Condition category
Circulatory System
Date applied
28/07/2020
Date assigned
07/09/2020
Last edited
07/09/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart condition. It leads to abnormal thickening and scarring of the walls of the heart. As a result, the heart can have trouble pumping blood as well as it should. This causes patients to develop breathing difficulties, chest pain, and fainting, which often get worse with exercise, and therefore can limit physical activity. Current treatments only aim to relieve the symptoms. There are no treatments that correct the underlying damage to the heart. Patients, caregivers, and researchers have identified a “critical need” for trials of medicines that target the HCM disease process.

Several studies in other diseases have shown that copper imbalance is associated with heart thickening similar to HCM, and that treatment with trientine, an oral medicine that increases copper removal in urine, can reverse this thickening.

This study will investigate whether trientine reduces heart muscle thickening, improves exercise capacity, improves heart function, and reduces abnormal heart rhythms in patients with HCM. The study will also assess how trientine works in HCM.

This research study aims to recruit 172 patients with HCM aged 18-70 years in the UK. Participants in the study will be prescribed either trientine or placebo for 1 year to compare the difference.

Who can participate?
Patients with hypertrophic cardiomyopathy aged 18-70 years can participate

What does the study involve?
If patients agree to take part, they will be asked to sign a consent form. Once the consent form is signed, the trial team will check and confirm that this study is suitable for the patient. If it is, they will be entered into the study. Participants will be randomly assigned to receive either trientine or a dummy pill.

Participants will be in the study for 1 year. During this time, they will be asked to attend the hospital for 6 visits. Study tests include blood tests, urine test, heart trace (ECG), heart magnetic resonance imaging (MRI scan of the heart), 24-hour heart monitor, exercise test and pregnancy test if female and of childbearing age. A subgroup of participants will undergo an extra MRI scan.

What are the possible benefits and risks of participating?
Participants will receive closer follow-up than they would usually have and have more access to heart specialists than normal. They may have a more detailed assessment of their heart than they usually would.

Participants will help to determine whether trientine will be of benefit to other patients with HCM and will also contribute to a better understanding of HCM in general. This may lead to benefits for the participant and other people.

Trientine has been used in Wilson disease for more than 30 years. It is safe and well tolerated. Between 1-in-100 and 1-in-10 people experience nausea on starting trientine and between 1-in-1000 and 1-in-100 people develop a skin rash. Trientine can reduce blood iron levels. Between 1-in-1000 and 1-in-100 people develop anaemia (low blood iron level). Iron levels and blood counts will be monitored during the study. Iron supplementation in the form of tablets may be necessary in some cases. There have been isolated case reports of trientine being associated with inflammation of the bowel. All of the possible side effects resolve on reducing the dose or stopping it and are not associated with long term effects.

Where is the study run from?
Manchester University NHS Foundation Trust (UK) and 3 other NHS foundation trusts in the UK

When is the study starting and how long is it expected to run for?
From July 2018 to December 2023

Who is funding the study?
The National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) Programme (UK)

Who is the main contact?
Miss Carly Lawrence
tempest@liverpool.ac.uk

Trial website

www.tempest-trial.org.uk

Contact information

Type

Scientific

Primary contact

Dr Chris Miller

ORCID ID

Contact details

Wythenshawe Hospital
Cardiology Department
Southmoor Road
Roundthorn Industrial Estate
Wythenshawe
Manchester
M23 9LT
United Kingdom
+44 (0)161 291 2034
christopher.miller@manchester.ac.uk

Additional identifiers

EudraCT number

2020-002242-17

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS 45988, IRAS 283265

Study information

Scientific title

A randomised, double-blind, placebo-controlled, phase 2 evaluation of the efficacy and mechanism of trientine in patients with hypertrophic cardiomyopathy

Acronym

TEMPEST

Study hypothesis

Trientine will reduce LV mass, which will be associated with improved exercise capacity, reduced arrhythmia burden, and improved cardiac function. The reduction in LV mass will be mediated by a reduction in myocardial cellular mass and fibrosis and improved myocardial energetics, which will be determined by increased copper excretion.

Ethics approval

Approved 21/07/2020, Greater Manchester South Research Ethics Committee (3rd Floor, Barlow House 4 Minshull Street Manchester M1 3DZ; +44 (0)2071048127; gmsouth.rec@hra.nhs.uk), ref: 20/NW/0275

Study design

Multicentre interventional randomized controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details (tempest@liverpool.ac.uk) to request a participant information sheet’

Condition

Hypertrophic cardiomyopathy

Intervention

The study will last for 1 year and involves 6 visits to the hospital.

