Condition category
Musculoskeletal Diseases
Date applied
Date assigned
Last edited
Retrospectively registered
Overall trial status
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
The conventional management of rheumatoid arthritis (RA) is based on combinations of simple painkillers (analgesics), non-steroidal anti-inflammatory drugs (NSAIDs) and disease modifying anti-rheumatic drugs (DMARDs), with or without steroids. With such conventional therapy many RA patients have an aggressive course with progressive joint destruction and marked disability developing over 5-10 years. Although it is generally accepted that DMARDs help to slow the course of RA, when DMARDs are used one after another, many patients continue to deteriorate. Together these observations have led to a shift in the management of RA. Firstly, rheumatologists start DMARD therapy as early as possible. Secondly, there is increasing use of combinations of two or more DMARDs given at the same time. The emergence of new therapies for RA has led to renewed optimism in the ultimate ability to control the disease process. There is little doubt that the best management of RA will require combination DMARD therapy. This will need to be started within the first year of disease onset. At present it is not clear what will be the best combination therapy. With an increasing number of new biological agents available to patients, or at various stages of development, the combination of such agents with non-biological DMARDs such as methotrexate, sulphasalazine and gold, should be evaluated. The study will look at whether the addition of a daily injection of Anakinra to normal DMARD (Disease Modifying Anti Rheumatoid Drug) therapy will result in a reduction in the number and severity of joint erosions in patients who have been recently diagnosed with rheumatoid arthritis.
The study will also look at other aspects in the management of rheumatoid arthritis, such as control of the level of inflammation and quality of life and collect information on health economics. This will be done using standard validated questionnaires.

Who can participate?
159 patients (males and females aged over 18 years with early rheumatoid arthritis (disease duration of less than 12 months at study entry) in participating centres.

What does the study involve?
Participants receive either only Methotrexate, or Methotrexate with additional daily injections of Anakinra. Each participant will spend 12 months on treatment and then be monitored for a further 12 months. Participants will be assessed at the beginning of the study and 6, 12 and 18 months after this.

What are the possible benefits and risks of participating?
Patients with early rheumatoid arthritis benefit from taking methotrexate which reduces joint inflammation and pain and improves disability. Anakinra has similar benefits in active rheumatoid arthritis. In established disease the two drugs are more effective in combination that when given singly. Their combined impact in early arthritis is unknown. Like all disease modifying drugs methotrexate can cause minor side effects like rashes and can cause rare side effects like liver damage. We regularly monitor blood tests to minimize the risk of toxicity. Like all biologic treatments Anakinra can increase the risk of infections. It also often causes temporary injection site reactions.

Where is the study run from?
King's Musculoskeletal Clinical Trials Unit, Kings College London (UK)

When is the study starting and how long is it expected to run for?
October 2003 to January 2010

Who is funding the study?
Amgen Limited (UK)

Who is the main contact?
Prof. David Scott

Trial website

Contact information



Primary contact

Prof David Scott


Contact details

Academic Rheumatology
Weston Education Centre
King’'s College London
Denmark Hill
United Kingdom

Additional identifiers

EudraCT number

2004-001123-38 number

Protocol/serial number

Version 10 (23/08/2006)

Study information

Scientific title

Effect of anakinra (soluble interleukin-1 receptor antagonist) as combination therapy: second UK combination therapy in early rheumatoid arthritis



Study hypothesis

This study will test the hypothesis that in patients with early Rheumatoid Arthritis (RA) methotrexate-anakinra therapy will reduce the progression of erosive disease. Specifically it will decrease the number of patients developing new erosions by 40% compared with methotrexate monotherapy alone over 12 months.

Ethics approval

South East MREC, 25/10/2002, ref: MREC 02/01/89

Study design

Prospective randomised controlled multicentre trial

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet


Rheumatoid arthritis


1. Sequential monotherapy:
Patients will be given initially 7.5 mg/week methotrexate, increasing every two weeks by 2.5 mg to 15 mg/week.

2. Sequential monotherapy plus Anakinra:
Patients randomised to receive Anakinra with methotraxate-based sequential monotherapy, initially will be given 100 mg/day of Anakinra by subcutaneous injection and 7.5 mg/week methotrexate, increasing every two weeks by 2.5 mg to 15 mg/week. The dose of Anakinra is fixed and will not be escalated throughout the study.

