Contact information
Type
Scientific
Primary contact
Dr C F Allaart
ORCID ID
Contact details
Leiden University Medical Center (LUMC)
Department of Rheumatology
C1-39
PO Box 9600
Leiden
2300 RC
Netherlands
+31 (0)71 526 3598
c.f.allaart@lumc.nl
Additional identifiers
EudraCT number
2006-006186-16
ClinicalTrials.gov number
Protocol/serial number
1
Study information
Scientific title
IMPROVED: Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease
Acronym
IMPROVED
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.
Ethics approval
Not provided at time of registration
Study design
Randomised controlled parallel-group single-blinded multicentre 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 to request a patient information sheet
Condition
Rheumatoid arthritis, undifferentiated arthritis
Intervention
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.
Intervention type
Drug
Phase
Not Applicable
Drug names
Methotrexate, prednisone, sulphasalazine, adalimumab, hydroxychloroquine
Primary outcome measure
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 measures
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
Overall trial start date
01/01/2007
Overall trial end date
01/07/2009
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
535
Participant 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
Recruitment start date
01/01/2007
Recruitment end date
01/07/2009
Locations
Countries of recruitment
Netherlands
Trial participating centre
Leiden University Medical Center (LUMC)
Leiden
2300 RC
Netherlands
Sponsor information
Organisation
Leiden University Medical Center (LUMC) (The Netherlands)
Sponsor details
Department of Rheumatology
PO Box 9600
Leiden
2300 RC
Netherlands
Sponsor type
Hospital/treatment centre
Website
http://www.lumc.nl/english/start_english.html#http://www.lumc.nl/english/start_english.html
Funders
Funder type
Industry
Funder name
Abbott (The Netherlands)
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
Basic results (scientific)
Publication list
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
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/26925251
2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28962586
2018 results in: http://www.ncbi.nlm.nih.gov/pubmed/29482627
Publication citations
-
Results
Wevers-de Boer K, Visser K, Heimans L, Ronday HK, Molenaar E, Groenendael JH, Peeters AJ, Westedt ML, Collée G, de Sonnaville PB, Grillet BA, Huizinga TW, Allaart CF, Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study)., Ann. Rheum. Dis., 2012, 71, 9, 1472-1477, doi: 10.1136/annrheumdis-2011-200736.
-
Results
Heimans L, Wevers-de Boer KV, Visser K, Goekoop RJ, van Oosterhout M, Harbers JB, Bijkerk C, Speyer I, de Buck MP, de Sonnaville PB, Grillet BA, Huizinga TW, Allaart CF, A two-step treatment strategy trial in patients with early arthritis aimed at achieving remission: the IMPROVED study., Ann. Rheum. Dis., 2014, 73, 7, 1356-1361, doi: 10.1136/annrheumdis-2013-203243.
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Results
Heimans L, Wevers-de Boer KV, Visser K, Ronday HK, Steup-Beekman GM, van Oosterhout M, Huizinga TW, Giltay EJ, van der Mast RC, Allaart CF, The relationship between disease activity and depressive symptoms severity and optimism--results from the IMPROVED study., Clin. Rheumatol., 2013, 32, 12, 1751-1757, doi: 10.1007/s10067-013-2337-9.
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Results
Akdemir G, Verheul MK, Heimans L, Wevers-de Boer KV, Goekoop-Ruiterman YP, van Oosterhout M, Harbers JB, Bijkerk C, Steup-Beekman GM, Lard LR, Huizinga TW, Trouw LA, Allaart CF, Predictive factors of radiological progression after 2 years of remission-steered treatment in early arthritis patients: a post hoc analysis of the IMPROVED study, RMD Open, 2016, 2, 1, e000172.