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Effects of Abatacept on Myocarditis in Rheumatoid Arthritis (AMiRA)

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ClinicalTrials.gov Identifier: NCT03619876
Recruitment Status : Not yet recruiting
First Posted : August 8, 2018
Last Update Posted : May 16, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Laura Geraldino-Pardilla, Columbia University

Tracking Information
First Submitted Date  ICMJE August 3, 2018
First Posted Date  ICMJE August 8, 2018
Last Update Posted Date May 16, 2019
Estimated Study Start Date  ICMJE June 2019
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2018)
Change in myocardial FDG uptake in RA patients treated with abatacept vs adalimumab. [ Time Frame: Baseline, 16 weeks from BL-randomization ]
Using FDG PET cardiac imaging to identify myocardial inflammation at baseline and post-treatment, the study will quantitatively compare the change in myocardial FDG uptake in biologic naïve RA patients without clinical CVD and with inadequate methotrexate response, following randomization to 16-week treatment with abatacept vs the TNF-inhibitor adalimumab. Conventional CVD risk factors and measures of RA disease activity and severity will be ascertained.
Original Primary Outcome Measures  ICMJE
 (submitted: August 3, 2018)
Compare the change in myocardial FDG uptake in RA patients treated with abatacept vs adalimumab. [ Time Frame: 16 weeks from BL-randomization ]
Using FDG PET cardiac imaging to identify myocardial inflammation at baseline and post-treatment, we will quantitatively compare the change in myocardial FDG uptake in biologic naïve RA patients without clinical CVD and with inadequate methotrexate response, following randomization to 16-week treatment with abatacept vs the TNF-inhibitor adalimumab. Conventional CVD risk factors and measures of RA disease activity and severity will be ascertained.
Change History Complete list of historical versions of study NCT03619876 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 13, 2018)
Prevalence of T cell subpopulations associated with myocardial FDG uptake in RA patients treated with abatacept vs adalimumab. [ Time Frame: Baseline, 16 weeks from BL-randomization ]
This is to test whether elevations in different T cell subsets are associated with myocardial FDG uptake in RA patients treated with abatacept vs adalimumab. Subsequently, the transcriptional phenotype of candidate subpopulations.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 3, 2018)
Identify T cell subpopulations associated with myocardial FDG uptake in RA patients treated with abatacept vs adalimumab. [ Time Frame: 16 weeks from BL-randomization ]
We will test whether elevations in different T cell subsets are associated with myocardial FDG uptake in RA patients treated with abatacept vs adalimumab. Subsequently, the transcriptional phenotype of candidate subpopulations.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of Abatacept on Myocarditis in Rheumatoid Arthritis
Official Title  ICMJE Effects of Abatacept on Myocarditis in Rheumatoid Arthritis
Brief Summary This study aims to evaluate the effects of abatacept, a CTLA4-Ig fusion protein that binds CD80/86 (B7-1/B7-2), on subclinical myocarditis in rheumatoid arthritis (RA) through its effect on T cell subpopulations. RA patients without clinical CVD, biologic naïve, and with inadequate response to methotrexate (MTX), will undergo cardiac FDG PET/CT imaging to assess myocardial inflammation. Studies that investigate the impact of treatment on subclinical myocarditis in RA, a possible contributor to heart failure, while exploring potential underlying mechanisms (i.e., different T cell subpopulations), are needed for a better understanding of their relevance in the pathogenesis of heart failure in RA and survival improvement in these patients with excess risk for cardiovascular death. If the investigator hypothesis is confirmed and treatment with abatacept decreases and/or suppresses or prevents myocardial inflammation in RA, this will have multidisciplinary implications that could lead to changes in the current management of RA patients at high risk for cardiovascular events. Similarly, identification of T cell subpopulations in RA patients with myocardial FDG uptake will shed light into the underlying cellular mechanisms of myocardial injury and serve to guide the use of therapies that prevent their pathogenicity. The objectives of this study are to compare the change in myocardial FDG uptake in RA patients treated with abatacept vs adalimumab, and identify T cell subpopulations associated with myocardial FDG uptake in each treatment arm. RA patients will be randomized in an unblinded, 1:1 ratio to treatment with abatacept vs adalimumab. A cardiac FDG PET/CT will be performed at baseline and 16 weeks post-biologic treatment. T cell subpopulations associated with myocardial FDG uptake will be evaluated at both points in time with their transcriptional phenotype outlined by RNAseq.
Detailed Description

Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects ~1% of the population. Regardless of the novel therapies developed in the last decades, studies report an increased standard mortality ratio as high as 3.0 when compared with the general population. Cardiovascular disease (CVD) is the leading cause of mortality in RA subjects in whom the average lifespan is reduced by 8-15 years compared to matched controls. RA patients are at increased risk for developing heart failure and inflammatory myocarditis potentially contributes to this excess risk. Although subclinical myocarditis remains poorly characterized to date in RA, costimulatory molecules such as CD80/86 (B7s) and CD40 are known to play a pivotal role for cytokine production and antigen-specific T cell activation in viral myocarditis, and in murine models, blocking CD40L/B7-1 and CTLA4 significantly decreases myocardial inflammation, damage, and mortality. In addition, the recent increase in the use of immune checkpoint inhibitors for the treatment of numerous cancers, has raised awareness of the occurrence of fulminant autoimmune lymphocytic myocarditis as a complication of these drugs including anti-CTLA4 due to a presumed uncontrolled immune response resulting in T-cell mediated myocardial injury. Interestingly, pilot data showed lower myocardial FDG uptake in RA patients on the a CTLA4-Ig fusion protein abatacept compared with other DMARDs. These data raise the possibility of immunotherapy for the treatment of myocarditis in RA, suggesting a role for T cell infiltration in its pathogenesis, and a particular benefit for treatment with abatacept vs non-abatacept biologic DMARDs.

