Whole Heart Radiotherapy for End-stage Heart Failure (ESHF-WHRT)

March 1, 2024 updated by: Tarek Hijal, McGill University Health Centre/Research Institute of the McGill University Health Centre

Phase 1 Feasibility and Safety of Whole Heart Radiotherapy for End-stage Heart Failure: First In-human Treatments

End-stage heart failure (ESHF) causes recurrent hospitalizations, cardiac arrhythmias, and intolerance to standard HF therapies are common as the disease progresses. Management focuses on controlling symptoms, correcting precipitants, avoiding triggers, and improving quality-of-life. The combination of recent preclinical and clinical data suggests that localized cardiac RT is relatively safe and has positive conductive and anti-proliferative effects in the "sick" heart. In this Phase 1 study, the investigators aim to assess the feasibility and safety of 5 Gy whole heart radiotherapy in six (6) ESHF participants with limited options for further medical therapy to control their disease. The investigators hypothesize that 5 Gy whole heart radiotherapy can improve LVEF and decrease blood markers of heart failure and inflammation including B-type natriuretic peptide (BNP), C-reactive protein (CRP), and troponins, while also having a very tolerable side effect profile.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

HEART FAILURE Heart Failure (HF) is a heterogeneous syndrome manifested by vascular congestion and/or peripheral hypoperfusion in the setting of structural and/or functional cardiac abnormalities. Congestion commonly presents with dyspnea, reduced exercise tolerance, and edema while hypoperfusion results in end-organ dysfunction. HF is a major public health problem and because of its age-dependent increase in incidence and prevalence, it's one of the leading causes of death and hospitalization among the elderly. As a consequence of the worldwide increase in life expectancy, and due to improvements in the treatment of HF in recent years, the proportion of participants that reach an advanced phase of the disease, so-called ESHF, is steadily growing.

HF is characterized by impairment in cardiac structure and function which, in its advanced phases, results in decreased cardiac output (hypoperfusion) and/or fluid buildup (congestion). Initially cardiac output (CO) is maintained through the Frank-Starling mechanism with LV dilation and wall thickening. Eventually myocardial contractility declines and stroke volume (SV) decreases . A compensatory increase in heart rate (HR) may initially help maintain cardiac output, but this too will ultimately fail to preserve output. Currently, patients with HF are most often categorized as having heart failure with reduced (HFrEF; LVEF <40%), mid-range (HFmrEF; LVEF 40-49%) or preserved ejection fraction (HFpEF; LVEF ≥50%). The four classical hemodynamic profiles of heart failure can be categorized in a two-by-two matrix based on filling pressures (presence or absence of congestion) and perfusion status (adequate/inadequate). Furthermore, patients are classified by the New York Heart Association (NYHA) based on the presence or absence of symptoms during rest and physical activity (Figure 2). Patients with ESHF typically live in the NYHA Class III-IV and in a fine balance between the "wet and warm" (i.e. relatively preserved perfusion but congested) and "wet and cold" (i.e. low perfusion and congested) categories.

The two principal pathways mediating the pathophysiology of heart failure are the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). These systems are innately related, having the ability to further activate each other and ultimately resulting in a chronic state of increased effective circulating volume. Over time, myocardial alterations result in reduced responsiveness to these adaptive mechanisms, and thus a drop in cardiac output ensues. Not surprisingly the principal HF therapies target these pathways. The primary therapies have been comprised of the triad of ACE inhibitors (or angiotensin receptor blockers [ARB] if intolerant), beta-adrenoreceptor antagonists (beta-blockers), and mineralocorticoid receptor antagonists (MRAs) titrated to target doses. Unfortunately, in ESHF, medical optimization is often not tolerated because of worsening hypotension, hyperkalemia, and renal dysfunction. There is often a need to reduce the dose or eliminate these therapies which is a well-established marker of poor prognosis. Once diagnosed with ESHF focus turns towards defining the optimal therapeutic approach with options including orthotopic heart transplant (OHT), left ventricular assist device (LVAD) and/or palliation. Ultimately, a combination of these three strategies is often required.

