November 8, 2023Open Access
Dose escalation for stereotactic arrhythmia radioablation of recurrent ventricular tachyarrhythmia - a phase II clinical trial
Key Result
The DEFT-STAR phase II dose-escalation trial will evaluate the safety of increasing the stereotactic arrhythmia radioablation dose up to 35.1 Gy for recurrent ventricular tachyarrhythmia.
Structured PICO
Does dose-escalated stereotactic arrhythmia radioablation safely prevent sustained ventricular arrhythmias in patients with ischemic or non-ischemic cardiomyopathy and recurrent sVA?
P
Population
A planned phase II dose-escalation trial aiming to enroll 15 adult patients with cardiomyopathy and recurrent sustained ventricular arrhythmias refractory to catheter ablation, followed for up to 24 months.
I
Intervention
Stereotactic arrhythmia radioablation (STAR) with dose escalation of the internal target volume (ITV) dose from 27.0 Gy to a maximum of 35.1 Gy (by step-wise reduction of the prescribing isodose line from 85% down to 65%) while keeping the planning target volume (PTV) prescription dose constant at 25 Gy.
O
Outcome
Safety measured by registered radiation associated adverse events (AE) up to 90 days after study intervention, including radiation associated serious adverse events graded as at least 4 or 5 according to CTCAE v5, radiation pneumonitis or pericarditis requiring hospitalization, and decrease in LVEF ≥ 10% as assessed by echocardiography or cardiac MRI.safety
The DEFT-STAR trial protocol describes a phase II dose-escalation strategy for stereotactic arrhythmia radioablation aimed at safely inducing transmural scar formation to reduce recurrent ventricular arrhythmias.
Limitations
- Single-arm design without a control group
- Small planned sample size of 15 patients
Abstract
BACKGROUND: Stereotactic arrhythmia radioablation (STAR) is delivered with a planning target volume (PTV) prescription dose of 25 Gy, mostly to the surrounding 75-85% isodose line. This means that the average and maximum dose received by the target is less than 35 Gy, which is the minimum threshold required to create a homogenous transmural fibrosis. Similar to catheter ablation, the primary objective of STAR should be transmural fibrosis to prevent heterogenous intracardiac conduction velocities and the occurrence of sustained ventricular arrhythmias (sVA) caused by reentry. We hypothesize that the current dose prescription used in STAR is inadequate for the long-term prevention of sVA and that a significant increase in dose is necessary to induce transmural scar formation. OBJECTIVE: A single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose-escalation strategy aimed at inducing transmural scar formation. The ultimate objective of this trial is to decrease the likelihood of sVA recurrence in patients at risk. METHODS: Patients with ischemic or non-ischemic cardiomyopathy and recurrent sVA, with an ICD and history of ≥ 1 catheter ablation for sVA will be included. This is a prospective, multicenter, one-arm, dose-escalation trial utilizing the i3 + 3 design, a modified 3 + 3 specifically created to overcome limitations in traditional dose-finding studies. A total of 15 patients will be recruited. The trial aims to escalate the ITV dose from 27.0 Gy to an ITV prescription dose-equivalent level of maximum 35.1 Gy by keeping the PTV prescription dose constant at 25 Gy while increasing the dose to the target (i.e. the VT substrate without PTV margin) by step-wise reduction of the prescribing isodose line (85% down to 65%). The primary outcome of this trial is safety measured by registered radiation associated adverse events (AE) up to 90 days after study intervention including radiation associated serious adverse events graded as at least 4 or 5 according to CTCAE v5, radiation pneumonitis or pericarditis requiring hospitalization and decrease in LVEF ≥ 10% as assessed by echocardiography or cardiac MRI at 90 days after STAR. The sample size was determined assuming an acceptable primary outcome event rate of 20%. Secondary outcomes include sVA burden at 6 months after STAR, time to first sVA recurrence, reduction in appropriate ICD therapies, the need for escalation of antiarrhythmic drugs, non-radiation associated safety and patient reported outcome measures such as SF-36 and EQ5D. DISCUSSION: DEFT-STAR is an innovative prospective phase II trial that aims to evaluate the optimal radiation dose for STAR in patients with therapy-refractory sVA. The trial has obtained IRB approval and focuses on determining the safe and effective radiation dose to be employed in the STAR procedure. TRIAL REGISTRATION: NCT05594368.