TNF-blocking Therapy in Combination With Disease-modifying Antirheumatic Drugs in Early Rheumatoid Arthritis

Study Overview
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Brief Summary
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The FIN-RACo trial is an investigator initiated multicenter (n=15 centers in Finland) prospective study on the treatment of patients with early rheumatoid arthritis (RA) with combination therapy with disease modifying antirheumatic drugs starting with methotrexate, sulphasalazine, hydroxychloroquine and prednisolone (COMBI). During the first 6 months, the patients are randomized to treatment with infliximab/placebo added on the combination treatment. The study is prospective for 5 years, with extension to 10 years. The target is to induce remission in both treatment arms. To reach this target, the investigators use frequent changes of doses and anti-rheumatic drugs and use of intra-articular glucocorticoid injections. The primary endpoints are the proportions of patients with remission at 2 and 5 years in both treatment arms.

Detailed Description
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We want to study, whether early treatment with infliximab for 6 months started parallel with the combination therapy of methotrexate, sulphasalazine, hydroxychloroquine and prednisolone (COMBI) can induce quick remission in patients with early RA, if the remission can be sustained after 6 months on patients continuing the COMBI treatment and can diminish the risk of progression of erosive changes in patients with early RA, and if we can reduce costs of the 2 treatment arms with respect to costs due to the disease. 100 patients with early RA will be included in the study. The patients are randomised into COMBI + placebo or into COMBI +infliximab. All patients are treated openly with COMBI, starting with a combination of methotrexate, sulfasalazine, hydroxychloroquine and prednisolone. In addition, the patients are randomized into a) infliximab or b) similar placebo. The COMBI treatment will be continued for 2 years, but the infliximab/placebo will be given only during the first 6 months. After 2 years, if the patient is in remission, the prednisolone will be gradually tapered off. If the patient is still in remission, the conventional DMARDs can be sequentially tapered down. If the remission is lost, the last DMARD is reinstituted. If the patient is not in remission of COMBI, after 26 weeks, treatments are free, including the institution of a biological drug. The patients will be evaluated clinically at week 0, 4, 6, 10, 14, 18, 22 and 26 (at the day of infusion, prior to the infusion) and at months 8, 10, 12, 15, 18, 21, and 24 and at annually thereafter till 10 years. If a patient has adverse events due to individual drugs in the COMBI, the treatment can be substituted by another DMARD.The disease activity will be measured according to the ACR core set of disease activity. Radiology of hands (PA projection) and feet (PA projection) at baseline and at 1, 2, 3, 4, 5, 7 and 10 years. We also will record adverse events, sick leaves, loss of income, costs, and work disability.

Official Title
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Use of TNF-blocking Therapy in Combination With DMARDs in Patients With Early Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Trexan+Salazopyrin+Oxiklorin+prednisolone + infliximab
* Drug: Trexan+Salazopyrin+Oxiklorin+prednisolone + placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of RA fulfilling the ACR classification criteria for RA Patients within age group of 18-60 years Patients not permanently work disabled or retired Duration of symptoms < 12 months, and who have not received DMARD previously Patients with active disease (see below) Criteria for active disease at entry: > 6 swollen joints (66 joint count) > 6 tender joints (68 joint count) duration of early morning stiffness > 45 min and/or ESR > 30 mm/h and/or CRP > 20 mg/l Exclusion Criteria: Previous treatment with DMARDs Previous treatment with oral glucocorticoids during the previous 6 months Less than 30 days from previous intra-articular injection with corticosteroids Allergy to sulphonamides Allergy to acetylsalicylic acid Allergy to methotrexate Allergy to antimalarials Previous treatment with biologicals Serum creatinine value > upper limit of normal (registered in 2 different blood samples) Serum transaminase levels > 2x upper limit of normal (registered in 2 different samples) Known/previous malignancy excluding basalioma or in situ cervical cancer >5 years previously Cardiac failure (NYHA III-IV) Previous history of tuberculosis and/or exposition to tuberculosis and/or typical changes of previous/active tuberculosis in chest radiology Active infection Pregnancy Leukopenia (WBC < 4 x 109/l) Thrombocytopenia (platelets < 100 x 109/l) Active peptic ulcer Type I or type II diabetes under poor control Heavy use of alcohol Fertile women not practising contraception or who are planning pregnancy Male patients wishing to have children during the therapy Other autoimmune rheumatic disease Other chronic disease which judged by the physician could influence the patient's compliance or intervene the study course Patient is not cooperative

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Trexan+Salazopyrin+Oxiklorin+prednisolone + infliximab<br>Combination therapy with 3 DMARDs (starting with methotrexate 10-25 mg/week, sulphasalazine 1-2 g/day and hydroxychloroquine 35 mg/kg/week)+ Prednisolon 7.5 mg/day + infliximab 3 mg/kg at weeks 4, 6, 10, 18, 26 | Drug: Trexan+Salazopyrin+Oxiklorin+prednisolone + infliximab<br>* methotrexate 10-25 mg/week, sulfasalazine 1-2 g/day, hydroxychloroquine 35 mg/kg/week, prednisolone 7.5 mg/day, and infliximab 3 mg/kg during first 6 months<br>* Other names: Trexan, Salazopyrin, Oxiklorin, Prednison, Remicade;|
| Placebo Comparator: Trexan+Salazopyrin+Oxiklorin+prednisolone + placebo<br>Combination therapy with 3 DMARDs (starting with methotrexate 10-25 mg/week, sulphasalazine 1-2 g/day and hydroxychloroquine 25 mg/kg/week)+ Prednisolon 7.5 mg/day + placebo at weeks 4, 6, 10, 18, 26 | Drug: Trexan+Salazopyrin+Oxiklorin+prednisolone + placebo<br>* methotrexate 10-25 mg/week, sulfasalazine 1-2 g/day, hydroxychloroquine 35 mg/kg/week, prednisolone 7.5 mg/day, and placebo infusion during first 6 months<br>* Other names: Trexan, Salazopyrin, Oxiklorin, Prednison, 0.9% NaCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission by ACR criteria |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiology (erosions) |  | 2 years | 
| Sustained remission | Number of patients with sustained ACR remission from month 3 till the end of the study | 2 years | 
| Costs | Cumulative direct and indirect costs at 2 years | 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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infliximab, rheumatoid arthritis, methotrexate, sulfasalazine, hydroxychloroquine