Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

W P Te Rijdt; E T Hoorntje; R de Brouwer; A Oomen; A Amin; J F van der Heijden; J C Karper; B D Westenbrink; H H W Silljé; A S J M Te Riele; A C P Wiesfeld; I C van Gelder; T P Willems; P A van der Zwaag; J P van Tintelen; J H Hillege; H L Tan; D J van Veldhuisen; F W Asselbergs; R A de Boer; A A M Wilde; M P van den Berg

doi:10.1007/s12471-021-01584-5

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

Neth Heart J. 2022 Feb;30(2):84-95. doi: 10.1007/s12471-021-01584-5. Epub 2021 Jun 18.

Authors

W P Te Rijdt^{1

2}, E T Hoorntje^{3

4}, R de Brouwer⁵, A Oomen⁶, A Amin⁷, J F van der Heijden⁸, J C Karper⁵, B D Westenbrink⁵, H H W Silljé⁵, A S J M Te Riele⁸, A C P Wiesfeld⁵, I C van Gelder⁵, T P Willems⁹, P A van der Zwaag³, J P van Tintelen^{4

10}, J H Hillege⁵, H L Tan^{4

7}, D J van Veldhuisen⁵, F W Asselbergs^{8

11}, R A de Boer⁵, A A M Wilde⁷, M P van den Berg⁵

Affiliations

¹ Department of Genetics, University of Groningen, Groningen UMC, Groningen, The Netherlands. w.p.te.rijdt@umcg.nl.
² Netherlands Heart Institute, Utrecht, The Netherlands. w.p.te.rijdt@umcg.nl.
³ Department of Genetics, University of Groningen, Groningen UMC, Groningen, The Netherlands.
⁴ Netherlands Heart Institute, Utrecht, The Netherlands.
⁵ Department of Cardiology, University of Groningen, Groningen UMC, Groningen, The Netherlands.
⁶ Department of Cardiology, Antonius Hospital, Sneek, The Netherlands.
⁷ Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
⁸ Department of Cardiology, Division Heart & Lungs, Utrecht UMC, Utrecht, The Netherlands.
⁹ Department of Radiology, University of Groningen, Groningen UMC, Groningen, The Netherlands.
¹⁰ Department of Genetics, University of Utrecht, Utrecht UMC, Utrecht, The Netherlands.
¹¹ Institute of Cardiovascular Science and Institute of Health Informatics, Faculty of Population Health Sciences, University College London, London, UK.

Abstract

Background: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers.

Aims: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease.

Methods: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years.

Baseline results: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021.

Conclusion: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Keywords: Cardiomyopathy; Design; Intervention study; Phospholamban; Pre-emptive treatment; Presymptomatic carriers.

Associated data

ClinicalTrials.gov/NCT01857856