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RecruitingInterventionalPhase 3

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

NCT ID: NCT05335928Sponsor: Massachusetts General HospitalLast updated: 2025-09-10

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 In retrospective unpublished clinical data, the administration of abatacept to participants with ICI myocarditis on corticosteroids was associated with a reduction in risk of MACE.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

Sex: AllAge: 18 Years and olderHealthy volunteers: No
Inclusion Criteria: 1. Must have provided informed consent in a manner approved by the Investigator's Institutional Review Board (IRB) prior to any study-related procedure being performed. If a participant is unable to provide informed consent due to his/her medical condition, the participant's legally authorized representative may consent on behalf of the study participant, as permitted by local law and institutional Standard Operating Procedures; 2. Aged greater than or equal to 18 years at the time of informed consent; 3. Recent use of an FDA-approved immune checkpoint inhibitor (ICI, defined as administered an immune checkpoint inhibitor ≤ 6 months of myocarditis diagnosis), alone or in combination with other cancer therapies (i.e. chemotherapy, radiation therapy or targeted therapy). The FDA-approved ICI could be given as part of a clinical trial but not in combination with a new investigational agent which may cause myocarditis; 4. A diagnosis of myocarditis. 5. Hospitalized at the time of randomization; 6. On 1000 mg of solumedrol per day for myocarditis or with an intent to initiate 1000 mg of solumedrol per day for myocarditis within 24 hours of first administration of study drug; 7. Serum evidence of ongoing myocardial injury: Serum evidence of ongoing myocardial injury will be defined as an institutional troponin (either conventional or high-sensitivity troponin I or T, using the standard institutional assay) with a value that is ≥5 times the upper limit of the reference standard normal for that institution. The troponin assay may be adjusted based on sex depending on institutional standards. This value of troponin of ≥5 times above the institutional upper limits of normal value must be noted within 10 days prior to potential randomization. The 10-day period can be in the outpatient or inpatient setting. For example, a participant with a troponin value that on one occasion was ≥5 times the upper limits of institutional normal in the 10-day window prior to potential randomization (whether in the inpatient or outpatient setting), but later decreases below that threshold, typically due to starting corticosteroids, would still be considered eligible; 8. The following laboratory parameters, not older than 48 hours at the time of randomization, and measured as part of usual care: * Total white blood cell (WBC) count \>2,500/μl * Absolute neutrophil count (ANC) \>1,500/μL * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \<20 times the upper limit of the institutional normal ranges; 9. Women of childbearing potential (i.e., not postmenopausal, or surgically sterilized) must have a negative highly sensitive urine or serum pregnancy test prior to randomization. Participating women of childbearing potential must be willing to consistently use effective methods of contraception from screening until at least 90 days after administration of the last dose of study drug. Participating men must also be willing to consistently use effective methods of contraception from screening until at least 90 days after administration of the last dose of study drug; and 10. Must be willing and able to abide by all study requirements and restrictions. Exclusion Criteria: 1. Must not have experienced any of the following (as defined in the section on the primary endpoint) in the 30-day period prior to randomization: * A sudden cardiac arrest * Cardiogenic shock as defined. A significant bradyarrhythmia (Mobitz type II second degree atrioventricular block or third degree (complete) atrio-ventricular (AV) block, for which an intervention with a temporary or permanent pacemaker is completed or recommended). * A significant tachyarrhythmia (ventricular fibrillation of any duration or sustained ventricular tachycardia (\>30 seconds, \>120 beats per minute); or a ventricular tachyarrhythmia requiring intervention. 2. Recent (≤2 month) exposure to abatacept or belatacept. 3. Concurrent or recent (≤2 month) use of the following non-corticosteroid immunosuppressive therapies prior to randomization: mycophenolate, JAK STAT inhibitors (including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib), tacrolimus, anti-thymocyte globulin, alemtuzumab, infliximab, and plasma exchange. The use of intravenous immunoglobulin is permitted prior to randomization and during study treatment. 4. Currently enrolled in another interventional study utilizing systemic agents for the management of ICI-related toxicities. 5. Female who is pregnant, breastfeeding, or is considering becoming pregnant during the study or for approximately 90 days after the last dose of study drug. 6. Male who is considering fathering a child or donating sperm during the study or for approximately 30 days after the last dose of study drug. 7. Any active, chronic, or recurrent viral infection that, based on the investigator's clinical assessment, makes the participant an unsuitable candidate for the study. These may include hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a single episode) herpes zoster, and disseminated (even a single episode) herpes simplex. Active HBV and HCV are defined as: HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for Hepatitis B core antibody (HBc Ab) positive (+) participants; HCV: HCV ribonucleic acid (RNA) detectable in any participant with anti-HCV antibody (HCV Ab). Patients with active Covid-19 infection will be excluded. This is defined as the period of ongoing symptoms in the setting of a positive Covid-19 test, or until 10 days after symptom onset and after resolution of fever for at least 24 hours, without the use of fever-reducing medications. 8. Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections; 9. Receipt of any live vaccine within four weeks prior to the first dose of study drug, or expected need of live vaccination during study participation including at least 90 days after the last dose of IV study drug. 10. Any medical condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or interpretation of the study results, or that would, in the opinion of the Investigator, increase the risk of the participant by participating in the study. 11. Any factors that, in the Investigator's opinion, are likely to interfere with study procedures, such as history of noncompliance with scheduled appointments.

