adalimumab does not enhance the clinical response. Therefore, periodic treatment with adalimumab in combination with close monitoring after drug-discontinuation, in newly diagnosed CD might improve outcome, reduce drug-related side effects while still preventing overtreatment.

The aim of this study is to compare the long-term efficacy and safety of periodic adalimumab as initial treatment in newly diagnosed CD patients compared to standard step-care with corticosteroid/budesonide as the initial treatment

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Diseases; Crohn Disease
• Intervention / Treatment: Drug: Adalimumab; Drug: standard step-up care

• Study Type: Interventional
• Enrollment (Anticipated): 158
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: M J Pierik, MD, PhD; Phone Number: +31 43 387 4362; Email: m.pierik@mumc.nl
• Study Contact Backup: Name: L M Janssen, MD; Email: laura.janssen@maastrichtuniversity.nl

Study Locations

• Netherlands
  • Maastricht, Netherlands
    • Recruiting
    • Maastricht University Medical Centre+
    • Contact: L Janssen; Phone Number: +31433884190; Email: laura.janssen@maastrichtuniversity.nl
    • Contact: M Pierik; Phone Number: +31433875021; Email: m.pierik@mumc.nl
    • Principal Investigator: M. Pierik
    • Sub-Investigator: L. Janssen
    • Sub-Investigator: J. Haans
  • Nieuwegein, Netherlands
    • Recruiting
    • St. Antonius Ziekenhuis
    • Contact: P van Boeckel
    • Principal Investigator: P van Boeckel
  • Roermond, Netherlands
    • Recruiting
    • Laurentius Ziekenhuis
    • Contact: THC Munnecom
    • Principal Investigator: THC Munnecom
  • Sittard, Netherlands
    • Recruiting
    • Zuyderland Medical Center
    • Contact: AA van Bodegraven
    • Principal Investigator: AA van Bodegraven
    • Sub-Investigator: M Romberg-Camps
  • Veldhoven, Netherlands
    • Recruiting
    • Máxima Medisch Centrum
    • Contact: P Boekema
    • Principal Investigator: P Boekema
  • Venlo, Netherlands
    • Recruiting
    • VieCuri
    • Contact: M Aquarius
    • Principal Investigator: M Aquarius

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Newly diagnosed CD patients or CD patients with a flare, visiting the outpatient clinic or endoscopy ward of the participating centres
• CD diagnosis according to ECCO-guidelines + complete ileo-colonoscopy + complete small bowel imaging at diagnosis (MRI or CT-enterography )
• Naïve to biologicals
• Sufficient knowledge of Dutch language
• 18 years old ≤ 70 years old
• Smartphone with internet access
• Use of myIBDcoach or willingness to start using myIBDcoach

Exclusion Criteria:

• Use of prednisone for longer than 4 weeks in the year before screening
• Use of budesonide (≥6 mg daily) for a duration longer than 3 months in the year before screening
• Use of thiopurines in the 3 years before screening
• Indication for primary treatment with biologicals or surgery
• Malignancy in 5 years before treatment. Exception is adequately treated non-melanoma skin cancer
• Contra-indication for TNF-blockers or immunosuppressive agents
• Contra-indication for MRI- and CT-enterography
• Patients with short bowel syndrome or an ostomy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Adalimumab; Episodic adalimumab monotherapy as first line treatment for 6 months	Drug: Adalimumab; episodic treatment with subcutaneous adalimumab for 6 months; Other Names: Humira
ACTIVE_COMPARATOR: Standard step-up care; Step-up care as first line treatment, starting with corticosteroids.	Drug: standard step-up care; conventional step-up care starting with corticosteroids

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of yearly-quarters of corticosteroid free remission as a measure of treatment efficacy	Remission is defined as combined clinical (MIAH scores (≤3)) and biochemical (C-reactive protein ≤5 mg/L (i.e. within normal range) and fecal calprotectin ≤ 200 μg/g) remission.	at week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative structural bowel damage as a measure of disease progression	Disease progression on MRI-enterography based on the Lémann score (Crohn's Disease Digestive Damage Score); the Lémann score is an instrument to measure cumulative structural bowel damage in Crohn's disease. The score takes into account the damage location (upper digestive tract, small bowel, colon/rectum and anal/perianal), extent and severity. Grades 0 (normal) to 3 (maximal) are given to each segment of the digestive tract, with grade 3 representing the most damage, or resection/bypass.	at week 96
Incidence of drug related serious adverse events	Drug related serious adverse events	at week 24, 48 and 96
Incidence of serious disease related adverse events	Crohn disease related hospitalisation and surgery	at week 24, 48 and 96
Integer amount of direct health care costs (in €)	Direct costs include expenses for medication, diagnostic procedures, number of outpatient clinic visits, hospitalisations and surgeries. Direct costs will be combined with indirect costs to report total health care costs.	at week 96
Integer amount of indirect health care costs (in €)	Indirect costs consist of costs due to presenteeism and absenteeism and are assessed by questionnaires in the telemedicine tool myIBDcoach used for monitoring of IBD patients. Indirect costs will be combined with direct costs to report total health care costs.	at week 96
Corticosteroid use	Cumulative corticosteroid dose	at week 24, 48 and 96
Endoscopic remission as assessed by SES-CD	Proportion of endoscopic remission based on SES-CD (simple endoscopic score for CD). Endoscopic remission is defined as a score below 3 and the absence of ulcers.	at week 24
Time to remission	Time to remission	at week 96
Quality of life as assessed by QoL EQ-5D-5L questionnaire	Quality of life as assessed by the QoL EQ-5D-5L questionnaire in which the level of severity is chosen for five domains (mobility, self-care, usual activities, pain, anxiety/depression). A higher level (maximal 5) indicates more severe problems in that particular domain.	at week 24, 48 and 96

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Maastricht University; ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: M J Pierik, MD, PhD, Maastricht University Medical Centre

Publications and helpful links

General Publications

• Janssen L, Romberg-Camps M, van Bodegraven A, Haans J, Aquarius M, Boekema P, Munnecom T, Brandts L, Joore M, Masclee A, Jonkers D, Pierik M. Control Crohn Safe with episodic adalimumab monotherapy as first-line treatment study (CoCroS): study protocol for a randomised controlled trial. BMJ Open. 2021 May 4;11(5):e042885. doi: 10.1136/bmjopen-2020-042885.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 23, 2019
• Primary Completion (ANTICIPATED): May 1, 2024
• Study Completion (ANTICIPATED): September 1, 2026

Study Registration Dates

• First Submitted: April 5, 2019
• First Submitted That Met QC Criteria: April 12, 2019
• First Posted (ACTUAL): April 17, 2019

Study Record Updates

• Last Update Posted (ACTUAL): September 7, 2022
• Last Update Submitted That Met QC Criteria: September 6, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Anti-Inflammatory Agents; Antirheumatic Agents; Adalimumab
• Other Study ID Numbers: NL64005.068.18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available to other researchers on demand. Patients will be asked to give informed consent to share the collected data with third parties for future research.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No