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Below are the reference and statements:
<reference>
John P Farrant, Susanna Dodd, Anna Rosala-Hallas, Carly Vaughan, Catherine Spowart, Emma
Bedson, Dannii Clayton, Anna B Reid, Cli ord J Garratt, Betty Raman, Masliza Mahmod,
Mohammed Akhtar, Ladislav Valkovič, Zakariye Ashkir, Robert Cooper, Anvesha Singh, Sanjay
Prasad, Thomas Green, Dana Dawson, James C Moon, Olatz Baroja, Beatriz Duran, Josephine
Naish, Chris F Harrington, Scot Garg, Catriona Graham, Saidi Mohiddin, Marc R Dweck, Nicola
Greenlaw, Sven Plein, Colin Berry, Matthias Schmitt, Stefan Neubauer, Christopher A Miller

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Trientine for hypertrophic cardiomyopathy: a phase 2 trial

European Heart Journal (2026) 00, 1–12
https://doi.org/10.1093/eurheartj/ehag512

CLINICAL RESEARCH
Heart failure and cardiomyopathies

John P. Farrant 1,2, Susanna Dodd3, Anna Rosala-Hallas4, Carly Vaughan4,
Catherine Spowart4, Emma Bedson4, Dannii Clayton4, Anna B. Reid1,2,
Clifford J. Garratt1,2, Betty Raman 5,6, Masliza Mahmod 5,6, Mohammed Akhtar5,6,
Ladislav Valkovič5,7, Zakariye Ashkir5,6, Robert Cooper 8,9, Anvesha Singh 10,
Sanjay Prasad 11,12, Thomas Green13, Dana Dawson 14,15, James C. Moon 16,17,
Olatz Baroja2, Beatriz Duran2, Josephine Naish 1,2, Chris F. Harrington18,19,
Scot Garg 20,21, Catriona Graham 22, Saidi Mohiddin17,23, Marc R. Dweck24,
Nicola Greenlaw25, Sven Plein 26, Colin Berry 27,28, Matthias Schmitt1,2,
Stefan Neubauer 5,6, and Christopher A. Miller 1,2,29,*; for the TEMPEST Investigators§
1

Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of
Manchester, Oxford Road, Manchester, M13 9PT, UK; 2Northwest Heart Centre, Manchester University NHS Foundation Trust, Southmoor Road, Wythenshawe,
Manchester M23 9LT, Manchester, UK; 3Department of Health Data Sciences, Institute of Population Health, Faculty of Health and Life Sciences, University of Liverpool,
Liverpool, UK; 4Liverpool Clinical Trials Centre, Clinical Directorate, Faculty of Health and Life Sciences, University of Liverpool, Block C, Waterhouse Building, 1-5
Brownlow Street, Liverpool, L69 3GLUK; 5Oxford Centre for Clinical MR Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of
Oxford, Oxford, UK; 6Oxford University Hospitals Foundation Trust, NIHR Oxford Biomedical Research Centre, Oxford, UK; 7Department of Imaging Methods, Institute
of Measurement Science, Slovak Academy of Sciences, Bratislava, Slovakia; 8Cardiology Department, Liverpool Heart and Chest Hospital, Thomas Dr, Liverpool, UK;
9
Liverpool Centre for Cardiovascular Science, Liverpool John Moores University, Merseyside, UK; 10Division of Cardiovascular Sciences, University of Leicester, National
Institute for Health and Care Research Biomedical Research Centre Leicester, and Leicester British Heart Foundation Centre of Research Excellence, Leicester, UK;
11
Cardiology Department, Royal Brompton and Harefield NHS Foundation Trust, London, UK; 12National Heart and Lung Institute, Imperial College London, London, UK;
13
Cardiology Department, Northumbria Healthcare NHS Trust, Northumberland, UK; 14School of Medicine, University of Aberdeen, Scotland, Aberdeen, UK;
15
Cardiology Department, Aberdeen Royal Infirmary, Scotland, Aberdeen, UK; 16Institute of Cardiovascular Science, University College London, London, UK;
17
St.Bartholomew’s Hospital, Barts Heart Centre, London, UK; 18SAS Trace Element Laboratory, Surrey Research Park, Guildford, UK; 19Berkshire and Surrey Pathology
Services, Royal Surrey NHS Foundation Trust, Guildford, UK; 20Department of Cardiology, Royal Blackburn Hospital, Blackburn, UK; 21School of Medicine and Dentistry,
University of Lancashire,Preston, UK; 22Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, UK; 23William Harvey Institute, Queen Mary University
of London, London, UK; 24British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; 25Robertson Centre for Biostatistics,
University of Glasgow, Glasgow, UK; 26Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, UK; 27British Heart
Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK; 28Cardiology Department, Golden Jubilee National Hospital, Clydebank, UK;
and 29Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative Medicine, School of Biology, Faculty of Biology, Medicine & Health,
Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 16 January 2026; revised 20 April 2026; accepted 17 June 2026

Abstract
Background and
Aims

Pathophysiological features of hypertrophic cardiomyopathy include left ventricular hypertrophy, myocardial
fibrosis, and myocardial energy deficiency. Depletion of cardiomyocyte copper I ions leads to impaired mito­
chondrial function, a state associated with left ventricular hypertrophy. Unbound or loosely bound copper II
ions activate profibrotic pathways. Trientine dihydrochloride improves intracellular copper I ion trafficking
and availability, and chelates copper II ions. In preclinical studies, trientine improved myocardial mitochondrial
function and reduced left ventricular hypertrophy and fibrosis. The efficacy and safety of trientine in persons
with hypertrophic cardiomyopathy are unknown.
.....................................................................................................................................................................

* Corresponding author. Tel: +0044 161 291 3244, Email: Christopher.Miller@manchester.ac.uk
§
TEMPEST Investigators are listed in the supplemental file.
© The Author(s) 2026. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits
unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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Trientine for hypertrophic cardiomyopathy:
a phase 2 trial

2

Farrant et al.

Methods

Structured Graphical Abstract
Key Question
What are the efficacy, mechanism of action and safety of trientine in patients with hypertrophic cardiomyopathy (HCM)?

Key Finding
In a phase 2, multicenter, double-blind, randomized controlled trial in patients with HCM, treatment with trientine resulted in a significant
reduction in left ventricular mass indexed to body surface area (LVMi). The efficacy of trientine increased with higher baseline LVMi. The
effect of trientine was mediated via a reduction in myocardial cellular mass. Trientine was safe and well tolerated.

Take Home Message
Phase 3 trials are required to determine whether these favourable effects translate into clinical benefit.

