Abatacept in Immune Checkpoint Inhibitor Myocarditis (ATRIUM)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Cancer; Myocarditis Acute
• Intervention / Treatment: Drug: Abatacept plus; Drug: Placebo

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 In retrospective unpublished clinical data, the administration of abatacept to participants with ICI myocarditis on corticosteroids was associated with a reduction in risk of MACE.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

• Study Type: Interventional
• Enrollment (Estimated): 390
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hannah K Gilman, MS; Phone Number: 6177261019; Email: hkgilman@mgh.harvard.edu

Study Locations

• Canada
  • British Colombia
    • Vancouver, British Colombia, Canada, V5Z 1M9
      • Recruiting
      • University of British Colombia
      • Contact: Margot Davis
      • Principal Investigator: Margot Davis, MD
  • Ontario
    • Hamilton, Ontario, Canada, L8V 1C3
      • Recruiting
      • McMaster University
      • Contact: Darryl Leong
      • Principal Investigator: Darryl Leong, MD
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California Los Angeles
      • Contact: Eric Yang, MD
      • Principal Investigator: Eric Yang, MD
    • Los Angeles, California, United States, 02127
      • Recruiting
      • Cedars-Sinai Medical Center
      • Contact: Kiranbir Josan, MD
      • Principal Investigator: Kiranbir Josan, MD
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • MedStar Health Research Institute, Georgetown University
      • Contact: Hayder Hashim
      • Principal Investigator: Hayder Hashim
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center
      • Contact: Mohammed v
      • Principal Investigator: Mohammed Alomar
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • University of Chicago
      • Contact: Jeanne DeCara
      • Principal Investigator: Jeanne DeCara
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Recruiting
      • Franciscan Health
      • Contact: Ryan Daly
      • Principal Investigator: Ryan Daly, MD
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Recruiting
      • University of Kansas Medical Center
      • Contact: Charles Porter
      • Principal Investigator: Charles Porter, MD
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0200
      • Recruiting
      • University of Kentucky
      • Contact: Amit Arbune
      • Principal Investigator: Amit Arbune, MD
  • Maine
    • Portland, Maine, United States, 04102
      • Recruiting
      • Maine Health
      • Contact: Maxwell Afari
      • Principal Investigator: Maxwell Afari, MD
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins
      • Contact: Joban Vaishnav
      • Principal Investigator: Joban Vaishnav
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Daniel Zlotoff, MD, PhD; Phone Number: 617-726-2000; Email: dzlotoff@mgh.harvard.edu
      • Sub-Investigator: Kerry Reynolds, MD
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Anju Nohria, MD; Email: ANOHRIA@PARTNERS.ORG
      • Principal Investigator: Anju Nohria, MD
    • Boston, Massachusetts, United States, 02118
      • Recruiting
      • Boston Medical Center
      • Contact: Omar Siddiqi
      • Principal Investigator: Omar Siddiqi, MD
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Beth Israel Deaconess Medical Center
      • Contact: Abul Aritizia, MD
      • Principal Investigator: Aarti Asnani, MD
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
      • Contact: Salim Hayek, MD; Email: shayek@med.umich.edu
      • Principal Investigator: Salim Hayek, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
      • Principal Investigator: Joerg Herrmann, MD
      • Contact: Joerg Herrmann
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Robert Wood Johnson University Hospital
      • Contact: Amna Zafar
      • Principal Investigator: Amna Zafar
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Dipti Gupta, MD
      • Principal Investigator: Dipti Gupta, MD
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Jayant Raikhelkar
      • Principal Investigator: Jayant Raikhelkar
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7075
      • Recruiting
      • University of North Carolina Chapel Hill
      • Contact: Brian Jensen, MD
      • Principal Investigator: Brian Jensen, MD
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic
      • Contact: Rohit Moudgil
      • Principal Investigator: Rohit Moudgil
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Recruiting
      • Lehigh Valley Health Network
      • Contact: Nicholas Trask
      • Principal Investigator: Deborah Sundlof
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Michael Fradley
      • Principal Investigator: Michael Fradley
    • Pittsburgh, Pennsylvania, United States, 15212
      • Recruiting
      • Allegheny-Singer Research Institution
      • Contact: Valentyna Ivanova
      • Principal Investigator: Ivanova Ivanova, MD
