A Multi-center Phase 3 Study of 18F-florbetaben Positron Emission Tomography/Computed Tomography (PET-CT) to Non-invasively Diagnose Cardiac AL Amyloidosis

Amyloidoses are systemic or acquired disorders characterized by the deposition in the extracellular spaces of amyloid fibers formed by proteins codified by mutated genes or non-mutated but misfolded proteins. Cardiac involvement in amyloidosis is an important determinant of the clinical presentation and can be found in patients with amyloid light-chain (AL) or transthyretin (ATTR) amyloidosis, the latter due to the deposition of normal proteins (formerly known as senile amyloidosis) or mutated proteins. Cardiac amyloidosis (CA) has a poor prognosis that further worsens if the diagnosis and treatment are delayed. Nuclear medicine techniques have emerged as important tools for the diagnosis and characterization of CA. It has been recently demonstrated that cardiac uptake of bone tracers allows to identify the deposition of transthyretin in the heart, while it is not useful for the diagnosis of AL-CA, which currently requires the histological demonstration of amyloid fibers in a tissue sample taken with invasive procedures such as an endomyocardial biopsy. Recently, some PET tracers developed to identify beta-amyloid deposits in the brain proved able to detect an uptake even in the heart; nonetheless their possible use to diagnose CA is still debated. One of those tracers is florbetaben labelled with 18F, which displays a high binding affinity with beta-amyloid in the brain, while the experience on its use to identify extracranial amyloid deposits is still limited. Three studies have reported a cardiac uptake of 18F-florbetaben in AL or ATTR amyloidosis. Tracer uptake could be detected starting from 15 minutes after tracer administration. In a case series of 60 patients (20 with AL-CA, 20 with ATTR-CA and 20 with CA suspected but excluded) we demonstrated that the evidence of a myocardial uptake in a late acquisition can effectively discriminate AL- from ATTR-CA or other conditions. Indeed, patients with AL-CA displayed an intense and persistent myocardial uptake in static acquisitions at all time points, while patients with ATTR-CA and those without CA displayed a rapid reduction of the uptake after the early acquisition.

This study aims to compare the performance of PET/CT with 18F-florbetaben to diagnose AL-CA compared with the current diagnostic standard, which requires a tissue biopsy.

Primary objective:

To define the agreement (with its 95% confidence interval) between two diagnostic approaches to the diagnosis of AL-CA in patients with a monoclonal protein: the traditional invasive approach and a non-invasive approach using the visual assessment of 18F-florbetaben PET/TC.

Secondary objectives:

• To define the diagnostic performance of PET/CT with 18F-florbetaben (visual evaluation) in terms of sensitivity, specificity, positive and negative predictive value;
• To define cut-offs from myocardial uptake quantification to confirm or discard AL-CA among patients with suspected CA and a monoclonal protein, compared to the standard diagnostic algorithm, from quantitative uptake values;
• To assess the changes in the degree of myocardial 18F-florbetaben uptake over 12 months in patients with AL-CA;
• To assess the safety and tolerability of PET/CT with 18F-florbetaben in patients evaluated for suspected CA.