Top Down Versus Step Up Strategies in Crohn's Disease

The Ideal Management of Crohn's Disease: Top Down Versus Step Up Strategies. A Prospective Controlled Trial in the Benelux

The study prospectively compares two treatment algorithms for newly diagnosed Crohn's disease: one 'aggressive' treatment with early introduction of immunomodulators and biologicals and one 'standard treatment' with corticosteroids and only later introduction of immunosuppressives and biologicals if disease activity requires that.

Study Overview

• Status: Completed
• Conditions: Crohn's Disease
• Intervention / Treatment: Drug: infliximab+azathioprine; Drug: methylprednisolone or budesonide

Detailed Description

This two year open-label randomized trial compares the early use of combined immunosuppression to conventional management in patients with active Crohn's disease who have not previously received glucocorticoids, antimetabolites, or infliximab. Patients assigned to combined immunosuppression receive azathioprine and 3 infusions of 5 milligrams per kilogram of body weight of infliximab at weeks 0, 2, and 6. Retreatment with infliximab and, if ultimately necessary, corticosteroids are used to control disease activity. Patients assigned to conventional management receive corticosteroids followed, in sequence, by azathioprine and infliximab. The primary outcome measure is remission without corticosteroids and without bowel resection at weeks 26 and 52.

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Bonheiden, Belgium, 2820
    • Imelda GI Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age 16 - 75 years
• diagnosis of Crohn's disease within the past 4 years
• no previous treatment with corticosteroids, antimetabolites, or biologic agents.
• Active Crohn's disease, defined by a Crohn's Disease Activity Index (CDAI)20 score of greater than 200 points for a minimum of 2 weeks prior to randomization.

Exclusion Criteria:

• immediate need for surgery
• symptomatic stenosis or ileal/colonic strictures with prestenotic dilatation;
• signs, symptoms or laboratory tests indicating severe, medical disease;
• documented chronic infection
• a positive stool culture for pathogens
• a positive tuberculin test or a chest radiograph consistent with tuberculosis.
• malignancy
• allergy to murine proteins
• pregnancy
• substance abuse

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Patients received three infusions of infliximab 5 milligrams per kilogram (weeks 0, 2 and 6) in combination with azathioprine 2-2.5 milligrams per kilogram per day from day 0 onwards. If the patients responded and tolerated both drugs, azathioprine was continued for the duration of the trial. Patients who were intolerant to azathioprine received methotrexate at an initial dose of 25 milligrams administered subcutaneously each week for 12 weeks with dose reduction to 15 milligrams per week thereafter. Following initial therapy, patients who developed worsening symptoms were retreated with additional infusions of infliximab. If symptoms persisted methylprednisolone was initiated and azathioprine or methotrexate was continued.	Drug: infliximab+azathioprine; infliximab 5 mg/kg at week 0,2 and 6 + azathioprine 2-2.5 mg/kg; Other Names: remicade/imuran
Active Comparator: 2; Induction with methylprednisolone (MP) or budesonide (BUD): MP 32 mg/day for 3 weeks was followed by tapering by 4 mg per week to 0; BUD 9 mg per day for 8 weeks with tapering to 0 by 3 mg per week thereafter.Patients who worsened during the tapering had the dose increased to the initial dose and tapered again. If patients worsened, azathioprine (2-2.5 mg per day) was introduced. Patients who relapsed following withdrawal of steroids received a second course in combination with azathioprine. For patients who failed 4 weeks of steroids, MP dose was given at 64 mg/day for 2 weeks, tapered by 8 mg per week; azathioprine was added. Patients who remained symptomatic despite 16 weeks of azathioprine received infliximab (5 mg/kg IV at weeks 0, 2 and 6). Patients who relapsed despite methotrexate or those intolerant to both azathioprine and methotrexate also received infliximab, without antimetabolite therapy. Infliximab was repeated upon relapse of symptoms in these patients.	Drug: methylprednisolone or budesonide; methylprednisolone 32 mg followed by taper or budesonide 9 mg/day followed by taper; Other Names: Medrol, entocort, budenofalk

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
remission without corticosteroids and without surgical resection	month 6 and 12 after inclusion

Secondary Outcome Measures

Outcome Measure	Time Frame
the time to relapse after successful induction therapy	within 24 months
the proportion of patients receiving infliximab, methylprednisolone and antimetabolites	within 24 months
the median serum C-reactive protein concentration	24 months
the proportion of patients experiencing adverse events	24 months
the mean endoscopic severity scores and the proportion of patients without ulcers	after 24 months

Collaborators and Investigators

• Sponsor: Belgian Inflammatory Bowel Disease Research and Development (BIRD) VZW
• Collaborators: Schering-Plough; Centocor BV
• Investigators: Principal Investigator: Geert R DHaens, MD, PhD, Belgian Inflammatory Bowel Disease Research and Development (BIRD) VZW

Publications and helpful links

General Publications

• D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, De Vos M, van Deventer S, Stitt L, Donner A, Vermeire S, Van De Mierop FJ, Coche JR, van der Woude J, Ochsenkuhn T, van Bodegraven AA, Van Hootegem PP, Lambrecht GL, Mana F, Rutgeerts P, Feagan BG, Hommes D; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet. 2008 Feb 23;371(9613):660-667. doi: 10.1016/S0140-6736(08)60304-9.

Study record dates

Study Major Dates

• Study Start: May 1, 2001
• Study Completion (Actual): January 1, 2004

Study Registration Dates

• First Submitted: November 6, 2007
• First Submitted That Met QC Criteria: November 6, 2007
• First Posted (Estimate): November 7, 2007

Study Record Updates

• Last Update Posted (Estimate): November 7, 2007
• Last Update Submitted That Met QC Criteria: November 6, 2007
• Last Verified: November 1, 2007

More Information

Terms related to this study

• Keywords: Crohn's disease; biologicals; immunomodulators
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Methylprednisolone; Budesonide; Infliximab; Azathioprine
• Other Study ID Numbers: P01872