Left ventricular ejection fraction (LVEF) is generally viewed as a clinically useful phenotypic marker indicative of underlying pathophysiological mechanisms and sensitivity to therapy.

End-stage heart failure (ESHF) manifests as severe and often relentless symptoms of dyspnea, fatigue, abdominal discomfort and ultimately cardiac cachexia with renal and hepatic dysfunction frequently further complicating the process. Recurrent hospitalizations, cardiac arrhythmias, and intolerance to standard HF therapies are common as the disease progresses. Management focuses on controlling symptoms, correcting precipitants, avoiding triggers, and improving quality-of-life (QOL).

RADIATION THERAPY Radiation therapy involves delivering high energy x-rays precisely to a target with minimal dose to the surrounding clinical tissues. Accuracy in radiation therapy requires effective patient immobilization, precise target localization, and highly conformed dosimetry and isotropic dose fall-off. Dose calculations involve algorithms that account for effects of tissue heterogeneities, and the linear accelerators that deliver the treatment are also equipped with multileaf collimators and have the ability of using multiple non-overlapping beams of radiation as well as intensity modulated radiation therapy to maximize accuracy of target dose deposition while minimizing surrounding organ dose.

Radiation therapy is used in many malignant and benign conditions with a variety of dose and fractionation schemes. For malignant diseases in the palliative setting, radiation therapy is delivered to painful or progressive sites of disease in a highly focused manner with significant benefit on controlling pain, local progression, and quality of life. Typical doses for these types of treatment vary and can be limited to 8 Gy in a single fraction. These treatments are tolerated extremely well by almost all patients with almost no side effects.

Radiation therapy (RT) is utilized half of all patients with a cancer diagnosis. RT is effective in reducing populations of highly proliferative cells, a common feature of malignant disease. RT is also used successfully to treat many non-malignant disorders, including hyperproliferative and inflammatory conditions. The RT doses required for these non-malignant disorders are often much smaller and carry a lighter burden of adverse effects. Recently, a number of human and murine studies indicate that in heart failure (HF), proliferating macrophages and fibroblasts are major mediators of collateral tissue injury and progressive disease. Strategies that ablate these highly proliferative precursors in preclinical models attenuate features of heart failure progression.

The use of high-dose stereotactic radiation therapy in patients with cardiac arrhythmias, specifically ventricular tachycardia (VT), has been shown to reduce arrhythmia burden in several human clinical trials and case series. In these studies, a single dose (25 Gy) of non-invasive electrophysiologically guided localized RT was safe, substantially reduced VT, improved left ventricular ejection fraction (LVEF) and improved quality of life (QOL) in 50-70% of patients with no other options for therapy. The initial hypothesis for this effect was that RT would create a scar, similar to how invasive catheter therapies are utilized to ablate arrhythmias. However, subsequent mechanistic studies suggest that rather than simply scarring the targeted tissue, RT stimulates physiologic changes including increased sodium channel (NaV1.5) and connexin-43 (Cx-43) expression, increasing conduction velocity within the heart. These physiologic changes were also seen outside of the 25Gy target areas, suggesting that smaller doses of radiation is sufficient to stimulate these effects. Retrospective analysis of the RT dosimetry from patients treated for VT demonstrated that 5 Gy was reflective of the approximate whole heart dose received outside of the targeted scar in these patients. A recent hypothesis postulated that 5 Gy may be sufficient to upregulate pro-conductive proteins and signaling pathways while attenuating cardiac remodeling via decreasing levels of macrophages and fibroblasts; the primary proliferative precursors to adverse cardiac remodeling in many models of cardiac injury. This was investigated in murine heart failure models, which demonstrated that 5 Gy of cardiac radiation delivered after injury attenuated adverse cardiac remodeling, improved LVEF, reduced fibrosis, and decreased proliferation of macrophages and fibroblasts.

