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	https://doi.org/10.1186/ISRCTN18186313
Secondary identifying numbers	2005-001086-34

Submission date: 26/11/2005
Registration date: 16/02/2006
Last edited: 08/04/2010

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Musculoskeletal Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Study website

Contact information

Dr Dirk Foell
Scientific

University Hospital Muenster
Department of Pediatrics
Albert-Schweitzer-Str. 33
Muenster
48149
Germany

Phone	+49 (0)251 8356584
Email	dfoell@uni-muenster.de

Study information

Study design	Prospective, randomised, clinical multi-centre study
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Not specified
Study type	Treatment
Scientific title
Study acronym	MTX-withdrawal-study
Study objectives	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(s)	Ethics Committee at the University of Muenster, reference number 0VIIIRot
Health condition(s) or problem(s) studied	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
Pharmaceutical study type(s)
Phase	Not Specified
Drug / device / biological / vaccine name(s)	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 study start date	01/01/2005
Completion date	31/12/2008

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Both
Target number of participants	300
Key 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.
Key exclusion criteria	Patients should not have received intra-articular corticosteroids up to three months prior to inclusion
Date of first enrolment	01/01/2005
Date of final enrolment	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
Türkiye
United Kingdom

Study participating centre

University Hospital Muenster

Muenster
48149
Germany

Sponsor information

Pediatric Rheumatology International Trials Organisation (PRINTO) (Italy) and Wyeth Pharma
Other

IRCCS G. Gaslini
Pediatria II Largo Gaslini, 5
Genova
16147
Italy

Website	http://www.printo.it

Funders

Funder type

Research organisation

Pediatric Rheumatology International Trials Organisation (PRINTO) (EU grant number 2001CVG4-808)

No information available

Wyeth Pharma provided funding for patient insurance

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	07/04/2010		Yes	No