Trientine for HCM: a phase 2 trial (the TEMPEST trial)
Randomized

Participants
• Adults with HCM
• Wall thickness ≥15mm
• NYHA Class I–III
• Any LVOT gradient

Primary outcome

Trientine (n = 79)
52 weeks

Change in LVMi
measured using CMR

Placebo (n = 75)

(n = 154)

Trientine (n = 79)

Placebo (n = 75)

Between group difference

P value

-4.4 ± 7.7 g/m2

-1.5 ± 6.1 g/m2

-3.2 (-5.6 to -0.8) g/m2

0.009

Adjusted treatment effect by baseline LVMi quartile
Favours trientine

Favours placebo

25 centile (72 g/m )
th

2

50th centile (85 g/m2)
75th centile (102 g/m2)
-8

-7

-6

-5

-4 -3 -2 -1
0
Change in LVMi (g/m2)

1

2

3

CMR, cardiovascular magnetic resonance; HCM, hypertrophic cardiomyopathy; LVMi, left ventricular mass indexed to body surface area; LVOT, left ventricular outflow tract;
NYHA, New York Heart Association
Farrant JP, et al. European Heart Journal.

.....................................................................................................................................................................

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In this multicentre, placebo-controlled phase 2 trial, adults with hypertrophic cardiomyopathy, a left ventricular
wall thickness of 15 mm or greater, and who were in New York Heart Association class I to III were randomly
assigned to receive trientine 400 mg twice daily or placebo for 52 weeks. Patients with any left ventricular out­
flow tract (LVOT) gradient were eligible. The primary endpoint was the change in left ventricular mass indexed
to body surface area measured using cardiovascular magnetic resonance.
.....................................................................................................................................................................
Results
A total of 154 patients underwent randomization. The mean age was 53.4 years, median maximum left ventricular
wall thickness was 20.0 mm, median maximum LVOT gradient was 6.0 mmHg, 18.6% of patients had a resting
LVOT gradient ≥30 mmHg, and 61.7% were in New York Heart Association class I. At 52 weeks, the mean change
in the left ventricular mass indexed to body surface area was −4.4 ± 7.7 g/m2 in the trientine group and −1.5 ±
6.1 g/m2 in the placebo group (between-group difference −3.2 g/m2; 95% confidence interval −5.6 to −0.8;
P = .009). The efficacy of trientine increased at higher levels of baseline left ventricular mass (baseline left ven­
tricular mass indexed to body surface area by treatment allocation interaction P = .015). The effect of trientine
was mediated via a reduction in myocardial cellular mass (average causal mediated effect −3.9 g/m2; 95% confi­
dence interval −6.8 to −0.9). The incidence of adverse events was similar in the two groups.
.....................................................................................................................................................................
Conclusions
Among patients with hypertrophic cardiomyopathy, treatment with trientine resulted in a significantly greater
reduction in left ventricular mass indexed to body surface area than placebo. (Funded by NIHR; TEMPEST
ClinicalTrials.gov number, NCT04706429).

3

Trientine for hypertrophic cardiomyopathy

Keywords

Hypertrophic cardiomyopathy • Copper chelation • Cardiac magnetic resonance • Indexed left ventricular
mass • Efficacy • Mechanism of action • Safety • Phase 2 trial

Introduction

Methods
Trial design and oversight
The TEMPEST trial was a phase 2, multicentre, parallel group,
double-blind, randomized, placebo-controlled trial. The design of
the trial has been described previously.13 The trial was designed
by the research team with patient and public involvement, spon­
sored by Manchester University NHS Foundation Trust, and funded
by the UK National Institute for Health and Care Research (funder
reference NIHR127575). Trial management, independent data man­
agement, and independent statistical analysis were performed by
Liverpool Clinical Trials Centre, a United Kingdom Clinical
Research Collaboration fully registered Clinical Trials Unit. The
study protocol was approved by a research ethics committee

Participants
Patients were eligible for enrolment if they were aged 18–75 years;
had a confirmed clinical diagnosis of hypertrophic cardiomyopathy
in keeping with the European Society of Cardiology guidelines with
a left ventricular wall thickness of at least 15 mm in the absence of
another cause of hypertrophy,14 and were in New York Heart
Association class I, II, or III. Key exclusion criteria included a left ven­
tricular ejection fraction of <50%; persistent atrial fibrillation; previ­
ous or planned septal reduction therapy; pacemaker or implantable
cardioverter-defibrillator (ICD); anaemia; iron deficiency; copper de­
ficiency; and contraindication to magnetic resonance imaging. No
LVOT gradient threshold was specified in the recruitment criteria; pa­
tients with any LVOT gradient were eligible for inclusion. Detailed eli­
gibility criteria are provided in Supplementary data online, Table S1.

Procedures
Eligible patients were randomized in a 1:1 ratio to receive either tri­
entine or placebo for 52 weeks using block randomization, stratified
by site, with computer-generated randomization allocations and ran­
domly varying block sizes. Randomization was done using web ran­
domization software accessed using a secure website provided via
the clinical trials unit. Trientine was taken orally as two Cufence
200 mg hard capsules two times per day (total daily dose of trientine
was 800 mg, which is equivalent to 1200 mg of trientine dihy­
drochloride). An identical placebo was also taken orally as two cap­
sules two times per day. All background medications were
continued. Baseline assessments included laboratory investigations,
electrocardiography, 24-h heart rhythm monitoring, cardiovascular
magnetic resonance imaging and cardiopulmonary exercise testing,
all of which were analysed in blinded core labs. Baseline assessments
were repeated at the final visit (Week 52). A subgroup of participants
(n = 84) additionally underwent 31-phosphorus magnetic resonance
spectroscopy at baseline and the final visit, which was also analysed
at a blinded core lab. All procedures, including core lab methods and
cardiovascular magnetic resonance measurement reproducibility,
have been described previously.13,15 The visit schedule including
safety monitoring is detailed in Supplementary data online, Table S2.

