Phase I/II Study of EP-guided Noninvasive Cardiac Radioablation for Treatment of Ventricular Tachycardia

Study Overview
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Brief Summary
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Phase I/II Study of EP-guided Noninvasive Cardiac Radioablation (ENCORE) for Treatment of Ventricular Tachycardia

Detailed Description
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Patients with Ventricular Tachycardia (VT) who have failed standard therapy (medicines, invasive catheter ablation) have limited options, with one-year survival below 20%. Preclinical data demonstrate that single fraction stereotactic body radiotherapy (SBRT) to discrete portions of the heart is feasible and may result in a reduction or elimination of VT. The efficacy may be further improved when guided by cardiac electrophysiologic (EP) testing. In total, the mapping and ablation proposed for this EP-guided Noninvasive Cardiac Radioablation (ENCORE) is a rapid and totally non-invasive method. Overall safety and early efficacy of ENCORE have not been rigorously studied in a prospective trial to-date. The purpose of this phase I/II study is to demonstrate the short-term safety and preliminary efficacy of ENCORE for patients with life-threatening, treatment-refractory VT.

Official Title
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Phase I/II Study of EP-guided Noninvasive Cardiac Radioablation for Treatment of Ventricular Tachycardia

Conditions
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Ventricular Tachycardia, Cardiomyopathy, Premature Ventricular Contractions

Intervention / Treatment
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* Radiation: stereotactic body radiotherapy (SBRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DOCUMENTED VT: Patient must have documented sustained monomorphic ventricular tachycardia as documented on either a 12-lead ECG or intracardiac ICD interrogation - OR- Monomorphic PVCs documented on a 12-lead ECG. ANTIARRHYTHMIC MEDICATION: Patient must have failed or become intolerant to at least one antiarrhythmic medication (amiodarone, sotalol, or mexiletine). -AND- CATHETER ABLATION: Patient must have failed at least one invasive catheter ablation procedure, or have a contraindication to a catheter ablation procedure (e.g., LV thrombus, severe pulmonary disease), or have VT thought to arise from a protected location (e.g., epicardial VT with history of previous cardiac surgery). MINIMUM VT BURDEN: Patient must have either: At least 3 VT episodes (sustained VT, ICD ATP or ICD shock) over previous 6 months prior to enrollment -OR- >20% PVC burden with a cardiomyopathy (LVEF<50%) Patient must be deemed medically fit for stereotactic body radiation therapy by the treating physician. Patient must be > 18 years old. Patient must be able to understand and be willing to sign an IRB approved written informed consent document. - Exclusion Criteria: Patient must not have past history of radiotherapy within the projected treatment field. Advanced symptomatic heart failure as defined as NYHA Class IV heart failure (inotrope dependent and/or current left-ventricular assist device (LVAD)) Polymorphic VT or ventricular fibrillation (VF) as a clinical heart rhythm (as determined by 12-lead ECG and/or ICD interrogation). More than 3 distinct clinical VT morphologies observed (ECG or ICD interrogation or invasive EP study) OR more than 5 distinct induced VT morphologies during ECGI testing. Advanced myocardial scar substrate that would require stereotactic delivery to a target volume deemed unsafe by the treating physician. Unlikely to live 12 months, in the absence of VT, as best based on clinical judgment by the treating and enrolling physicians. Patient must not be pregnant and/or breastfeeding and must have a negative pregnancy test within 14 days of study entry. -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: stereotactic body radiotherapy (SBRT)<br>Noninvasive SBRT will be delivered in a single fraction to a region of the heart determined by EP-guidance, using noninvasive electrical mapping combined with anatomic imaging. | Radiation: stereotactic body radiotherapy (SBRT)<br>* (Cardiac ablative radiotherapy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Serious Adverse Events | Demonstrate acute (≤ 90 days) safety of noninvasive stereotactic cardiac ablation radiotherapy (ENCORE). The primary safety endpoint is defined by a ≤ 20% rate of serious adverse events (SAEs) using CTCAE v4.0 criteria that are possibly/probably/definitely related to study treatment, based on previously published data for expected invasive catheter-based VT-ablation procedures. | < or = 90 days | 
| Number of Participants With Reduction in Ventricular Tachycardia (VT) Burden | Primary efficacy endpoint is defined by the number of subjects with a reduction in VT burden comparing the period six months before ENCORE treatment to the six months after ENCORE treatment as adjudicated by continuous ICD monitoring (number of ATP and ICD shocks and sustained (>30 second) nontreated slow VT). There will be a six-week blanking period after therapy to allow for ablation effect. For patients with PVC-induced cardiomyopathy, the primary efficacy will be any reduction in PVC burden based on ambulatory heart monitors. | 12 months (6mo prior to and 6mo post SBRT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Determine six-month and twelve-month survival (overall mortality endpoint) after treatment with ENCORE. | 12 months | 
| Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Toxicities that occur after treatment, but are not acutely ascribed to treatment that are possibly/probably/definitely related to study treatment, based on previously published data for expected invasive catheter-based VT-ablation procedures, using the CTCAE v4.0 criteria. | 90 days to 12 months | 
| Health Related Quality of Life (HRQOL) | 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. | 6 week, 6 month, 12 month | 
| Number of Participants With a 50% Reduction in Ventricular Tachycardia (VT) Burden | Evaluate stricter efficacy endpoint of ENCORE treatment, as defined by number of patients who have had 50% reduction in any VT therapies (ATP or ICD shocks or sustained (>30sec) nontreated slow VT) after ENCORE treatment (6 months before vs. 6 months after treatment, with a 6 week blanking period immediately after treatment). For patients with PVC-induced cardiomyopathy, the stricter efficacy will be >50% reduction in PVC burden based on ambulatory heart monitors. | 6 months | 
| Number of Participants With a 95% Reduction in Ventricular Tachycardia (VT) Burden | Evaluate strictest efficacy endpoint of ENCORE treatment, as defined by number of patients who have had 95% reduction in any VT (ATP or ICD shocks or sustained (>30 sec) slow VT) after ENCORE treatment (6 months before vs. 6 months after treatment, with a 6 week blanking period immediately after treatment). For patients with PVC-induced cardiomyopathy, the strictest efficacy will be abolition of PVC burden (<1%) based on ambulatory heart monitors. | 6 months | 
| Number of Participants With Reduction in ICD Shocks and LVEF Improvement | Evaluate the most clinically useful efficacy endpoint of ENCORE treatment, namely, number of patients with reduction specifically in ICD shocks (6 months before vs. 6 months after treatment, with a 6 week blanking period immediately after treatment). For patients with PVC-induced cardiomyopathy, the most clinically useful efficacy will be improvement in cardiac function in the setting of any improvement in PVC burden. | 6 months | 
| Number of Participants With Reduction in Ventricular Tachycardia (VT) Therapies Between 6 and 12 Months | Evaluate longer-term durability endpoint of ENCORE treatment, as defined by number of patients with reduction in VT therapies (ATP or ICD shock or sustained (>30 sec) slow VT and ICD shock alone) during the early phase (treatment to 6 months, with 6 week blanking period) vs. the late phase (6 months to 1 year). For patients with PVC-induced cardiomyopathy, the longer-term durability efficacy will be persistence of any reduction in PVC burden based on ambulatory heart monitors during early phase vs. late phase. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ventricular Tachycardia, Ablation, Noninvasive