The Ideal Management of Crohn’s Disease: Top Down Versus Step Up Strategies. A Prospective Controlled Trial in the Benelux.|
|- candidate number||1593|
|- NTR Number||NTR379|
|- Date ISRCTN created||19-dec-2005|
|- date ISRCTN requested||28-okt-2005|
|- Date Registered NTR||12-sep-2005|
|- Secondary IDs||N/A |
|- Public Title||The Ideal Management of Crohn’s Disease: Top Down Versus Step Up Strategies. A Prospective Controlled Trial in the Benelux.|
|- Scientific Title||The Ideal Management of Crohn’s Disease: Top Down Versus Step Up Strategies. A Prospective Controlled Trial in the Benelux.|
|- hypothesis||Newly diagnosed Crohn's disease patients will benifit more from a 'top-down' approach where they receive the most potent therapy available, than from the current 'step-up' strategy where they start with the least potent treatment and build up to the most potent therapy if necessary.|
|- Healt Condition(s) or Problem(s) studied||Crohn's disease|
|- Inclusion criteria||1. Men and women age 16 -75;|
2. New diagnosis of Crohn’s disease, endoscopically and histologically OR
radiologically (in the case of small bowel disease) proven;
- diagnosis of Crohn’s disease in the previous 4 years but NEVER treated with corticosteroids/budesonide or immunomodulators (azathioprine/6-mercaptopurine / methotrexate / cyclosporine / FK 506 / Mycophenolate Mofetil) or biologics (Remicade or any other investigational drugs);
3. CDAI > 200 for more than four weeks (to exclude self-limited problems) in new patients or > 200 for more than two weeks for patients with known CD;
4. Symptoms do NOT improve with 5-ASA therapy in appropriate doses (Pentasa 4 grams per day for 6 weeks) or are considered too serious to be treated with 5-ASA alone. Antibiotics can be given at the discretion of the investigator;
5. Willing to sign the informed consent form;
6. Ability to comply with study visits and other protocol requirements;
7. Women of childbearing potential must be willing to use adequate birth control measures in the 6 month period following each infliximab infusion. If pregnant, they will be excluded from further Infliximab infusions.
|- Exclusion criteria||1. Need for surgery at diagnosis or in the immediate future: complications such as abdominal abscess or stricture with obstruction;
2. Current signs or symptoms of severe, uncontrolled or progressive renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic or cerebral disease;
3. Serious infections such as viral hepatitis, pneumonia, pyelonephritis in the last 3 months;
4. Recent or ongoing tuberculosis (< 2 years) or treatment for tuberculosis.
- Less serious infections should be treated appropriately, after which the patient can be included upon the discretion of the investigator;
5. Use of biologics, corticosteroids or immunemodulators for other diseases;
6. Documented HIV infection;
7. Any currently known malignancy or premalignant lesion or any history of malignancy in the last 5 years;
8. Active pregnancy or immediate pregnancy wish; pregnancy should be deferred until at least 6 months after the last infliximab infusion.
-Patient on azathioprine have to continue this medication should they become pregnant during the study;
9. Allergy to murine proteins
10. Known recent substance abuse (drugs or alcohol);
11. Symptomatic stenosis or ileal/colonic strictures with prestenotic dilatation;
12. Positive stool culture for enteric pathogens.
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-mei-2001|
|- planned closingdate||1-feb-2006|
|- Target number of participants||130|
|- Interventions||Randomization strategy 1: |
TOP-DOWN Start infliximab 5 mg/kg three infusions at week 0, 2 and 6 + azathioprine 2 to 2.5 mg/kg day from day 0 onwards.
If patients improve and tolerate both drugs:
Conintue azathioprine, repeat infliximab 1 infusion 5 mg/kg if relapse.
If patients respond (decrease of CDAI >50 if CDAI 200-250 at start, or > 75 if CDAI 250-350 at start, or >100 if CDAI at start >350)but do not tolerate azathioprine, even when given as split dose, with meals or as an evening dose, or in case of pancreatitis: stop azathioprine, start MTX IM 25 mg/week for 12 weeks, then tapered to 15 mg/week IM together with folic acid 2 mg/day PO.