  • Texas
    • Dallas, Texas, United States, 72535
      • Recruiting
      • University of Texas Southwestern
      • Contact: Saketh Nadimpalli; Email: Saketh.Nadimpalli@UTSouthwestern.edu
      • Principal Investigator: Vlad Zaha, MD
    • Houston, Texas, United States, 77030
      • Not yet recruiting
      • MD Anderson Cancer Center
      • Contact: Nicolas Palaskas; Email: NLPalaskas@mdanderson.org
      • Principal Investigator: Nicolas Palaskas, MD
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Recruiting
      • University of Utah
      • Contact: Anees Daud, MD
      • Principal Investigator: Anees Daud, MD
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Recruiting
      • University of West Virginia
      • Contact: Brijesh Patel
      • Principal Investigator: Brijesh Patel, MD
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Recruiting
      • Aurora St Luke's Medical Center
      • Contact: Manmeet Singh
      • Principal Investigator: Manmeet Singh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Abatacept plus standard of care; Abatacept (10 mg/kg) will be administered IV after randomization, again at 24 hours after first study drug treatment, at 14 days after first study drug treatment and an optional 4th dose at 28 days.	Drug: Abatacept 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; Other Names: Orencia
Placebo Comparator: Placebo plus standard of care; Placebo will be administered at the same intervals.	Drug: Placebo; Drug: Standard of care Local standard of care per written policies or guidelines Other Name: SoC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The individual components of the primary endpoint.	The rates of the following between groups: cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrhythmias, significant bradyarrhythmias, or incident heart failure	6 months
Myocarditis illness severity using a 7-point ordinal severity scale containing each of the individual endpoints in a hierarchical ranking order.	The worst score on a 7-point ordinal myocarditis severity scale during the 6 month period from first study treatment. The 7-point ordinal myocarditis severity scale is as follows with more severe outcomes ranked with a higher number: - No component of the primary endpoint;; - Incident heart failure;; - Significant bradyarrhythmia;; - Significant ventricular tachyarrhythmias;; - Cardiogenic shock;; - Sudden cardiac arrest;; - Cardiovascular death;	6 months
The increase in serum troponin levels	The proportion of participants in each group with a >50% increase in serum troponin value at any time during the incident hospitalization and following administration of study drug.	6 months
The combination of the rates of the primary outcome plus the proportion of patients with a troponin increase.	The rates of a composite of cardiovascular death, non-fatal sudden cardiac arrest, cardiogenic shock, significant ventricular arrhythmias, significant bradyarrhythmias, or incident heart failure plus the proportion of participants in each group with a >50% increase in serum troponin value at any time during the incident hospitalization and following administration of study drug.	6 months
Clinical status at 90 days after first infusion of study drug	Clinical status at visit 6 (day 90) on an ordinal scale with highest being the worst: - Alive and off corticosteroids for myocarditis;; - Alive and on corticosteroids (provide dose) for myocarditis;; - Alive and on cellcept (provide dose) for myocarditis;; - Alive and on both corticosteroids (provide dose) and cellcept (provide dose) for myocarditis; - Dead (cancer, cardiovascular or other).	6 months
Clinical status at 6 months after first infusion of study drug	Clinical status at visit 7 (6 months) with the highest being the worst: - Alive and off corticosteroids for myocarditis;; - Alive and on corticosteroids (provide dose) for myocarditis;; - Alive and on cellcept (provide dose) for myocarditis;; - Alive and on both corticosteroids (provide dose) and cellcept (provide dose) for myocarditis; - Dead (cancer, cardiovascular or other).	6 months
Fatal and non-fatal DVT and PE	The proportion of patients in each group with a fatal and non-fatal DVT and PE will be compared.	6 months
Other immune-related adverse events between the two groups	Rates of other immune-related adverse events between the two groups will be compared.	6 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2022
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: April 5, 2022
• First Submitted That Met QC Criteria: April 12, 2022
• First Posted (Actual): April 20, 2022

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Abatacept; Immune therapy; Myocarditis; Immune checkpoint Inhibitor; Immune related adverse events
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Myocarditis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Abatacept
• Other Study ID Numbers: 2021P003690

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No