Plain English Summary

Not provided at time of registration

Trial website

http://www.printo.it

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; 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.

Intervention type

Drug

Phase

Not Specified

Drug names

Methotrexate (MTX)

Primary outcome measures

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

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, 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.

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

http://www.printo.it

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

Results - basic reporting

Publication summary

2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20371785

Publication citations

  1. 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.

Editorial Notes