The Efficacy and Mechanism of Trientine in Patients With Hypertrophic Cardiomyopathy (TEMPEST)

A Randomised, Double-blind, Placebo-controlled, Phase 2 Evaluation of the Efficacy and Mechanism of Trientine in Patients With Hypertrophic Cardiomyopathy

This research study has been designed to test whether a drug called trientine dihydrochloride (also called Cufence) reduces heart muscle thickening, improves exercise capacity, improves heart function and reduces abnormal heart rhythms in patients with hypertrophic cardiomyopathy (HCM). The study is also assessing how trientine works in HCM. Participants will be prescribed either trientine or placebo, for a period of 12 months.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypertrophic Cardiomyopathy
• Intervention / Treatment: Drug: Trientine; Drug: Placebo

Detailed Description

HCM is the most common inherited cardiovascular disorder. It is characterised by left ventricular (LV) myocardial hypertrophy and fibrosis. Patients can experience symptoms of effort intolerance, progressive heart failure and abnormal heart rhythms. There are currently no treatments that alter the natural history of HCM. Patients and the cardiovascular field have identified a "critical need" for clinical studies of drug therapies that target HCM pathophysiological mechanisms.

Trientine dihydrochloride is a copper-chelating agent licensed for Wilson disease, a genetic disorder of copper excretion, in which patients exhibit a cardiac phenotype that mimics HCM. Proof of concept has been established through an MRC-funded study to suggest that use of trientine may also be beneficial in HCM.

• Study Type: Interventional
• Enrollment (Actual): 154
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Carly Lawrence; Phone Number: 00 44 (0) 151 794 9763; Email: tempest@liverpool.ac.uk

Study Locations

• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • NHS Grampian
  • Leicester, United Kingdom, LE3 9QP
    • University Hospitals of Leicester NHS Foundation Trust
  • Liverpool, United Kingdom, L14 3PE
    • Liverpool Heart and Chester Hospital NHS Foundation Trust
  • London, United Kingdom, SW3 6NP
    • Royal Brompton and Harefield NHS Foundation Trust
  • Manchester, United Kingdom, M23 9LT
    • Manchester University NHS Foundation Trust
  • North Shields, United Kingdom, NE29 8NH
    • Northumbria Healthcare NHS Foundation Trust
  • Oxford, United Kingdom, OX3 9DU
    • Oxford University Hospitals Nhs Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent.
2. Age 18-75 inclusive.
3. Hypertrophic cardiomyopathy (HCM), as defined by the European Society of Cardiology HCM guidelines as: "a wall thickness ≥15 mm in one or more LV myocardial segments that is not explained solely by loading conditions". The same definition is applied to first-degree relatives of patients with HCM i.e. all participants are required to have a LV wall thickness ≥15 mm. Wall thickness is as measured on the most recent cardiovascular magnetic resonance (CMR) scan performed prior to the baseline visit. If CMR has not been performed previously, wall thickness measurement should be taken from the most recent echocardiogram performed prior to the baseline visit. (It is recognised that in the European Society of Cardiology guidelines a clinical diagnosis of HCM in first-degree relatives requires a wall thickness that is less than this value, however ≥15 mm is applied here in order to ensure that all participants have an unequivocal phenotype).
4. New York Heart Association class I, II or III at the most recent clinical assessment performed prior to the baseline visit.

Exclusion Criteria:

