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IMPROVED: Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease
DOI 10.1186/ISRCTN11916566
ClinicalTrials.gov identifier
EudraCT number
Public title IMPROVED: Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease
Scientific title
Serial number at source 1
Study hypothesis There is a clinically and statistically significant difference in the percentage of patients who achieve and maintain clinical remission (defined as Disease Activity Score [DAS] less than 1.6) and in functional ability and progression of radiological joint damage after one year of follow-up in recent-onset arthritis patients (Rheumatoid Arthritis [RA] and Undifferentiated Arthritis [UA]) who, having failed to achieve remission on a combination of methotrexate and a tapered high dose of prednisone, receive extended medication in a combination of methotrexate, sulphasalazine, hydroxychloroquine and low dose prednisone, or who switch to a combination of methotrexate and adalimumab.
Lay summary Not provided at time of registration
Ethics approval Not provided at time of registration
Study design Randomised, controlled, parallel group, single blinded multicentre trial
Countries of recruitment Netherlands
Disease/condition/study domain Rheumatoid arthritis, Undifferentiated arthritis
Participants - inclusion criteria 1. Patients more than or equal to 18 years of age with either RA according to the revised criteria of the American College of Rheumatology (ACR) of less than two years duration, or UA, suspected by the rheumatologist to have an early presentation of RA
2. All patients must have at least one (out of 66) swollen joint and at least one other (out of 68) painful joint, and a combined DAS of more than 1.6
3. All patients must be Disease Modifying Anti-Rheumatic Drugs (DMARDs) and corticosteroid naÏve
Participants - exclusion criteria 1. Previous therapy with DMARDs or with corticosteroids (exception: one dose of parenteral corticosteroids within the last six months, but not within the last two months, or an oral dose of prednisone of less than or equal to 10 mg/day for less than or equal to two weeks within the same period allowed)
2. Pregnancy or wish to become pregnant during the study, or childbearing potential without adequate contraception
3. Concomitant treatment with another experimental drug
4. History or presence of malignancy within the last five years
5. Bone marrow hypoplasia
6. Elevated hepatic enzyme levels (Aspartate Aminotransferase [AST], Alanine Aminotransferase [ALT] more than three times normal value)
7. Serum creatinine level more than 150 umol/l or estimated creatinin clearance of less than 75%
8. Uncontrolled diabetes mellitus (according to the rheumatologist)
9. Uncontrolled hypertension (according to the rheumatologist)
10. Heart failure (New York Heart Association [NYHA] functional class III or IV)
11. Alcohol or drug abuse
12. History of infected joint prothesis within the previous three months
13. Serious infections, such as hepatitis, pneumonia, pyelonephritis in the previous three months
14. Chronic infectious disease such as chronic renal infection, chronic chest infection with bronchiectasis or sinusitis
15. History of active tuberculosis requiring treatment within previous three years, or signs and symptoms of latent infection with tuberculosis, based on medical history, physical examination, Purified Protein Derivative (PPD) skin test, X-thorax
16. History of opportunistic infections such as herpes zoster within previous two months
17. Evidence of active cytomegalovirus, active pneumocystis carinii, or drug resistant atypical mycobacterium infection etc
18. Evidence of hepatitis B infection
19. Documented Human Immunodeficiency Virus (HIV) infection, Acquired Immune Deficiency Syndrome (AIDS) of AIDS Related Complex (ARC)
20. History of lymphoproliferative disease including lymphoma or signs suggestive of possible lymphoproliferative disease
21. Multiple sclerosis or neurological symptoms suspect for demyelinising disease
Anticipated start date 01/01/2007
Anticipated end date 01/07/2009
Status of trial Completed
Patient information material
Target number of participants 535
Interventions Four-monthly evaluations of Disease Activity Score and safety. Medication adjustments by protocol, based on DAS calculation, aimed at DAS less than 1.6 (remission).

Initial treatment with Methotrexate (MTX) and a tapered high dose of prednisone. If DAS more than 1.6, randomisation to either combination with MTX, Sulphasalazine (SSA), hydroxychloroquine and a tapered high dose of prednisone, or combination with MTX with adalimumab. In case of DAS less than 1.6: taper medication and discontinue if DAS remains less than 1.6.
Primary outcome measure(s) 1. Percentage of patients in remission (DAS less than 1.6)
2. Functional ability as measured by Health Assessment Questionnaire (HAQ)
3. Radiological damage progression as measured by Sharp/van der Heijde score
Secondary outcome measure(s) 1. Quality of life, as measured with McMaster-Toronto Arthritis (MACTAR), Short Form health survey (SF-36), EuroQol questionnaire
2. Time-trade-off
3. Costs
4. ACR arthritis core-set
Sources of funding Abbott (The Netherlands)
Trial website
Publications 2012 results in: http://www.ncbi.nlm.nih.gov/pubmed/22402145
2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/23716067
2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/23881438
Contact name Dr  C F  Allaart
  Address Leiden University Medical Center (LUMC)
Department of Rheumatology, C1-39
P.O. Box 9600
  City/town Leiden
  Zip/Postcode 2300 RC
  Country Netherlands
  Tel +31 (0)71 526 3598
  Fax +31 (0)71 526 6752
  Email c.f.allaart@lumc.nl
Sponsor Leiden University Medical Center (LUMC) (The Netherlands)
  Address Department of Rheumatology
P.O. Box 9600
  City/town Leiden
  Zip/Postcode 2300 RC
  Country Netherlands
  Sponsor website: http://www.lumc.nl/english/start_english.html#http://www.lumc.nl/english/start_english.html
Date applied 28/12/2006
Last edited 01/09/2014
Date ISRCTN assigned 28/12/2006
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