This multicenter, prospective, controlled, randomized, double-blind study aims at provingthat the success level measured by steroid-free remission in patients with steroiddependentulcerative colitis (UC) is higher with methotrexate than with placebo…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Success at the 16th and the 24th week of treatment is the main criteria.
The success is measured by:
- Remission according to a Mayo Disease Activity Index <= 2 with no items >1,
and
- complete stop of prednisone or prednisolone for 7 days or more.
and
- no other immunosuppressive or colectomy between inclusion and the 24th week
Secondary outcome
- Success on the 16th week measured according to 6.1
- Success on the 24th week measured according to 6.1
- Clinical remission on each visit
- Steroid cumulative dose in both groups at 16th and 24th weeks.
- CRP measurements on each visit
- Side effects in both groups
Background summary
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that slightly
reduces life
expectancy, strongly reduces its quality and can lead to serious complications
such as acute
colitis, dysplasia and colon cancer. About 40'000 patients are affected in
France Among
them, 15% suffer from a chronic active form that often leads to an extended
steroid
therapy, and its known side effects. Azathioprine has already proven its
efficacy in this
indication but brings a lasting remission without steroid in only 41% of the
patients (1-4).
What are the medications available for the patients who failed in maintaining a
remission
with azathioprine ? Cyclosporin is designed for severe or steroid-resistant
forms. (5). The
results of two recent studies have showed that infliximab is more efficacious
than placebo in
active UC (6, 7). Infliximab is expensive, its efficacy in steroid-dependent UC
has not been
specifically tested yet, and its tolerance on the long term remains uncertain.
Methotrexate
proved its efficacy in Crohn's disease with an intramuscular dose of 25mg/week
(8). In UC a
controlled trial has been negative with an oral dose of 12.5mg/week (9).
Another study
compared mercaptopurine, methotrexate (15mg/week) and 5-aminosalicylate in 72
steroiddependent
patients with CD or UC (10). The remission rates obtained were 58% after 30
weeks with methotrexate (not significantly different from 5-ASA) and 14% after
106 weeks
(not significantly different from 5-ASA). Few data are available on the
efficacy of
methotrexate in UC, at a dose which is active in Crohn's disease (25mg
intramuscular/week). Several uncontrolled series have been published, including
91 patients
whose remission failed under azathioprine.
The results from these studies suggest that methotrexate is active with a 20 to
25 mg intramuscular dose
per week. Methotrexate is largely used, outside from the field of oncology,
with more than
20 years experience in inflammatory diseases (rheumatoid polyarthritis,
psoriasis).
Methotrexate is cheap and its patent has fallen in the public domain. Only
institutional
research will be able to finance a study in this new indication.
This is a prospective, controlled, randomized, double-blind study of
methotrexate with an
intramuscular dose of 25mg/week vs placebo in patients with steroid-dependent
UC.
Study objective
This multicenter, prospective, controlled, randomized, double-blind study aims
at proving
that the success level measured by steroid-free remission in patients with
steroiddependent
ulcerative colitis (UC) is higher with methotrexate than with placebo.
Study design
A CONTROLLED, RANDOMIZED, DOUBLE-BLIND, MULTICENTER STUDY.
Intervention
Methotrexate and placebo. Regimen will be 1 intramuscular injection
every week, always on the same weekday.
A 5mg tablet of folic acid (will be prescribed every week, 24 hours to 48 hours
after the
methotrexate (or the placebo) injection in order to reduce the side effects
Study burden and risks
The side effects of methotrexate are well known. \Some patients do not tolerate
this drug because of digestive problems (nausea, vomiting), rarely hepatitis or
pneumonia, mouth ulcers, stomatitis. A decrease of white cell number can be
observed therefore a monitoring by blood draws is necessary (every 2 weeks for
the first month, then
every month during the rest of the study). The methotrexate can cause foetus
malformations if the father or the mother is under such treatment. Consequently
it is mandatory to avoid pregnancy during the methotrexate treatment and during
3 months after its termination.
2 Place saint Jacques
25030 Besancon
Frankrijk
2 Place saint Jacques
25030 Besancon
Frankrijk
Listed location countries
Age
Inclusion criteria
INCLUSION CRITERIA
Patients, male or female, will be eligible if they meet the following criteria:
* Between 18 and 75 years of age.
* UC diagnosed according to the Lennard-Jones criteria (Appendix 1) with endoscopic
colorectal lesions, whatever their extension may be.
* A Mayo Disease Activity Index <= 4, with no item >1 for the clinical part of the score
and from 0 to 2 for the endoscopic part at the time of inclusion.
* Steroid-dependence defined by at least 1 unsuccessful attempt to stop systemic
steroid therapy during the last 12 weeks. Steroid therapy might have been
completely stopped if it has been restarted within the last 30 days.
* To be receiving a treatment of prednisone at a dose between 10 and 40mg, stable
for at least 2 weeks at the time of inclusion.
* Under an adequate contraception for male or female subjects of childbearing
potential: mechanic methods of contraception (condom, female condom,
diaphragm, spermicidal gel) and oral contraception started at least 15 days before
inclusion. This contraception will be continued throughout the study duration and at
least 3 months after study termination.
Exclusion criteria
EXCLUSION CRITERIA
* Indication to a colectomy.
* Alcoholism (more than 21 glasses per week for male subjects and 14 glasses per
week for female subjects). 1 glass corresponds to 3 cl of strong alcohol, 10 cl glass
of wine or a half pint of beer.
* Pregnant or breast-feeding female subjects.
* No efficacious contraception.
* NSAIDS or cotrimoxazole intake upon inclusion, or probenecide intake within 1
month prior to inclusion.
* Anti-TNFα treatment within 2 months prior to inclusion.
* Azathioprine, mercaptopurine, cyclosporin or thalidomide within 1 month prior to
inclusion.
* Modification of mesalazine or olsalazine dosage within 1 month prior to inclusion.
* Chronic (broncho) pneumopathy.
* Renal failure (creatininaemia > upper limit of normal laboratory values limit).
* Liver disease apart from primary sclerosing cholangitis.
* Unexplained rise higher than twice the normal level for transaminases, alkaline
phosphatases and/or bilirubin.
* Folate level < normal level.
* Infection by HIV, HBV (except in case of positive antibodies anti-HBs), HCV with
serologies not older than 3 months.
* Past history of malignant condition (including leukaemia, lymphoma and
myelodysplasia) except for baso-cellular cutaneous cancers.
* Obesity (BMI>30).
* Diabetes mellitus.
* Known hypersensitivity to methotrexate.
* Non-compliant subject.
* Participation in another therapeutic study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-003607-40-NL |
| ClinicalTrials.gov | NCT00498589 |
| CCMO | NL23095.058.08 |