Clinical trial NCT00920478: Targeting Synovitis in Early Rheumatoid Arthritis
Official title: Targeting Synovitis in Early Rheumatoid Arthritis (TaSER). Intensive Management of Early Rheumatoid Arthritis Using Either Clinical or Musculoskeletal Ultrasound Assessment of Synovitis - a Randomised Study With Blinded Outcome Assessments
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Polyarthritis
Keywords: Rheumatoid arthritis
Musculoskeletal Ultrasound
Synovitis
DMARD
Etanercept
Biomarkers
Undifferentiated Inflammatory Polyarthritis
Lead sponsor: NHS Greater Glasgow and Clyde
Sponsor class: OTHER
Collaborators: name: University of Glasgow
name: Chief Scientist Office of the Scottish Government
name: Wyeth is now a wholly owned subsidiary of Pfizer
name: Translational Medicine Research Collaboration
First posted: 2009-06-15
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with rheumatoid arthritis are at risk of developing permanent joint damage and disability. This study hopes to identify the most effective way of using existing arthritis medication to minimise the chances of developing permanent disability. Patients will have their arthritis activity assessed using an ultrasound machine. If there is still evidence of active arthritis the participant's arthritis medication will be increased until the arthritis is in remission. The effectiveness of this approach will be compared to the traditional method of assessing arthritis using clinical examination.

Furthermore, it is extremely important to identify those patients most at risk of aggressive disease. The investigators hope to produce a more accurate measurement of disease prognosis by examining the relationship between a series of blood tests and how well controlled rheumatoid arthritis appears after 18 months of therapy. Some patients will also be asked to donate samples of joint fluid and joint lining for additional analysis.

Detailed description: PURPOSE 1 - to determine whether it is possible to achieve better control of inflammatory joint disease activity in early rheumatoid arthritis by using musculoskeletal ultrasound, instead of clinical examination, to identify the presence, or absence, of synovitis

NULL HYPOTHESIS 1 - using musculoskeletal ultrasound to confirm / refute the presence of ongoing synovitis will NOT allow better control of early rheumatoid arthritis nor prevent progression of destructive joint disease despite patients receiving more intensive disease modifying therapy regimens

PURPOSE 2 - to determine whether baseline measures of certain biochemical and pathological factors, associated with the development of inflammatory synovitis, are predictive of response to therapy in early rheumatoid arthritis and short term outcome measures of inflammatory joint disease activity, functional ability and quality of life

NULL HYPOTHESIS 2 - serial measures of biochemical and pathological factors, associated with the development of inflammatory synovitis, will NOT correlate with short term outcome measures of disease activity and therefore cannot be used to predict a patient's prognosis nor identify those at risk of progressive, destructive joint disease

TRIAL DESIGN - randomised, prospective single blinded trial of treatment strategy with a nested study correlating baseline measures and 18 month outcomes

Investigators will not be blinded to treatment group. Treatment decisions and escalation of therapy will be dictated by a standardised protocol. The sequence of therapy escalation will be identical for both groups. The groups will differ on the threshold needed to progress to the next treatment step

Assessors of disease activity, radiological and pathological outcomes will be blinded to treatment group and their findings will form the basis of each groups final outcome measures

TREATMENT PROTOCOL - the sequence of therapy escalation will be the same for each group. The groups differ by the 'trigger' required to progress to the next treatment step. Therapy will escalated in each group if the measured disease activity exceeds that groups threshold trigger. Changes in DMARD therapy doses and/or combinations take three months to reach maximum effect; therefore, at least a three month gap will be left between each treatment escalation

PRIMARY OUTCOME MEASURE

1. Magnetic Resonance Imaging of Dominant Wrist - baseline and 18 months. Images will be scored using the OMERACT RAMRIS(Rheumatoid Arthritis Magnetic Resonance Imaging Score) atlas. The change in each patient's synovitis and erosion scores will be pooled and compared for each intervention group
2. 44 joint Disease Activity Score - Mean change of DAS44 with time will represent the rate of response to treatment. Mean area under curve DAS44 will represent overall level of disease activity throughout the study period

SECONDARY OUTCOME MEASURES

1. European League Against Rheumatism Response Rates - A EULAR Good response is defined as a greater than 1.2 change in DAS44 and a final DAS44 less than 2.4. Disease remission is defined as DAS44 less than 1.6
2. Functional Measures - Health Assessment Questionnaire and EuroQoL-5D questionnaires at enrollment and then every 3 months.
3. Plain Xrays - plain xrays of hands, wrists and feet at baseline and 18 months. Change in Sharp score between baseline and 18 month films will be reported
4. Biomarker analysis - analyses will include specific genetic factors(genomic DNA), gene expression (RNA analysis), novel autoantibody assays, cytokine / emerging inflammatory protein profiling, lipid / lipoprotein based markers, metabolic assays and assessment of bone and cartilage turnover markers.

