Remission Induction in Very Early Rheumatoid Arthritis

NCT00523692 | Unknown Phase 4

• 4 other identifiers: RRK2939REC reference 06/Q2404/95EudraCT number 2006-001428-38CTA number 16719/0201/001-0001
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

Rheumatoid arthritis (RA) is a debilitating chronic immune mediated inflammatory disease which affects 1% of the European population. RA is associated with significant joint damage, disability and an enhanced mortality. Current treatment strategies target patients once synovitis has been present for several months and it is clear that the patient has developed persistent disease. After the first 3 months of symptoms, we and others have shown that the persistence of chronic inflammation in the rheumatoid synovium is driven by hyperplastic stromal tissue which inhibits leukocyte apoptosis leading to the accumulation of inflammatory cells in the joint. Therapies at this stage of disease, with conventional disease modifying anti-rheumatic drugs (DMARDs) as well as drugs targeting TNF-alpha reduce disease activity but are unable to cure RA. We have now identified that the very early phase of synovitis in patients destined to develop RA (within the first 12 weeks of symptoms) represents a pathologically distinct phase of disease. This suggests that late disease is not just more of early disease and gives, for the first time, a clear rationale for very early intervention. Building on these recent observations, we propose to test the hypothesis that the disease processes in the very early stages of RA are fundamentally different to those in established chronic disease. This will be done by assessing whether treatment during this phase with the well-established gold standard modality of anti-TNF-alpha therapy and methotrexate can permanently switch off inflammation, preventing the development of RA and thereby effecting a cure of the disease.

Conditions

Rheumatoid Arthritis

Keywords

Early arthritis; Rheumatoid arthritis; Rheumatoid factor; Anti CCP antibody; Remission; Anti-TNF therapy; methotrexate

Outcome Measures

Primary Outcomes (1)

• The percentage of patients in drug free clinical remission at week 48 having withdrawn therapy at week 24 i.e. the induction of drug free remission.

  week 48

Secondary Outcomes (6)

• The percentage of patients in clinical remission at week 24 (when all drugs will be withdrawn if remission has been achieved).

  week 24

• The percentage of patients in radiological remission (no ultrasound evidence of synovitis) at week 24.

  week 24

• Clinical disease activity measures, including ACR responder rates (20%, 50%, and 70%), Disease Activity Score in 28 joints (DAS28), functional assessments (HAQ) and health status (EuroQuol-5D) at week 24.

  week 24

• The percentage of patients in drug free radiological remission (no ultrasound evidence of synovitis) at week 48 having withdrawn therapy at week 24.

  week 48

• Clinical disease activity measures, including ACR responder rates (20%, 50%, and 70%), Disease Activity Score in 28 joints (DAS28), functional assessments (HAQ) and health status (EuroQuol-5D) at weeks 48 and 96.

  weeks 48 and 96.

Study Arms (2)

1

EXPERIMENTAL

Intensive therapy

Drug: Etanercept, methotrexate and depomedrone

2

ACTIVE COMPARATOR

Standard therapy

Drug: depemedrone

Interventions

Etanercept, methotrexate and depomedrone DRUG

Etanercept (50mg weekly; subcutaneous) Methotrexate (7.5-25mg weekly; oral) Depomedrone (up to 120mg; intraarticular / intramuscular)

1

depemedrone DRUG

depomedrone (up to 120mg im/ia) methotrexate (added after symptoms have been present for 12 weeks)

2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age over 18 years
• Synovial swelling of at least 1 joint confirmed by clinical assessment
• Duration of symptoms attributable to inflammatory joint disease (pain, swelling or early morning stiffness of \>1 hour) of \< 12 weeks.
• Seropositivity for RF and anti-CCP Ab
• Women of childbearing potential or men capable of fathering children must be using adequate birth control measures (eg, abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, surgical sterilization) during the study.
• Female subjects of childbearing potential must test negative for pregnancy

You may not qualify if:

• Previous history of inflammatory arthritis.
• Previous use of DMARDs or anti-TNF-agents.
• Any current inflammatory condition with signs or symptoms that might confound the diagnosis (e.g. connective tissue disorders).
• Clinical evidence of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, prior to study entry.
• Administration, or expected administration, of any live virus or bacterial vaccination within 3 months before the first administration of study agent, or during the trial.
• A history of an infected joint prosthesis, or administration of antibiotics for a suspected infection of a joint prosthesis, if that prosthesis has not been removed or replaced.
• Known infection with HIV, hepatitis B, or hepatitis C.
• A serious infection that in the opinion of the investigator precludes receipt of a TNF blocking agent.
• Serious and uncontrolled co-existing disease that in the opinion of the investigator preclude the use of TNF-blocking medication, methotrexate or depomedrone (including pulmonary disease on chest radiograph, congestive cardiac failure (NYHA grade 3 or 4), history of demyelinating disease such as multiple sclerosis or optic neuritis).
• Bleeding disorder of the use of anti-coagulants
• Any known malignancy or a history of malignancy within the previous 5 years (with the exception of a basal cell carcinoma that has been treated with no evidence of recurrence).
• Any other contraindication to etanercept, methotrexate or parenteral depomedrone.
• Patients will also be excluded with the following laboratory results: haemoglobin \<8.5 gm/dl, total white cell count \<3.5 x 109/litre, serum transaminase value more than twice the upper limit of normal, and serum creatinine \>150 micromoles/litre.

Sponsors & Collaborators

• University Hospital Birmingham: lead
• Wyeth is now a wholly owned subsidiary of Pfizer: collaborator

Study Sites (2)

University Hopsital Birmingham NHS Foundation Trust

Birmingham, West Midlands, B15 2TH, United Kingdom

Location

Sandwell and West Birmingham Hospitals NHS Trust

Birmingham, West Midlands, B18 7QH, United Kingdom

Location

Related Publications (3)

• Raza K, Falciani F, Curnow SJ, Ross EJ, Lee CY, Akbar AN, Lord JM, Gordon C, Buckley CD, Salmon M. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther. 2005;7(4):R784-95. doi: 10.1186/ar1733. Epub 2005 Apr 7.

  PMID: 15987480 BACKGROUND

• Raza K, Breese M, Nightingale P, Kumar K, Potter T, Carruthers DM, Situnayake D, Gordon C, Buckley CD, Salmon M, Kitas GD. Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol. 2005 Feb;32(2):231-8.

  PMID: 15693082 BACKGROUND

• Raza K, Buckley CE, Salmon M, Buckley CD. Treating very early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2006 Oct;20(5):849-63. doi: 10.1016/j.berh.2006.05.005.

  PMID: 16980210 BACKGROUND

MeSH Terms

Conditions

Arthritis, Rheumatoid; Arthritis

Interventions

Etanercept; Methotrexate

Condition Hierarchy (Ancestors)

Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Karim Raza, MRCP PhD

  University of Birmingham

  PRINCIPAL INVESTIGATOR

• Christopher D Buckley, FRCP PhD

  University of Birmingham

  STUDY DIRECTOR

Central Study Contacts

Karim Raza, MRCP PhD

CONTACT

00 44 1214143837; k.raza@bham.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: August 30, 2007
• First Posted: August 31, 2007
• Study Start: September 1, 2007
• Last Updated: August 31, 2007

Record last verified: 2007-08

Locations

GB (2)