Effects of Abatacept on Myocarditis in Rheumatoid Arthritis

NCT03619876 | Terminated Phase 4 Results FDA Drug

• 1 other identifier: AAAS2235
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to evaluate the effects of abatacept, a CTLA4-Ig fusion protein that binds cluster of differentiation antigen 80 (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 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computerized tomography (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 RNA sequencing.

Conditions

Rheumatoid Arthritis; Myocardial Inflammation

Keywords

CTLA4-Ig; Abatacept; Myocarditis; RA

Outcome Measures

Primary Outcomes (1)

• Change in Myocardial FDG Uptake in Rheumatoid Arthritis (RA) Patients Treated With Abatacept vs Adalimumab.

  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 cardiovascular disease (CVD) risk factors and measures of RA disease activity and severity will be ascertained.

  Baseline, 16 weeks

Secondary Outcomes (1)

• Prevalence of T Cell Subpopulations Associated With Myocardial FDG Uptake in RA Patients Treated With Abatacept vs Adalimumab.

  Baseline, 16 weeks

Study Arms (2)

Non- Tumor necrosis factor (TNF) inhibitor arm

ACTIVE COMPARATOR

Treatment with abatacept will consist of weekly subcutaneous (SQ) injections at a dose of 125mg.

Drug: Abatacept

TNF inhibitor arm

ACTIVE COMPARATOR

Treatment with a adalimumab, as the TNF-inhibitor arm, will consist of every 2 weeks SQ injections at a dose of 40mg.

Drug: Adalimumab

Interventions

Abatacept DRUG

125 MG/ML subcutaneous injections

Also known as: Orencia

Non- Tumor necrosis factor (TNF) inhibitor arm

Adalimumab DRUG

40 Mg/0.8 mL Subcutaneous Kit

Also known as: Humira

TNF inhibitor arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Columbia University: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Columbia University Medical Center

New York, New York, 10023, United States

Location

Related Publications (14)

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  PMID: 9632066 BACKGROUND

• Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003 Mar 11;107(9):1303-7. doi: 10.1161/01.cir.0000054612.26458.b2.

  PMID: 12628952 BACKGROUND

• Sihvonen S, Korpela M, Laippala P, Mustonen J, Pasternack A. Death rates and causes of death in patients with rheumatoid arthritis: a population-based study. Scand J Rheumatol. 2004;33(4):221-7. doi: 10.1080/03009740410005845.

  PMID: 15370716 BACKGROUND

• Solomon DH, Goodson NJ, Katz JN, Weinblatt ME, Avorn J, Setoguchi S, Canning C, Schneeweiss S. Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis. 2006 Dec;65(12):1608-12. doi: 10.1136/ard.2005.050377. Epub 2006 Jun 22.

  PMID: 16793844 BACKGROUND

• Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular disease prevalence in rheumatoid arthritis. J Rheumatol. 2003 Jan;30(1):36-40.

  PMID: 12508387 BACKGROUND

• LEBOWITZ WB. The heart in rheumatoid arthritis (rheumatoid disease). A clinical and pathological study of sixty-two cases. Ann Intern Med. 1963 Jan;58:102-23. doi: 10.7326/0003-4819-58-1-102. No abstract available.

  PMID: 13928929 BACKGROUND

• CATHCART ES, SPODICK DH. Rheumatoid heart disease. A study of the incidence and nature of cardiac lesions in rheumatoid arthritis. N Engl J Med. 1962 May 10;266:959-64. doi: 10.1056/NEJM196205102661901. No abstract available.

  PMID: 13877345 BACKGROUND

• SOKOLOFF L. CARDIAC INVOLVEMENT IN RHEUMATOID ARTHRITIS AND ALLIED DISORDERS: CURRENT CONCEPTS. Mod Concepts Cardiovasc Dis. 1964 Apr;33:847-50. No abstract available.

  PMID: 14144874 BACKGROUND

• Han B, Jiang H, Liu Z, Zhang Y, Zhao L, Lu K, Xi J. CTLA4-Ig relieves inflammation in murine models of coxsackievirus B3-induced myocarditis. Can J Cardiol. 2012 Mar-Apr;28(2):239-44. doi: 10.1016/j.cjca.2011.11.014. Epub 2012 Feb 14.

  PMID: 22336520 BACKGROUND

• Matsui Y, Inobe M, Okamoto H, Chiba S, Shimizu T, Kitabatake A, Uede T. Blockade of T cell costimulatory signals using adenovirus vectors prevents both the induction and the progression of experimental autoimmune myocarditis. J Mol Cell Cardiol. 2002 Mar;34(3):279-95. doi: 10.1006/jmcc.2001.1511.

  PMID: 11945021 BACKGROUND

• Abe S, Hanawa H, Hayashi M, Yoshida T, Komura S, Watanabe R, Lie H, Chang H, Kato K, Kodama M, Maruyama H, Nakazawa M, Miyazaki J, Aizawa Y. Prevention of experimental autoimmune myocarditis by hydrodynamics-based naked plasmid DNA encoding CTLA4-Ig gene delivery. J Card Fail. 2005 Sep;11(7):557-64. doi: 10.1016/j.cardfail.2005.04.005.

  PMID: 16198253 BACKGROUND

• Liu W, Gao C, Zhou BG, Li WM. Effects of adenovirus-mediated gene transfer of ICOSIg and CTLA4Ig fusion protein on experimental autoimmune myocarditis. Autoimmunity. 2006 Mar;39(2):83-92. doi: 10.1080/08916930500507870.

  PMID: 16698663 BACKGROUND

• Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, Becker JR, Slosky DA, Phillips EJ, Pilkinton MA, Craig-Owens L, Kola N, Plautz G, Reshef DS, Deutsch JS, Deering RP, Olenchock BA, Lichtman AH, Roden DM, Seidman CE, Koralnik IJ, Seidman JG, Hoffman RD, Taube JM, Diaz LA Jr, Anders RA, Sosman JA, Moslehi JJ. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016 Nov 3;375(18):1749-1755. doi: 10.1056/NEJMoa1609214.

  PMID: 27806233 BACKGROUND

• Varricchi G, Galdiero MR, Tocchetti CG. Cardiac Toxicity of Immune Checkpoint Inhibitors: Cardio-Oncology Meets Immunology. Circulation. 2017 Nov 21;136(21):1989-1992. doi: 10.1161/CIRCULATIONAHA.117.029626. No abstract available.

  PMID: 29158212 BACKGROUND

MeSH Terms

Conditions

Arthritis, Rheumatoid; Myocarditis

Interventions

Abatacept; Adalimumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Cardiomyopathies; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Immunoproteins

Results Point of Contact

• Title: Laura Geraldino-Pardilla, MD
• Organization: Columbia University

lbg2124@cumc.columbia.edu

212-305-4308

Study Officials

• Laura Geraldino-Pardilla, MD

  CUMC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Unblinded- open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: 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.

Study Record Dates

• First Submitted: August 3, 2018
• First Posted: August 8, 2018
• Study Start: July 10, 2019
• Primary Completion: September 15, 2021
• Study Completion: September 15, 2021
• Last Updated: May 8, 2023
• Results First Posted: May 8, 2023

Record last verified: 2023-04

Locations

US (1)