Endpoints
The primary outcome measure was the change in left ventricular
mass indexed to body surface area (LVMi; g/m2) from baseline to
Week 52, measured using cardiovascular magnetic resonance.
Pre-specified secondary outcomes included change, from baseline

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Hypertrophic cardiomyopathy is the most common inherited
heart disease globally. Characterized by left ventricular hyper­
trophy, pathophysiological features include cardiomyocyte dis­
array, myocardial energy deficiency, oxidative stress and
myocardial fibrosis.1,2 Cardiac myosin inhibitors improve heart
failure symptoms and the functional capacity of patients with
hypertrophic cardiomyopathy and left ventricular outflow tract
(LVOT) obstruction by reducing hypercontractility.3,4 Cardiac
myosin inhibitors have established that causal treatment of
hypertrophic cardiomyopathy is achievable, but there remains
a need for approaches that target additional mechanisms, par­
ticularly for patients without LVOT obstruction, which appear
to comprise the majority of patients.5,6
Copper is widely used as a catalytic or structural cofactor by
enzymes and proteins involved in processes that are central to
the pathophysiology of hypertrophic cardiomyopathy, including
mitochondrial respiration, antioxidant defence, and extracellular
matrix crosslinking.7 Depletion of cardiomyocyte copper I ions
(Cu+), which contribute ∼95% of total body copper, leads to im­
paired mitochondrial function and dysregulated energy produc­
tion and is associated with myocardial hypertrophy. In contrast,
unbound or loosely bound copper II ions (Cu2+), which are pre­
sent extracellularly, powerfully catalyse oxidative stress, inhibit
enzymatic antioxidants, and activate profibrotic pathways.7
Trientine dihydrochloride is a highly selective chelator of Cu2+
that also improves intracellular Cu+ trafficking and availability
through improved copper transporter and chaperone function.8
In preclinical models of increased cardiac afterload and diabetes,
trientine was associated with improved myocardial mitochon­
drial function, reduced myocardial oxidative stress, improved or­
ganization of cardiomyocytes, reduced left ventricular
hypertrophy, and reduced myocardial fibrosis.9,10 In patients
with diabetic cardiomyopathy, trientine led to a reduction in
left ventricular mass.11 In a small, open-label trial in patients
with hypertrophic cardiomyopathy, trientine was well toler­
ated.12 The Efficacy and Mechanism of Trientine in Patients
with Hypertrophic Cardiomyopathy (TEMPEST) trial was de­
signed to evaluate the efficacy, mechanism of action, and safety
of trientine in patients with hypertrophic cardiomyopathy.

(NHS Health Research Authority, reference 20/NW/0275), and trial
conduct was overseen by a trial steering committee and an inde­
pendent data and safety monitoring committee. The investigational
medicinal product was provided in kind by Univar Solutions B.V.
Univar Solutions B.V. had no role in trial design and was not involved
in the preparation, drafting, or editing of this manuscript. Univar
Solutions B.V. conducted a factual accuracy check of the manu­
script, but any decisions to incorporate comments were made solely
at the discretion of the authors. All patients provided written in­
formed consent, and the trial was conducted in accordance with
the principles of Good Clinical Practice and the World Medical
Association Declaration of Helsinki. All authors reviewed and ap­
proved the manuscript and assume full responsibility for the accur­
acy and completeness of the data and for the fidelity of the trial to
the protocol, which is available as Supplementary data online, file.

4

Statistical analysis
We determined that 64 patients per group would provide the trial
with 80% power to detect a minimum difference, between trientine
and placebo groups, of 2.5 g/m2 in terms of change in LVMi from
baseline following 52 weeks of treatment, at a 5% significance level
(two-sided), assuming a standard deviation of within-patient differ­
ences from baseline of 5 g/m2. To allow for treatment discontinu­
ation in up to 25% of patients, the number of patients was
originally inflated to 86 per group (i.e. total n = 172); however, trial re­
tention was found to be better than expected, therefore the protocol
was modified to reduce the treatment discontinuation rate to 15%,
meaning that 76 patients per group were required (i.e. total n = 152).
The trial was analysed and reported according to the
Consolidated Standard of Reporting Trials (CONSORT) and
International Conference on Harmonization E9 guidelines. The
Statistical Analysis Plan, which prospectively detailed all analyses,
and which was signed in advance of database lock, is available as
Supplementary data online, file. All analyses were performed accord­
ing to the intention-to-treat principle, using complete case analysis.
The primary and secondary outcomes were compared between treat­
ment groups using analyses of covariance, adjusting for baseline va­
lues of the outcome variable, site, and treatment allocation. Including
a baseline value by treatment allocation interaction term in the ana­
lyses of covariance models indicated that the homogeneity of regres­
sion slopes assumption was not met for the primary outcome, and
some of the secondary outcomes were stated. Therefore, the 25th,
50th, and 75th quartiles of baseline values were computed, and three
centred baseline variables were produced (quartile minus each base­
line variable, in turn). The baseline variable in the analyses of covari­
ance model (including the interaction) was then replaced by each
centred baseline variable in turn. A sensitivity regression analysis, ad­
justing for baseline variables that predicted the primary outcome or
missingness, was used to assess the robustness of the primary out­
come results to missing data.16 An additional sensitivity analysis
was performed to estimate the causal effect of treatment on the pri­
mary outcome by appropriately allowing for dose received using in­
strumental variable regression, thus accounting for informative
premature treatment discontinuation. Potential mediators of the im­
pact of trientine on LVMi were hypothesized to include myocardial
fibrosis (myocardial extracellular mass), myocardial cellular mass,
phosphocreatine to adenosine triphosphate ratio, and urine copper
excretion. In order to test whether these variables predicted change
in LVMi, mediation analysis was conducted, adjusting for baseline
covariates that predicted both the mediator and LVMi. Sensitivity
analyses were conducted to assess the potential impact of unmeas­
ured confounding between mediator and outcome. Adverse events
were coded according to preferred terms in the Medical Dictionary
for Regulatory Activities (version 27). The number and percentage
of participants experiencing each safety outcome (from the period
of informed consent to the final study visit) were reported, and

changes in safety outcomes were described using summary statistics.
The conventional 5% significance level was used. Hypothesis testing
on secondary outcomes was considered exploratory. All analyses
were performed using SAS (version 9.4, SAS Institute, Cary, NC, USA).

Results
Patients
From 17 February 2021 to 27 April 2023, 969 patients were
pre-screened at six sites in the UK. One hundred ninety patients
attended for a screening visit, of whom 154 patients were ran­
domly assigned to receive trientine or placebo (see
Supplementary data online, Figure S1). At the end of the trial,
2 patients were lost to follow-up, 11 had withdrawn from the
trial, 2 were determined to have an exclusory cardiomyopathic
cause of myocardial hypertrophy, and 3 had received an ICD,
which precluded measurement of the primary outcome. A total
of 136 patients were included in the final efficacy analysis.
The demographic and clinical characteristics of the two groups
were well balanced at baseline (Table 1 and Supplementary data
online, Table S4). Mean age was 53.4 years, 23.4% were female,
and 37% of patients who had undergone genetic testing had a con­
firmed pathogenic variant in a sarcomeric gene. Median LVMi was
85.8 g/m2, median left ventricular maximum wall thickness was
20.0 mm, median maximum LVOT gradient was 6.0 mmHg,
61.7% of patients were in New York Heart Association class I,
and estimated 5-year risk of sudden cardiac death was 2.0%.17
No patient received a cardiac myosin inhibitor during the trial.

