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Top Down Versus Step Up Strategies in Crohn's Disease

Primary Purpose

Crohn's Disease

Status
Completed
Phase
Phase 4
Locations
Belgium
Study Type
Interventional
Intervention
infliximab+azathioprine
methylprednisolone or budesonide
Sponsored by
Belgian Inflammatory Bowel Disease Research and Development (BIRD) VZW
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Crohn's Disease focused on measuring Crohn's disease, immunomodulators, biologicals

Eligibility Criteria

16 Years - 75 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Imelda GI Clinical Research Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

1

2

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

remission without corticosteroids and without surgical resection

Secondary Outcome Measures

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

Full Information

First Posted
November 6, 2007
Last Updated
November 6, 2007
Sponsor
Belgian Inflammatory Bowel Disease Research and Development (BIRD) VZW
Collaborators
Centocor BV, Schering-Plough
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1. Study Identification

Unique Protocol Identification Number
NCT00554710
Brief Title
Top Down Versus Step Up Strategies in Crohn's Disease
Official Title
The Ideal Management of Crohn's Disease: Top Down Versus Step Up Strategies. A Prospective Controlled Trial in the Benelux
Study Type
Interventional

2. Study Status

Record Verification Date
November 2007
Overall Recruitment Status
Completed
Study Start Date
May 2001 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
January 2004 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Belgian Inflammatory Bowel Disease Research and Development (BIRD) VZW
Collaborators
Centocor BV, Schering-Plough

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Crohn's Disease
Keywords
Crohn's disease, immunomodulators, biologicals

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
129 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
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.
Arm Title
2
Arm Type
Active Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
infliximab+azathioprine
Other Intervention Name(s)
remicade/imuran
Intervention Description
infliximab 5 mg/kg at week 0,2 and 6 + azathioprine 2-2.5 mg/kg
Intervention Type
Drug
Intervention Name(s)
methylprednisolone or budesonide
Other Intervention Name(s)
Medrol, entocort, budenofalk
Intervention Description
methylprednisolone 32 mg followed by taper or budesonide 9 mg/day followed by taper
Primary Outcome Measure Information:
Title
remission without corticosteroids and without surgical resection
Time Frame
month 6 and 12 after inclusion
Secondary Outcome Measure Information:
Title
the time to relapse after successful induction therapy
Time Frame
within 24 months
Title
the proportion of patients receiving infliximab, methylprednisolone and antimetabolites
Time Frame
within 24 months
Title
the median serum C-reactive protein concentration
Time Frame
24 months
Title
the proportion of patients experiencing adverse events
Time Frame
24 months
Title
the mean endoscopic severity scores and the proportion of patients without ulcers
Time Frame
after 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Geert R DHaens, MD, PhD
Organizational Affiliation
Belgian Inflammatory Bowel Disease Research and Development (BIRD) VZW
Official's Role
Principal Investigator
Facility Information:
Facility Name
Imelda GI Clinical Research Center
City
Bonheiden
ZIP/Postal Code
2820
Country
Belgium

12. IPD Sharing Statement

Citations:
PubMed Identifier
18295023
Citation
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.
Results Reference
derived

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Top Down Versus Step Up Strategies in Crohn's Disease

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