Condition category
Musculoskeletal Diseases
Date applied
28/12/2006
Date assigned
28/12/2006
Last edited
01/03/2016
Prospective/Retrospective
Prospectively 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

Dr C F Allaart

ORCID ID

Contact details

Leiden University Medical Center (LUMC)
Department of Rheumatology
C1-39
P.O. Box 9600
Leiden
2300 RC
Netherlands
+31 (0)71 526 3598
c.f.allaart@lumc.nl

Additional identifiers

EudraCT number

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

Not specified

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below 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 measures

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

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
P.O. 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

Results - basic reporting

Publication summary

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

Publication citations

  1. 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.

  2. 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.

  3. 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.

  4. 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.

Additional files

Editorial Notes

01/03/2016: Publication reference added.