Efficacy
The mean change in LVMi, measured using cardiovascular mag­
netic resonance, from baseline to Week 52 was −4.4 ± 7.7 g/m2
among patients in the trientine group and −1.5 ± 6.1 g/m2 among
those in the placebo group. Mean between-group difference was
−3.2 g/m2 [95% confidence interval (CI) −5.6 to −0.8; P = .009].
As is evident from Figure 1, the efficacy of trientine for reducing
LVMi increased at higher levels of baseline LVMi (baseline LVMi
by treatment allocation interaction P = .015), with the effect of tri­
entine becoming significant at a minimum baseline LVMi of
81.6 g/m2 (mean between-group difference in LVMi); at the
25th centile of baseline LVMi: −1.2 g/m2 (95% CI −4.1 to 1.6;
P = .33); at the 50th centile of baseline LVMi: −2.9 g/m2 (95% CI
−5.2 to −0.5; P = .019); and at the 75th centile of baseline
LVMi: −5.0 g/m2 (95% CI −7.7 to −2.2; P < .001) (Table 2). A sen­
sitivity analysis adjusting for missing primary outcome data
yielded consistent results (Table 3). The causal analysis was also
consistent, demonstrating, for example, that for each additional
100 capsules of trientine taken (i.e. 25 days of treatment), there
was a mean reduction in LVMi at 52 weeks of 0.5 g/m2 (95% CI
−0.7 to −0.3; P < .001) in patients with baseline LVMi at the
75th centile (Table 3). In a replication analysis, artificial intelligence
measurement of LVMi yielded consistent results (Table 3).
Baseline LVOT gradient did not have a significant impact on LVMi.
Secondary outcomes are presented in Tables 3, S5, and S6.
Treatment with trientine led to a significant increase in urine
copper–creatinine ratio compared to placebo (mean difference
165.0 nmol/mM creatinine; 95% CI 132.6–197.4), with the ef­
fect seen by Week 13 and persisting throughout the treatment
period (see Supplementary data online, Figure S2). Compared

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to Week 52, in measurements of exercise capacity; left atrial volume
and function; left ventricular mass, wall thickness, volumes and func­
tion; myocardial cellular mass; myocardial fibrosis; myocardial ener­
getics; atrial and ventricular arrhythmia burden; high-sensitivity
troponin; and urine copper excretion. Change in LVMi measured via
artificial intelligence analysis of cardiovascular magnetic resonance
images (MyCardium AI, 1CMR, version 010100zc) was included as
an additional secondary outcome (replication analysis) following a trial
steering committee meeting in May 2023 (included in the Statistical
Analysis Plan in advance of database lock). Safety outcome measure­
ments included adverse events and changes in vital signs, laboratory
investigations, and electrocardiogram measurements. A complete
list of pre-specified primary, secondary, and safety outcome measure­
ments is provided in Supplementary data online, Table S3.

Farrant et al.

5

Trientine for hypertrophic cardiomyopathy

Table 1

Demographic and clinical characteristics of the participants at baseline

Characteristic

Trientine
(n = 79)

Placebo
(n = 75)

Age, years

55 (48–63)

56 (45–63)

Female sex, n (%)

23 (29.1)

13 (17.3)

Hypertension

31 (39.2)

21 (28.0)

Systolic blood pressure, mmHg

137 (123–153)

135 (123–152)

Paroxysmal atrial fibrillation

11 (13.9)

5 (6.7)

Transient ischaemic attack

1 (1.3)

5 (6.7)

Diabetes mellitus

5 (6.3)

3 (4.0)

Did participant have genetic testing?

51 (64.6)

51 (68.0)

No pathogenic variant or variant of uncertain significance identified

28 (58.3)

30 (60.0)

Pathogenic variant in MYPBC3

12 (25.0)

10 (20.0)

Pathogenic variant in MYH7

4 (8.3)

6 (12.0)

Other pathogenic variant

4 (8.3)

4 (8.0)

Beta blockers

45 (57.0)

37 (49.3)

Cholesterol-lowering medications

25 (31.6)

27 (36)

Calcium channel blockers

12 (15.2)

17 (22.7)

Angiotensin-converting enzyme inhibitors

9 (11.4)

11 (14.7)

0 (0.0)

0 (0.0)

I

48 (60.8)

47 (62.7)

II

21 (26.6)

23 (30.7)

III

10 (12.7)

5 (6.7)

IV

0 (0)

0 (0)

...............................................................................................................................................................

Medical history, n (%)

Concomitant medications, n (%)

Cardiac myosin inhibitor
New York Heart Association functional class, n (%)

a

Calculated risk of sudden cardiac death at 5 years, %17

2.1 (1.5–2.7)

2.0 (1.6–2.6)

Maximum resting left ventricular outflow tract gradient, mmHg

7.0 (4.0–26.0)

5.0 (4.0–14.0)

Maximum resting left ventricular outflow tract gradient <30 mmHg, n (%)

45 (76.3)

51 (86.4)

Maximum resting left ventricular outflow tract gradient >30 mmHg, n (%)

14 (23.7)

8 (13.6)

Maximum valsalva left ventricular outflow tract gradient, mmHg

8.5 (4.0–48.0)

9.0 (4.0–33.0)

Serum iron, µmol/L

18.4 (14.1–22.6)

18.5 (14.5–22.1)

Serum copper, µmol/L

15.1 (13.4–17.5)

14.5 (13.5–16.6)

Serum caeruloplasmin, g/L

0.3 (0.2–0.3)

0.3 (0.2–0.3)

Urine copper–creatinine ratio, nmol/mM Cr

12.8 (9.9–17.2)

11.7 (9.7–14.1)

High sensitivity troponin, ng/L

10.0 (8.0–14.0)

11.0 (7.0–18.0)

84.2 (69.6–99.7)

86.8 (74.5–112.0)

20 (18–23)

20 (18–22)

Laboratory investigations

Cardiovascular magnetic resonance variables
Left ventricular mass indexed to body surface area, g/m2
Left ventricular maximal wall thickness, mm

Continued

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Genetic testing, n (%)

6

Farrant et al.

