TNF-blocking Therapy in Combination With Disease-modifying Antirheumatic Drugs in Early Rheumatoid Arthritis (NEO-RACo)

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

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.

Study Overview

• Status: Unknown
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Trexan+Salazopyrin+Oxiklorin+prednisolone + infliximab; Drug: Trexan+Salazopyrin+Oxiklorin+prednisolone + placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Finland
  • Heinola, Finland, FI-18120
    • Rheumatism Foundation Hospital
  • Helsinki, Finland, FI-00029 HUS
    • Helsinki University Central Hospital
  • Helsinki, Finland, FI-00280
    • Orton Invalid Foundation Hospital
  • Hämeenlinna, Finland, FI-13530
    • Hämeenlinna Central Hospital
  • Jyväskylä, Finland, FI-40620
    • Jyväskylä Central Hospital
  • Kuopio, Finland, FI-703211
    • Kuopio University Hospital
  • Lappeenranta, Finland, FI-53130
    • Lappeenranta Central Hospital
  • Oulu, Finland, FI-90029 OYS
    • Oulu University Hospital
  • Rauma, Finland, FI-26100
    • Satakunta Central Hospital
  • Rovaniemi, Finland, FI-96100
    • Rovaniemi Central Hospital
  • Seinäjoki, Finland, FI-60220
    • Seinäjoki Central Hospital
  • Tampere, Finland, FI-33521
    • Tampere University Hospital
  • Turku, Finland, FI-21540
    • Turku University Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Trexan+Salazopyrin+Oxiklorin+prednisolone + infliximab; 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; 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; Other Names: Trexan, Salazopyrin, Oxiklorin, Prednison, Remicade
Placebo Comparator: Trexan+Salazopyrin+Oxiklorin+prednisolone + placebo; 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; 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; Other Names: Trexan, Salazopyrin, Oxiklorin, Prednison, 0.9% NaCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HAQ	Health assessment questionnaire(HAQ)	1, 2, 3, 4 and 5 years
Work disability	Permanent work disability	2, 3, 4 and 5 years
Good response	Number of patients with sustained good response (>=ACR50%) from month 3 till the end of study	5 years
Number of arthroplasties	Cumulative number of arthroplasties at 5 years	5 years
Direct and indirect costs	Cumulative direct an indirect costs at 5 years	5 years
Adverse events	Monitoring of safety and adverse events	10 years
ACR Remission		10 years
DAS28 remission		2, 3, 4, 5, 7 and10 years
HAQ	Health assessment questionnaire (HAQ)	10 years
Work disability	Cumulative permanent work disability up till 10 years	10 years
Number of arthroplasties	Cumualite number of arthroplasties by 10 years	10 years
Direct and indirect costs	Cumulative direct and indirect costs by 10 years	10 years
Radiology (erosions)	radiologic changes in hands and feet	10 years

Collaborators and Investigators

• Sponsor: University of Helsinki
• Collaborators: University of Turku; Oulu University Hospital; Kuopio University Hospital; Seinajoki Central Hospital; Satakunta Central Hospital; Jyväskylä Central Hospital; Kanta-Häme Central Hospital; South Carelia Central Hospital; Rheumatism Foundation Hospital; Orton Invalid Foundation; Lappi Central Hospital
• Investigators: Study Director: Marjatta Leirisalo-Repo, MD, Prof, University of Helsinki; Study Chair: Timo Möttönen, MD, Prof, University of Turku; Study Chair: Markku Korpela, MD, PhD, Tampere University; Study Chair: Riitta Luosujärvi, MD, PhD, Helsinki University Central Hospital; Study Chair: Oili Kaipiainen-Seppänen, MD, PhD, Kuopio University Hospital; Study Chair: Markku Kauppi, MD, PhD, Päijänne Tavastia Central Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2003
• Primary Completion (Actual): May 1, 2007
• Study Completion (Anticipated): December 1, 2015

Study Registration Dates

• First Submitted: May 22, 2009
• First Submitted That Met QC Criteria: May 22, 2009
• First Posted (Estimate): May 25, 2009

Study Record Updates

• Last Update Posted (Estimate): April 1, 2015
• Last Update Submitted That Met QC Criteria: March 31, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: rheumatoid arthritis; methotrexate; hydroxychloroquine; infliximab; sulfasalazine
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Dermatologic Agents; Narcotic Antagonists; Antiprotozoal Agents; Antiparasitic Agents; Alcohol Deterrents; Antimalarials; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Naltrexone; Infliximab; Hydroxychloroquine; Sulfasalazine
• Other Study ID Numbers: NEO-RACo