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Safety of Withdrawal of Pharmacological Treatment for Recovered HER2 Targeted Therapy Related Cardiac Dysfunction (HER-SAFE)

Primary Purpose

Cardiotoxicity, HER2-positive Breast Cancer, Heart Failure

Status
Not yet recruiting
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Phased withdrawal of heart failure medications
Sponsored by
University College, London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cardiotoxicity focused on measuring Cardiotoxicity, HER2-positive Breast Cancer, Heart Failure, Cancer, Therapy-Related

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Adult participants (>18 years) A prior diagnosis of human epidermal growth factor receptor 2 (HER2)- targeted therapy related cardiac dysfunction, who currently receive standard heart failure/cardioprotective medications (any combination of angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs] and/or beta-blockers). Cardiac function has 'recovered'. 'Recovery' is defined as absence of heart failure symptoms with left ventricular ejection fraction (LVEF) improved to 50% or greater and N-terminal pro B-type natriuretic peptide (NTproBNP) <125ng/L, for greater than 6 months. Exclusion Criteria: Advanced/ metastatic HER2 positive breast cancer requiring ongoing HER2 therapies or with life expectancy <12months. Patients classed as high/very high cardiovascular risk according to the International Cardio-Oncology Society (ICOS) risk stratification Patients with LVEF <50% prior to HER2-therapy initiation or on completion of anthracycline treatment Patients with ongoing indications for the cardioprotective medication - ACE inhibitors, ARBs and/or beta-blockers Patients with absolute contraindications to cardiovascular magnetic resonance scans (CMR).

Sites / Locations

  • St Bartholemew's Hospital
  • University College London Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Treatment Withdrawal

Treatment Continuation

Arm Description

Participants will undergo phased withdrawal of heart failure/ cardioprotective treatments according to a pre-specified algorithm based on the 'Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy' (TRED-HF) study protocol (Halliday et al 2019). Medications will be down titrated in a phased process every 2 weeks over 16 weeks maximum. Drug doses will be reduced by 50% every 2 weeks, until the patient is taking 25% or less of the maximum recommended dose at which point they will be stopped. Monitoring with fortnightly virtual consultations will confirm dose reduction and provide support. Participants will undergo clinical assessment at 6, 14 and 24 weeks and 6, 9 and 12 months with weight, blood pressure, and biomarker measurement. At baseline, 6- and 12-month visits detailed cardiovascular phenotyping using cardiovascular magnetic resonance scans and symptom and disutility questionnaires will be undertaken.

Participants will continue their current heart failure/ cardioprotective treatments. Participants will undergo clinical assessment at 6, 14 and 24 weeks and 6, 9 and 12 months with weight, blood pressure, and biomarker measurement. At baseline, 6- and 12-month visits detailed cardiovascular phenotyping using cardiovascular magnetic resonance scans and symptom and disutility questionnaires will be undertaken.

Outcomes

Primary Outcome Measures

Relapse in Cardiotoxicity
Number of participants with relapse in cardiotoxicity, defined based on International Cardio-Oncology Society 2021 Guidelines as (at least one of): Asymptomatic left ventricular ejection fraction (LVEF) reduction by ≥10 percentage points to a LVEF of <50% Asymptomatic LVEF reduction by ≥5 percentage points to an LVEF of <50% plus new relative decline in global longitudinal strain (GLS) by >15% from baseline AND/OR new rise in cardiac biomarkers (>2 fold increase in N-terminal pro B-type natriuretic peptide [NTproBNP] to >400ng/L, or high sensitivity Troponin >99th percentile) Clinical heart failure (based on symptoms and clinical examination) with at least one of the following: fall in LVEF ≥5%, increase in cardiac biomarkers (as above), relative fall in GLS > 15%, new arrhythmia (excluding ectopy)