Table 1

Continued

Characteristic

Trientine
(n = 79)

Placebo
(n = 75)

75.5 (72.0–80.0)

74.0 (70.0–78.0)

59.1 (48.2–74.9)

57.8 (47.6–67.9)

125.4 (98.0–146.7)

130.7 (109.6–161.1)

21.6 (18.1–27.5)

23.6 (20.2–28.8)

1.6 (1.4–2.0)

1.5 (1.3–1.9)

Peak oxygen uptake, mL/min/kg

19.9 (15.1–25.0)

20.8 (16.0–26.1)

Ventilatory efficiencyc

27.2 (23.5–30.6)

27.1 (24.3–30.2)

...............................................................................................................................................................
Left ventricular ejection fraction, %

2

Left atrial volume indexed to body surface area, mL/m

2

Left ventricular cellular mass indexed to body surface area, g/m

Left ventricular extracellular mass indexed to body surface area, g/m
b

Magnetic resonance spectroscopy variable

Phosphocreatine to adenosine triphosphate ratio
Exercise capacity variables

Values are median (interquartile range) or n (%). Percentages may not total 100 because of rounding.
a
New York Heart Association functional classes range from I to IV, with higher values indicating greater disability.
b
A subgroup of 84 participants underwent 31-phosphorus magnetic resonance spectroscopy for measurement of myocardial phosphocreatine to adenosine
triphosphate ratio.
c
Ventilatory efficiency is measured as minute ventilation/carbon dioxide production (VE/CO2 slope).

with placebo, trientine led to a significant reduction in left ven­
tricular maximum wall thickness (−0.6 mm; 95% CI −1.2 to −0.1)
and left ventricular myocardial cellular mass (−3.7 g/m2; 95% CI
−6.4 to −1.1). The impact of trientine on myocardial extracellu­
lar mass was dependent on baseline myocardial extracellular
mass, with a numerically greater reduction in extracellular
mass with trientine compared to placebo as baseline extracellu­
lar mass increased (e.g. −1.0 g/m2; 95% CI −1.9 to 0.0 at the
75th centile of baseline extracellular mass), but the difference
was not significant. There were no between-group differences
in atrial volumes and function, exercise capacity, circulating
high-sensitivity troponin, or myocardial phosphocreatine to ad­
enosine triphosphate ratio.

Mechanism of action
The trientine-induced reduction in LVMi was mediated via a re­
duction in myocardial cellular mass (average causal mediated ef­
fect −3.9 g/m2; 95% CI −6.8 to −0.9). It was not mediated via
changes in urine copper excretion, systolic blood pressure, myo­
cardial extracellular mass or myocardial phosphocreatine to ad­
enosine triphosphate ratio (see Supplementary data online,
Table S7).

Safety
Trientine was well tolerated. Of the 11 patients who withdrew
from the trial, including 8 in the trientine group and 3 in the pla­
cebo group, only 1 patient, who was in the trientine group, did so
because of a possible trial mediation-related adverse event
(nausea and dizziness) (see Supplementary data online,
Table S8). Adverse events resulted in two patients in the trien­
tine group (psoriasis skin flare, anaemia), and two patients in
the placebo group (nausea, anxiety), discontinuing treatment
early (see Supplementary data online, Table S9). No deaths oc­
curred during the trial. Four patients (5%) in the trientine group,
and seven patients (10%) in the placebo group, experienced one
or more serious adverse events, none of which were related to

trientine or placebo (Table 4 and S10). Overall, 56 (72%) patients
receiving trientine and 49 (67%) patients receiving placebo re­
ported an adverse event (Table 4 and S11). Ninety-three per
cent of adverse events reported by patients receiving trientine,
and 91% of adverse events reported by patients receiving pla­
cebo, were mild. The number of cardiovascular adverse events
was low and did not differ between groups. Gastrointestinal ad­
verse events were more common in the trientine group.
Trientine was not associated with a change in left ventricular
ejection fraction, systolic blood pressure, or electrocardiogram
measurements (Table 3). The number of ventricular ectopic beats
declined among patients in both treatment groups (trientine:
−0.6 ± 4.1 ventricular ectopic beats per 1000 beats; placebo:
−1.5 ± 17.9 ventricular ectopic beats per 1000 beats), and there
was no change in the number of episodes of non-sustained ven­
tricular tachycardia in either group and no difference between
groups (see Supplementary data online, Table S6). The number
of atrial ectopic beats increased slightly among patients in the tri­
entine group compared to patients in the placebo group (2.1 add­
itional atrial ectopic beats per 1000 beats; 95% CI 1.2–3.7), but
there was no change in the number of episodes of atrial fibrilla­
tion in either group, and no difference between groups (see
Supplementary data online, Table S6). Anaemia was more com­
mon among patients receiving trientine compared to placebo
(6.4% vs 2.7%; mean between-group difference in haemoglobin
−5.6 g/L; 95% CI −8.0 to −3.3), as was hypocupraemia (10.3%
vs 1.4%; mean between-group difference in serum copper
−0.79 g/L; 95% CI −1.4 to −0.2), but there were no differences
in serum caeruloplasmin or iron (Table 3 and S12). There was no
clinically relevant difference in the utilisation of concomitant
medications between baseline and week 52. (Table S13).

Discussion
In this phase 2 randomized, placebo-controlled trial involving
patients with hypertrophic cardiomyopathy, trientine reduced

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2

7

Trientine for hypertrophic cardiomyopathy

Table 2

Primary endpoint

Variable

Trientine (n = 79)

Placebo (n = 75)

.............................

.............................

Patients
no.

Patients
no.

Mean change
(± SD)

Mean change
(± SD)

Between-group difference
(95% CI)

P-value

...............................................................................................................................................................
Change in LVMi from baseline to
Week 52, g/m2

68

−4.4 ± 7.7

68

−1.5 ± 6.1

−3.2 (−5.6 to −0.8)

.009

25th centile

−1.2 (−4.1 to 1.6)

.40

50th centile

−2.9 (−5.2 to −0.5)

.02

75th centile

−5.0 (−7.7 to −2.2)

<.001

Effect by baseline LVMi quartilea

LVMi, left ventricular mass indexed to body surface area; SD, standard deviation.
a
The effect of trientine on LVMi increased with higher baseline LVMi (baseline LVMi by treatment allocation interaction P = .015). Therefore, the overall between-group
difference is presented, and the between-group differences after replacing baseline LVMi with 25th, 50th, and 75th quartile centred baseline LVMi in the analysis of
covariance models in turn are presented. See Methods and Discussion for details.

left ventricular hypertrophy. The effect of trientine was
greater at higher levels of baseline left ventricular mass. The
reduction in left ventricular hypertrophy was mediated by a
reduction in myocardial cellular mass. Trientine was safe

and well-tolerated. The findings provide initial evidence for
a novel approach to the treatment of hypertrophic cardiomy­
opathy targeting copper metabolism (Structured Graphical
Abstract).

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Figure 1 Change in left ventricular mass indexed to body surface area from baseline to Week 52

8

Farrant et al.

