Clinical trial NCT05258422: Stereotactic Arrhythmia Radioablation for Ventricular Tachycardia (StAR-VT)
Official title: Stereotactic Arrhythmia Radioablation for Ventricular Tachycardia (StAR-VT): a Single Centre, Phase II, Dose De-escalation, Non-inferiority, Clinical Trial.
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: Ventricular Tachycardia
Arrhythmia
Arrhythmic Storm
Radiation Toxicity
Keywords: stereotactic body radiotherapy, ventricular tachycardia
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
First posted: 2022-02-28
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This study will assess the non-inferiority of treatment with single fraction of 20 Gy delivered with stereotactic body radiotherapy in comparison with historical controls treated with a single fraction of 25 Gy. Based on historical controls, the investigators anticipate an incidence rate of approximately five VT events per person-year in participants treated with 25 Gy historical comparator. Based on a Poisson distribution and using a non-inferiority margin of 8.5 events per-year (corresponding to an incident rate ratio of 1.7), recruitment of nine participants will provide 80% power when using a one-sided type I error set at 0.05.
Primary purpose: TREATMENT

Brief summary: In 2017 a novel treatment approach to a series of 5 patients with refractory VT was introduced, using ablative radiation with a stereotactic body radiation therapy (SBRT) technique to arrhythmogenic scar regions defined by noninvasive cardiac mapping. More recently, Robinson et al. reported on the results of their Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia (ENCORE-VT) trial, also using a similar SBRT technique in a series of 17 patients with refractory VT. Both studies report a marked reduction in VT burden, a decrease in antiarrhythmic drug use, and an improvement in quality of life. Since then, numerous other centres have detailed their initial experience with this technique. These initial results suggest that this new treatment paradigm has the potential to improve morbidity and mortality for patients suffering from treatment-refractory VT by means of a minimally invasive technique, but requires further validation for widespread use.

The appropriate dose for therapeutic effect of this new treatment is not well established as only a single dose prescription of 25 Gy in 1 fraction has been described with benefit. In this phase 2 trial, the investigators plan on expanding the experience with this technique but also by contributing to understanding the relationship between dose-effect relationship through a dose de-escalation stratification, to 20 Gy in 1 fraction, with the goal of minimizing possible adverse events and radiation dose to surrounding healthy tissue while maintaining a clinical benefit.

Detailed description: Ventricular tachycardia (VT) is a potentially life-threatening arrhythmia characterized by electrical re-entry within patches of heterogeneous myocardial fibrosis leading to sustained consecutive ventricular beats at a rate \> 100 per minute. VT is classified based on hemodynamic stability, duration (less than or greater than 30 seconds), morphology (monomorphic or polymorphic), and mechanism (scar-related re-entry, automaticity, triggered activity.

In patients with monomorphic VT, implantable cardioverter-defibrillators (ICDs) have become the cornerstone of therapy in decreasing mortality, through the prevention of sudden death from potentially lethal sustained arrhythmia in select patients. However, ICDs have no effect on the underlying arrhythmogenic substrate or fibrotic scar and thus are primarily a symptom-control therapy; patients may develop recurrent and debilitating shocks associated with an increase in mortality. Currently, catheter ablation (CA) for VT is used as an adjunctive therapy for patients who are refractory to medical therapy. A recent systematic review and meta-analysis of randomized controlled trials and observation studies comparing medical therapy and catheter ablation for VT shows that CA is superior to medical therapy for scar-related VT with respect to VT recurrence and the life-threatening VT storm. Despite this, there is still a high reported incidence of VT recurrence in both medically-treated (48%) and ablation-treated (39%) patients, suggesting that the current treatment paradigm is suboptimal for good control of this debilitating arrhythmia.

In 2017, Cuculich et al. introduced a novel treatment approach to a series of 5 patients with refractory VT, using ablative radiation with a stereotactic body radiation therapy (SBRT) technique to arrhythmogenic scar regions defined by noninvasive cardiac mapping. More recently, Robinson et al. reported on the results of their Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia (ENCORE-VT) trial, also using a similar SBRT technique in a series of 17 patients with refractory VT. Both studies report a marked reduction in VT burden, a decrease in antiarrhythmic drug use, and an improvement in quality of life. These initial results suggest that this new treatment paradigm has the potential to vastly improve morbidity and mortality for patients suffering from VT by means of a minimally invasive technique, but requires further validation for widespread use.

Additionally, the appropriate dose for therapeutic effect of this new treatment is not well established as only a single dose prescription of 25 Gy in 1 fraction has been described with benefit. In this phase 2 trial, the investigators plan on expanding the experience with this technique but also by contributing to understanding the relationship between dose-effect relationship through a dose de-escalation stratification, to 20 Gy in 1 fraction, with the goal of minimizing possible adverse events and radiation dose to surrounding healthy tissue while maintaining a clinical benefit.

Eligibility criteria: Inclusion Criteria:

* 18 years of age
* Ishemic or non-ischemic cardiomyopathy
* Recurrent episodes of monomorphic ventricular tachycardia having failed standard treatment with at least 1 antiarrhythmic drug
* Previous endocardial and/or epicardial electrophysiology study and ablation.

Participants who have a contraindication to electrophysiology studies (ventricular thrombus, absence of vascular access, valvular heart disease or mechanical heart valve that precludes left-ventricular access) may be eligible for the protocol provided the arrhythmic substrate can be defined through non-invasive methods.

Exclusion Criteria:

* Previous RT in the treatment field that precludes furth RT
* Active connective tissue disease
* Interstitial pulmonary fibrosis
* Pregnant or breastfeeding individuals
* Participants who plan to become pregnant or breast feed during the study duration

Primary outcomes:
measure: Change in arrhythmia burden measured by the number of VT events
timeFrame: 6 months and 12 months following study intervention
measure: Change in arrhythmia burden measured by the number of ICD events
timeFrame: 6 months and 12 months following study intervention
measure: Acute radiation toxicity within the first 90 days measured by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
timeFrame: 90 days following study intervention.
Secondary outcomes:
measure: Late radiation toxicity occurring after the first 90 days until 5 years measured by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
timeFrame: 90 days - 5 years following study intervention
measure: Changes in number and doses of antiarrhythmic drugs
timeFrame: 1 year, 3 years, and 5 years following study intervention
measure: Patient-Reported Quality of life as measured by the short form-36 questionnaire
timeFrame: 6 months, 1 year, 3 years, and 5 years following study intervention
measure: Patient-Reported Quality of life as measured by the Arrhythmia-specific questionnaire in Tachycardia and arrhythmia (ASTA)
timeFrame: 6 months, 1 year, 3 years, and 5 years following study intervention
Other outcomes:
measure: Overall Survival
timeFrame: 5 years following radiation therapy
Locations:
city: Montreal
country: Canada
facility: Cedars Cancer Center, McGill University Health Centre
state: Quebec
Study officials:
affiliation: MUHC division of radiation oncology/RIMUHC
name: Joanne Alfieri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MUHC division of cardiology
name: Martin L Bernier, MD
role: PRINCIPAL_INVESTIGATOR
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