Secondary Outcome Measures

Cardiac Biomarkers (N-terminal pro B-type natriuretic peptide [NT-proBNP])
Change from baseline at 6 and 12 months in the cardiac biomarker NT-proBNP (measured in pg/L)
Cardiac Biomarkers (Troponin T)
Change from baseline at 6 and 12 months in the cardiac biomarkers Troponin T (measured in ng/L).
Quality of life (Kansas City Cardiomyopathy Questionnaire)
Change from baseline at 6 and 12 months in the quality of life questionnaire score - the Kansas City Cardiomyopathy Questionnaire (Minimum 0 - Maximum 100; 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent).
Quality of life (Minnesota Living with Heart Failure Questionnaire)
Change from baseline at 6 and 12 months in quality of life questionnaire score - the Minnesota Living with Heart Failure Questionnaire (Minimum 0 - Maximum 105, Higher score indicates worse outcome).
Heart rate
Change from baseline at 6 and 12 months in baseline resting heart rate (beats per minute)
Blood Pressure
Change from baseline at 6 and 12 months in blood pressure (Systolic and diastolic, mmHg)
Left Ventricular Volumes (By Cardiac MRI)
Change from baseline at 6 and 12 months in CMR-derived left ventricular volumes (measured in ml and ml/m2)
Left Ventricular Ejection Fraction (By Cardiac MRI)
Change from baseline at 6 and 12 months in CMR-derived left ventricular ejection fraction (measured in %)
Left Ventricular Strain (By Cardiac MRI)
Change from baseline at 6 and 12 months in CMR-derived left ventricular strain (measured in %)
T1 mapping (By Cardiac MRI)
Change from baseline at 6 and 12 months in CMR-derived native T1 mapping (measured in ms)
Medication Disutility
Medication disutility is the inconvenience to the patient of taking a given medication. This will be assessed with a structured questionnaire with qualitative responses regarding medication side effects, cost (financial and personal) and the benefits required to offset this.

Full Information

First Posted
February 8, 2023
Last Updated
May 19, 2023
Sponsor
University College, London
Collaborators
British Heart Foundation, Barts & The London NHS Trust, University College London Hospitals
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1. Study Identification

Unique Protocol Identification Number
NCT05880160
Brief Title
Safety of Withdrawal of Pharmacological Treatment for Recovered HER2 Targeted Therapy Related Cardiac Dysfunction
Acronym
HER-SAFE
Official Title
Randomised Control Trial for the Safety of Withdrawal of Pharmacological Treatment for Recovered HER2 Targeted Therapy Related Cardiac Dysfunction
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
June 2023 (Anticipated)
Primary Completion Date
September 2025 (Anticipated)
Study Completion Date
September 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University College, London
Collaborators
British Heart Foundation, Barts & The London NHS Trust, University College London Hospitals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Breast cancer is the most common cancer in the United Kingdom (UK), but improvements in treatment mean 3 in 4 people survive for more than 10 years. Many people receive treatments called human epidermal growth factor receptor 2 (HER2) targeted therapies for their breast cancer, however these can affect heart function. This 'cardiotoxicity' is generally temporary and mild, but patients receive drugs to help their heart recover. Currently it is not known how long patients should receive these treatments. Patients with other types of heart failure are treated lifelong, but this may not be necessary here as the damaging cancer drugs have stopped. Taking drugs for many years can have an impact on people's quality of life, particularly for young patients. It is therefore important to understand the best treatment length. The investigators will study people whose heart function has recovered after HER2 therapy heart problems and are not at high risk for heart disease. The investigators will carefully stop their heart drugs whilst monitoring them closely with special heart scans and blood tests to detect problems early. The investigators will also study how patients are currently treated using national data. The results of this study will help doctors better guide breast cancer survivors about treatment of heart damage from HER2 cancer therapies.
Detailed Description
Trial design: Two centre open label randomised control trial to evaluate the phased withdrawal versus continuation of heart failure treatment for 'recovered' human epidermal growth factor receptor 2 (HER2) therapy-related cardiac dysfunction in non-high risk patients following completion of HER2 therapy. The trial will include cardiovascular magnetic resonance scans (CMR) with automated in-line analytics to improve the sensitivity for detection of early relapse, and detailed patient questionnaires assessing medication disutility to better understand participant motivations and concerns related to treatment continuation and withdrawal. Trial population: The trial will recruit 90 adult participants (>18 years) with a prior diagnosis of HER2-targeted therapy related cardiac dysfunction, who currently receive standard heart failure/ cardioprotective medications (any combination of Angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs] and/or beta-blockers), and whose cardiac function has 'recovered'. 'Recovery' is defined as absence of heart failure symptoms with left ventricular ejection fraction (LVEF) improved to 50% or greater and N-terminal pro B-type natriuretic peptide (NTproBNP) <200ng/L, for greater than 6 months. Patients will be recruited from Barts Health and University College London Hospitals (UCLH) cardio-oncology and breast cancer clinics. Exclusion criteria: Patients with advanced/ metastatic HER2 positive breast cancer requiring ongoing HER2 therapies or with life expectancy <12months will be excluded. Patients classed as high/very high cardiotoxicity risk according to the European Society of Cardiology/International Cardio-Oncology Society Position Statement (Lyon et al, 2020), LVEF <50% prior to HER2-therapies or on completion of anthracycline treatment, or indications for ongoing ACE inhibitors, ARBs and/or beta-blockers, nor those with absolute contraindications to CMR. Interventions and Duration of treatment: Participants will undergo phased withdrawal of heart failure/ cardioprotective treatments according to a pre-specified algorithm based on the 'Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy' (TRED-HF) study protocol (Halliday et al 2019). This had been designed following extensive consultation with independent experts and attempts to mimic 'real-world' medication withdrawal in clinical practice. Medications will be down titrated in a phased process every 2 weeks over a maximum of 16 weeks. Drug doses will be reduced by 50% in a stepwise manner every 2 weeks, until the patient is taking 25% or less of the maximum recommended dose at which point the medication will be stopped. Monitoring with fortnightly virtual consultations will confirm drug dose reduction and provide support. Participants will undergo clinical assessment at 6, 14 and 24 weeks and 6, 9 and 12 months with weight, blood pressure, and biomarker measurement. At baseline, 6- and 12-month visits detailed cardiovascular phenotyping using CMR and symptom and disutility questionnaires will be undertaken.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiotoxicity, HER2-positive Breast Cancer, Heart Failure, Cancer, Therapy-Related
Keywords
Cardiotoxicity, HER2-positive Breast Cancer, Heart Failure, Cancer, Therapy-Related