Table 3

Key secondary endpoints

Variable

Trientine (n = 79)

Placebo (n = 75)

................................. .............................
Patients
no.

Mean change
(± SD)

Patients
no.

Mean change
(± SD)

Between-group
difference
(95% CI)

P-value

...............................................................................................................................................................
Secondary analyses of the primary outcome

66

−2.5 ± 9.2

66

1.5 ± 6.1

3.5 (−5.7 to −1.2)

.003

25th centile

0.1 (−2.9 to 3.1)

.95

50th centile

−3.2 (−5.7 to −0.7)

.01

75th centile

−7.7 (−10.6 to −4.8)

<.001

−2.8 (−5.1, −0.5)

.02

25th centile

−1.1 (−3.9 to 1.7)

.44

50th centile

−2.4 (−4.8 to −0.1)

.04

Effect by baseline LVMi quartileb

Sensitivity analysis: change in LVMi adjusted for
missing data, g/m2

68

−4.4 ± 7.7

68

−1.5 ± 6.1

Effect by baseline LVMi quartileb

75th centile

−4.2 (−6.8 to −1.6)

.002

−0.4 (−0.6, −0.2)

<.001

25th centile

−0.2 (−0.4 to 0.05)

.12

50th centile

−0.3 (−0.5 to −0.1)

.001

75th centile

−0.5 (−0.7 to −0.3)

<.001

165.0 (132.6–197.4)

-

Causal analysis: change in LVMi for each
additional 100 capsules of trientine
takenc, g/m2

53

-

68

-

Effect by baseline LVMi quartileb

Key secondary outcomes
Urine copper/creatinine ratio

64

Left ventricular maximal wall thickness, mm

177.7 (106.0)

44

5.1 (23.0)

68

−0.6 ± 1.8

68

0.04 ± 1.6

−0.6 (−1.2 to −0.1)

-

67

−2.7 ± 7.4

63

0.1 ± 8.6

−3.7 (−6.4 to −1.1)

-

67

−0.9 ± 2.3

63

−0.5 ± 2.6

−0.4 (−1.3 to 0.5)

-

25th centile

0.2 (−0.8 to 1.2)

-

50th centile

−0.3 (−1.2 to 0.6)

-

75th centile

−1.0 (−1.9 to 0.0)

-

Indexed LV myocardial cellular mass, g/m

2
2

Indexed LV myocardial extracellular mass, g/m

b

Effect by baseline extracellular mass quartile

Indexed LA volume, mL/m2

65

−0.3 ± 8.0

68

1.2 ± 8.1

−1.0 (−3.7 to 1.7)

-

Peak oxygen uptake, mL/min/kg

60

−0.9 ± 4.4

61

−0.1 ± 4.1

−1.2 (−2.7 to 0.3)

-

Ventilatory efficiency

59

0.5 ± 6.3

60

−0.7 ± 4.5

1.1 (−0.6 to 2.8)

-

High-sensitivity troponin, ng/L

69

−0.8 ± 8.7

69

0.7 ± 13.6

−0.9 (−4.6 to 2.9)

-

Phosphocreatine to adenosine triphosphate
ratioe

27

0.1 ± 0.5

33

0.1 ± 0.4

0.1 (−0.1 to 0.3)

-

Left ventricular ejection fraction, %

68

−0.1 ± 5.1

68

−0.1 ± 4.5

0.2 (−1.4 to 1.7)

-

No. non-sinus supraventricular beats per 1000
beats

69

3.1 ± 24.0

67

0.1 ± 3.6

2.1 (1.2 to 3.7)

-

No. ventricular-origin beats per 1000 beats

69

−0.6 ± 4.1

67

−1.5 ± 17.9

0.5 (0.3 to 0.9)

-

No. episodes of NSVT

69

1.8 ± 0.8

67

0.8 ± 3.6

0.9 (0.5 to 1.7)

-

d

Continued

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Replication analysis: change in LVMi measured
using AI image analysisa—g/m2

9

Trientine for hypertrophic cardiomyopathy

Table 3

Continued

Variable

Trientine (n = 79)

Placebo (n = 75)

................................. .............................
Patients
no.

Mean change
(± SD)

Patients
no.

Mean change
(± SD)

Between-group
difference
(95% CI)

P-value

...............................................................................................................................................................
No. episodes of atrial fibrillationf

69

1.0 ± 0.0

67

1.0 ± 0.0

Serum haemoglobin, g/L

70

−5.0 ± 8.3

68

−0.5 ± 6.8

−5.6 (−8.0 to −3.3)

-

Serum copper, µmol/L

70

−0.9 ± 2.2

68

0.1 ± 1.5

−0.8 (−1.4 to −0.2)

-

Serum ceruloplasmin, g/L

68

0 ± 0.13

66

−0.01 ± 0.07

0.02 (−0.02 to 0.05)

-

Serum iron, µmol/L

70

−0.9 ± 7.2

68

−0.8 ± 8.3

−0.01 (−2.1 to 2.1)

-

Systolic blood pressure, mmHg

70

−7.1 ± 18.0

68

−0.9 ± 16.5

−3.2 (−8.2 to 1.8)

-

-

-

Trials of cardiac myosin inhibitors reporting improvements in
heart failure symptoms and functional capacity have included
symptomatic patients with obstructive hypertrophic cardiomy­
opathy (mean resting LVOT peak gradient over 50 mmHg).3,4
Early or asymptomatic hypertrophic cardiomyopathy represents
a substantial unmet need for disease-modifying therapies. In the
present trial, most patients reported no symptoms with ordinary
physical activity, did not have LVOT obstruction, and were at
low risk of sudden cardiac death, suggesting trientine may
have a role in this group. At the same time, the observation
that the effect of trientine on left ventricular mass increased
with higher baseline mass suggests that patients with more ad­
vanced phenotypes may derive greater benefit. Further work is
required to define the optimal target population for trientine
therapy. The monitoring requirements for trientine are straight­
forward, comprising periodic (e.g. haematological indices and
copper parameters) blood tests, without the need for surveil­
lance imaging. This approach is consistent with maintaining cop­
per homeostasis and identifying potential deficiency, which is a
principal safety consideration with longer-term therapy.
We did not specify an LVOT gradient in the recruitment cri­
teria; patients with any LVOT gradient were eligible. We suspect
the low median LVOT gradient reflects the nature of patients
with hypertrophic cardiomyopathy seen in UK clinical practice,
and the requirement for participants to undergo cardiovascular
magnetic resonance. Patients with ICDs at baseline were ex­
cluded, which likely excluded patients with more advanced phe­
notypes, including LVOT obstruction. This is in keeping with the
NHLBI HCMR Registry (n = 2762), in which only 18% of patients
had a LVOT gradient above 30 mmHg.5
Left ventricular mass and wall thickness are both central to
the pathogenesis of hypertrophic cardiomyopathy and inde­
pendently predictive of adverse outcomes, suggesting that a
reduction in left ventricular mass and wall thickness may be

