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A randomised trial of 6 months versus 12 months withdrawal of methotrexate in patients with Juvenile Idiopathic Arthritis (JIA)
in clinical remission
ISRCTN ISRCTN18186313
DOI 10.1186/ISRCTN18186313
ClinicalTrials.gov identifier
EudraCT number
Public title A randomised trial of 6 months versus 12 months withdrawal of methotrexate in patients with Juvenile Idiopathic Arthritis (JIA)
in clinical remission
Scientific title
Acronym MTX-withdrawal-study
Serial number at source 2005-001086-34
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.
Lay summary
Ethics approval Ethics Committee at the University of Muenster, reference number 0VIIIRot
Study design Prospective, randomised, clinical multi-centre study
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
Disease/condition/study domain Juvenila Idiopathic Arthritis (JIA)
Participants - 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, physician’s 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 physician’s 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.
Participants - exclusion criteria Patients should not have received intra-articular corticosteroids up to three months prior to inclusion
Anticipated start date 01/01/2005
Anticipated end date 31/12/2008
Status of trial Completed
Patient information material
Target number of participants 300
Interventions 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; physician’s 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, physician’s 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.
Primary outcome measure(s) Number of relapses
Secondary outcome measure(s) 1. Time to relapse
2. Prediction of relapse by MRP8 or MRP14 serum concentrations
Sources of funding 1. Pediatric Rheumatology International Trials Organisation (PRINTO) (EU grant number 2001CVG4-808)
2. Wyeth Pharma provided funding for patient insurance
Trial website http://www.printo.it
Publications 2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20371785
Contact name Dr  Dirk  Foell
  Address University Hospital Muenster
Department of Pediatrics
Albert-Schweitzer-Str. 33
  City/town Muenster
  Zip/Postcode 48149
  Country Germany
  Tel +49 (0)251 8356584
  Fax +49 (0)251 8356549
  Email dfoell@uni-muenster.de
Sponsor Pediatric Rheumatology International Trials Organisation (PRINTO) (Italy) and Wyeth Pharma
  Address IRCCS G. Gaslini
Pediatria II Largo Gaslini, 5
  City/town Genova
  Zip/Postcode 16147
  Country Italy
  Sponsor website: http://www.printo.it
Date applied 26/11/2005
Last edited 08/04/2010
Date ISRCTN assigned 16/02/2006
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