Clinical trial NCT00908089: TNF-blocking Therapy in Combination With Disease-modifying Antirheumatic Drugs in Early Rheumatoid Arthritis
Official title: Use of TNF-blocking Therapy in Combination With DMARDs in Patients With Early Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Keywords: rheumatoid arthritis
methotrexate
sulfasalazine
hydroxychloroquine
infliximab
Lead sponsor: University of Helsinki
Sponsor class: OTHER
Collaborators: name: Seinajoki Central Hospital
name: Oulu University Hospital
name: Jyväskylä Central Hospital
name: Kuopio University Hospital
name: Satakunta Central Hospital
name: University of Turku
name: Rheumatism Foundation Hospital
name: Orton Invalid Foundation
name: South Carelia Central Hospital
name: Lappi Central Hospital
name: Kanta-Häme Central Hospital
First posted: 2009-05-25
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Remission by ACR criteria
timeFrame: 2 years
Secondary outcomes:
measure: Radiology (erosions)
timeFrame: 2 years
measure: Sustained remission
timeFrame: 2 years
measure: Costs
timeFrame: 2
Other outcomes:
measure: HAQ
timeFrame: 1, 2, 3, 4 and 5 years
measure: Work disability
timeFrame: 2, 3, 4 and 5 years
measure: Good response
timeFrame: 5 years
measure: Number of arthroplasties
timeFrame: 5 years
measure: Direct and indirect costs
timeFrame: 5 years
measure: Adverse events
timeFrame: 10 years
measure: ACR Remission
timeFrame: 10 years
measure: DAS28 remission
timeFrame: 2, 3, 4, 5, 7 and10 years
measure: HAQ
timeFrame: 10 years
measure: Work disability
timeFrame: 10 years
measure: Number of arthroplasties
timeFrame: 10 years
measure: Direct and indirect costs
timeFrame: 10 years
measure: Radiology (erosions)
timeFrame: 10 years
Locations:
city: Heinola
country: Finland
facility: Rheumatism Foundation Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Helsinki
country: Finland
facility: Orton Invalid Foundation Hospital
city: Hämeenlinna
country: Finland
facility: Hämeenlinna Central Hospital
city: Jyväskylä
country: Finland
facility: Jyväskylä Central Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Lappeenranta
country: Finland
facility: Lappeenranta Central Hospital
city: Oulu
country: Finland
facility: Oulu University Hospital
city: Rauma
country: Finland
facility: Satakunta Central Hospital
city: Rovaniemi
country: Finland
facility: Rovaniemi Central Hospital
city: Seinäjoki
country: Finland
facility: Seinäjoki Central Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Central Hospital
Study officials:
affiliation: University of Helsinki
name: Marjatta Leirisalo-Repo, MD, Prof
role: STUDY_DIRECTOR
affiliation: University of Turku
name: Timo Möttönen, MD, Prof
role: STUDY_CHAIR
affiliation: Tampere University
name: Markku Korpela, MD, PhD
role: STUDY_CHAIR
affiliation: Helsinki University Central Hospital
name: Riitta Luosujärvi, MD, PhD
role: STUDY_CHAIR
affiliation: Kuopio University Hospital
name: Oili Kaipiainen-Seppänen, MD, PhD
role: STUDY_CHAIR
affiliation: Päijänne Tavastia Central Hospital
name: Markku Kauppi, MD, PhD
role: STUDY_CHAIR
References:
citation: Leirisalo-Repo M, Kautiainen H, Laasonen L, Korpela M, Kauppi MJ, Kaipiainen-Seppanen O, Luosujarvi R, Luukkainen R, Karjalainen A, Blafield H, Uutela T, Ilva K, Julkunen HA, Paimela L, Puolakka K, Moilanen E, Hannonen PJ, Mottonen T; NEO-RACo Study Group. Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study). Ann Rheum Dis. 2013 Jun;72(6):851-7. doi: 10.1136/annrheumdis-2012-201365. Epub 2012 Jun 30.
citation: Rantalaiho V, Kautiainen H, Jarvenpaa S, Korpela M, Malmi T, Hannonen P, Kaipiainen-Seppanen O, Yli-Kerttula T, Mottonen T, Mustila A, Karjalainen A, Paimela L, Uutela T, Leirisalo-Repo M; NEO-RACo Study Group. Failure in longterm treatment is rare in actively treated patients with rheumatoid arthritis, but may be predicted by high health assessment score at baseline and by residual disease activity at 3 and 6 months: the 5-year followup results of the randomized clinical NEO-RACo trial. J Rheumatol. 2014 Dec;41(12):2379-85. doi: 10.3899/jrheum.140267. Epub 2014 Oct 1.
citation: Rantalaiho V, Kautiainen H, Korpela M, Hannonen P, Kaipiainen-Seppanen O, Mottonen T, Kauppi M, Karjalainen A, Laiho K, Laasonen L, Hakola M, Peltomaa R, Leirisalo-Repo M; NEO-RACo Study Group. Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial. Ann Rheum Dis. 2014 Nov;73(11):1954-61. doi: 10.1136/annrheumdis-2013-203497. Epub 2013 Aug 1.
citation: Vuolteenaho K, Tuure L, Nieminen R, Laasonen L, Leirisalo-Repo M, Moilanen E; NEO-RACo Study Group. Pretreatment resistin levels are associated with erosive disease in early rheumatoid arthritis treated with disease-modifying anti-rheumatic drugs and infliximab. Scand J Rheumatol. 2022 May;51(3):180-185. doi: 10.1080/03009742.2021.1929456. Epub 2021 Jul 15.
citation: Sandstrom T, Rantalaiho V, Yli-Kerttula T, Kautiainen H, Malmi T, Karjalainen A, Uusitalo T, Julkunen H, Kaipiainen-Seppanen O, Paimela L, Puolakka K, Uutela T, Mottonen T, Hannonen P, Leirisalo-Repo M, Laasonen L, Kauppi M; NEO-RACo Study Group. Cervical Spine Involvement among Patients with Rheumatoid Arthritis Treated Actively with Treat-to-target Strategy: 10-year Results of the NEO-RACo Study. J Rheumatol. 2020 Aug 1;47(8):1160-1164. doi: 10.3899/jrheum.190139. Epub 2019 Nov 15.
citation: Rantalaiho V, Sandstrom T, Koski J, Hannonen P, Mottonen T, Kaipiainen-Seppanen O, Yli-Kerttula T, Kauppi MJ, Uutela T, Malmi T, Julkunen H, Laasonen L, Kautiainen H, Leirisalo-Repo M; NEO-RACo Study Group. Early Targeted Combination Treatment With Conventional Synthetic Disease-Modifying Antirheumatic Drugs and Long-Term Outcomes in Rheumatoid Arthritis: Ten-Year Follow-Up Results of a Randomized Clinical Trial. Arthritis Care Res (Hoboken). 2019 Nov;71(11):1450-1458. doi: 10.1002/acr.23782.