The Ideal Management of Crohn's Disease: Top Down Versus Step Up Strategies. A Prospective Controlled Trial in the Benelux
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Enrollment
- 129
- Locations
- 1
- Primary Endpoint
- remission without corticosteroids and without surgical resection
Study Overview
Brief Summary
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.
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 Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 16 Years to 75 Years (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
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.
Intervention: infliximab+azathioprine (Drug)
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.
Intervention: methylprednisolone or budesonide (Drug)
Outcomes
Primary Outcomes
remission without corticosteroids and without surgical resection
Time Frame: month 6 and 12 after inclusion
Secondary Outcomes
- 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)