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

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ClinicalTrials.gov Identifier: NCT04706429
Recruitment Status : Recruiting
First Posted : January 12, 2021
Last Update Posted : March 17, 2021
Sponsor:
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

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.

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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


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.




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.



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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04706429


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

Locations
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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
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Principal Investigator: Chris Miller Manchester University NHS Foundation Trust
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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    Key Record Dates
Last Update Posted: March 17, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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:
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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