REVEAL - Research With I-124 EVuzamitide to Elucidate Cardiac AmyLoidosis

A Phase 3, Open-Label, Multicenter Study of I-124 Evuzamitide as an Imaging Agent for the Diagnosis of Cardiac Amyloidosis Using Positron Emission Tomography Computed Tomography (PET/CT)

The purpose of this multicenter, open-label, single-arm, single-dose study is to assess the sensitivity and specificity of I-124 evuzamitide for the diagnosis of cardiac amyloidosis compared to current clinical standards for diagnosis of cardiac amyloidosis. Participants will receive a positron emission tomography computed tomography (PET/CT) scan 4 hours (± 60 minutes) after administration of I-124 evuzamitide. The primary study hypotheses are that the sensitivity and specificity of I-124 evuzamitide PET/CT imaging of cardiac amyloidosis will be greater than 65% and 55%, respectively, in participants with suspected cardiac amyloidosis.

This multicenter, open-label, single-arm, single-dose study will assess the sensitivity and specificity of I-124 evuzamitide for the diagnosis of cardiac amyloidosis compared to current clinical standards for diagnosis of cardiac amyloidosis.

The study consists of (i) up to a 45-day screening period, (ii) a treatment emergent period that consists of a 1-day treatment visit and safety follow-up procedures through Day 30 ± 5 days, and (iii) a Standard of Truth (SoT) Diagnostic Evaluation Period that extends from the screening period (Day -45) until either the last cardiac amyloidosis diagnostic test is completed or through Day 60, whichever is earlier. Thus, the total participant duration is up to approximately 3.5 months. The study will enroll approximately 200 participants with suspected cardiac amyloidosis at approximately 20 United States clinical sites.

I-124 evuzamitide is the only study intervention; neither reference therapy nor placebo will be administered. Potassium iodide (KI) will be given orally for 3 days beginning >30 minutes prior to intravenous administration of study intervention. PET/CT scans will be obtained approximately 4 hours after administration of study intervention.

Sensitivity and specificity of I-124 evuzamitide will be determined using the classification of participants based on visual evaluation of the PET/CT images and cardiac amyloid disease status based on the clinical truth standard. An independent Clinical Adjudication Committee with expertise in cardiology, amyloidosis, and/or cardiac imaging will review the information obtained during the diagnostic evaluation (e.g., clinical history and laboratories, EMB, extracardiac biopsy, ECHOs, CMR, and bone-avid tracer cardiac SPECT) to determine if the data support a diagnosis of cardiac amyloidosis. The clinical truth standard will be based on all available information provided to the Clinical Adjudication Committee by the diagnostic evaluation. Three independent readers who are blinded to all clinical data will review deidentified PET/CT images for the presence/absence of cardiac uptake of I-124 evuzamitide.

Inclusion Criteria:

• Understands the study procedures and can give signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Male or female ≥18 years of age.
• Is suspected of having cardiac amyloidosis and is undergoing or will undergo a diagnostic evaluation for cardiac amyloidosis (e.g., echocardiogram [ECHO], cardiac magnetic resonance imaging [CMR], bone-avid tracer cardiac single-photon emission computerized tomography (SPECT), extracardiac biopsy, or endomyocardial biopsy [EMB]). Participants may be enrolled before or during their diagnostic evaluation for cardiac amyloidosis.
• Able to undergo PET/CT imaging as part of the study, including ability to lie supine for approximately 1 hour.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 30 days after administration of I-124 evuzamitide.
• For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm during the treatment period and for at least 120 days after the last dose of study intervention.

Exclusion Criteria:

• Established diagnosis of cardiac amyloidosis.
• Established diagnosis of systemic amyloidosis with known organ involvement (e.g., renal AL or ATTR peripheral neuropathy). Participants who are amyloid positive only from peripheral tissue, such as abdominal fat, carpal tunnel tissue, or laminectomy tissue, are allowed as long as they do not have other known organ involvement.
• Receiving therapy with an approved treatment (e.g., tafamadis) or in a clinical trial for treatment for ATTR cardiac amyloidosis at time of enrollment. For AL and ATTR amyloidosis: Patients may enter the screening period of a clinical trial for treatment after the ICF is signed and they are enrolled in this trial, but they may not receive an experimental therapy until after the Day 30 safety follow-up visit in this trial.
• Is pregnant or breast-feeding.
• Is mentally or legally incapacitated, has significant emotional problems at the time of the study, or has a history of psychosis.
• Has a known allergy to KI.
• Receiving hemodialysis or peritoneal dialysis.
• Estimated glomerular filtration rate (eGFR) less than 15 mL/min/1.73 m^2.
• Myocardial infarction within 3 months of screening.
• Has severe claustrophobia or any condition, medical or otherwise, that would prevent completion of the study assessments.
• Has any illness that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the participant.
• Has received heparin or heparin analogs (e.g., enoxaparin, dalteparin, fondaparinux) within 7 days prior to I-124 evuzamitide administration.
• Known uncorrected thyroid disorders (other than mild elevation of thyroid stimulating hormone with normal thyroxine [T4]).