Condition category
Cancer
Date applied
07/08/2017
Date assigned
08/08/2017
Last edited
10/08/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Breast cancer is common. The lifetime risk of women developing breast cancer in the UK is 1 in 8. Survival continues to improve. This improved survival is in part down to chemotherapy drugs called anthracyclines. This medication can cause the unwanted side effect of heart muscle injury. Breast cancer survivors have increased rates of heart problems including heart muscle failure. The aim of this study is to test whether tablet medications called angiotensin receptor blockers (ARBs) and B-blockers can prevent heart muscle injury related to chemotherapy. These medications are well established treatments for improving symptoms and survival in patients with heart failure. A blood test called cardiac troponin I is used to detect very slight heart muscle injury. In this study only patients with increased levels of this marker are treated with ARBs and B-blockers.

Who can participate?
Breast cancer patients aged over 18 who are scheduled for anthracycline treatment

What does the study involve?
Participants undergo a detailed magnetic resonance imaging (MRI) scan of their heart before starting chemotherapy. Patients receiving anthracycline have blood samples taken routinely 2 to 3 days before each cycle. Cardiac troponin I levels are measured using these blood samples. Patients who have increased levels of cardiac troponin I are randomly allocated to treatment with either a combination of ARB and B-blocker or standard care. Heart muscle function is measured using an MRI scan 6 months later to find out whether ARBs and B-blockers can prevent the decline. Patients are followed up to measure health events such as heart failure.

What are the possible benefits and risks of participating?
The study will show whether a convenient blood test can detect those at risk of heart failure. It is not known whether patients will benefit directly from taking part in this study but they will have more regular monitoring of how their heart is working compared to other patients receiving anthracycline treatment. Participants have to make 4-5 extra visits to the cancer centre to complete questionnaires and have additional blood samples taken. The patients who are allocated to receive the study medication will have an additional 3-4 visits to provide a blood sample and have the dose of study medication changed.

Where is the study run from?
1. Edinburgh Cancer Centre (UK)
2. Beatson Institute for Cancer Research (UK)
3. Leeds Institute of Cancer and Pathology (UK)
4. Velindre Hospital (UK)

When is the study starting and how long is it expected to run for?
April 2017 to November 2020

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Dr Morag MacLean
Cardiac-CARE@ed.ac.uk

Trial website

http://edin.ac/cardiac-care-trial

Contact information

Type

Public

Primary contact

Dr Morag MacLean

ORCID ID

Contact details

Edinburgh Clinical Trials Unit
Room D36
Level 2
Outpatients Building
Western General Hospital
Crewe Road South
Edinburgh
EH4 2XU
United Kingdom
+44 (0)131 537 3846
Cardiac-CARE@ed.ac.uk

Additional identifiers

EudraCT number

2017-000896-99

ClinicalTrials.gov number

Protocol/serial number

35705; AC16148

Study information

Scientific title

A multicentre prospective randomised open-label blinded end-point controlled trial of high-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent cardiac toxicity in breast cancer patients receiving anthracycline adjuvant therapy (Cardiac CARE)

Acronym

Cardiac CARE

Study hypothesis

Angiotensin receptor blockers (ARB) and B-blockers can prevent heart muscle injury related to chemotherapy in breast cancer patients, and cardiac Troponin I levels can predict those patients at risk of ventricular dysfunction.

For pilot study protocol, see additional file ISRCTN24439460_PROTOCOL_PILOT_v3.0_11Apr2017.docx

Ethics approval

East of Scotland Research Ethics Service REC 2, 19/06/2017, ref: 17/ES/0071

Study design

Randomised; Interventional; Design type: Treatment, Prevention, Drug

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 to request a patient information sheet

Condition

Specialty: Cancer, Primary sub-specialty: Breast Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasm of breast, Cardiovascular/ Other and unspecified disorders of the circulatory system

Intervention

Breast cancer patients scheduled for anthracycline treatment will be approached to take part. If they give consent they will have a detailed magnetic resonance imaging (MRI) scan of their heart prior to starting chemotherapy. Patients not in the trial would routinely have radionuclide scans to monitor heart function. Patients receiving anthracycline have blood taken routinely 2 to 3 days before each cycle. Cardiac troponin I levels will be measured on these blood samples. It is estimated a third of enrolled patients (n= ~56) will develop an elevated plasma cTnI concentration and they will be randomised (1:1 randomised group design minimized by binary criteria [age, baseline LVEF, and randomisation at cycle 2 or 6]) to receive either:

1. Treatment with a combination of ARB (Candesartan) and B-blocker (Carvedilol). Candesartan will be started at 8 mg o.d. and increased at 3-day intervals to 16 mg and 32 mg o.d. Carvedilol will be initiated simultaneously at 6.25 mg b.d., and increased to 12.5 mg b.d. and 25 mg b.d.
2. Standard care: no intervention, LVEF monitored according to local SOPs. Participants in the standard care arm will additionally have study-specific procedures: cTnI measurements and patient questionnaires at 2, 4 and 6 months post-anthracycline treatment, and a cardiac MRI at 6 months post-anthracycline treatment.