HYPOTHESIS The combination of recent preclinical and clinical data suggests that localized cardiac RT is relatively safe and has positive conductive and anti-proliferative effects in the "sick" heart. In this Phase 1 study, the investigators aim to assess the feasibility and safety of 5 Gy whole heart radiotherapy in six (6) ESHF particip with limited options for further medical therapy to control their disease. The investigators hypothesize that 5 Gy whole heart radiotherapy can improve LVEF and decrease blood markers of heart failure and inflammation including B-type natriuretic peptide (BNP), C-reactive protein (CRP), and troponins, while also having a very tolerable side effect profile.

Study Type

Interventional

Enrollment (Estimated)

6

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Joanne Alfieri, MD
  • Phone Number: 53333 514-934-1934

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • at least 65 years of age
  • End-stage heart failure NYHA class 3-4,
  • LVEF ≤ 30%
  • on maximum medical therapy with progressive symptoms/disease as defined by their primary cardiologist

Exclusion Criteria:

  • previous RT in the treatment field that precludes further RT
  • active connective tissue disease
  • interstitial pulmonary fibrosis
  • Participants who are unable to be positioned in a manner where treatment can be safely delivered

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Whole Heart Radiation Therapy
Whole heart radiotherapy, 5 Gy in 1 fraction
Other: Whole Heart Radiation Therapy
Radiation to the whole heart in one treatment with a prescribed dose of 5 Gy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in mean left ventricle ejection fraction
Time Frame: 6 weeks, 12 weeks, 24 weeks
Efficacy Endpoint
6 weeks, 12 weeks, 24 weeks
Acute adverse events definitely or probably related to radiation therapy at 30 days as per CTCAE v 5.0
Time Frame: 30 days
Safety Endpoint
30 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 6 months
Death from any cause after treatment
6 months
Hospital stays
Time Frame: 6 months
length of hospitalization after treatment due to heart failure exacerbation
6 months
Subacute adverse events
Time Frame: 30-90 days after treatment
Adverse events definitely or probably related to radiation therapy
30-90 days after treatment
Late adverse events
Time Frame: 90 days to 6 months after treatment
Adverse events definitely or probably related to radiation therapy
90 days to 6 months after treatment
Medication Changes - dose
Time Frame: 6 months
changes in dose of medications following radiotherapy
6 months
Medication Changes - number
Time Frame: 6 months
changes innumber of medications following radiotherapy
6 months
Quality of life CHFQOLQ-20
Time Frame: day 0, 6 weeks, 12 weeks, 24 weeks
quality of life based on questionnaire results following treatment
day 0, 6 weeks, 12 weeks, 24 weeks
Quality of life - SF-36
Time Frame: day 0, 6 weeks, 12 weeks, 24 weeks
quality of life based on questionnaire results following treatment
day 0, 6 weeks, 12 weeks, 24 weeks
Troponin changes
Time Frame: 6 weeks, 12 weeks, 24 weeks
Changes in value of blood marker.
6 weeks, 12 weeks, 24 weeks
Lactate changes
Time Frame: 6 weeks, 12 weeks, 24 weeks
Changes in value of blood marker.
6 weeks, 12 weeks, 24 weeks
Renal Function
Time Frame: 6 weeks, 12 weeks, 24 weeks
Changes in value of blood marker.
6 weeks, 12 weeks, 24 weeks
b-natrurietic peptide
Time Frame: 6 weeks, 12 weeks, 24 weeks
Changes in value of blood marker.
6 weeks, 12 weeks, 24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

McGill University Health Centre/Research Institute of the McGill University Health Centre

Investigators

  • Principal Investigator: Tarek Hijal, MD, McGill University Health Centre/Research Institute of the McGill University Health Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2024

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2024

Study Registration Dates

First Submitted

December 21, 2023

First Submitted That Met QC Criteria

March 1, 2024

First Posted (Actual)

March 7, 2024

Study Record Updates

Last Update Posted (Actual)

March 7, 2024

Last Update Submitted That Met QC Criteria

March 1, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ESHF-WHRT (2024-10362)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

no public sharing, will share anonymized data if necessary for other collaborative projects in future following REB review

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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