TIMERA: Ticagrelor in Methotrexate-Resistant Rheumatoid Arthritis

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT02874092
• Collaborator: (none)
• Enrollment: 9
• Location: 1
• Arms: 2
• Actual Duration (Months): 31.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Ticagrelor; Drug: MTX therapy	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Ticagrelor in Methotrexate-Resistant Rheumatoid Arthritis
• Actual Study Start Date: Nov 15, 2016
• Actual Primary Completion Date: Apr 19, 2019
• Actual Study Completion Date: Jun 19, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Disease Activity Score for 28-joint Counts (DAS28) [30 Days]

   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.

Secondary Outcome Measures

1. Visual Analog Scale Disease Activity [30 Days]

   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.

2. Change in Brachial Artery Diameter [Baseline, 30 Days]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York University School of Medicine	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health

Investigators

• Principal Investigator: Jeffrey Berger, MD, New York University Medical School

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 27, 2018

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT02874092
• Other Study ID Numbers: 15-01003
• First Posted: Aug 22, 2016
• Last Update Posted: Oct 25, 2021
• Last Verified: Sep 1, 2021

• 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
• Keywords provided by NYU Langone Health: Methotrexate (MTX); Ticagrelor
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Ticagrelor

Study Results

Participant Flow

Arm/Group Title	Rheumatoid Arthritis	Osteoarthritis
Arm/Group Description	-Receiving Methotrexate at stable doses of 10 to 25 mg weekly for at least 12 weeks Ticagrelor MTX therapy	-Diagnosis of osteoarthritis made by physician. MTX therapy
Period Title: Overall Study
STARTED	7	2
COMPLETED	7	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Rheumatoid Arthritis	Osteoarthritis	Total
Arm/Group Description	-Receiving Methotrexate at stable doses of 10 to 25 mg weekly for at least 12 weeks Ticagrelor MTX therapy	-Diagnosis of osteoarthritis made by physician. MTX therapy	Total of all reporting groups
Overall Participants	7	2	9
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48 (16)	48 (16)
Sex: Female, Male (Count of Participants)
Female	6 85.7%	2 100%	8 88.9%
Male	1 14.3%	0 0%	1 11.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 71.4%	0 0%	5 55.6%
Not Hispanic or Latino	2 28.6%	2 100%	4 44.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 14.3%	2 100%	3 33.3%
White	6 85.7%	0 0%	6 66.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%	2 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	Disease Activity Score for 28-joint Counts (DAS28)
Description	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.
Time Frame	30 Days

Outcome Measure Data

Analysis Population Description

The Osteoarthritis arm was removed; no data was collected for this arm due to low enrollment

Arm/Group Title	Rheumatoid Arthritis
Arm/Group Description	-Receiving Methotrexate at stable doses of 10 to 25 mg weekly for at least 12 weeks Ticagrelor MTX therapy
Measure Participants	7
Baseline	5.7 (0.4)
30 days	4.3 (0.8)

2. Secondary Outcome

Title	Visual Analog Scale Disease Activity
Description	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.
Time Frame	30 Days

Outcome Measure Data

Analysis Population Description

The Osteoarthritis arm was removed; no data was collected for this arm due to low enrollment

Arm/Group Title	Rheumatoid Arthritis
Arm/Group Description	-Receiving Methotrexate at stable doses of 10 to 25 mg weekly for at least 12 weeks Ticagrelor MTX therapy
Measure Participants	7
Baseline	47 (22)
30 days	23 (18)

3. Secondary Outcome

Title	Change in Brachial Artery Diameter
Description	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
Time Frame	Baseline, 30 Days

Outcome Measure Data

Analysis Population Description

The Osteoarthritis arm was removed; no data was collected for this arm due to low enrollment

Arm/Group Title	Rheumatoid Arthritis
Arm/Group Description	-Receiving Methotrexate at stable doses of 10 to 25 mg weekly for at least 12 weeks Ticagrelor MTX therapy
Measure Participants	7
Baseline	2.5 (0.9)
30 days	2.5 (1.1)

Adverse Events

Time Frame	30 days
Arm/Group Title	Rheumatoid Arthritis		Osteoarthritis
Arm/Group Description	-Receiving Methotrexate at stable doses of 10 to 25 mg weekly for at least 12 weeks Ticagrelor MTX therapy		-Diagnosis of osteoarthritis made by physician. MTX therapy
All Cause Mortality
	Rheumatoid Arthritis		Osteoarthritis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/2 (0%)
Serious Adverse Events
	Rheumatoid Arthritis		Osteoarthritis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Rheumatoid Arthritis		Osteoarthritis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.