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

• ClinicalTrials.gov Identifier: NCT04706429
• Recruitment Status: Recruiting
• First Posted: January 12, 2021
• Last Update Posted: March 17, 2021
• Sponsor: Manchester University NHS Foundation Trust
• Collaborators: National Institute for Health Research, United Kingdom; University of Manchester; University of Liverpool; Univar BV; University of Oxford
• Information provided by (Responsible Party): Manchester University NHS Foundation Trust

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hypertrophic Cardiomyopathy	Drug: Trientine; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 172 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomised, Double-blind, Placebo-controlled, Phase 2 Evaluation of the Efficacy and Mechanism of Trientine in Patients With Hypertrophic Cardiomyopathy
• Actual Study Start Date: December 1, 2020
• Estimated Primary Completion Date: December 1, 2023
• Estimated Study Completion Date: May 31, 2024

Arms and Interventions

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Urine copper excretion [ Time Frame: 12 months ]
   Cumulative urine copper excretion, measured using urinary copper, assessed from baseline to weeks 13, 26, 39 and 52.
2. Exercise capacity [ Time Frame: 12 months ]
   Change in exercise capacity, measured using cardiopulmonary exercise testing (CPET), assessed from baseline to week 52.
3. 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 [ Time Frame: 12 months ]
   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.
4. Circulating high sensitivity troponin [ Time Frame: 12 months ]
   Change in circulating high sensitivity troponin, assessed from baseline to week 52.
5. LV global longitudinal strain and strain rate, wall thickness, mass, volumes and ejection fraction (EF) [ Time Frame: 12 months ]
   Change in LV global longitudinal strain and strain rate, wall thickness, mass, volumes and ejection fraction (EF) measured using CMR, assessed from baseline to week 52.
6. Peak left ventricular outflow [ Time Frame: 12 months ]
   Change in peak left ventricular outflow tract gradient, measured using CMR, assessed from baseline to week 52.
7. Atrial volume and function [ Time Frame: 12 months ]
   Change in atrial volume and function, measured using CMR, assessed from baseline to week 52.

Other Outcome Measures:

1. LV myocardial cellular mass [ Time Frame: 12 months ]
   Change in LV myocardial cellular mass, measured using CMR, from baseline to week 52.
2. LV myocardial extracellular mass [ Time Frame: 12 months ]
   Change in LV myocardial extracellular mass, measured using CMR, from baseline to week 52.
3. LV myocardial extracellular volume [ Time Frame: 12 months ]
   Change in LV myocardial extracellular volume, measured using CMR, from baseline to week 52.
4. LV late gadolinium enhancement [ Time Frame: 12 months ]
   Change in LV late gadolinium enhancement, measured using CMR, from baseline to week 52.
5. PCr/ATP ratio [ Time Frame: 12 months ]
   Change in PCr/ATP ratio, measured using 31P MRS (sub-group), from baseline to week 52.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Written informed consent.
2. Age 18-70 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.

Contacts and Locations

Contacts

Contact: Carly Lawrence; 00 44 (0) 151 794 9763; tempest@liverpool.ac.uk

Locations

United Kingdom

Liverpool Heart and Chester Hospital NHS Foundation Trust; Not yet recruiting

Liverpool, United Kingdom, L14 3PE

Contact: Robert Cooper Rob.Cooper@lhch.nhs.uk

Principal Investigator: Robert Cooper

Royal Brompton and Harefield NHS Foundation Trust; Not yet recruiting

London, United Kingdom, SW3 6NP

Contact: Sanjay Prasad S.Prasad@rbht.nhs.uk

Principal Investigator: Sanjay Prasad

Manchester University NHS Foundation Trust; Recruiting

Manchester, United Kingdom, M23 9LT

Contact: Matthias Schmitt matthias.schmitt@mft.nhs.uk

Principal Investigator: Matthias Schmitt

Oxford University Hospitals NHS Foundation Trust; Not yet recruiting

Oxford, United Kingdom, OX3 9DU

Contact: Masliza Mahmod masliza.mahmod@cardiov.ox.ac.uk

Principal Investigator: Masliza Mahmod

Sponsors and Collaborators

Manchester University NHS Foundation Trust

National Institute for Health Research, United Kingdom

University of Manchester

University of Liverpool

Univar BV

University of Oxford

Investigators

• Principal Investigator: Chris Miller; Manchester University NHS Foundation Trust

More Information

• Responsible Party: Manchester University NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT04706429
• Other Study ID Numbers: B00844; 2020-002242-17 ( EudraCT Number ); ISRCTN57145331 ( Registry Identifier: ISRCTN ); NIHR127575 ( Other Grant/Funding Number: NIHR EME Programme )
• First Posted: January 12, 2021
• Last Update Posted: March 17, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Additional relevant MeSH terms:

Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy; Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases; Trientine; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action