For both trial arms the local hospital consultant may vary the rate that the methotrexate is increased and the final dose depending on the clinical situation. If there is persistent active disease, the dosage can be increased by the supervising rheumatologist to a maximum of 25 mg/week. If, in the opinion of the local hospital consultant, there are significant side effects to methotrexate or there is either no response or a very inadequate response, patients will discontinue methotrexate and take a second DMARD. This DMARD can be any of sulphasalazine, leflunomide, azathioprine, penicillamine, ciclophosphomide or gold.

If, in the opinion of the local hospital consultant, there are significant side effects to the second DMARD or there is either no response or a very inadequate response, patients will discontinue the second DMARD and take a third DMARD, which can be any of the DMARDS listed above. The order in which the DMARDS are prescribed is at the discretion of the supervising consultant.

Intervention type



Not Applicable

Drug names

Anakinra (soluble interleukin-1 receptor antagonist) and methotrexate

Primary outcome measures

The difference in the number and severity of joint erosions as measured with the van der Heijdi Modified Sharp score.

Secondary outcome measures

1. Increases in the combined van der Heijde Modified Sharp score and in its three individual components
2. Decreases in disease activity measured by modified Disease Activity Score (DAS) and
American College of Rheumatology (ACR) response criteria
3. Changes in function measured by Health Assessment Questionnaire (HAQ)
4. Quality of life measured by Short Form health survey (SF-36) and EuroQol questionnaire
5. Health economics analysis measured by collection of standardised data set (used previously)

Overall trial start date


Overall trial end date


Reason abandoned


Participant inclusion criteria

1. RA by the 1987 criteria of the American College of Rheumatology
2. Disease duration of less than 12 months
3. The clinical need for treatment with a Slow Acting Anti-Rheumatic Drug (SAARD) as shown by evidence of active RA with three out of the following four criteria:
3.1. At least three swollen joints on a 28 joint score
3.2. At least six tender joints on a 28 joint score
3.3. At least 45 minutes morning stiffness
3.4. Erythrocyte Sedimentation Rate (ESR) of at least 28 mm/h
4. Patients must be willing and able to give informed consent
5. Aged at least 18

Participant type


Age group




Target number of participants


Participant exclusion criteria

1. Other forms of inflammatory arthritis (e.g. psoriatic arthritis, systemic lupus erythematosus)
2. Previous treatment with methotrexate
3. Contraindications or known intolerance to any of the drugs allowed on this trial (including Non Steroidal Anti-Inflammatory Drugs [NSAID], Steroids and Disease Modifying Anti-Rheumatic Drugs [DMARDs])
4. Other serious medical disorders (e.g. hepatic failure, gout, cardiac failure, tuberculosis, current malignant disease)
5. Any acute or chronic infection, including pneumonias
6. Females of child bearing and males of child fathering potential who are not taking adequate contraceptive protection
7. Neutrophil count less than 1.5 x 10^12/dl or platelet count less than 100 x 10^12/dl
8. Abnormal liver function test (gamma-Glutamyl Transferase [gGT] more than three times or Aspartate aminotransferase [AST]/Alanine aminotransferase [ALT] more than two times upper limit of normal)
9. Abnormal chest x-ray results
10. Patients with severe renal impairment (creatinine clearance less than 30 ml/min). Patients with a creatinine clearance between 30 and 50 ml/min can be entered into the trial but must be closely monitored
11. Patients taking low-dosage oral steroids for the treatment of RA. Patients taking a short-course of oral steroids for another condition may be included providing the daily dosage of steroids is less than 20 mg total

Recruitment start date


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

King’'s College London
United Kingdom

Sponsor information


King's College London (UK)

Sponsor details

United Kingdom

Sponsor type




Funder type


Funder name

Amgen (International)

Alternative name(s)

Amgen Inc., Applied Molecular Genetics Inc.

Funding Body Type

private sector organisation

Funding Body Subtype



United States of America

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

2016 results in:

Publication citations

Additional files

Editorial Notes

05/05/2016: Publication reference added. 14/10/2008: the overall trial end date was changed from 01/10/2007 to 01/01/2010. 11/06/2007: the overall trial end date was changed from 01/09/2006 to 01/10/2007.