If symptoms flare (see section 8.1.4) in spite of MTX/azathioprine, repeat infliximab 1 infusion 5 mg/kg.
If patients do not improve on the above mentioned strategy:
Cross over to prednisone 40 mg/day or methylprednisolone 32 mg/day at least 4 weeks after the last infliximab infusion.
Continue azathioprine (or MTX)
Taper as outlined below.
Randomization strategy 2:
First line treatment:
1. Entocort CIR/Budenofalk 9 mg per day OM for ileal or ileocolonic involvement OR Medrol 32 mg/Prednisone 40 mg per day for colonic involvement alone or in case of severe EIM, poor general well-being or fever.
2. Antibiotics (Flagyl or quinolones) to be added at the discretion of the investigator.
3. Initial therapy with IV methylprednisolone for up to 14 days allowed. TPN/enteral nutrition allowed as adjunctive therapy.
If improvement: tapering following guidelines.
Second line treatment:
1. if symptoms flare (increase of CDAI >50 and CDAI > 200) during
corticosteroid tapering, go back to starting dose and try to taper again. Exclude complications such as abscesses or strictures.
2. if relapse during second attempt to taper, add azathioprine 2-2.5 mg/kg/day PO
3. if relapse within 4 months after steroid withdrawal, start steroids again, this time in combination with azathioprine.
4. if refractory to corticosteroids after 4 weeks, increase the dose to 80 mg of prednisone (64 mg methylprednisolone) and add azathioprine
Adding azathiopine: start 2 to 2.5 mg/kg/day, together full dose of corticosteroids. Try to taper the steroids again according to guidelines.
Third line treatment:
1. pts with severe adverse events on azathioprine:
Stop azathioprine, start MTX 25 mg/week. After three injections, start tapering corticosteroids again.
2. pts who cannot be withdrawn from steroids in spite of azathioprine for at least 4 months in optimal dose: Continue azathioprine, start Infliximab 5 mg/kg at weeks 0, 2 and 6 without increasing the steroids ! Continue to taper steroids after 3 infliximab infusions.
Fourth line treatment:
pts with severe relapse in spite of MTX or intolerant to azathioprine and MTX.
Start Infliximab 5 mg/kg at weeks 0, 2 and 6. One single 5 mg/kg infusion to be
repeated upon relapse of symptoms. Continue MTX if tolerated.
|- Primary outcome||Remission (CDAI < 150) at 6 months starting at randomization. The treatment phase of the study will last two years, but follow-up will be extended as long as feasible.|
|- Secondary outcome||1. Remission (CDAI < 150) at 9, 12, 15, 18, 21 and 24 months following randomization;|
2. IBDQ and EUROQoL measured every three months;
3. Number of draining fistulas at any point of evaluation;
4. Serious adverse events caused by medication with causality assessment
5. Prednisone/Budesonide/Prednisolone free days;
6. Number of days absent from work, school or normal daily activities due to disease related problems (should also be assessed for the month prior to randomization);
7. Number and type of surgeries for Crohn’s disease or related problems;
8. Number of days in the hospital for Crohn’s related problems and for any other problems;
9. Total cost of medication, surgeries and hospitalisation during the 2 year period and possibly beyond (pharmaco-economic evaluation) + visits to specialist/general practitioner.
|- Trial web site||N/A|
|- status||inclusion stopped: follow-up|
|- CONTACT FOR PUBLIC QUERIES|| M.J. Spek, van der|
|- CONTACT for SCIENTIFIC QUERIES||MD. PhD. Daan W. Hommes|
|- Sponsor/Initiator ||Academic Medical Center (AMC), Department of Gastroenterology|
(Source(s) of Monetary or Material Support)
|- Brief summary||N/A|
|- Main changes (audit trail)|
|- RECORD||12-sep-2005 - 6-nov-2008|
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