Contact information
Type
Scientific
Primary contact
Dr Dirk Foell
ORCID ID
Contact details
University Hospital Muenster
Department of Pediatrics
Albert-Schweitzer-Str. 33
Muenster
48149
Germany
+49 (0)251 8356584
dfoell@uni-muenster.de
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
2005-001086-34
Study information
Scientific title
Acronym
MTX-withdrawal-study
Study hypothesis
Treatment with the disease modifying anti-rheumatic drug (DMARD) methotrexate (MTX) in doses of 10 to 15 mg/m^2 given once weekly has been proven to be safe and effective in JIA. With this regime it is possible to attain relieve of clinical symptoms and normalisation of laboratory parameters in a number of cases. In contrast to the situation in adulthood, clinical remission on and off medication in JIA is possible. Therefore, it has been reported that discontinuation of MTX should be considered after an adequate period of remission.
About 50% of the patients experience a relapse after discontinuation of the immunosuppressive therapy. It is not yet clear if a longer duration of MTX treatment in the status of remission is able to reduce the overall risk of relapses over the course of the disease. Thus, treatment with MTX is continued for a variable time span after documentation of remission and according to the personal beliefs of the attending physicians.
Recently a definition of clinical remission for JIA has been proposed based on clinical examination and laboratory parameters. We also demonstrated that analyses of the phagocyte-specific proteins myeloid related-protein 8 (MRP 8) and MRP 14 provide excellent markers for the disease activity of JIA.
The present study was designed for the follow-up of two groups of patients with JIA, in whom remission was achieved using MTX. In group 1, treatment with MTX will be discontinued as early as six months after documentation of remission on medication. In group 2, treatment with MTX will be discontinued later than 12 months after documentation of remission on medication.
Ethics approval
Ethics Committee at the University of Muenster, reference number 0VIIIRot
Study design
Prospective, randomised, clinical multi-centre study
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
Condition
Juvenila Idiopathic Arthritis (JIA)
Intervention
The study is designed as a prospective, randomised clinical trial with follow up documentation of 2 groups of patients.
Group 1:
At three months: first confirmation of remission on medication on the basis of signs of disease activity (no joints with active arthritis, no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA, no active uveitis, no elevation in ESR and/or CRP attributable to JIA; physicians global assessment of disease activity indicates no disease activity). At this point only on a combination of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), low-dose steroids (0.2 mg/kg per day or 10 mg per day whichever is lower), and MTX (max 15 mg/m^2 per week) is allowed, all the other drugs (e.g. biologics, intra-articular joint injections) must have been withdrawn before this date according to the physician decision. During the following three months low dose steroids and NSAIDS must be withdrawn according to the attending physician decision.
Time point zero months treatment with MTX is continued with dose range of 10 to 15 mg/m^2 per week (by oral, subcutaneous, intra-muscular or intravenous admission) after this time point. One NSAID is allowed.
Time point three months documentation of the clinical course after three months in remission.
6 months later confirmation of remission, discontinuation of MTX (and NSAID if applicable).
In further follow up examinations in intervals of three months the clinical course is documented over at least one year.
Group 2:
At time three months: first confirmation of remission on medication on the basis of signs of disease activity (no joints with active arthritis, fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA, no active uveitis, no elevation in ESR and/or CRP attributable to JIA, physicians global assessment of disease activity indicates no disease activity). At this point only on a combination of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), low-dose steroids (0.2 mg/kg per day or 10 mg per day whichever is lower), and MTX (max 15 mg/m^2 per week) is allowed, all the other drugs (e.g. biologics, intra-articular joint injections) must have been withdrawn before this date according to the physician decision. During the following three months, low dose steroids and NSAIDs must be withdrawn according to the attending physician decision.
Time point zero months treatment with MTX is continued with dose range of 10-15 mg/m^2 per week (by oral, subcutaneous, intra-muscular or intravenous admission) after this time point. One NSAID is allowed.
Time point three months - documentation of the clinical course after three months in remission.
Time point six months - documentation of the clinical course after six months in remission.
Time point nine months - documentation of the clinical course after nine months in remission.
Twelve months later (time point 12) - approval of remission, discontinuation of MTX (and NSAID if applicable).
In further follow up examinations in intervals of three months, the clinical course is documented over at least one year.
Intervention type
Drug
Phase
Not Specified
Drug names
Methotrexate (MTX)
Primary outcome measure
Number of relapses
Secondary outcome measures
1. Time to relapse
2. Prediction of relapse by MRP8 or MRP14 serum concentrations
Overall trial start date
01/01/2005
Overall trial end date
31/12/2008
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Patients will be included at first confirmation of remission on medication i.e. after clinically documented inactive disease for at least three months (no joints with active arthritis, no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA, no active uveitis, no elevation in Erythrocyte Sedimentation Rate [ESR] and/or C-Reactive Protein [CRP] attributable to JIA, physicians global assessment of disease activity indicates no disease activity).
At three months, patients may be only be on a combination of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), low-dose steroids (0.2 mg/kg per day or 10 mg per day whichever is lower), and MTX (max 15 mg/m^2 per week); all the other drugs (e.g. biologics) must have been withdrawn before this date according to the physicians decision.
Before inclusion into this study (study time point 0 months), patients will be considered to be in clinically documented remission on medication. At this time point, all medications other than NSAIDs and MTX with a dose range of 10 to 15 mg/m^2 per week have to be withdrawn. After discontinuation of MTX (study time point 6 i.e. after 6 months in group 1; study time point 12 i.e. after 12 months in group 2) treatment with NSAIDs should be stopped.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
300
Participant exclusion criteria
Patients should not have received intra-articular corticosteroids up to three months prior to inclusion
Recruitment start date
01/01/2005
Recruitment end date
31/12/2008
Locations
Countries of recruitment
Argentina, Brazil, Chile, Croatia, Cuba, Czech Republic, Denmark, Finland, France, Georgia, Germany, Greece, Hungary, India, Israel, Italy, Kuwait, Latvia, Mexico, Montenegro, Netherlands, Poland, Portugal, Romania, Russian Federation, Saudi Arabia, Serbia, Slovakia, Spain, Switzerland, Turkey, United Kingdom
Trial participating centre
University Hospital Muenster
Muenster
48149
Germany
Sponsor information
Organisation
Pediatric Rheumatology International Trials Organisation (PRINTO) (Italy) and Wyeth Pharma
Sponsor details
IRCCS G. Gaslini
Pediatria II Largo Gaslini
5
Genova
16147
Italy
Sponsor type
Other
Website
Funders
Funder type
Research organisation
Funder name
Pediatric Rheumatology International Trials Organisation (PRINTO) (EU grant number 2001CVG4-808)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Wyeth Pharma provided funding for patient insurance
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20371785
Publication citations
-
Results
Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, Stanevicha V, Mihaylova D, Ferriani V, Tsakalidou FK, Foeldvari I, Cuttica R, Gonzalez B, Ravelli A, Khubchandani R, Oliveira S, Armbrust W, Garay S, Vojinovic J, Norambuena X, Gamir ML, García-Consuegra J, Lepore L, Susic G, Corona F, Dolezalova P, Pistorio A, Martini A, Ruperto N, Roth J, , Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial., JAMA, 2010, 303, 13, 1266-1273, doi: 10.1001/jama.2010.375.