AbatacepT foR ImmUne Checkpoint Inhibitor Associated Myocarditis (ATRIUM): A Phase 3, Investigator-Initiated, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept in ICI Myocarditis
Summary
The primary aim is to test whether abatacept, as compared to placebo, is associated with a reduction in major adverse cardiac events (MACE) among participants hospitalized with myocarditis secondary to an immune checkpoint inhibitor (ICI). The primary outcome, MACE, is a composite of first occurrence of cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrythmias, significant bradyarrythmias, or incident heart failure.
Detailed description
This investigator-initiated randomized trial is being conducted to test whether abatacept, as compared to placebo, is associated with a reduction in MACE among participants who develop myocarditis after treatment with an ICI. Immune checkpoint inhibitors leverage the immune system to treat a wide variety of cancers. Myocarditis is an uncommon immune related adverse event (irAE) secondary to treatment with an ICI. The guideline recommended treatment for ICI myocarditis is cessation of the ICI and administration of corticosteroids. However, despite administration of corticosteroids, the rate of MACE with ICI myocarditis is high. Data from multiple independent international cohorts have shown that the rate of MACE with ICI myocarditis despite administration of corticosteroids ranges from 25-50%.For comparison, the rate of MACE with myocarditis unrelated to an ICI is \<5%. Abatacept is a selective co-stimulation modulator that inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking its interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. In animal studies of ICI myocarditis, the administration of abatacept led to a reduction in cardiac immune activation and an increase in survival. In retrospective unpublished clinical data, the administration of abatacept to participants with ICI myocarditis on corticosteroids was associated with a reduction in risk of MACE. There are no prospective studies testing whether abatacept is effective among participants with ICI myocarditis. Therefore, the primary aim of this trial is to test in a randomized double-blind placebo-controlled study whether abatacept, administered concurrently with corticosteroids, is associated with a reduction in MACE among participants with recently diagnosed ICI myocarditis
Arms & interventions
- DrugAbatacept plus
Up to 4 study drug infusions at 10 mg/kg, IV Drug: Standard of care Local standard of care per written policies or guidelines Other Name: SoC
- DrugPlacebo
Drug: Standard of care Local standard of care per written policies or guidelines Other Name: SoC
Outcome measures
Primary
Major adverse cardiac events
The rates of a composite of cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrhythmias, significant bradyarrhythmias, or incident heart failure.
Time frame: 6 months
Secondary
The individual components of the primary endpoint.
Time frame: 6 months
Myocarditis illness severity using a 7-point ordinal severity scale containing each of the individual endpoints in a hierarchical ranking order.
Time frame: 6 months
The increase in serum troponin levels
Time frame: 6 months
The combination of the rates of the primary outcome plus the proportion of patients with a troponin increase.
Time frame: 6 months
Clinical status at 90 days after first infusion of study drug
Time frame: 6 months
Clinical status at 6 months after first infusion of study drug
Time frame: 6 months
Fatal and non-fatal DVT and PE
Time frame: 6 months
Other immune-related adverse events between the two groups
Time frame: 6 months
Eligibility criteria
Study locations (29)
Cedars-Sinai Medical Center
Los Angeles, California, 02127
University of California Los Angeles
Los Angeles, California, 90095
MedStar Health Research Institute, Georgetown University
Washington D.C., District of Columbia, 20010
Moffitt Cancer Center
Tampa, Florida, 33612
University of Chicago
Chicago, Illinois, 60637
Franciscan Health
Indianapolis, Indiana, 46237
University of Kansas Medical Center
Kansas City, Kansas, 66160
University of Kentucky
Lexington, Kentucky, 40536-0200
Maine Health
Portland, Maine, 04102
Johns Hopkins
Baltimore, Maryland, 21287
Massachusetts General Hospital
Boston, Massachusetts, 02114
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02115
Boston Medical Center
Boston, Massachusetts, 02118
Brigham and Women's Hospital
Boston, Massachusetts, 02215
University of Michigan
Ann Arbor, Michigan, 48109
Mayo Clinic
Rochester, Minnesota, 55905
Robert Wood Johnson University Hospital
New Brunswick, New Jersey, 08901
Columbia University Irving Medical Center
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University of North Carolina Chapel Hill
Chapel Hill, North Carolina, 27599-7075
Cleveland Clinic
Cleveland, Ohio, 44195
Lehigh Valley Health Network
Bethlehem, Pennsylvania, 18017
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Allegheny-Singer Research Institution
Pittsburgh, Pennsylvania, 15212
University of Texas Southwestern
Dallas, Texas, 72535
MD Anderson Cancer Center
Houston, Texas, 77030
University of Utah
Salt Lake City, Utah, 84132
University of West Virginia
Morgantown, West Virginia, 26506
Aurora St Luke's Medical Center
Milwaukee, Wisconsin, 53215
References
- Heymans S, Van Linthout S, Kraus SM, Cooper LT, Ntusi NAB. Clinical Characteristics and Mechanisms of Acute Myocarditis. Circ Res. 2024 Jul 5;135(2):397-411. doi: 10.1161/CIRCRESAHA.124.324674. Epub 2024 Jul 4.(PubMed)