IMP will be dispensed on the day of randomisation and will continue until completion/withdrawal from the study.

Duration of treatment: 25 – 37 weeks
Duration of follow-up: None

Intervention type

Drug

Phase

Phase II

Drug names

Candesartan, carvedilol

Primary outcome measure

LVEF measured using cardiac MRI scan at baseline and 6 months after final anthracycline dose

Secondary outcome measures

1. Specificity of cTnI assay for left ventricular dysfunction: 6-months post treatment LVEF will be recorded with cardiac MRI in all non-randomised participants and compared to baseline LVEF to define the specificity of the hs-cTnI assay for identifying low-risk participants who do not develop left ventricular systolic dysfunction
2. The development of asymptomatic left ventricular dysfunction (a 10 percentage point fall or an LVEF less than 50%), measured with cardiac MRI at 6 months post-anthracycline treatment compared to baseline
3. Resolution of myocardial injury: whether plasma cTnI concentrations return to the normal reference range (<5 ng/L) at 2, 4 and 6 months after chemotherapy
4. Clinical endpoints of death, cardiovascular death and heart failure. Heart failure will be defined by the diagnosis of clinical (symptomatic) heart failure
5. Health economics: the feasibility of data capture and the quality of data obtainable in this patient population, to inform the design of further research including sample size calculation and/or value of information analysis
6. Heart rate and blood pressure at 2, 4 and 6 months following final dose of anthracycline

Overall trial start date

01/04/2017

Overall trial end date

01/11/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Female or male aged ≥18 years
2. Histological diagnosis of invasive breast cancer
3. ECOG performance status 0-1
4. Planned to commence anthracycline for adjuvant or neo-adjuvant treatment of breast cancer. Patients scheduled for >300 mg/m2 cumulative dose epirubicin or equivalent.
5. A life expectancy of at least 12 months
6. LVEF ≥ 50% on baseline MRI
7. Systolic blood pressure ≥ 105 mmHg and ≤170 mmHg
8. An eGFR >45 mL/min/1.73 m2
9. Provide written consent to take part in the study

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

168

Participant exclusion criteria

1. Pregnancy or breastfeeding
2. HER2 positive disease with planned trastuzumab therapy
3. Uncontrolled arterial hypertension defined as systolic blood pressure on treatment of >170 mmHg
3. Patients already taking B-blockers, ACEi or ARBs
4. Contra-indication to ARBs (eGFR ≤ 45 mL/min/1.73 m2, previous hypersensitivity, renal artery stenosis) or B-blockers (asthma, pathological heart block and pathological sinus bradycardia)
5. Clinically proven intolerance to lactose monohydrate
6. A history of symptomatic heart failure
7. Contraindication to or inability to tolerate MRI scanning
8. Suspected poor drug compliance
9. Active alcohol or drug abuse
10. Patients previously treated with anthracyclines or trastuzumab
11. Uncontrolled concomitant serious illness, as determined by the investigator
12. Female or male aged <18 years
13. Not provided written consent to take part in the study
14. Previously randomised into this trial

Recruitment start date

01/09/2017

Recruitment end date

01/09/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Edinburgh Cancer Centre
Edinburgh
EH4 2XU
United Kingdom

Trial participating centre

Beatson Institute for Cancer Research
Glasgow
G12 0YN
United Kingdom

Trial participating centre

Leeds Institute of Cancer and Pathology
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Velindre Hospital
Cardiff
CF14 2TL
United Kingdom

Sponsor information

Organisation

ACCORD - University of Edinburgh & NHS Lothian co-sponsors

Sponsor details

The Queen’s Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom

Sponsor type

University/education

Website

http://accord.scot/

Funders

Funder type

Government

Funder name

National Institute for Health Research; Grant Codes: 15_48_20

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

A manuscript is being prepared for publishing the protocol. Once recruitment starts the protocol will also be available on the department website (http://www.ed.ac.uk/usher/edinburgh-clinical-trials/our-studies/ukcrc-studies/cardiac-care). Any study documents can be requested by emailing cardiac-CARE@ed.ac.uk.

On completion of the study, the study data will be analysed and tabulated, and a clinical study report will be submitted to the NIHR (funder) by 01/11/2020. A report will also be submitted to the REC within 1 year of the end of the study and results will be uploaded to the European clinical trials database. Following publication of the NIHR report the study team will disseminate the results to participating sites and prepare any possible articles for peer reviewed journals. The study results may also be presented at scientific meetings. A lay summary of results will be published on the trial website and provided to the participating sites for dissemination to participants and within their clinics generally (where appropriate and according to their discretion).

IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from the CI Dr Peter Henriksen (Cardiac-CARE@ed.ac.uk). Following publication of the primary paper, a de-identified individual participant dataset will be submitted to data archiving for sharing purposes. The format of the data is currently unknown but will likely be available in common formats in use by statisticians working in UK universities. The de-identified dataset will remain available indefinitely. Access to the dataset will be under a controlled access model in line with ECTU (Edinburgh University) policies at the time.

Intention to publish date

01/01/2021

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

10/08/2017: Protocol file for pilot study uploaded.