Adalimumab to Mitigate Cardiovascular Risk in RA Patients With Well-Controlled Joint Disease

Jonathan Graf1 site in 1 country63 target enrollmentJuly 2013

ConditionsRheumatoid Arthritis Cardiovascular Disease

InterventionsAdalimumab Placebo

DrugsAdalimumab Placebo

Overview

Phase: Phase 4
Intervention: Adalimumab
Conditions: Rheumatoid Arthritis
Sponsor: Jonathan Graf
Enrollment: 63
Locations: 1
Primary Endpoint: Change in Endothelial Function
Status: Completed
Last Updated: 5 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

Rheumatoid arthritis patients are at increased risk of cardiovascular disease because of systemic inflammation that can persist even in patients with well-controlled joint disease. We hypothesize that adding an anti-tumor necrosis factor medication, adalimumab, to standard non-biologic therapy for rheumatoid arthritis will improve endothelial function (reduce cardiovascular risk) in these patients. The design of the trial is as follows: 18 month prospective, randomized, double-blind crossover trial comparing the addition of adalimumab to the addition of placebo. The primary endpoint is a change in endothelial cell function, as detected by brachial artery FMD, at 6 months of adalimumab treatment compared to 6 months of placebo.

Detailed Description

Excess mortality associated with RA is due largely to CVD that is not explained by traditional risk factors. Although articular manifestations usually dominate the clinical picture, RA is a systemic inflammatory disease, and systemic inflammation is the thought to be the underlying mechanism responsible for the increased CVD risk associated with RA. Because chronic inflammation can persist in treated RA patients with little or no clinically detectable joint inflammation, treatment to targets based largely on clinically measured joint activity may not adequately suppress the systemic inflammation associated with progression of atherosclerosis. The ACR recommends treatment to a therapeutic target of low disease activity as determined by standardized clinical assessments. We hypothesize that treated RA patients who have reached this ACR target of low disease activity nonetheless have persisting systemic inflammation that contributes to atherogenesis. We further hypothesize that acceleration of RA-directed therapy with systemic anti-inflammatory treatments (TNF inhibition) in patients with low disease activity will improve endothelial function, reduce vascular inflammation and improve the functionality of HDL particles, key biological features in the progression of atherosclerosis and its clinical manifestations. Trial design: Prospective, randomized, double-blind crossover trial comparing the addition of adalimumab to the addition of placebo. Study population: 60 RA patients on non-biological DMARDs with low disease activity as determined by a standardized clinical assessment (Disease Activity Score 28 joints \[DAS28\] \< 3.2). Primary endpoint: Primary endpoint is change in endothelial cell function, as detected by brachial artery FMD, at 6 months of adalimumab treatment compared to 6 months of placebo. We postulate that anti-TNF therapy with adalimumab will lead to an absolute increase of 2% in FMD, which typically translates into a 15% reduction in cardiovascular event rates.

Registry

clinicaltrials.gov

Start Date

July 2013

End Date

July 2017

Last Updated

5 years ago

Study Type

Interventional

Study Design

Crossover

Sex

All

Investigators

Sponsor

Jonathan Graf

Responsible Party

Sponsor Investigator

Principal Investigator

Jonathan Graf

Associate Professor of Medicine

University of California, San Francisco

Eligibility Criteria

Inclusion Criteria

•Subject must be able and willing to give written informed consent and comply with the requirements of the study protocol.
•Diagnosis of Rheumatoid Arthritis by ACR 1987 or ACR/EULAR 2010 criteria.
•Low RA disease activity as defined by DAS28 \< 3.2
•No anti-TNF medication or other biologic agent (abatacept, rituximab, or tocilizumab) within the 12 months prior to enrollment.
•If taking methotrexate, then on a stable dose between 7.5 mg and 25 mg (PO or SQ) weekly for at least 3 months prior to randomization. If on a DMARD other than methotrexate, then that DMARD must be at a stable therapeutic dose for at least 3 months prior to randomization.
•If taking prednisone, then a stable dose of less than or equal to 10 mg/daily for at least 1 month prior to randomization
•If NSAID taken on a regular, daily schedule, then patient must be on a stable dose for one week prior to FMD studies. PRN use is excluded within 1 week of FMD studies.
•Age \> 18
•Subject must be able and willing to self-administer SQ injections or have available qualified person(s) or caregiver to administer SQ injections
•Negative serum pregnancy test (for women of child bearing age)

Exclusion Criteria

•Use of an anti-TNF or other biologic medication (Including but not limited to abatacept, rituximab, or tocilizumab) within the previous 12 months.
•Prior history of MI, CVA, CABG, PTCA, or peripheral vascular disease
•SBP \> 140/90 at two months prior to study enrollment
•Diabetes mellitus requiring insulin therapy
•The following laboratory parameters at the Screening visit
•Neutropenia (absolute neutrophil count \< 1,500/microliter \[ L\]);
•Thrombocytopenia (platelets \< 100,000/ L);
•Anemia (hemoglobin \< 8 g/dL);
•Greater than or equal to 3 times the upper limit of normal (ULN) for either of the following liver function tests (LFTs): aspartate transaminase (AST) or alanine transaminase (ALT);
•Renal insufficiency (serum creatinine\> 2.0 mg/dL)