Study design of the CARDIO-TTRansform cardiac magnetic resonance imaging substudy

Abstract

Abstract Background Cardiac magnetic resonance (CMR) with extracellular volume (ECV) mapping can track treatment response in patients with cardiac amyloidosis by assessing changes in cardiac amyloid burden along with associated changes in structure and function. The CARDIO-TTRansform trial is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial designed to assess the efficacy and safety of eplontersen in transthyretin amyloid cardiomyopathy (ATTR-CM). Eplontersen is a ligand-conjugated antisense oligonucleotide designed to reduce hepatic production of transthyretin protein, the amyloid fibril precursor protein in ATTR-CM. Patients with hereditary or wild-type ATTR-CM on available standard of care were randomized 1:1 to receive 45 mg of eplontersen or placebo via subcutaneous injection every 4 weeks. Patients in the main study with no contraindication to CMR were invited to participate in this sub-study. Purpose The primary objective is to measure the change in amyloid burden (defined as % change in ECV from baseline) over time in patients receiving eplontersen versus placebo. Methods Participants will undergo CMR with ECV mapping at baseline, 25, 49, 97 and 140 weeks (Figure 1). Images will be acquired under a standardized protocol comprising cine imaging with steady state free precession sequence, late gadolinium enhancement imaging (LGE) and T1 mapping. T1 mapping will be performed before the administration of contrast and will be repeated 15 minutes post-contrast using the same slice locations, to produce ECV maps. Results In the main study, 1432 patients were randomized from 120 sites across 20 countries. Of these patients, 157 patients were enrolled in the CMR sub-study, from 6 centers across 4 countries. Images will be read centrally at the end of the study. All participants in the study will also receive serial transthoracic echocardiography with strain analysis to correlate findings with conventional imaging techniques, and a subset of patients from the CMR substudy will be co-enrolled in a scintigraphy substudy for further characterization of amyloid deposition in their heart. Conclusion The CARDIO-TTRansform CMR substudy represents the largest CMR study of ATTR-CM. The CMR sub-study has enrolled a broad global population of patients with hereditary and wild-type ATTR-CM and will provide key information on the impact of eplontersen on the cardiac amyloid load and the associated change in structure and function.