StereoTactic Arrhythmia Radiotherapy in the NetherLands no. 2 (STARNL-2)

Ventricular tachycardia (VT) is a malignant cardiac arrhythmia subjecting our patients to a high risk of sudden death, increased morbidity and reduced quality of life. Unfortunately, failure of treatment is common and VT recurrences remain an important concern. In these patients, stereotactic arrhythmia radiotherapy appears to be an effective and safe treatment. The mechanism of action however remains unknown and should be elucidated.

The objective of this phase 2, single arm, monocenter, pre-post intervention study is to evaluate the efficacy and safety of stereotactic arrhythmia radiotherapy and obtain insights in the mechanism of action by evaluating electro-anatomical alterations of stereotactic arrhythmia radiotherapy in patients with therapy refractory ventricular tachycardia.

Study Overview

• Status: Recruiting
• Conditions: Ventricular Tachycardia; Arrythmia, Cardiac
• Intervention / Treatment: Radiation: Stereotactic Arrhythmia Radiotherapy

Detailed Description

Ventricular tachycardia (VT) is a malignant cardiac arrhythmia leading to a sudden abolition of cardiac function directly followed by a shortage of oxygen supply to essential organs such as the brain and heart. For this reason, VT is a cardiac emergency and should be treated within seconds to minutes before irreversible and potentially fatal organ damage follows. Current treatment options are limited to anti-arrhythmic drugs, an implantable cardioverter defibrillator (ICD), and invasive catheter ablation. Unfortunately, invasive cardiac VT ablation has the lowest success rate and the highest complication rates among all arrhythmia ablations.

Since the first case series published by Cuculich et al. (2017) and the first prospective trial published by Robinson et al. (2019), stereotactic arrhythmia radiotherapy (STAR) has evolved as a new treatment modality for patients with ventricular tachycardia refractory to conventional therapies. Patients are treated with a single radiotherapy fraction of 25 Gy at the determined pro-arrhythmic cardiac region with the use of standard stereotactic radiotherapy techniques. Experience with STAR is steadily growing worldwide. In the systematic review by Van der Ree et al. (2020), a reduction of >85% in VT episodes with a simultaneously promising safety profile was shown.

The mechanism of action of STAR is not yet fully known and is yet to be elucidated. The pathophysiological mechanism of VT relies on re-entry due to zigzag conduction by the surviving myocardial fibers in previously damaged heart tissue. At first, it was hypothesized that inducing cell-death by ionizing radiation leads to dense transmural fibrosis. As mature myocardial fibrosis is not able to propagate electrical activation this may lead to the abolishment of the zigzag conduction herewith reducing the chance of re-entry and VT. Fibrosis maturation takes several weeks to months to complete. However, the anti-arrhythmic effects seem to occur earlier. In preclinical studies, early electrophysiological alterations were demonstrated (Zhang et al. 2021). The gap-junction protein connexion-43 (Cx43) and the voltage gated sodium channels were upregulated, leading to a supraphysiological state with increased conduction velocity. Since a slow conduction pathway is required for re-entry, this could explain the timing of the observed effect, although the exact mechanism of action remains to be elucidated.

In the STARNL-2 study we aim to confirm our STARNL-1 pilot (6 patients) efficacy and safety data in a larger cohort and obtain insights in the electro-anatomical alterations of stereotactic arrhythmia radiotherapy in patients with therapy refractory ventricular tachycardia.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pieter G Postema, MD PhD; Phone Number: 0031 0031 20 566 4338; Email: p.g.postema@amsterdamumc.nl

Study Locations

• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1105AZ
      • Recruiting
      • Amsterdam UMC location University of Amsterdam
      • Contact: Pieter G Postema, MD PhD; Phone Number: 0031 0031 20 566 4338; Email: p.g.postema@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years
• Implanted ICD
• World Health Organization (WHO) / Eastern Cooperative Oncology Group (ECOG) performance status grade 0-3 in the past 3 months (from fully active to capable of limited self-care, see below for full explanation)
• At least 3 episodes of treated VT within the last 3 months

• Recurrence of VT after

  • Failed or intolerant to least one class 1 or class 3 anti-arrhythmic drug AND
  • At least one catheter ablation procedure OR considered to be unsuitable for a catheter ablation procedure (e.g. no sufficient vascular access, considered unfit to undergo prolonged general anesthesia, comorbid conditions resulting in unacceptable peri-procedural risks)
• Able and willing to undergo all necessary evaluations, treatment and follow-up for the study and of follow-up thereafter

Exclusion Criteria:

• Pregnancy
• History of radiation treatment in the thorax or upper abdominal region
• Interstitial pulmonary disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stereotactic Arrhythmia Radiotherapy; Patients will undergo stereotactic arrhythmia radiotherapy and subsequent follow-up.	Radiation: Stereotactic Arrhythmia Radiotherapy; Single radiation treatment of 25 Gy with external beam radiation therapy to the pro-arrhythmic region as determined by the cardiologist-electrophysiologist and radiation-oncologist combined; Other Names: Cardiac Radioablation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in the number of treated VT episodes	The main efficacy measure is a reduction in the number of treated VT episodes by ≥50% at the end of follow-up of 1 year (including a blanking period of 3 months). Net follow-up is 9 months compared to 9 months before treatment.	18 months (excluding 3 months of blanking period)
Rate of treatment related serious adverse events (SAEs)	The main safety measure is defined by a ≤20% rate of treatment related serious adverse events (SAEs), determined as the number of treatment related serious adverse events per number of treatment related adverse events.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in the number of treated and non-treated VT episodes	Reduction in the number of treated and non-treated VT episodes by ≥70% at the end of follow-up compared to the year before treatment.	18 months (excluding 3 months of blanking period)
Reduction in anti-arrhythmic drugs	A reduction of the daily dose by ≥50% (amiodarone or mexiletine) at the end of follow-up compared to baseline.	12 months
Quality of Life improvement	Quality of life improvement of ≥25% in the categories health change and social functioning as measured by the SF-36 questionnaire at the end of follow-up compared to baseline.	12 months
Cardiac safety	>25% relative decrease in left ventricular ejection fraction measured by echocardiography at end of follow-up as compared to baseline	12 months
Pulmonary safety	>25% relative decrease in forced expiratory volume in 1 second (FEV1) measured by pulmonary functions tests at end of follow-up as compared to baseline.	12 months
Pulmonary safety	>25% relative decrease in diffusing capacity (DLCO) measured by pulmonary functions tests at one year after treatment as compared to baseline	12 months

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Dutch Heart Foundation
• Investigators: Principal Investigator: Pieter G Postema, MD PhD, University of Amsterdam

Publications and helpful links

General Publications

• Cuculich PS, Schill MR, Kashani R, Mutic S, Lang A, Cooper D, Faddis M, Gleva M, Noheria A, Smith TW, Hallahan D, Rudy Y, Robinson CG. Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. N Engl J Med. 2017 Dec 14;377(24):2325-2336. doi: 10.1056/NEJMoa1613773.
• Robinson CG, Samson PP, Moore KMS, Hugo GD, Knutson N, Mutic S, Goddu SM, Lang A, Cooper DH, Faddis M, Noheria A, Smith TW, Woodard PK, Gropler RJ, Hallahan DE, Rudy Y, Cuculich PS. Phase I/II Trial of Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia. Circulation. 2019 Jan 15;139(3):313-321. doi: 10.1161/CIRCULATIONAHA.118.038261.
• van der Ree MH, Blanck O, Limpens J, Lee CH, Balgobind BV, Dieleman EMT, Wilde AAM, Zei PC, de Groot JR, Slotman BJ, Cuculich PS, Robinson CG, Postema PG. Cardiac radioablation-A systematic review. Heart Rhythm. 2020 Aug;17(8):1381-1392. doi: 10.1016/j.hrthm.2020.03.013. Epub 2020 Mar 20.
• Zhang DM, Navara R, Yin T, Szymanski J, Goldsztejn U, Kenkel C, Lang A, Mpoy C, Lipovsky CE, Qiao Y, Hicks S, Li G, Moore KMS, Bergom C, Rogers BE, Robinson CG, Cuculich PS, Schwarz JK, Rentschler SL. Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis. Nat Commun. 2021 Sep 24;12(1):5558. doi: 10.1038/s41467-021-25730-0.

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2023
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: June 27, 2022
• First Submitted That Met QC Criteria: June 27, 2022
• First Posted (Actual): June 30, 2022

Study Record Updates

• Last Update Posted (Estimated): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Ventricular Arrhythmias; Stereotactic Radiotherapy; Ventricular Tachycardia; Stereotactic body radiotherapy; Cardiac Radioablation; Stereotactic Arrhythmia Radiotherapy; Cardiac ablative radiotherapy
• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Tachycardia; Pathological Conditions, Signs and Symptoms; Tachycardia, Ventricular; Arrhythmias, Cardiac
• Other Study ID Numbers: NL80617.018.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No