Samples will be collected at baseline, 3 months and 12 months (if not commenced on etanercept), immediately before commencing etanercept, 3 months and 6 months after commencing etanercept and 3 months after cessation. Final disease outcome measures for each patient will be correlated with baseline biomarker values to determine if any predictive relationships exist.

All values will be entered into a logistical regression analysis to try and create a statistical predictive model. Serial biomarker analyses will demonstrate how the different components of the pathogenetic process respond to the different stages of DMARD therapy.

Eligibility criteria: Inclusion Criteria:

1. Patients attending Early RA clinics with newly diagnosed RA or anti-CCP +ve Undifferentiated Arthritis (UA)
2. Active disease (DAS28 \> 3.2)
3. DMARD naïve or DMARD monotherapy for less than 6 weeks
4. Aged 18 or more

Exclusion Criteria:

1. Significant liver disease and/or abnormality of liver function tests
2. AST / ALT \> x2 normal, Alkaline Phosphatase \> x2.5 normal
3. Renal impairment - serum creatinine \> 200 μmol/l, eGFR \< 30
4. Cytopenias - white cell count \< 4.0, haemoglobin \< 10, platelet \< 150
5. Pregnancy or planned pregnancy
6. Contraindication to MRI
7. Other co-morbid condition that in the opinion of the investigator would preclude the use of sequential or combination DMARD therapy

Primary outcomes:
measure: MRI RAMRIS Erosion Score
timeFrame: Baseline and 18 months
measure: 44 Joint Disease Activity Score
timeFrame: Baseline, 3, 6, 9, 12, 15 and 18 months
Secondary outcomes:
measure: Plain Xray - Hands and Feet - modified Sharp score
timeFrame: Baseline and 18 months
measure: Health Assessment Questionnaire
timeFrame: Baseline, 3, 6, 9, 12, 15 and 18 months
measure: Euro-Qol 5D
timeFrame: Baseline, 3, 6, 9, 12, 15 and 18 months
measure: EULAR response and remission rates
timeFrame: Baseline and 18 months
measure: Biomarker analysis - correlation between baseline values and 18 month radiological outcomes
timeFrame: Baseline
measure: Adverse event rates
timeFrame: Throughout period of study
Other outcomes:
Locations:
city: Glasgow
country: United Kingdom
facility: Department of Rheumatology, Gartnavel General Hospital
city: Glasgow
country: United Kingdom
facility: Department of Rheumatology, Stobhill Hospital
city: Glasgow
country: United Kingdom
facility: Centre for Rheumatic Diseases, Glasgow Royal Infirmary
Study officials:
affiliation: Gartnavel General Hospital, Glasgow
name: Duncan R Porter, MBChB, MRCP
role: STUDY_CHAIR
affiliation: University of Glasgow
name: James E Dale, MBChB, MRCP
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Glasgow
name: Iain B McInnes, PhD, FRCP
role: STUDY_CHAIR
References:
citation: Dale J, Stirling A, Zhang R, Purves D, Foley J, Sambrook M, Conaghan PG, van der Heijde D, McConnachie A, McInnes IB, Porter D. Targeting ultrasound remission in early rheumatoid arthritis: the results of the TaSER study, a randomised clinical trial. Ann Rheum Dis. 2016 Jun;75(6):1043-50. doi: 10.1136/annrheumdis-2015-208941. Epub 2016 Mar 29.
citation: Dale J, Purves D, McConnachie A, McInnes I, Porter D. Tightening up? Impact of musculoskeletal ultrasound disease activity assessment on early rheumatoid arthritis patients treated using a treat to target strategy. Arthritis Care Res (Hoboken). 2014 Jan;66(1):19-26. doi: 10.1002/acr.22218.