Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy

John Farrant; Susanna Dodd; Carly Vaughan; Anna Reid; Matthias Schmitt; Clifford Garratt; Mohammed Akhtar; Masliza Mahmod; Stefan Neubauer; Robert Cooper; Sanjay K. Prasad; Anvesha Singh; Ladislav Valkovič; Betty Raman; Zakariye Ashkir; Dannii Clayton; Olatz Baroja; Beatriz Duran; Catherine Spowart; Emma Bedson; Josephine Naish; Chris F. Harrington; Christopher Miller; TEMPEST investigators

doi:10.1136/heartjnl-2022-322271

Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy

John Farrant, Susanna Dodd, Carly Vaughan, Anna Reid, Matthias Schmitt, Clifford Garratt, Mohammed Akhtar, Masliza Mahmod, Stefan Neubauer, Robert Cooper, Sanjay K. Prasad, Anvesha Singh, Ladislav Valkovič, Betty Raman, Zakariye Ashkir, Dannii Clayton, Olatz Baroja, Beatriz Duran, Catherine Spowart, Emma BedsonJosephine Naish, Chris F. Harrington, Christopher Miller, TEMPEST investigators

Division of Cardiovascular Sciences (L5)

University of Liverpool

Research output: Contribution to journal › Article › peer-review

Abstract

Aims: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM.

Methods: The Efficacy and Mechanism of trientine in PatiEntS with hypertrophic cardiomyopaThy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association Class I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in LV mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics.

Conclusion: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM.

Original language	English
Pages (from-to)	1175-1182
Journal	Heart
Volume	109
Issue number	15
Early online date	3 May 2023
DOIs	https://doi.org/10.1136/heartjnl-2022-322271
Publication status	Published - 12 Jul 2023

Keywords

Hypertrophic cardiomyopathy
randomised controlled trial
trientine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/heartjnl-2022-322271

Cite this

Farrant, J., Dodd, S., Vaughan, C., Reid, A., Schmitt, M., Garratt, C., Akhtar, M., Mahmod, M., Neubauer, S., Cooper, R., Prasad, S. K., Singh, A., Valkovič, L., Raman, B., Ashkir, Z., Clayton, D., Baroja, O., Duran, B., Spowart, C., ... TEMPEST investigators (2023). Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy. Heart, 109(15), 1175-1182. https://doi.org/10.1136/heartjnl-2022-322271

@article{16f64fbab1db44458347efbd08b7d64a,

title = "Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy",

abstract = "Aims: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM.Methods: The Efficacy and Mechanism of trientine in PatiEntS with hypertrophic cardiomyopaThy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association Class I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in LV mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. Conclusion: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM.",

keywords = "Hypertrophic cardiomyopathy, randomised controlled trial, trientine",

author = "John Farrant and Susanna Dodd and Carly Vaughan and Anna Reid and Matthias Schmitt and Clifford Garratt and Mohammed Akhtar and Masliza Mahmod and Stefan Neubauer and Robert Cooper and Prasad, {Sanjay K.} and Anvesha Singh and Ladislav Valkovi{\v c} and Betty Raman and Zakariye Ashkir and Dannii Clayton and Olatz Baroja and Beatriz Duran and Catherine Spowart and Emma Bedson and Josephine Naish and Harrington, {Chris F.} and Christopher Miller and {TEMPEST investigators}",

year = "2023",

month = jul,

day = "12",

doi = "10.1136/heartjnl-2022-322271",

language = "English",

volume = "109",

pages = "1175--1182",

journal = "Heart",

issn = "1355-6037",

publisher = "BMJ ",

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}

Farrant, J, Dodd, S, Vaughan, C, Reid, A, Schmitt, M, Garratt, C, Akhtar, M, Mahmod, M, Neubauer, S, Cooper, R, Prasad, SK, Singh, A, Valkovič, L, Raman, B, Ashkir, Z, Clayton, D, Baroja, O, Duran, B, Spowart, C, Bedson, E, Naish, J, Harrington, CF, Miller, C & TEMPEST investigators 2023, 'Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy', Heart, vol. 109, no. 15, pp. 1175-1182. https://doi.org/10.1136/heartjnl-2022-322271

TY - JOUR

T1 - Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy

AU - Farrant, John

AU - Dodd, Susanna

AU - Vaughan, Carly

AU - Reid, Anna

AU - Schmitt, Matthias

AU - Garratt, Clifford

AU - Akhtar, Mohammed

AU - Mahmod, Masliza

AU - Neubauer, Stefan

AU - Cooper, Robert

AU - Prasad, Sanjay K.

AU - Singh, Anvesha

AU - Valkovič, Ladislav

AU - Raman, Betty

AU - Ashkir, Zakariye

AU - Clayton, Dannii

AU - Baroja, Olatz

AU - Duran, Beatriz

AU - Spowart, Catherine

AU - Bedson, Emma

AU - Naish, Josephine

AU - Harrington, Chris F.

AU - Miller, Christopher

AU - TEMPEST investigators

PY - 2023/7/12

Y1 - 2023/7/12

N2 - Aims: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM.Methods: The Efficacy and Mechanism of trientine in PatiEntS with hypertrophic cardiomyopaThy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association Class I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in LV mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. Conclusion: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM.

AB - Aims: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM.Methods: The Efficacy and Mechanism of trientine in PatiEntS with hypertrophic cardiomyopaThy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association Class I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in LV mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. Conclusion: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM.

KW - Hypertrophic cardiomyopathy

KW - randomised controlled trial

KW - trientine

U2 - 10.1136/heartjnl-2022-322271

DO - 10.1136/heartjnl-2022-322271

M3 - Article

SN - 1355-6037

VL - 109

SP - 1175

EP - 1182

JO - Heart

JF - Heart

IS - 15

ER -

Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy

Abstract

Keywords

UN SDGs

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