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Two centre open label randomised control trial to evaluate the phased withdrawal versus continuation of heart failure treatment for 'recovered' human epidermal growth factor receptor 2 (HER2) therapy-related cardiac dysfunction in non-high risk patients following completion of HER2 therapy.
Masking
None (Open Label)
Masking Description
Open label
Allocation
Randomized
Enrollment
90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment Withdrawal
Arm Type
Experimental
Arm Description
Participants will undergo phased withdrawal of heart failure/ cardioprotective treatments according to a pre-specified algorithm based on the 'Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy' (TRED-HF) study protocol (Halliday et al 2019). Medications will be down titrated in a phased process every 2 weeks over 16 weeks maximum. Drug doses will be reduced by 50% every 2 weeks, until the patient is taking 25% or less of the maximum recommended dose at which point they will be stopped. Monitoring with fortnightly virtual consultations will confirm dose reduction and provide support. Participants will undergo clinical assessment at 6, 14 and 24 weeks and 6, 9 and 12 months with weight, blood pressure, and biomarker measurement. At baseline, 6- and 12-month visits detailed cardiovascular phenotyping using cardiovascular magnetic resonance scans and symptom and disutility questionnaires will be undertaken.
Arm Title
Treatment Continuation
Arm Type
No Intervention
Arm Description
Participants will continue their current heart failure/ cardioprotective treatments. Participants will undergo clinical assessment at 6, 14 and 24 weeks and 6, 9 and 12 months with weight, blood pressure, and biomarker measurement. At baseline, 6- and 12-month visits detailed cardiovascular phenotyping using cardiovascular magnetic resonance scans and symptom and disutility questionnaires will be undertaken.
Intervention Type
Other
Intervention Name(s)
Phased withdrawal of heart failure medications
Intervention Description
As per arm/group description
Primary Outcome Measure Information:
Title
Relapse in Cardiotoxicity
Description
Number of participants with relapse in cardiotoxicity, defined based on International Cardio-Oncology Society 2021 Guidelines as (at least one of): Asymptomatic left ventricular ejection fraction (LVEF) reduction by ≥10 percentage points to a LVEF of <50% Asymptomatic LVEF reduction by ≥5 percentage points to an LVEF of <50% plus new relative decline in global longitudinal strain (GLS) by >15% from baseline AND/OR new rise in cardiac biomarkers (>2 fold increase in N-terminal pro B-type natriuretic peptide [NTproBNP] to >400ng/L, or high sensitivity Troponin >99th percentile) Clinical heart failure (based on symptoms and clinical examination) with at least one of the following: fall in LVEF ≥5%, increase in cardiac biomarkers (as above), relative fall in GLS > 15%, new arrhythmia (excluding ectopy)
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Cardiac Biomarkers (N-terminal pro B-type natriuretic peptide [NT-proBNP])
Description
Change from baseline at 6 and 12 months in the cardiac biomarker NT-proBNP (measured in pg/L)
Time Frame
12 months
Title
Cardiac Biomarkers (Troponin T)
Description
Change from baseline at 6 and 12 months in the cardiac biomarkers Troponin T (measured in ng/L).
Time Frame
12 months
Title
Quality of life (Kansas City Cardiomyopathy Questionnaire)
Description
Change from baseline at 6 and 12 months in the quality of life questionnaire score - the Kansas City Cardiomyopathy Questionnaire (Minimum 0 - Maximum 100; 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent).
Time Frame
12 months
Title
Quality of life (Minnesota Living with Heart Failure Questionnaire)
Description