In a single RHeumatoid arthritis studY of THe Myocardium (RHYTHM study), a total of 119 RA patients without clinical CVD underwent cardiac FDG-PET/CT, with myocardial inflammation assessed qualitatively and quantitatively by visual inspection and by calculation of the standardized-uptake-value (SUV) units. Qualitative myocardial FDG uptake was observed in 39% of the patients. Animal data showing decreased myocardial inflammation, damage, and mortality, and improved cardiac function with CD40L/B7-1 and CTLA4 blockage, coupled with preliminary findings of lower myocardial inflammation in RA patients on abatacept vs other DMARDs, suggest that abatacept treatment has potential myocardial benefits. In RA patients, the proportion of peripheral T cell subsets significantly differs from normal controls and include differentiation to memory effector subsets, acquisition of NK receptors, exhaustion markers, and enhanced inflammatory cytokine expression. Importantly, T cell lymphocytic infiltration described in autoimmune myocarditis resulting as a complication of CTLA4 immune checkpoint inhibition, suggests a role for T cell subsets in the pathogenesis of myocarditis in RA with potential differences depending on mechanism of action of the DMARD in use. Studies that investigate the impact of treatment on subclinical myocarditis in RA, a possible contributor to heart failure, while exploring potential underlying mechanisms (i.e., different T cell subpopulations), are needed for a better understanding of their relevance in the pathogenesis of heart failure in RA and survival improvement in these patients with excess risk for cardiovascular death. If the investigator hypothesis is confirmed and treatment with abatacept decreases and/or suppresses or prevents myocardial inflammation in RA, this will have multidisciplinary implications that could lead to changes in the current management of RA patients at high risk for cardiovascular events. Similarly, identification of T cell subpopulations in RA patients with myocardial FDG uptake will shed light into the underlying cellular mechanisms of myocardial injury and serve to guide the use of therapies that prevent their pathogenicity.

This is a single-center study. Twenty RA patients will be recruited over a planned recruitment period of 24 months, and randomized with aims of enrolling 10 patients per year, the enrollment rate is estimated as 1 patient per month. The target population consists of patients who are deemed methotrexate-inadequate responders by the patient's treating rheumatologist, and who have not yet stepped up to additional treatment with a biologic DMARD.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
RA patients will be randomized in an unblinded, 1:1 ratio to treatment with abatacept vs adalimumab. A cardiac FDG PET/CT will be performed at baseline and 16(±2) weeks post-biologic treatment. T cell subpopulations associated with myocardial FDG uptake will be evaluated at both points in time with their transcriptional phenotype outlined by RNAseq.
Masking: None (Open Label)
Masking Description:
Unblinded- open label
Primary Purpose: Treatment
Condition  ICMJE
  • Rheumatoid Arthritis
  • Myocardial Inflammation
Intervention  ICMJE
  • Drug: Abatacept
    125 MG/ML subcutaneous injections
    Other Name: Orencia
  • Drug: Adalimumab
    40 Mg/0.8 mL Subcutaneous Kit
    Other Name: Humira
Study Arms  ICMJE
  • Active Comparator: Non-TNF inhibitor arm
    Treatment with abatacept will consist of weekly subcutaneous (SQ) injections at a dose of 125mg.
    Intervention: Drug: Abatacept
  • Active Comparator: TNF inhibitor arm
    Treatment with a adalimumab, as the TNF-inhibitor arm, will consist of every 2 weeks SQ injections at a dose of 40mg.
    Intervention: Drug: Adalimumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: August 3, 2018)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent signed by the subject.
  • Patients age > 18 years.
  • Fulfilling the American College of Rheumatology 2010 classification criteria for RA.
  • MTX for ≥ 8 weeks at ≥ 15mg weekly or on at least 7.5mg of methotrexate weekly for ≥8 weeks with a documented intolerance of higher MTX doses, and on a stable dose for the previous 4 weeks;
  • Naïve to biologic treatment.
  • If the subject is a woman with childbearing potential, a urine sample will be taken for a pregnancy test. The results of the pregnancy test must be negative.

Exclusion Criteria:

  • Prior biologic use.
  • Any prior self-reported physician diagnosed CV event (myocardial infarction; angina; stroke or Transient Ischemic Attack (TIA); heart failure; prior CV procedure (i.e., coronary artery bypass graft, angioplasty, valve replacement, pacemaker).
  • Active history of cancer.
  • Prior use of immune checkpoint inhibitors.
  • Known pregnancy, HIV, hepatitis B, hepatitis C, active (or untreated latent) tuberculosis.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Laura Geraldino-Pardilla, MD 212-305-4308 lbg2124@columbia.edu
Contact: Christopher Depender 646-379-4960 cd2686@cumc.columbia.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03619876
Other Study ID Numbers  ICMJE AAAS2235
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Laura Geraldino-Pardilla, Columbia University
Study Sponsor  ICMJE Columbia University
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Laura Geraldino-Pardilla, MD CUMC
PRS Account Columbia University
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP