Cardiomyopathy, Premature Ventricular Contractions, Ventricular Tachycardia
Conditions
Keywords
Ventricular Tachycardia, Ablation, Noninvasive
Brief summary
Phase I/II Study of EP-guided Noninvasive Cardiac Radioablation (ENCORE) for Treatment of Ventricular Tachycardia
Detailed description
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.
Interventions
RADIATIONstereotactic body radiotherapy (SBRT)
(Cardiac ablative radiotherapy)
Sponsors
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Noninvasive Cardiac Radioablation, all subjects
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. DOCUMENTED VT: 1. Patient must have documented sustained monomorphic ventricular tachycardia as documented on either a 12-lead ECG or intracardiac ICD interrogation \- OR- 2. Monomorphic PVCs documented on a 12-lead ECG. 2. ANTIARRHYTHMIC MEDICATION: Patient must have failed or become intolerant to at least one antiarrhythmic medication (amiodarone, sotalol, or mexiletine). -AND- 3. 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). 4. MINIMUM VT BURDEN: Patient must have either: 1. At least 3 VT episodes (sustained VT, ICD ATP or ICD shock) over previous 6 months prior to enrollment -OR- 2. \>20% PVC burden with a cardiomyopathy (LVEF\<50%) 5. Patient must be deemed medically fit for stereotactic body radiation therapy by the treating physician. 6. Patient must be \> 18 years old. 7. Patient must be able to understand and be willing to sign an IRB approved written informed consent document. \-
Exclusion criteria
1. Patient must not have past history of radiotherapy within the projected treatment field. 2. Advanced symptomatic heart failure as defined as NYHA Class IV heart failure (inotrope dependent and/or current left-ventricular assist device (LVAD)) 3. Polymorphic VT or ventricular fibrillation (VF) as a clinical heart rhythm (as determined by 12-lead ECG and/or ICD interrogation). 4. 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. 5. Advanced myocardial scar substrate that would require stereotactic delivery to a target volume deemed unsafe by the treating physician. 6. Unlikely to live 12 months, in the absence of VT, as best based on clinical judgment by the treating and enrolling physicians. 7. Patient must not be pregnant and/or breastfeeding and must have a negative pregnancy test within 14 days of study entry. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Serious Adverse Events | < or = 90 days | 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. |
| Number of Participants With Reduction in Ventricular Tachycardia (VT) Burden | 12 months (6mo prior to and 6mo post SBRT) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Health Related Quality of Life (HRQOL) | 6 week, 6 month, 12 month | 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. |
| Number of Participants With a 50% Reduction in Ventricular Tachycardia (VT) Burden | 6 months | 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. |
| Overall Survival | 12 months | Determine six-month and twelve-month survival (overall mortality endpoint) after treatment with ENCORE. |
| Number of Participants With Reduction in ICD Shocks and LVEF Improvement | 6 months | 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. |
| Number of Participants With Reduction in Ventricular Tachycardia (VT) Therapies Between 6 and 12 Months | 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. |
| Number of Participants With a 95% Reduction in Ventricular Tachycardia (VT) Burden | 6 months | 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. |
| Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | 90 days to 12 months | 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. |
Countries
United States
Participant flow
Recruitment details
Twenty-one patients were consented between July 11, 2016 and December 20, 2017. These patients were evaluated as either inpatient or outpatient. Once patients met initial enrollment criteria, screening procedures were conducted to determine if the patient was eligible for SBRT.
Pre-assignment details
Nineteen patients were consented, screened, and deemed eligible for SBRT. Two additional patients signed consent and went through screening procedures; however, were later deemed ineligible to obtain SBRT.
Participants by arm
| Arm | Count |
|---|---|
| Patients Overall Who Received SBRT 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.
Stereotactic Body Radiotherapy (SBRT): (Cardiac ablative radiotherapy) | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Patients Overall Who Received SBRT |
|---|---|
| Age-Adjusted Charlson Comorbidity Index | 4 Score |
| Age, Continuous | 66 years |
| BMI | 33.0 kg/m^2 |
| Current Antiarrhythmic Drugs >1 Antiarrhythmic Drug at Baseline | 11 Count of Participants |
| Current Antiarrhythmic Drugs Class I | 11 Count of Participants |
| Current Antiarrhythmic Drugs Class III (excluding amiodarone) | 7 Count of Participants |
| Current Antiarrhythmic Drugs High-Dose Amiodarone (>/=300mg per day) | 10 Count of Participants |
| Current Antiarrhythmic Drugs Low-Dose Amiodarone (<300mg per day) | 2 Count of Participants |
| Device Biventricular ICD | 10 Participants |
| Device No Device | 1 Participants |
| Device Single- or Dual-Chamber ICD | 8 Participants |
| Left Ventricular Ejection Fraction | 25 Percentage of Ejection Fraction |
| New York Heart Association (NYHA) Class NYHA I | 1 Participants |
| New York Heart Association (NYHA) Class NYHA II | 4 Participants |
| New York Heart Association (NYHA) Class NYHA III | 10 Participants |
| New York Heart Association (NYHA) Class NYHA IV | 4 Participants |
| Number of Previous Catheter Ablations | 1 Invasive Procedures |
| Other Medications Angiotensin Converting Enzyme Inhibitor | 10 Count of Participants |
| Other Medications Angiotensin Receptor Blocker | 7 Count of Participants |
| Other Medications Beta Blocker | 18 Count of Participants |
| Other Medications Oral Anticoagulation | 14 Count of Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 17 Participants |
| Study Eligibility Criteria ICD Therapies (>3 shocks or ATP in 6 months) | 5 Participants |
| Study Eligibility Criteria Incessant Ventricular Tachycardia (VT) | 2 Participants |
| Study Eligibility Criteria PVC-Related Cardiomyopathy | 2 Participants |
| Study Eligibility Criteria VT Storm (>3 episodes of VT in 24 hours) | 10 Participants |
| Total Number of Prior Catheter Ablation Approaches Endocardial | 25 Invasive Ablation Approaches |
| Total Number of Prior Catheter Ablation Approaches Epicardial | 4 Invasive Ablation Approaches |
| Type of Cardiomyopathy Ischemic Cardiomyopathy | 11 Participants |
| Type of Cardiomyopathy Nonischemic Cardiomyopathy | 8 Participants |
| Type of Nonischemic Cardiomyopathy Idiopathic | 5 Participants |
| Type of Nonischemic Cardiomyopathy Myocarditis (Chronic) | 2 Participants |
| Type of Nonischemic Cardiomyopathy Valvular | 1 Participants |
| Variable Chronic Kidney Disease (Stage >/=3) | 9 Count of Participants |
| Variable Chronic Obstructive Pulmonary Disease/Emphysema | 4 Count of Participants |
| Variable Diabetes Mellitus, Type II | 7 Count of Participants |
| Variable Hypertension | 10 Count of Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 19 |
| other Total, other adverse events | 19 / 19 |
| serious Total, serious adverse events | 15 / 19 |
Outcome results
Primary
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.
Time frame: 12 months (6mo prior to and 6mo post SBRT)
Population: Percent reduction of VT episodes or PVC burden 6 months post-SBRT compared to 6 months prior to SBRT.~Patients who were alive at 6 months were evaluated comparing ICD treatments or PVC burden 6 months before and 6 months post-SBRT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Number of Events | Number of Participants With Reduction in Ventricular Tachycardia (VT) Burden | 15 Participants |
| Patients With PVC-Related Cardiomyopathy Indication | Number of Participants With Reduction in Ventricular Tachycardia (VT) Burden | 2 Participants |
Primary
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.
