Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation-2 (TELSTAR-2) (TELSTAR-2)

Treatment of ELectrographic STatus Epilepticus After Cardiopulmonary Resuscitation-2: Multicenter Randomised Clinical Trial and Health Economic Evaluation of Anti-seizure Treatment in Comatose Cardiac Arrest Patients With SE on Continuous EEG

The goal of this comparative effectiveness trial is to study electrographic status epilepticus (ESE) treatment in comatose patients after cardiac arrest. The main questions the trial aims to answer are:

• Does ESE treatment improve outcome?
• What is the impact of ESE treatment on healthcare costs?

Participants in the the intervention group will receive standard care completed with anti-seizure treatment. The control group will receive standard care without anti-seizure treatment.

Study Overview

• Status: Recruiting
• Conditions: Coma; Electrographic Status Epilepticus
• Intervention / Treatment: Drug: anti-seizure medication + sedative agent(s)

Detailed Description

Rationale: Around 7500 comatose patients after cardiac arrest and resuscitation are admitted to intensive care units (ICUs) in the Netherlands and Belgium, yearly. Approximately half eventually dies from severe brain injury. EEG is used as a predictor of outcome, helping decide whether life sustaining therapies should be pursued or withdrawn. EEG shows epileptiform patterns meeting criteria for electrographic status epilepticus (ESE) in up to 10% of patients, with 80-100% case fatality. With the TELSTAR-1 trial, we showed that anti-seizure treatment of unselected patients with epileptiform patterns is not associated with a better outcome. However, it remains unclear whether treatment of (possible) ESE will improve outcome, or if ESE simply represents irreversible severe brain damage, in which case such treatment will be futile. This translates into ongoing practice variation. To provide comatose cardiac arrest survivors with the best medical treatment options, while at the same time preventing unnecessary costly ICU treatment, unequivocal evidence of efficacy or futility of ESE treatment is needed.

Objectives: It is the primary objective to study whether ESE treatment improves outcome of comatose patients after cardiac arrest. It is the secondary objective to study the impact on healthcare costs of ESE treatment.

Main trial endpoints: The primary outcome measure will be functional recovery expressed as the score on the extended Glasgow Outcome Scale (eGOS) at six months after cardiac arrest. The primary effect parameter will be the common odds ratio for any shift towards a better outcome in the intervention group, analyzed by multivariable ordinal logistic regression.

Secondary trial endpoints: Secondary outcome measures include data on quality of life, cognitive functioning, and the use of resources. Cost-effectiveness will be assessed, separately for Belgium and for the Netherlands, adhering to 'KCE' and 'Zorginstituut' guidelines for pharmaco-economic evaluations, respectively.

Trial design: This will be a comparative effectiveness study, comparing two standard treatment regimens. We will conduct a prospective multicentre trial with randomized treatment allocation, open label treatment, and blinded endpoint assessment on twenty intensive care units in the Netherlands and Belgium.

Trial population: The study population consists of adult comatose patients after out of hospital cardiac arrest and successful cardiopulmonary resuscitation, admitted on the intensive care unit of any of the participating centres, with ESE on continuous EEG. Continuous EEG is part of standard care in all participating hospitals. For the definition of ESE, we adhere to international consensus criteria.

Interventions: Treatment in the intervention group will consist of standard care completed with anti-seizure treatment according to protocols for clinically overt status epilepticus with the goal of definitive seizure suppression. This consists of a stepwise approach, step 1 being a single dose of a parenteral benzodiazepine (lorazepam, midazolam, or diazepam) and a first parenteral anti-seizure medication (levetiracetam, valproate, or lacosamide), step 2, a second parenteral anti-seizure medication plus a first continuous parenteral sedative agent (midazolam or propofol), and step 3, a second continuous parenteral sedative agent (midazolam, propofol, or ketamine). Each next step will be taken as soon as possible (within 30 minutes) if the previous step was insufficiently effective to suppress ESE. The control group will receive standard care without anti-seizure treatment.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jeannette Hofmeijer, MD; Phone Number: +31 53 489 4835; Email: j.hofmeijer@utwente.nl
• Study Contact Backup: Name: Nicolas Gaspard, MD; Phone Number: +32 2 555 46 22; Email: nicolas.gaspard@hubruxelles.be

