Tocilizumab REMission in Early RA

Study Overview
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Brief Summary
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The TREMERA study focuses on patients with newly diagnosed, untreated, rheumatoid arthritis (RA). Recent international treatment recommendations emphasise the need to diagnose RA early and start treatment immediately (this being associated with better response rates); and to aim for the goal of remission i.e. the absence of signs and symptoms of active inflammatory disease activity which is associated with better outcomes for the patient. Remission is more achievable with significant treatment advances that have been made in the form of highly effective biologic therapies. Tocilizumab (TCZ) is a newly introduced biologic drug that is used in established RA. The TREMERA study primarily aims to investigate the biological changes seen in blood and tissue following TCZ therapy this will contribute to a better understanding of how the drug works as well as disease processes; and will also identify whether administering a biologic drug such as TCZ can also switch off immunological parameters associated with a disrupted immune system of RA. The study will assess the effectiveness of TCZ given on its own or in combination with methotrexate (MTX; a standard therapy usually given with biologic treatments)in patients with early onset RA to determine the proportion that achieve remission. This study also aims to find out how quickly remission can be achieved with TCZ and the depth of remission achieved. This will be done using usual clinical assessment but also imaging such as ultrasound and magnetic resonance imaging (MRI) which can detect inflammation not apparent on clinical assessment.

Official Title
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Prospective, Single-centre, Open-Label, Randomised, Pilot Study Assessing the Changes in Expression of Janus Kinase/Signal Transducers and Activators of Transcription (JAK-STAT) and Speed & Depth of Remission Induced by Tocilizumab & Methotrexate Combination and Tocilizumab Monotherapy in Patients With Early Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of rheumatoid arthritis (2010 ACR/EULAR RA classification criteria) Symptom duration ≤12months No previous disease modifying antirheumatic drug (DMARD) therapy Active RA at baseline (defined as: DAS28 ≥ 3.2) Active hand and/or wrist joint evaluable by US and MRI (with no planned surgery during the study period) Patients without any contraindication to MRI Exclusion Criteria: Patients unwilling or unable to receive MTX for the duration of the study. Patients with inflammatory joint disease of different origin, mixed connective tissue disease, Reiter's syndrome, psoriatic arthritis, systemic lupus erythematosis, or any arthritis with onset prior to 16 years of age. Suspicion of diagnosis of tuberculosis (TB): positive quantiferon +/abnormal chest x-ray, as per clinician judgement. Prior history of TB with confirmed full chemotherapy +/latent TB adequately treated may be included as per physician's discretion. Intramuscular, oral or intraarticular (of non-target joint) corticosteroid within 28 days of the screening visit; intra-articular steroid of the chosen target joint within 12 weeks of screening. Patients with serious infections within 3 month of enrolment (screening) or persistent infections. Patients at significant risk of infection (e.g. leg ulceration, indwelling urinary catheter, septic joint within 1 year (or ever if prosthetic joint still in situ). Known positive serology for hepatitis B or C, or HIV

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCZ monotherapy<br>Tocilizumab (TCZ) monotherapy 8mg/kg 4-weekly for a total of 48 weeks. | Drug: Tocilizumab<br> <br> |
| Experimental: TCZ+MTX combination therapy<br>Tocilizumab (TCZ) and methotrexate (MTX) combination therapy 8mg/kg 4-weekly for a total of 48 weeks. | Drug: Tocilizumab<br> <br> Drug: Methotrexate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate change in expression of JAK 1 and 3 (as well as STAT and p38 MAPK). | Changes up to week 60 | To week 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in inflammation in each treatment arm using ultrasound | Establish reduction in inflammation in each treatment arm using ultrasound using grey scale power doppler | To week 48 | 
| Disease Activity Score (DAS): DAS28/44 remission | Proportion of patients achieving DAS28/44 remission | To week 48 | 
| Questionnaires and research tools | Using tools including DAS28/44, SDAI, CDAI | Week 48 | 
| Health Assessment Questionniaire (HAQ) scores | The change from baseline in HAQ scores. | To week 48 | 
| VAS scores questionnaire | The change in VAS scores for pain, disease activity | To week 48 | 
| Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire | The change in RAQoL from baseline | To week 48 | 
| Bone densitometry | Bone densitometry scan of hands, spine, femoral neck | Week 48. | 
| Sharp score on plain radiographs | Change in modified Sharp score on plain radiographs | Week 48. |