Ticagrelor in Methotrexate-Resistant Rheumatoid Arthritis

Study Overview
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Brief Summary
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This is an open label study to assess the improvement in the Disease Activity Score for 28-joint counts (DAS28) with ticagrelor given at 90 mg twice daily in patients with RA who have active disease despite MTX therapy (as defined by the inclusion/exclusion criteria). There will also be a cross sectional analysis of baseline platelet activity in subjects with rheumatoid arthritis and osteoarthritis. Subjects in the OA cohort will not receive any study medication, and will only have one study visit. Patients will receive 90 mg ticagrelor orally bid. The patients will receive drug for 30-days. Methotrexate dose will remain stable throughout the study duration.

Detailed Description
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The two main goals of this study are to demonstrate the heightened cardiovascular risk in RA by comparing platelet activity, inflammation and endothelial function in baseline rheumatoid arthritis versus age- and sex-matched patients with osteoarthritis; and 2) to demonstrate the effect of ticagrelor in rheumatoid arthritis by the pre- and post- measures of clinical RA severity, platelet activity, inflammation and endothelial function in rheumatoid arthritis before and after ticagrelor therapy.

Official Title
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Ticagrelor in Methotrexate-Resistant Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Ticagrelor
* Drug: MTX therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria RA cohort Receiving MTX at stable doses of 10 to 25 mg weekly for at least 12 weeks Have a DAS28 of 3.2 or higher (The level of disease activity is considered to be low if the DAS28 is 3.2 or less) (Prevoo et al., 1995) OA cohort Diagnosis of osteoarthritis made by physician. Exclusion Criteria: RA cohort History of sensitivity to study medications or any of their excipients Previous intolerance to MTX Current treatment with antiplatelet therapy Absolute indication for anti-platelet therapy Need for chronic oral anticoagulant therapy Severe hepatic impairment (eg, ascites and/or clinical signs of coagulopathy) Renal failure (eGFR <30 or requiring dialysis) A known bleeding diathesis, hemostatic or coagulation disorder, or prior major bleeding Prior stroke Active pathological bleeding History of intracranial haemorrhage Life expectancy <12 months based on investigator's judgement Patients considered to be at risk of bradycardic events (e.g., known sick sinus syndrome or second or third degree atrioventricular [AV)] block) unless already treated with a permanent pacemaker Anemia (hematocrit < 27%) Platelet count < 100,000/ml Concomitant use of strong CYP 3A inhibitors or inducers History of thrombocytopenia or neutropenia Pregnant or nursing women, or females with a positive pregnancy test at screening Females of child bearing potential not using acceptable method of birth control prior to or during study Concern for inability of the patient to comply with study procedures and/or follow up (eg, alcohol or drug abuse) OA cohort: History of sensitivity to study medications or any of their excipients Current treatment with antiplatelet therapy Absolute indication for anti-platelet therapy Need for chronic oral anticoagulant therapy Severe hepatic impairment (eg, ascites and/or clinical signs of coagulopathy) Renal failure (eGFR <30 or requiring dialysis) A known bleeding diathesis, hemostatic or coagulation disorder, or prior major bleeding Prior stroke Active pathological bleeding History of intracranial haemorrhage Life expectancy <12 months based on investigator's judgement Anemia (hematocrit < 27%) Platelet count < 100,000/ml History of thrombocytopenia or neutropenia Pregnant or nursing women, or females with a positive pregnancy test at screening Females of child bearing potential not using acceptable method of birth control prior to or during study Concern for inability of the patient to comply with study procedures and/or follow up (eg, alcohol or drug abuse)

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rheumatoid Arthritis<br>-Receiving Methotrexate at stable doses of 10 to 25 mg weekly for at least 12 weeks | Drug: Ticagrelor<br> <br> Drug: MTX therapy<br> <br> |
| Active Comparator: Osteoarthritis<br>-Diagnosis of osteoarthritis made by physician. | Drug: MTX therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Activity Score for 28-joint Counts (DAS28) | The DAS28 is a composite score derived from 4 of these measures. This '28' version is a simplification of the original DAS score, which requires 44 joints to be counted. Other versions of the DAS28 allow the CRP to be used instead of the ESR, or the omission of either. To calculate the DAS28 your rheumatologist or specialist nurse will:- count the number of swollen joints (out of the 28), count the number of tender joints (out of the 28), take blood to measure the erythrocyte sedimentation rate (ESR) or C reactive protein (CRP), ask you (the patient) to make a 'global assessment of health' (indicated by marking a 10 cm line between very good and very bad). These results are then fed into a complex mathematical formula to produce the overall disease activity score. A DAS28 of greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission. The total scale range is from 2 to 10, with higher scores indicating more disease activity. | 30 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analog Scale Disease Activity | The VAS is a psychometric response scale that ranges from no pain (0) to worst pain (100); patients mark a line on a continuum to indicate how they are feeling. Provides global assessment of RA severity. | 30 Days | 
| Change in Brachial Artery Diameter | Endothelial function is characterized by flow-mediated vasodilation of the brachial artery, which is measured by comparing the brachial artery diameter at rest the diameter after increased forearm blood flow (reactive hyperemia). Brachial artery reactivity testing (BART) is a noninvasive technique for evaluating endothelial function | Baseline, 30 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methotrexate (MTX), Ticagrelor