Study Locations

• Belgium
  • Brussels, Belgium
    • Not yet recruiting
    • Universitair Ziekenhuis Brussel
    • Contact: T. Balthazar
  • Brussels, Belgium
    • Not yet recruiting
    • Centre Hospitalier Universitaire Saint-Pierre
    • Contact: A. Herpain
  • Brussels, Belgium
    • Not yet recruiting
    • Hopital Universitaire de Bruxelles
    • Contact: F. Taccone
    • Contact: N. Gaspard
  • Charleroi, Belgium
    • Not yet recruiting
    • Centre Hospitalier Universitaire Marie Curie
    • Contact: M. Piagnerelli
    • Contact: F. Bellante
  • Genk, Belgium
    • Not yet recruiting
    • Ziekenhuis Oost-Limburg
    • Contact: K. Ameloot
  • Gent, Belgium
    • Not yet recruiting
    • Universitair Ziekenhuis Gent
    • Contact: P. Druwé
    • Contact: A. Meurs
  • Liège, Belgium
    • Not yet recruiting
    • Centre Hospitalier Chrétien - MontLégia
    • Contact: P. Demaret
    • Contact: J. Truong
  • Liège, Belgium
    • Not yet recruiting
    • Centre Hospitalier Universitaire Sart-Tilmant
    • Contact: B. Lambermont
• Netherlands
  • Amsterdam, Netherlands
    • Not yet recruiting
    • Amsterdam University Medical Center
    • Contact: J. Horn
    • Contact: A. F. Van Rootselaar
  • Arnhem, Netherlands
    • Recruiting
    • Rijnstate Hospital
    • Contact: J. Hofmeijer
    • Contact: M. J. Blans
  • Eindhoven, Netherlands
    • Not yet recruiting
    • Catharina Hospital
    • Contact: L. C. Otterspeer
    • Contact: M. Van Eijck
  • Enschede, Netherlands
    • Recruiting
    • Medical spectrum Twente
    • Contact: M. C. Tjepkema-Cloostermans
    • Contact: A. Beishuizen
  • Groningen, Netherlands
    • Not yet recruiting
    • University Medical Center Groningen
    • Contact: W. M. Van den Bergh
    • Contact: G. Drost
  • Leiden, Netherlands
    • Not yet recruiting
    • Leiden University Medical Center
    • Contact: S. Tromp
    • Contact: J. Maas
  • Nieuwegein, Netherlands
    • Recruiting
    • St. Antonius Hospital
    • Contact: E. Scholten
    • Contact: A. Seeber
  • Nijmegen, Netherlands
    • Recruiting
    • Radboud University Medical Center
    • Contact: C.W. E. Hoedemaekers
    • Contact: C. Saris
  • Nijmegen, Netherlands
    • Not yet recruiting
    • Canisius Wilhelmina Hospital
    • Contact: F.A. P. Nijhuis
    • Contact: S. J. Booij
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus University Medical Center
    • Contact: M. Van der Jagt
    • Contact: R. van den Berg
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Maasstad Hospital
    • Contact: E. C. Thomeer
    • Contact: W. Moudrous
  • Venlo, Netherlands
    • Not yet recruiting
    • VieCuri Medical Center
    • Contact: N. Foudraine
    • Contact: E. Notting

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Coma (Glasgow Coma Scale score ≤ 8) after out of hospital cardiac arrest and resuscitation
2. Age ≥ 18 years
3. Continuous EEG with at least eight electrodes started < 24h after return of spontaneous circulation (ROSC)
4. ESE or possible ESE according to the Salzburg and ACNS criteria
5. Possibility to start treatment within three hours after detection of ESE

Exclusion Criteria:

1. Known history of another medical condition with limited life expectancy (< six months)
2. Any progressive brain illness, such as a brain tumor or neurodegenerative disease
3. Pre-admission Glasgow Outcome Scale score of 3 or lower
4. Reason other than the neurological condition to withdraw treatment
5. EEG background activity prior to the emergence of ESE indicative of extensive irreversible anoxic brain injury
6. Follow-up impossible due to logistic reasons, for example not living in the Netherlands or Belgium

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Intervention group; Standard care completed with stepwise anti-seizure treatment according to protocols for clinically overt status epilepticus. This consists of a stepwise approach consisting of 3 potential steps. Each next step will be taken as soon as possible (within 30 minutes of ESE first diagnosis or recurrence) if the previous step was insufficiently effective to sustainably suppress ESE.	Drug: anti-seizure medication + sedative agent(s); Stepwise approach: a single dose of a parenteral benzodiazepine (lorazepam, midazolam, or diazepam) and a first parenteral anti-seizure medication (levetiracetam, valproate, or lacosamide); a second parenteral anti-seizure medication plus a first continuous parenteral sedative agent (midazolam or propofol); a second continuous parenteral sedative agent (midazolam, propofol, or ketamine)
No Intervention: Control group; Standard care without anti-seizure treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
score on the extended Glasgow Outcome Scale (eGOS)	eGOS is an 8-points ordinal scale of functional recovery with possible scores ranging from 0 to 6. A higher score indicates better functional recovery	6 months after cardiac arrest

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
quality adjusted life years (QALYs)	this is a measure of cost-effectiveness	12 months after cardiac arrest

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
survival in months	this is a measure of survival	12 months after cardiac arrest
death (any cause), pneumonia, sepsis (according to sepsis 3 criteria), bleeding (any cause), cardiac arrhythmia (any associated with hemodynamic compromise), new cardiac arrest, or thrombopenia	these are safety outcomes	12 months after cardiac arrest
score on the Rankin Scale (mRS)	mRS is a 6-point ordinal functional recovery scale with possible scores ranging from 1 to 6. A lower score indicates better functional recovery.	6 and 12 months after cardiac arrest
score on the cerebral performance categories (CPC)	COC is a 5-point ordinal functional recovery scale with possible scores ranging from 1 to 5. A lower score indicates better functional recovery.	6 and 12 months after cardiac arrest
score on Montreal Cognitive Assessment telephone version	MoCA is a screening instrument to quantify overall cognitive functioning. Scores range from 0 to 30 with higher scores indicating better cognitive functioning.	6 months after cardiac arrest

Collaborators and Investigators

• Sponsor: University of Twente
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Belgium Health Care Knowledge Centre; Hôpital Universitaire de Bruxelles
• Investigators: Principal Investigator: Jeannette Hofmeijer, MD, University of Twente

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: August 2, 2024
• First Submitted That Met QC Criteria: August 7, 2024
• First Posted (Actual): August 12, 2024

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 13, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Seizures; Status Epilepticus; Physiological Effects of Drugs; Central Nervous System Depressants; Hypnotics and Sedatives
• Other Study ID Numbers: 2024-516068-27-01

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