clinically relevant.18–21 Trientine became more efficacious at re­
ducing left ventricular mass at higher levels of baseline left ven­
tricular mass; indeed, patients with LVMi <81.6 g/m2 did not
derive benefit. It is important to note that the use of centred
baseline variables derived from the 25th, 50th, and 75th quar­
tiles does not represent a post hoc or responder analysis. Rather,
it reflects the statistically appropriate approach following iden­
tification of a baseline left ventricular mass-treatment inter­
action, as demonstrated by the diverging treatment group
regression slopes with increasing baseline mass.
The reduction in LVMi observed with trientine was modest
(−3.2 g/m2) but similar in magnitude to that reported with mava­
camten in non-obstructive hypertrophic cardiomyopathy in
ODYSSEY-HCM (−3.8 g/m2),22,23 in contrast to the larger re­
ductions observed with myosin inhibitors in obstructive HCM,
where relief of LVOT obstruction likely contributes substantially
to left ventricular mass regression.24,25 Baseline LVMi was sub­
stantially higher in ODYSSEY-HCM than in the present study.
Taken together with the observation that baseline left ventricu­
lar mass may be an important determinant of the magnitude of
response to trientine, we hypothesize that the effect size of tri­
entine may have been larger in a population with a higher base­
line LVMi, although this requires further investigation. More
generally, LVMi is associated with adverse outcomes in HCM,
including arrhythmia and appropriate ICD therapy.18
Several randomized trials have targeted alternative mechan­
isms in hypertrophic cardiomyopathy, including metabolic
modulation (e.g. perhexiline, ranolazine, N-acetylcysteine, nine­
rafaxstat)26–29 and renin–angiotensin–aldosterone system in­
hibition (e.g. spironolactone, losartan, valsartan).30–32 To our
knowledge, the present trial is the first to report a significant re­
duction in left ventricular mass with a non-sarcomere-targeted
therapy. Our data indicate that the mechanism of action of trien­
tine was a reduction in myocardial cellular mass rather than

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LA, left atrial; LV, left ventricular; LVMi, left ventricular mass indexed to body surface area; NSVT, non-sustained ventricular tachycardia.
All indexation is to body surface area.
a
AI image analysis was not possible on images from two participants in each group.
b
The effect of trientine on LVMi and indexed LV myocardial extracellular mass increased with higher baseline LVMi (baseline LVMi by treatment allocation interaction
P = .015). Therefore, the overall between-group difference is presented, and the between-group differences after replacing baseline LVMi with 25th, 50th, and 75th
quartile centred baseline LVMi in the analysis of covariance models in turn are presented. See Methods and Discussion for details.
c
Coefficient of trientine use.
d
Ventilatory efficiency is measured as minute ventilation/carbon dioxide production (VE/CO2 slope).
e
A subgroup of participants underwent 31-phosphorus magnetic resonance spectroscopy for measurement of myocardial phosphocreatine to adenosine triphosphate
ratio.
f
Insufficient events to run an ANCOVA model.

10

Farrant et al.

Table 4

Adverse events

Event

Placebo
(n = 73)

Any adverse event

56 (71.8)

49 (67.1)

Any serious adverse event

4 (5.1)

7 (9.6)

Palpitations

8 (10.3)

10 (13.7)

Atrial fibrillation

2 (2.6)

2 (2.7)

Chest pain

0 (0)

3 (4.1)

First-degree atrioventricular block

1 (1.3)

1 (1.4)

Bradycardia

1 (1.3)

0 (0)

Peripheral oedema

1 (1.3)

0 (0)

Pre-syncope

0 (0)

1 (1.4)

Nausea

7 (9.0)

6 (8.2)

Abdominal pain upper

4 (5.1)

1 (1.4)

Diarrhoea

7 (9.0)

1 (1.4)

Gastro-oesophageal reflux

4 (5.1)

1 (1.4)

Dizziness

11 (14.1)

13 (17.8)

Headache

3 (3.8)

4 (5.5)

Lower respiratory tract infection

2 (2.6)

4 (5.5)

SARS-CoV-2 test positive

7 (9.0)

6 (8.2)

Anaemia

5 (6.4)

2 (2.7)

Copper decreased

8 (10.3)

1 (1.4)

Ceruloplasmin decreased

5 (6.4)

5 (6.8)

Iron decreased

1 (1.3)

2 (2.7)

.........................................................................

Cardiovascular

Gastrointestinal

Other

Blood tests

changes in myocardial fibrosis, blood pressure, or myocardial en­
ergetics. In this paucisymptomatic population, trientine did not
improve exercise capacity. Further work is needed to determine
the effect of trientine in more symptomatic patients with hyper­
trophic cardiomyopathy.
Unbound or loosely bound Cu2+ is known to activate profibro­
tic pathways, and preclinical studies have demonstrated that tri­
entine can reduce myocardial fibrosis.7,9–11 We therefore
hypothesized that trientine would reduce myocardial extracellu­
lar mass. However, no significant between-group difference was
observed. There was, however, a numerically greater reduction
in extracellular mass with trientine compared with placebo at
higher baseline levels of extracellular mass, suggesting that
any antifibrotic effect of trientine may be more pronounced,
or more readily detectable, in patients with more advanced dis­
ease and greater baseline fibrosis.
Trientine was well tolerated, with a low discontinuation rate.
Adverse event rates were low, and no unexpected safety issues
were identified. There was a modest reduction in haemoglobin

Supplementary data
Supplementary data are available at European Heart Journal online.

