Ticagrelor in Methotrexate-Resistant Rheumatoid Arthritis (TIMERA)

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Ticagrelor; Drug: MTX therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • New York University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Investigators: Principal Investigator: Jeffrey Berger, MD, New York University Medical School

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2016
• Primary Completion (Actual): April 19, 2019
• Study Completion (Actual): June 19, 2019

Study Registration Dates

• First Submitted: August 17, 2016
• First Submitted That Met QC Criteria: August 17, 2016
• First Posted (Estimate): August 22, 2016

Study Record Updates

• Last Update Posted (Actual): October 25, 2021
• Last Update Submitted That Met QC Criteria: September 27, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Ticagrelor; Methotrexate (MTX)
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor
• Other Study ID Numbers: 15-01003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No