Study locations (29)

Cedars-Sinai Medical Center

Los Angeles, California, 02127

Recruiting
Kiranbir Josan, MD · Contact
Kiranbir Josan, MD · Principal Investigator

University of California Los Angeles

Los Angeles, California, 90095

Recruiting
Eric Yang, MD · Contact
Eric Yang, MD · Principal Investigator

MedStar Health Research Institute, Georgetown University

Washington D.C., District of Columbia, 20010

Recruiting
Hayder Hashim · Contact
Hayder Hashim · Principal Investigator

Moffitt Cancer Center

Tampa, Florida, 33612

Recruiting
Mohammed v · Contact
Mohammed Alomar · Principal Investigator

University of Chicago

Chicago, Illinois, 60637

Recruiting
Jeanne DeCara · Contact
Jeanne DeCara · Principal Investigator

Franciscan Health

Indianapolis, Indiana, 46237

Recruiting
Ryan Daly · Contact
Ryan Daly, MD · Principal Investigator

University of Kansas Medical Center

Kansas City, Kansas, 66160

Recruiting
Charles Porter · Contact
Charles Porter, MD · Principal Investigator

University of Kentucky

Lexington, Kentucky, 40536-0200

Recruiting
Amit Arbune · Contact
Amit Arbune, MD · Principal Investigator

Maine Health

Portland, Maine, 04102

Recruiting
Maxwell Afari · Contact
Maxwell Afari, MD · Principal Investigator

Johns Hopkins

Baltimore, Maryland, 21287

Recruiting
Joban Vaishnav · Contact
Joban Vaishnav · Principal Investigator

Massachusetts General Hospital

Boston, Massachusetts, 02114

Recruiting
Daniel Zlotoff, MD, PhD · Contact
Kerry Reynolds, MD · Sub Investigator

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02115

Recruiting
Abul Aritizia, MD · Contact
Aarti Asnani, MD · Principal Investigator

Boston Medical Center

Boston, Massachusetts, 02118

Recruiting
Omar Siddiqi · Contact
Omar Siddiqi, MD · Principal Investigator

Brigham and Women's Hospital

Boston, Massachusetts, 02215

Recruiting
Anju Nohria, MD · Contact
Anju Nohria, MD · Principal Investigator

University of Michigan

Ann Arbor, Michigan, 48109

Recruiting
Salim Hayek, MD · Contact
Salim Hayek, MD · Principal Investigator

Mayo Clinic

Rochester, Minnesota, 55905

Recruiting
Joerg Herrmann · Contact
Joerg Herrmann, MD · Principal Investigator

Robert Wood Johnson University Hospital

New Brunswick, New Jersey, 08901

Recruiting
Amna Zafar · Contact
Amna Zafar · Principal Investigator

Columbia University Irving Medical Center

New York, New York, 10032

Recruiting
Jayant Raikhelkar · Contact
Jayant Raikhelkar · Principal Investigator

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

Recruiting
Dipti Gupta, MD · Contact
Dipti Gupta, MD · Principal Investigator

University of North Carolina Chapel Hill

Chapel Hill, North Carolina, 27599-7075

Recruiting
Brian Jensen, MD · Contact
Brian Jensen, MD · Principal Investigator

Cleveland Clinic

Cleveland, Ohio, 44195

Recruiting
Rohit Moudgil · Contact
Rohit Moudgil · Principal Investigator

Lehigh Valley Health Network

Bethlehem, Pennsylvania, 18017

Recruiting
Nicholas Trask · Contact
Deborah Sundlof · Principal Investigator

University of Pennsylvania

Philadelphia, Pennsylvania, 19104

Recruiting
Michael Fradley · Contact
Michael Fradley · Principal Investigator

Allegheny-Singer Research Institution

Pittsburgh, Pennsylvania, 15212

Recruiting
Valentyna Ivanova · Contact
Ivanova Ivanova, MD · Principal Investigator

University of Texas Southwestern

Dallas, Texas, 72535

Recruiting
Saketh Nadimpalli · Contact
Vlad Zaha, MD · Principal Investigator

MD Anderson Cancer Center

Houston, Texas, 77030

Not Yet Recruiting
Nicolas Palaskas · Contact
Nicolas Palaskas, MD · Principal Investigator

University of Utah

Salt Lake City, Utah, 84132

Recruiting
Anees Daud, MD · Contact
Anees Daud, MD · Principal Investigator

University of West Virginia

Morgantown, West Virginia, 26506

Recruiting
Brijesh Patel · Contact
Brijesh Patel, MD · Principal Investigator

Aurora St Luke's Medical Center

Milwaukee, Wisconsin, 53215

Recruiting
Manmeet Singh · Contact
Manmeet Singh · Principal Investigator

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)