Ignite Creation Date:
2024-05-06 @ 8:12 PM
Last Modification Date:
2024-10-26 @ 3:23 PM
Study NCT ID:
NCT06299176
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-03-07
First Post:
2023-12-21
Brief Title:
Whole Heart Radiotherapy for End-stage Heart Failure
Sponsor:
McGill University Health CentreResearch Institute of the McGill University Health Centre
Organization:
McGill University Health CentreResearch Institute of the McGill University Health Centre
Study Overview
Official Title:
Phase 1 Feasibility and Safety of Whole Heart Radiotherapy for End-stage Heart Failure First In-human Treatments
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ESHF-WHRT
Brief Summary:
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
Detailed Description:
HEART FAILURE Heart Failure HF is a heterogeneous syndrome manifested by vascular congestion andor peripheral hypoperfusion in the setting of structural andor 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 its 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 andor 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 adequateinadequate 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 ie relatively preserved perfusion but congested and wet and cold ie 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 andor 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 NaV15 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
HF is characterized by impairment in cardiac structure and function which in its advanced phases results in decreased cardiac output hypoperfusion andor 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 adequateinadequate 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 ie relatively preserved perfusion but congested and wet and cold ie 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 andor 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 NaV15 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None