Change from baseline at 6 and 12 months in quality of life questionnaire score - the Minnesota Living with Heart Failure Questionnaire (Minimum 0 - Maximum 105, Higher score indicates worse outcome).
Time Frame
12 months
Title
Heart rate
Description
Change from baseline at 6 and 12 months in baseline resting heart rate (beats per minute)
Time Frame
12 months
Title
Blood Pressure
Description
Change from baseline at 6 and 12 months in blood pressure (Systolic and diastolic, mmHg)
Time Frame
12 months
Title
Left Ventricular Volumes (By Cardiac MRI)
Description
Change from baseline at 6 and 12 months in CMR-derived left ventricular volumes (measured in ml and ml/m2)
Time Frame
12 months
Title
Left Ventricular Ejection Fraction (By Cardiac MRI)
Description
Change from baseline at 6 and 12 months in CMR-derived left ventricular ejection fraction (measured in %)
Time Frame
12 months
Title
Left Ventricular Strain (By Cardiac MRI)
Description
Change from baseline at 6 and 12 months in CMR-derived left ventricular strain (measured in %)
Time Frame
12 months
Title
T1 mapping (By Cardiac MRI)
Description
Change from baseline at 6 and 12 months in CMR-derived native T1 mapping (measured in ms)
Time Frame
12 months
Title
Medication Disutility
Description
Medication disutility is the inconvenience to the patient of taking a given medication. This will be assessed with a structured questionnaire with qualitative responses regarding medication side effects, cost (financial and personal) and the benefits required to offset this.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult participants (>18 years) A prior diagnosis of human epidermal growth factor receptor 2 (HER2)- targeted therapy related cardiac dysfunction, who currently receive standard heart failure/cardioprotective medications (any combination of angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs] and/or beta-blockers). Cardiac function has 'recovered'. 'Recovery' is defined as absence of heart failure symptoms with left ventricular ejection fraction (LVEF) improved to 50% or greater and N-terminal pro B-type natriuretic peptide (NTproBNP) <125ng/L, for greater than 6 months. Exclusion Criteria: Advanced/ metastatic HER2 positive breast cancer requiring ongoing HER2 therapies or with life expectancy <12months. Patients classed as high/very high cardiovascular risk according to the International Cardio-Oncology Society (ICOS) risk stratification Patients with LVEF <50% prior to HER2-therapy initiation or on completion of anthracycline treatment Patients with ongoing indications for the cardioprotective medication - ACE inhibitors, ARBs and/or beta-blockers Patients with absolute contraindications to cardiovascular magnetic resonance scans (CMR).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Benjamin Dowsing, MBBS MSc BSc
Phone
+447912148972
Email
benjamin.dowsing@nhs.net
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Charlotte Manisty
Organizational Affiliation
UCL
Official's Role
Principal Investigator
Facility Information:
Facility Name
St Bartholemew's Hospital
City
London
ZIP/Postal Code
EC1A 7BE
Country
United Kingdom
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Benjamin Dowsing, MBBS MSc BSc
Phone
+447912148972
Email
benjamin.dowsing@nhs.net
First Name & Middle Initial & Last Name & Degree
Charlotte Manisty
First Name & Middle Initial & Last Name & Degree
Benjamin Dowsing
Facility Name
University College London Hospital
City
London
ZIP/Postal Code
NW1 2BU
Country
United Kingdom
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Benjamin Dowsing, MBBS MSc BSc
Phone
07912148972
Email
benjamin.dowsing@nhs.net
First Name & Middle Initial & Last Name & Degree
Malcolm Walker
First Name & Middle Initial & Last Name & Degree
Benjamin Dowsing

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Safety of Withdrawal of Pharmacological Treatment for Recovered HER2 Targeted Therapy Related Cardiac Dysfunction

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