Cardiac RadiothErapy For hEart faiLure (CREFEL)

Preliminary data suggests that patients suffering from advanced refractory heart failure (HF) could benefit from single low dose whole heart external beam radiotherapy (EBRT).

Objective: To explore in our center the efficacy of administering a EBRT treatment of 5Gy to the whole heart in patients with advanced and refractory HF. The hypothesis is that 5Gy EBRT to the whole heart can improve the left ventricular ejection fraction (LVEF) of these patients by a clinically relevant 5%.

Main study endpoints: The primary aim is to explore the efficacy of EBRT treatment for advanced refractory HF. Secondary endpoints include an assessment of safety, overall survival, hospital admissions, late toxicity, quality of life and the effect of the treatment on other heart function indicators (left ventricular volumes, NT-proBNP, Troponine, High sensitive CRP).

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Ischemic Cardiomyopathy; Non-ischemic Cardiomyopathy
• Intervention / Treatment: Radiation: 5 Gray Whole Heart external beam radiotherapy

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Patrick Berkovic, MD PhD; Phone Number: +32 16 34 51 15; Email: patrick.berkovic@uzleuven.be
• Study Contact Backup: Name: Bert Vandenberk, MD PhD; Phone Number: +32 16 33 86 86; Email: bert.vandenberk@uzleuven.be

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Recruiting
    • UZ Leuven
    • Contact: Patrick Berkovic, MD PhD; Phone Number: +32 16 34 51 15; Email: patrick.berkovic@uzleuven.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient ≥ 18 years
• Advanced refractory HF NYHA class II, III or IV
• Stable HF for the last 6 months with maximal guideline-directed HF therapy
• Ischemic or dilated cardiomyopathy
• LVEF at baseline ≤ 35%
• Ability to give a written informed consent and willingness to return for follow-up

Exclusion Criteria:

• Eligible or in consideration for heart transplantation
• Pregnancy or breastfeeding
• Previous radiotherapy with cardiac involvement
• Any condition that is deemed a contraindication in the judgment of the investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 5Gy whole heart radiotherapy

Radiation: 5 Gray Whole Heart external beam radiotherapy; EBRT will be delivered with photon energies restricted to 6 Megavoltage (MV) using intensity modulated radiotherapy (IMRT) or Volumetric modulated arc therapy (VMAT). Patients will be treated with a single fraction treatment up to a dose of 5Gy prescribed to the 95% PTV-encompassing isodose line (PTVD95% ≥5Gy). The near-maximum dose is limited to 5.35Gy (PTV D2% ≤ 5.35Gy). The treatment can be performed both as an inpatient or outpatient procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular ejection fraction	The hypothesis, based on recent preclinical and clinical data, is that 5Gy whole heart radiotherapy in advanced refractory HF patients can improve the LVEF and increase QOL with a low to very low toxicity profile. The efficacy will be defined as an improvement of at least 5% of the LVEF over a period of 6 months.	Baseline, week 6, week 12, and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute toxicity	The tolerable acute toxicity will be assessed by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) (U.S. Department of Health and Human Services 2017). It is defined as toxicity occurring within 30 days after the radiation treatment.	toxicity occurring within 30 days after the radiation treatment.
Late toxicity	Late toxicity is defined as toxicity occurring after at least 30 days to 6 months after the radiation treatment and will be assessed by the CTCAE v5.0.	30 days to 6 months after the radiation treatment
Quality of life - SF-36	Health related quality-of-life (QOL) will be measured based on the SF-36. The 36-Item Short Form Survey (SF-36) is a set of generic, coherent, and easily administered quality of life measures that rely on patient self-reporting. The SF-36 evaluates 8 domains: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Scale values for each domain range from 0 to 100 where the higher score defines a more favorable health state.	Baseline, 6 weeks, 12 weeks, and 6 months
Quality of life - MLWHF	Health related quality-of-life (QOL) will be measured based on the Minnesota Living with Heart Failure (MLWHF) questionnaire. The MLWHFis a valid and reliable instrument consisting of 21 items for measuring QOL in patients with HF. It covers various domains including physical, emotional, social, and mental aspects of living with heart failure. Each item is scored on a scale (usually 0 to 5 or 0 to 6), with higher scores indicating a greater impact.	Baseline, 6 weeks, 12 weeks, and 6 months
All-cause mortality	Death from any cause within 6 months after treatment. The Kaplan-Meier method will be used to estimate overall survival (OS).	6 months after the radiation treatment
Heart failure hospitalisation	The number and length of hospitalization related to HF after treatment and within 6 months after treatment. HF-related admissions are defined as a hospital admission lasting for more than 24 h, with signs or symptoms of congestion necessitating an increase of the dose of loop diuretics.	Within 6 months after the radiation treatment
NT-proBNP levels	N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) will be measured as a biomarker of cardiac stress and heart failure severity. Levels are determined using standardized immunoassays and reported in picograms per milliliter (pg/mL). Higher NT-proBNP values generally indicate worse cardiac function and are associated with increased risk of adverse outcomes, whereas lower values suggest improved cardiac status.	Baseline, week 6, week 12, and 6 months
High-sensitive troponin levels	High-sensitivity cardiac troponin will be measured as a biomarker of myocardial injury. High-sensitivity troponin allow detection of very low concentrations and provide accurate quantification across a wide range. Elevated hs-cTn values are associated with acute or chronic myocardial injury and adverse cardiovascular outcomes, whereas stable or low levels indicate absence of significant myocardial damage.	Baseline, 6 weeks, 12 weeks, and 6 months
High-sensitivity C-reactive protein	High-sensitivity C-reactive protein (CRP) will be measured as a biomarker of systemic inflammation. High-sensitivity assays enable accurate detection of low CRP concentrations, reported in milligrams per liter (mg/L), which can reflect low-grade inflammation. Elevated hs-CRP levels are associated with increased cardiovascular risk and adverse outcomes, while lower levels indicate a more favorable inflammatory profile.	Baseline, 6 weeks, 12 weeks, and 6 months
Left ventricular volumes	Left Ventricular End-Diastolic Volume (LVEDV) and End-Systolic Volume (LVESV) will be measured by transthoracic echocardiography using the Simpson's biplane method. These indices provide quantitative measures of left ventricular size and systolic function. Increased LVEDV and LVESV may reflect adverse remodeling and impaired function, whereas lower or normalized values indicate improved ventricular performance.	Baseline, 6 weeks, 12 weeks, and 6 months
Ventricular arrhythmia burden	Ventricular arrhythmia burden will be measured by the cardiac implantable electronic device by assessing the Premature Ventricular Complexes (PVCs) burden; non-sustained Ventricular Tachycardia (nsVT), defined as ≥3 consecutive ventricular beats lasting <30 seconds; and sustainedventricular arrhythmia, defined as ≥30 seconds or requiring device intervention. Arrhythmia burden will be reported as the number of episodes detected during the specified follow-up period.	Baseline, 6 weeks, 12 weeks, and 6 months

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: October 21, 2024
• First Submitted That Met QC Criteria: October 25, 2024
• First Posted (Actual): October 28, 2024

Study Record Updates

• Last Update Posted (Actual): December 1, 2025
• Last Update Submitted That Met QC Criteria: November 28, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: heart failure; external beam radiotherapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure
• Other Study ID Numbers: S69569

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data underlying the results reported in the article (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 6 months after publication of the main results, for at least 5 years.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal. Proposals should be directed to the corresponding author. Access will be granted upon approval of a data use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• 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