Condition category
Musculoskeletal Diseases
Date applied
13/11/2009
Date assigned
27/11/2009
Last edited
27/11/2009
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Prof Timo Möttönen

ORCID ID

Contact details

TYKS
Paimio Hospital
Alvar aalto way 275
Paimio
21540
Finland

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

31.1.1993

Study information

Scientific title

Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a multicentre randomised open parallel-group treatment strategy trial

Acronym

FIN-RACo trial

Study hypothesis

Using the combination of disease modifying anti-rheumatic drugs (DMARDs) (sulphasalazine, hydroxychloroquine, and methotrexate) with low dose prednisolone at very early stage of rheumatoid arthritis may be the better treatment strategy in the induction of remission and improvement of disease clinical activity than single-drug treatment stategy of rheumatoid arthritis.

Ethics approval

The Joint Commission on Ethics of the Turku University and the Turku University Central Hospital approved on the 2nd March 1993 (ref: supp 1 § 34)

Study design

Multicentre randomised open parallel-group treatment strategy trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet (Finnish and Swedish only)

Condition

Rheumatoid arthritis

Intervention

Combination therapy started with sulphasalazine 500 mg twice daily, methotrexate 7.5 mg weekly, and hydroxichloroquine 300 mg daily, and prednisolone 5 mg daily. This initial combination, if tolerated, was continued for 3 months. If the clinical improvement at 3 months was under 50% in at least two of the three criteria (swollen joints, tender joints, and ESR or CRP), the respective doses of methotrexate and prednisolone were increased to 10 mg weekly and 7.5 mg daily. The protocol allowed flexible subsequent dose adjustment to mimic clinical practice. Thus, the highest dose at 9 months and thereafter was 2 g daily for sulphasalazine, 15 mg weekly for methotrexate, 300 mg daily for hydroxychloroquine, and 10 mg daily for prednisolone. If a patient reached remission during the first year with initial combination, the drug doses were tapered, and prednisolone and methotrexate could even be discontinued at 9 months and 18 months, respectively. Sulphasalazine (1 g daily), and hydroxychloroquine (300 mg daily) had to be continued for 2 years. In the patients who reached remission during the first year, but not with the initial combination, the drug doses were gradually tapered to those of the second year. If the induced remission was lost, the DMARD doses were increased with the intention of reaching remission. If one or several components of the combination had to be discontinued for any reason, a combination of three DMARDs was restarted by replacing sulphasalazine and hydroxychloroquine with auranofin (3 - 6 mg daily), and methotrexate with azathioprine (2 mg/kg daily). Other DMARDs could also be used as substitutes.

The single-treatment strategy was also targeted to achieve remission. The simultaneous use of oral prednisolone up to 10 mg was allowed in patients with continuously active disease, but simultaneous use of multiple DMARDs was not allowed. The decision to use prednisolone was made by the treating physician. The patients were treated continuously with one DMARD alone, with or without prednisolone. If a more beneficial effect was needed, the dose was increased or the DMARD was changed. Sulphasalazine (2 g daily) was used as the initial drug in all patients, and the dose was increase to 3 g daily at 3 months, if clinically indicated. If an adverse event occurred, or if the clinical response was less than 25% at 6 months, the protocol required that sulphasalazine was replaced with methotrexate 87.5 mg - 15 mg weekly).

Intraarticular injections of glucocorticoids into inflamed joints were allowed in both treatment arms.

All the patients were clinically assessed at baseline and at months 1, 3, 4, 5, 6, 9, 12, and 24 and the adjusments of drug doses were performed.

After two years, treatment was still aimed at achieving or maintaining remissions, but the choise and use of DMARDs was unrestricted. Thus, regardless of the original randomisation group, patients who had an insufficient response could be treated liberally with increased dosages of DMARDs (methotrexate up to 25 mg/week) and with DMARD combination when clinically indicated and tolerated.

Intervention type

Drug

Phase

Phase IV

Drug names

Sulphasalazine, hydroxychloroquine, methotrexate, prednisolone

Primary outcome measures

Induction of remission: American College of Rheumatology (ACR) preliminary criteria for remission were used. However, the patient might or might not be using any drug treatment, and fatigue and duration definition were excluded. The patient with remission was not, by definition, one with any swollen or tender joints. Assessed at 6 months, 12 months and thereafter annually for 11 years.