Declarations
Disclosure of interest
J.C.M. has received honoraria from BMS and Cytokinetics, and is
a shareholder in MyCardium AI Ltd and Guilford Street
Laboratories. S.G. has received consultancy fees from
Biosensors. C.B. is employed by the University of Glasgow,
which holds consultancy and research agreements for his
work with Abbott Vascular, AskBio, AstraZeneca, Boehringer

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Trientine
(n = 78)

and serum copper, with no corresponding reduction in serum
caeruloplasmin or iron. Anaemia is a recognized potential side
effect of trientine. Although haemoglobin declined modestly
with trientine as expected, such a reduction would typically be
associated with an increase rather than a decrease in left ven­
tricular mass. This suggests that the observed reduction in
LVMi is unlikely to be explained by haemoglobin-related effects.
Future studies should evaluate trientine in cohorts with more
advanced hypertrophic cardiomyopathy, where the potential for
treatment response may be greater. Such studies would benefit
from incorporating endpoints that capture patient-centred out­
comes, including health status, and relevant circulating biomar­
kers, to better define the clinical impact of treatment.
A limitation of this trial was that we did not measure health
status or natriuretic peptides. This was an academic-funded trial,
originally designed in a funding application submitted in 2018,
which predated regulatory guidance emphasizing patientreported outcomes and ‘feel and function’ endpoints in drug de­
velopment, and at a time when the role of natriuretic peptides in
hypertrophic cardiomyopathy trials was not yet well estab­
lished.33 Excluding patients with ICDs, to enable cardiovascular
magnetic resonance, is likely to have disproportionately ex­
cluded patients with more advanced disease; our results indicate
that patients with more advanced disease may have derived
greater benefit from trientine. The limited number of genotyped
patients precluded meaningful analysis of treatment effect ac­
cording to genotype. Another limitation is the lower proportion
of female participants, which should be interpreted in the con­
text of well-described sex differences in hypertrophic cardiomy­
opathy diagnosis and trial enrolment, including the use of
absolute wall thickness thresholds that do not account for
sex-related differences and lower rates of incidental diagnosis
in women. Female representation is often particularly low in
early-phase or mechanistic hypertrophic cardiomyopathy stud­
ies, especially when first-in-class therapies are evaluated. In
this study, most participants were in New York Heart
Association class I, and this represented the first evaluation of
trientine in hypertrophic cardiomyopathy. Notably, fewer than
one-third of participants in the HCMR Registry are female, indi­
cating that the sex distribution observed here is consistent with
broader patterns in hypertrophic cardiomyopathy research.5
In this phase 2 trial in patients with hypertrophic cardiomyop­
athy, treatment with trientine resulted in a significantly greater
reduction in left ventricular hypertrophy than placebo. These re­
sults warrant further investigation.

11

Trientine for hypertrophic cardiomyopathy

Ingelheim, Causeway Therapeutics, Coroventis, HeartFlow,
Menarini, Novartis, Siemens Healthcare, Zoll Medical, and
Valo Health. C.A.M. has participated on advisory boards/con­
sulted for AstraZeneca, Boehringer Ingelheim, Lilly Alliance,
Novartis, and PureTech Health, serves as an advisor for HAYA
Therapeutics, has received speaker fees from AstraZeneca,
Boehringer Ingelheim, and Novo Nordisk, conference attend­
ance support from AstraZeneca, and research support from
Amicus Therapeutics, AstraZeneca, Guerbet Laboratories
Limited, and Roche.

protocol was approved by a research ethics committee (NHS
Health Research Authority, reference 20/NW/0275), and trial
conduct was overseen by a trial steering committee and an inde­
pendent data and safety monitoring committee.

Data availability

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2. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ. Hypertrophic
cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease.
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https://doi.org/10.1186/s12874-017-0442-1
17. O'Mahony C, Jichi F, Pavlou M, Monserrat L, Anastasakis A, Rapezzi C, et al. A
novel clinical risk prediction model for sudden cardiac death in hypertrophic

Funding
A.S. was funded by a National Institute for Health and Care
Research (NIHR) Advanced Fellowship (NIHR300867) and ac­
knowledges support from the NIHR Leicester Biomedical
Research Centre: Leicester (NIHR203327) and the British
Heart Foundation Research Excellence Award (RE/24/
130031). B.R. is funded by a Wellcome Trust Career
Development Award fellowship (302210/Z/23/Z). B.R. and
S.N. acknowledge support from the NIHR Oxford Biomedical
Research Centre and BHF Centre of Research Excellence,
Oxford. L.V. is supported by the Sir Henry Dale Fellowship
grant from the Wellcome Trust and Royal Society (221805/Z/
20/Z) and also acknowledges support from Slovak Grant
Agencies VEGA (2/0084/26) and APVV (21-0299). D.D. is sup­
ported by the British Heart Foundation (PG/24/11930, FS/
CRTF/23/24508, FS/CRTF/22/24275, BHF PG/22/11117,
FS/RTF/20/30009, NH/19/1/34595), National Institute for
Health and Care Research Health Technology Assessment
(NIHR157523), and Tenovus (G23.03, G24.07). S.P. is funded
by a British Heart Foundation Chair (CH/16/2/32089) and ac­
knowledges support of the National Institute for Health
Research (NIHR) Leeds Clinical Research Facility and the
Leeds Biomedical Research Centre (BRC) (NIHR203331).
C.A.M. (Advanced Fellowship, NIHR301338) is funded by the
NIHR. The views expressed in this publication are those of the
authors and not necessarily those of the NIHR, NHS, or the
UK Department of Health and Social Care. C.A.M. acknowl­
edges support from the University of Manchester British
Heart Foundation Research Excellence Award (RE/24/
130017) and the NIHR Manchester Biomedical Research
Centre (NIHR203308).

Ethical Approval
The trial was designed by the research team with patient and
public involvement, sponsored by Manchester University NHS
Foundation Trust, and funded by the UK National Institute for
Health and Care Research (funder reference NIHR127575).
Trial management, independent data management, and inde­
pendent statistical analysis were performed by Liverpool
Clinical Trials Centre, a United Kingdom Clinical Research
Collaboration fully registered Clinical Trials Unit. The study

TEMPEST ClinicalTrials.gov number, NCT04706429.

References

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De-identified participant data will be made available on reason­
able request 1 year after the date of publication, with no end
date to availability, and may be used for any purpose.
Requests should be directed to the corresponding author.
Requestors will be required to sign a data access agreement.

Pre-registered Clinical Trial Number

12

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Farrant et al.
</reference>

<statements>
1. TEMPEST (phase 2, hypertrophic cardiomyopathy; Farrant JP et al.): multicentre, double-blind, placebo-controlled trial; 154 randomized (79 trientine, 75 placebo), 800 mg/day trientine base for 52 weeks.
2. Primary endpoint change in LV mass index by CMR: −4.4 g/m² (trientine) vs −1.5 g/m² (placebo), between-group difference −3.2 g/m² (95% CI −5.6 to −0.8; P=0.009), with greater effect at higher baseline LV mass and mediation via reduced myocardial cellular mass.
3. Well tolerated (more anemia and hypocupraemia with trientine).
4. The design was published in Heart 2023;109:1175–1182 (NCT04706429); the trial is the first non-sarcomere-targeted therapy to reduce LV mass in HCM, but phase 3 trials with clinical endpoints are required.
</statements>

Begin the assessment now. Output only the JSON list, without any conversational text or explanations.