TELSTAR: Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation

Sponsor
University of Twente (Other)
Overall Status
Completed
CT.gov ID
NCT02056236
Collaborator
Rijnstate Hospital (Other), Medisch Spectrum Twente (Other), Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other), Radboud University Medical Center (Other), University Medical Center Groningen (Other), St. Antonius Hospital (Other), VieCuri Medical Centre (Other), Université Libre de Bruxelles (Other), Maasstad Hospital (Other), Maastricht University Medical Center (Other), Canisius-Wilhelmina Hospital (Other)
172
11
2
93.8
15.6
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Study Details

Study Description

Brief Summary

The purpose of this study is to estimate the effect of medical treatment of electro-encephalographic status epilepticus on neurological outcome of patients with postanoxic encephalopathy after cardiac arrest.

Condition or Disease Intervention/Treatment Phase
  • Drug: Anti-epileptic drugs
  • Other: No anti-epileptic drugs
N/A

Detailed Description

Rationale: Electroencephalographic status epilepticus is described in 9-35% of patients with postanoxic encephalopathy after cardiac arrest and is associated with case fatality rates of 90-100%. It is unclear whether (some) electroencephalographic seizure patterns in these patients represent a condition which can be treated with antiepileptic drugs to improve outcome, or have to be regarded as an expression of severe ischemic damage, in which treatment with antiepileptic would be futile. Therefore, both treatment with and treatment without antiepileptic drugs are considered standard modalities in these patients. We aim to compare these standard strategies and hypothesize that aggressive and early treatment of electro-encephalographic status epilepticus with antiepileptic drugs improves outcome as compared to treatment without these drugs.

Objective: To estimate the effect of medical treatment of electro-encephalographic status epilepticus on neurological outcome of patients with postanoxic encephalopathy after cardiac arrest

Study design: We will perform a multicenter clinical trial with randomized treatment allocation, open label treatment and blinded endpoint evaluation (PROBE design). The intervention contrast will be aggressive medical treatment vs. no treatment of electroencephalographic status epilepticus, in addition to standard best medical management of comatose patients after cardiac arrest, including mild therapeutic hypothermia.

Study population: The study population will consist of adult patients with postanoxic encephalopathy after cardiac arrest, admitted to the intensive care unit, with electroencephalographic status epilepticus on continuous EEG, who are eligile for inclusion in this trial.

Intervention: Treatment of electroencephalographic status epilepticus will be based on guidelines for treatment of overt status epilepticus. The objective of this treatment will be to suppress all epileptiform activity in the EEG. If the electroencephalographic status epilepticus will return after tapering sedative treatment at 24 hours, the procedure will be repeated. If the status will return after 2 x 24 hours, it will be considered refractory.

Main study parameters/endpoints: The primary outcome measure will be neurological outcome defined as the score on the Cerebral Performance Category (CPC) at 3 months dichotomized as good (CPC 1-2 = no or moderate neurological disability) and poor (CPC 3-5 = severe disability, coma, or death).

Sample size: With a presumed reduction of poor outcome of 7%, from 99% - 92%, alpha of 5%, power of 80%, one tailed testing, and one interim analysis by an independent data safety and monitoring board, the objected number of inclusions is 172. With an estimation of an incidence of electroencephalographic status epilepticus of 20% in patients with postanoxic coma, the total number of patients to be monitored will be 860.

Nature and extent of the burden and risks associated with participation: Medical treatment of electroencephalographic status epilepticus may modify the high risk of death. Otherwise, this treatment of electroencephalographic status epilepticus may lead to prolonged hospitalization of several days of comatose patients that otherwise would have died. The risk of an increase of morbidity or mortality on the longer term is considered negligible.

Study Design

Study Type:
Interventional
Actual Enrollment :
172 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
TELSTAR: Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation
Study Start Date :
Apr 1, 2014
Actual Primary Completion Date :
Apr 24, 2021
Actual Study Completion Date :
Jan 24, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Anti-epileptic drugs

Step 1: Phenytoin (loading dose 15-20 mg/kg iv, maintenance doses 150 mg iv twice per day) PLUS one of the following benzodiazepines (bolus + continuous infusion): lorazepam or midazolam. Benzodiazepine dosing regimes should be based on national and local protocols for status epilepticus treatment Step 2: Propofol infusion (with a maximum rate of 8 mg/kg/hour) PLUS a second anti-epileptic drug in addition to fenytoin: Option 1: levetiracetam bolus 1500 mg, followed by 1000 mg 2 dd 1 intravenously or Option 2: valproic acid bolus 10-20 mg/kg in 30 min, followed by15 mg/kg/day in 2 dosages intravenously. Step 3: Thiopental, initial dosage 12,5 mg/kg/hr for the first 6 hours followed by 5 mg/kg/hr for 6 hours. After these loading dosages, treatment should be guided by the EEG pattern.