1. Previous or planned septal reduction therapy.
2. Previously documented myocardial infarction or severe coronary artery disease.
3. Uncontrolled hypertension, defined as a systolic blood pressure of >180mmHg or a diastolic blood pressure of > 100mmHg at Visit 1.
4. Known LV EF < 50%, as measured on the most recent CMR scan performed prior to the baseline visit. If CMR has not been performed previously, the most recent echocardiogram performed prior to the baseline visit should be used.
5. Previously documented persistent atrial fibrillation.
6. Anaemia, defined as haemoglobin being below the local site normal reference range, at Visit 1.
7. Iron deficiency, defined as serum iron being below the local site normal reference range, at Visit 1.
8. Copper deficiency, defined as serum copper being below the normal reference range, at Visit 1.
9. Pacemaker or implantable cardioverter defibrillator.
10. Known severe valvular heart disease, as demonstrated on the most recent heart imaging performed prior to the baseline visit.
11. Previously documented other cardiomyopathic cause of myocardial hypertrophy (e.g. amyloidosis, Fabry disease, mitochondrial disease).
12. History of hypersensitivity to any of the components of the investigational medicinal product (IMP).
13. Known contraindication to MRI scanning.
14. Pregnancy, lactation or planning pregnancy. Women of childbearing capacity are required to have a negative serum pregnancy test before treatment, must agree to pregnancy tests at study visits as defined in the Section 8 and must agree to maintain highly effective contraception as defined in Section 8 during the study.
15. Any medical condition, which in the opinion of the Investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Trientine; Trientine dihydrochloride 1200 mg per day. This shall be taken orally as two Cufence 200mg hard capsules two times per day. The IMP will be dispensed to participants every 13 weeks for the duration of the study period (52 weeks).	Drug: Trientine; Trientine dihydrochloride is a white to pale yellow crystalline hygroscopic powder.; Other Names: Cufence
Placebo Comparator: Placebo; The placebo shall be taken orally as two capsules two times per day. This will be dispensed to participants every 13 weeks for the duration of the study period (52 weeks).	Drug: Placebo; Placebo capsule, manufactured with the exact components of the trientine capsules, without the active ingredient / investigational medicinal product.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular mass indexed to body surface area (LVMi)	Change in LVMi (g/m2), measured using CMR, from baseline to week 52.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine copper excretion	Cumulative urine copper excretion, measured using urinary copper, assessed from baseline to weeks 13, 26, 39 and 52.	12 months
Exercise capacity	Change in exercise capacity, measured using cardiopulmonary exercise testing (CPET), assessed from baseline to week 52.	12 months
Number of non-sinus supraventricular heart beats, presence and amount of atrial fibrillation, number of ventricular-origin beats and presence and amount of non-sustained ventricular tachycardia	Change in number of non-sinus supraventricular heart beats, presence and amount of atrial fibrillation, number of ventricular-origin beats and presence and amount of non-sustained ventricular tachycardia, in 24 hours, measured using ambulatory heart monitoring, assessed from baseline to week 52.	12 months
Circulating high sensitivity troponin	Change in circulating high sensitivity troponin, assessed from baseline to week 52.	12 months
Peak left ventricular outflow	Change in peak left ventricular outflow tract gradient, measured using CMR, assessed from baseline to week 52.	12 months
Atrial volume and function	Change in atrial volume and function, measured using CMR, assessed from baseline to week 52.	12 months
LV global longitudinal strain, wall thickness, mass, volumes and ejection fraction (EF)	Change in LV global longitudinal strain, wall thickness, mass, volumes and ejection fraction (EF) measured using CMR, assessed from baseline to week 52.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
LV myocardial cellular mass	Change in LV myocardial cellular mass, measured using CMR, from baseline to week 52.	12 months
LV myocardial extracellular mass	Change in LV myocardial extracellular mass, measured using CMR, from baseline to week 52.	12 months
LV myocardial extracellular volume	Change in LV myocardial extracellular volume, measured using CMR, from baseline to week 52.	12 months
LV late gadolinium enhancement	Change in LV late gadolinium enhancement, measured using CMR, from baseline to week 52.	12 months
PCr/ATP ratio	Change in PCr/ATP ratio, measured using 31P MRS (sub-group), from baseline to week 52.	12 months

Collaborators and Investigators

• Sponsor: Manchester University NHS Foundation Trust
• Collaborators: University of Oxford; University of Liverpool; University of Manchester; National Institute for Health Research, United Kingdom; Univar BV
• Investigators: Principal Investigator: Chris Miller, Manchester University NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): October 31, 2024

Study Registration Dates

• First Submitted: January 11, 2021
• First Submitted That Met QC Criteria: January 11, 2021
• First Posted (Actual): January 12, 2021

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 23, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Hypertrophy; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Trientine
• Other Study ID Numbers: B00844; 2020-002242-17 (EudraCT Number); ISRCTN57145331 (Registry Identifier: ISRCTN); NIHR127575 (Other Grant/Funding Number: NIHR EME Programme)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No