Time frame: < or = 90 days
Population: Analysis is based on number of SAE events that occurred in 19 participants within 90 days after SBRT.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Number of Events | Number of Serious Adverse Events | Grade 3 treatment-related SAE | 2 Events |
| Number of Events | Number of Serious Adverse Events | Grade 4 treatment-related SAE | 0 Events |
| Number of Events | Number of Serious Adverse Events | Grade 5 treatment-related SAE | 0 Events |
| Number of Events | Number of Serious Adverse Events | Grade 5 SAE (not treatment-related) | 1 Events |
Secondary
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.
Time frame: 6 week, 6 month, 12 month
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Number of Events | Health Related Quality of Life (HRQOL) | Social Functioning | 64 Scores on a Scale |
| Number of Events | Health Related Quality of Life (HRQOL) | Health Change | 28 Scores on a Scale |
| Number of Events | Health Related Quality of Life (HRQOL) | General Health | 44 Scores on a Scale |
| Patients With PVC-Related Cardiomyopathy Indication | Health Related Quality of Life (HRQOL) | Social Functioning | 70 Scores on a Scale |
| Patients With PVC-Related Cardiomyopathy Indication | Health Related Quality of Life (HRQOL) | Health Change | 61 Scores on a Scale |
| Patients With PVC-Related Cardiomyopathy Indication | Health Related Quality of Life (HRQOL) | General Health | 52 Scores on a Scale |
| 6 Month | Health Related Quality of Life (HRQOL) | General Health | 49 Scores on a Scale |
| 6 Month | Health Related Quality of Life (HRQOL) | Social Functioning | 87 Scores on a Scale |
| 6 Month | Health Related Quality of Life (HRQOL) | Health Change | 77 Scores on a Scale |
| 12 Month | Health Related Quality of Life (HRQOL) | Social Functioning | 72 Scores on a Scale |
| 12 Month | Health Related Quality of Life (HRQOL) | Health Change | 65 Scores on a Scale |
| 12 Month | Health Related Quality of Life (HRQOL) | General Health | 54 Scores on a Scale |
Secondary
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.
Time frame: 90 days to 12 months
Population: Analysis is based on number of AE events that occurred in 18 participants \>90 days to 365 days post-SBRT.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Number of Events | Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Grade 1 Possibly Related AE | 15 Number of Events |
| Number of Events | Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Grade 1 Probably Related AE | 1 Number of Events |
| Number of Events | Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Grade 2 Possibly Related AE | 9 Number of Events |
| Number of Events | Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Grade 2 Definitely Related AE | 1 Number of Events |
| Number of Events | Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Grade 3 Possibly Related AE | 20 Number of Events |
| Number of Events | Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Grade 4 Possibly Related AE | 1 Number of Events |
| Number of Events | Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Grade 5 Possibly Related AE | 1 Number of Events |
| Number of Events | Number of Adverse Events That Are Possibly/Probably/Definitely Related to Study Treatment | Grade 2 Probably Related AE | 1 Number of Events |
Secondary
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.
Time frame: 6 months
Population: One patient was excluded because they expired prior to the outcome measure time frame.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Number of Events | Number of Participants With a 50% Reduction in Ventricular Tachycardia (VT) Burden | 17 Participants |
Secondary
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.
Time frame: 6 months
Population: One patient was excluded because they expired prior to the outcome measure time frame.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Number of Events | Number of Participants With a 95% Reduction in Ventricular Tachycardia (VT) Burden | 11 Participants |
Secondary
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.
Time frame: 6 months
Population: One patient was excluded because they expired prior to the outcome measure time frame.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Number of Events | Number of Participants With Reduction in ICD Shocks and LVEF Improvement | 13 Participants |
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Number of Events | Number of Participants With Reduction in Ventricular Tachycardia (VT) Therapies Between 6 and 12 Months | 16 Participants |
Secondary
Overall Survival
Determine six-month and twelve-month survival (overall mortality endpoint) after treatment with ENCORE.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Number of Events | Overall Survival | 18 Participants |
| Patients With PVC-Related Cardiomyopathy Indication | Overall Survival | 13 Participants |