Secondary outcome measures

Assessed at 1, 3, 4, 5, 6, 9, 12 months and thereafter annually for 11 years:
1. Proportion of patients achieving a meaningful clinical response (ACR50% response)
2. Development of radiographic joint damage
3. Frequency of adverse effects
4. Physical function (HAQ)
5. Work capacity

Overall trial start date

30/04/1993

Overall trial end date

28/03/2007

Reason abandoned

Eligibility

Participant inclusion criteria

1. American Rheumatism Association criteria for rheumatoid arthritis
2. Aged between 18 and 65 years, either sex
3. Duration of symptoms of less than 2 years
4. Active disease with three or more swollen joints and at least three of the following:
4.1. Erythrocyte sedimentation rate (ESR) at least 28 mm/h
4.2. C-reactive protein (CRP) above 19 mg/l
4.3. Morning stiffness of 29 minutes or more
4.4. More than five swollen joints
4.5. More than ten tender joints

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

199

Participant exclusion criteria

1. Patients who had used DMARDs in the past
2. Had undergone glucocorticoid therapy within the previous 2 weeks
3. Patients with serious comorbidity
4. Suspected inability to comply with the protocol
5. Hypersensitivity to any study medication
6. A history of cancer
7. Pregnant women
8. Women of childbearing age who were not using reliable methods of contraception

Recruitment start date

30/04/1993

Recruitment end date

28/03/2007

Locations

Countries of recruitment

Finland

Trial participating centre

TYKS, Paimio Hospital
Paimio
21540
Finland

Sponsor information

Organisation

Turku University Hospital (Finland)

Sponsor details

Kiinamyllykatu 4-8
Turku
20520
Finland

Sponsor type

Hospital/treatment centre

Website

http://www.vsshp.fi

Funders

Funder type

Government

Funder name

All costs are classed as usual treatment and are therefore covered under the Finnish National Health Insurance (NHI) scheme (Finland)

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

1. 1999 results in http://www.ncbi.nlm.nih.gov/pubmed/10334255
2. 2000 results in http://www.ncbi.nlm.nih.gov/pubmed/11083260
3. 2002 results in http://www.ncbi.nlm.nih.gov/pubmed/11953964
4. 2004 results in http://www.ncbi.nlm.nih.gov/pubmed/15248204
5. 2005 results in http://www.ncbi.nlm.nih.gov/pubmed/15641055
6. 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/19404945

Publication citations

  1. Results

    Möttönen T, Hannonen P, Leirisalo-Repo M, Nissilä M, Kautiainen H, Korpela M, Laasonen L, Julkunen H, Luukkainen R, Vuori K, Paimela L, Blåfield H, Hakala M, Ilva K, Yli-Kerttula U, Puolakka K, Järvinen P, Hakola M, Piirainen H, Ahonen J, Pälvimäki I, Forsberg S, Koota K, Friman C, Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group., Lancet, 1999, 353, 9164, 1568-1573.

  2. Results

    Neva MH, Kauppi MJ, Kautiainen H, Luukkainen R, Hannonen P, Leirisalo-Repo M, Nissilä M, Möttönen T, , Combination drug therapy retards the development of rheumatoid atlantoaxial subluxations., Arthritis Rheum., 2000, 43, 11, 2397-2401, doi: 10.1002/1529-0131(200011)43:11<2397::AID-ANR4>3.0.CO;2-V.

  3. Results

    Möttönen T, Hannonen P, Korpela M, Nissilä M, Kautiainen H, Ilonen J, Laasonen L, Kaipiainen-Seppänen O, Franzen P, Helve T, Koski J, Gripenberg-Gahmberg M, Myllykangas-Luosujärvi R, Leirisalo-Repo M, , Delay to institution of therapy and induction of remission using single-drug or combination-disease-modifying antirheumatic drug therapy in early rheumatoid arthritis., Arthritis Rheum., 2002, 46, 4, 894-898.

  4. Results

    Korpela M, Laasonen L, Hannonen P, Kautiainen H, Leirisalo-Repo M, Hakala M, Paimela L, Blåfield H, Puolakka K, Möttönen T, , Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study., Arthritis Rheum., 2004, 50, 7, 2072-2081, doi: 10.1002/art.20351.

  5. Results

    Puolakka K, Kautiainen H, Möttönen T, Hannonen P, Korpela M, Hakala M, Järvinen P, Ahonen J, Forsberg S, Leirisalo-Repo M, , Early suppression of disease activity is essential for maintenance of work capacity in patients with recent-onset rheumatoid arthritis: five-year experience from the FIN-RACo trial., Arthritis Rheum., 2005, 52, 1, 36-41, doi: 10.1002/art.20716.

  6. Results

    Rantalaiho V, Korpela M, Hannonen P, Kautiainen H, Järvenpää S, Leirisalo-Repo M, Hakala M, Puolakka K, Julkunen H, Luosujärvi R, Möttönen T, , The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial., Arthritis Rheum., 2009, 60, 5, 1222-1231, doi: 10.1002/art.24447.

Additional files

Editorial Notes