The initial visit will have a number of assessments including a review of medical history, review of medications, pulse, blood pressure, height and weight, blood tests, ECG, 24 h heart monitor, and a pregnancy test, if applicable.

If the assessments performed at Visit 1 show that the patient is eligible for the study, Visit 2 will be arranged within 4 weeks for the patient to be randomised.

Participants will be randomised to receive either trientine (two 200 mg capsules, twice daily, 800 mg/day total) or placebo, in a 1:1 ratio. Block randomisation, stratified by site, will be implemented, with computer generated randomisation allocations and randomly varying block sizes. The randomisation code will be generated by an independent LCTC statistician who is not involved with this trial.

At Visit 2 a review of medications, blood test, urine test, exercise test, and a pregnancy test, if applicable, will take place. Participants will also have an MRI scan of the heart known as cardiovascular magnetic resonance (CMR) scan. A subgroup of participants will undergo an extra MRI scan called phosphorus magnetic resonance spectroscopy (31P MRS).

Study medication will be dispensed by the pharmacy at visits 2, 3, 4, and 5.

Visits 3, 4, and 5 will take place 13 weeks apart. At these visits all current medications are reviewed, measurements of pulse, blood pressure, height, and weight are taken. There will be a review of safety, compliance, and review of the patient's diary. An ECG, blood, and urine test are also performed, as well as a pregnancy test, if applicable.

Visit 6 will include the same tests as visits 3, 4, and 5, with the addition of height and weight, an MRI scan, 24 h heart monitor, and the exercise test. The subgroup will undergo 31P MRS.

Intervention type

Drug

Phase

Phase II

Drug names

Trientine (Triethylinetetramine dihydrochloride)

Primary outcome measure

Change in left ventricular mass index (LVMi, g/m2) is measured using a cardiovascular magnetic resonance (CMR) scan at baseline and week 52

Secondary outcome measures

1. Cumulative urine copper excretion is measured using urinary copper in urine samples given at baseline, 13, 26, 39 and 52 weeks
2. Change in exercise capacity is measured using cardiopulmonary exercise testing (CPET) at baseline and week 52
3. Change in number of non-sinus supraventricular heartbeats, presence and amount of atrial fibrillation, number of ventricular-origin beats, and presence and amount of non-sustained ventricular tachycardia, in 24 h is measured using ambulatory ECG heart monitoring at baseline, 13, 26, 39 and 52 weeks
4. Change in circulating high sensitivity troponin measured from blood samples given at baseline, 13, 26, 39 and 52 weeks
5. Change in LV global longitudinal strain and strain rate, wall thickness, mass, volumes, and ejection fraction (EF) is measured using CMR at baseline and week 52
6. Change in peak left ventricular outflow tract gradient is measured using CMR at baseline and week 52
7. Change in atrial volume and function is measured using CMR at baseline and week 52

Overall trial start date

01/07/2018

Overall trial end date

01/12/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Written informed consent given
2. Aged between 18 and 70 years 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 172; UK Sample Size: 172

Participant 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 >180 mmHg or diastolic blood pressure of >100 mmHg 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

Recruitment start date

01/12/2020

Recruitment end date

01/12/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Liverpool Heart And Chest Hospital NHS Foundation Trust
Thomas Drive
Liverpool
L14 3PE
United Kingdom

Trial participating centre

Manchester University NHS Foundation Trust
Wythenshawe Hospital Southmoor Road
Manchester
M23 9LT
United Kingdom

Trial participating centre

Oxford University Hospitals NHSs Foundation Trust
John Radcliffe Hospital Headley Way Headington
Oxford
OX3 9DU
United Kingdom

Trial participating centre

Royal Brompton & Harefield NHS Foundation Trust
Royal Brompton Hospital Sydney Street
London
SW3 6NP
United Kingdom

Sponsor information

Organisation

Manchester University NHS Foundation Trust

Sponsor details

Cobbett House
Oxford Road
Manchester
M13 9WL
United Kingdom
+44 (0)161 276 3565
lynne.webster@mft.nhs.uk

Sponsor type

Hospital/treatment centre

Website

https://mft.nhs.uk/

Funders

Funder type

Government

Funder name

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: NIHR127575

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

National Institute for Health Research (NIHR) (UK)

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The results of the trial will be disseminated as early as possible in order to appropriately inform policy and practice. This will include academic journal publications and presentations at academic conferences, Lay summaries of the study findings will be posted to the trial website and links to these summaries will be posted on patient group websites. Presentations will be made to patient groups and a symposium that brings together key stakeholders will be held.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date

Intention to publish date

01/12/2024

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

29/07/2020: Trial’s existence confirmed by the National Institute for Health Research (NIHR).