Drug: Anti-epileptic drugs
Recommendations for the treatment of status epilepticus are based on recent international guidelines for treatment of overt status epilepticus. The objective of treatment with AED is to suppress all epileptiform activity. There is no clear proof that induction of a burst-suppression pattern is of additional value and induction of burst suppression is therefore not obligate. If the electroencephalographic status epilepticus returns after tapering sedative treatment at 24 hours, the procedure will be repeated. If the status returns after 2 x 24 hours, it will be considered refractory. Decisions regarding limitation or withdrawal of treatment will be done in accordance with the Dutch guideline "postanoxic coma". Reasons for withdrawal of treatment will be documented.
Other Names:
  • Lorazepam
  • Midazolam
  • Fenytoin
  • Propofol
  • Levetiracetam
  • Valproate
  • Thiopental
  • Active Comparator: No anti-epileptic drugs

    The non-intervention group will be treated conform standard guidelines of treatment of comatose patients after cardiac arrest, but without anti-epileptic drugs or EEG based deep sedation. Treatment to suppress clinical myoclonia or seizures with low dose propofol is left to the discretion of the treating physician. Decisions regarding limitation or withdrawal of treatment will be done in accordance with the Dutch guideline "postanoxic coma" in both treatment arms. Reasons for withdrawal of treatment will be documented.

    Other: No anti-epileptic drugs
    The non-intervention group will be treated conform standard guidelines of treatment of comatose patients after cardiac arrest, but without anti-epileptic drugs or EEG based deep sedation. Treatment to suppress clinical myoclonia or seizures with low dose propofol is left to the discretion of the treating physician. Decisions regarding limitation or withdrawal of treatment will be done in accordance with the Dutch guideline "postanoxic coma". Reasons for withdrawal of treatment will be documented.

    Outcome Measures

    Primary Outcome Measures

    1. Neurological outcome [three months]

      The primary outcome measure will be neurological outcome defined as the score on the Cerebral Performance Category (CPC) at 3 months dichotomized as good (CPC 1-2 = no or moderate neurological disability) and poor (CPC 3-5 = severe disability, coma, or death).

    Secondary Outcome Measures

    1. Long term outcome [12 months]

      Secondary outcome measures will include i) mortality; ii) the CPC score at 6 and 12 months; iii) length of stay on the ICU; iv) duration of mechanical ventilation; v) seizure recurrence within one year; vi) quality of life as measured by the Medical Outcomes Study 36-item short-form health survey (SF36), depression as measured by the Montgomery and Åsberg Depression Rating Scale (MADRS) , and cognitive functioning as measured by detailed neuropsychological examination after 12 months. Secondary outcome measures in survivors will be collected to thoroughly assess outcome and quality of life of survivors. These outcome measures will not be collected to test between-group differences, since the estimated number of survivors is small. Furthermore, a limited amount of data on the use of resources will be collected for analysis of cost-effectiveness, including place of residence at one year and admission in hospitals, rehabilitations centers, and nursing homes within the first year.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients after cardiac arrest with suspected postanoxic encephalopathy

    • Age 18 years or older

    • Continuous EEG with at least eight electrodes started within 24 hours after cardiac arrest

    • Electroencephalographic status epilepticus on continuous EEG

    • Possibility to start treatment within three hours after detection of electroencephalographic status epilepticus.

    Exclusion Criteria:
    • A known history of another medical condition with limited life expectancy (<6 months)

    • Any progressive brain illness, such as a brain tumor or neurodegenerative disease

    • Pre-admission Glasgow Outcome Scale score of 3 or lower

    • Reason other than neurological condition to withdraw treatment

    • Follow-up impossible due to logistic reasons

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Hôpital Erasme - Université libre de Bruxelles Brussels Lenniksebaan 808 Belgium 1070
    2 Radboud University Medical Center Nijmegen Geert Grooteplein-Zuid 10 Netherlands 6525 GA
    3 Medisch Spectrum Twente Enschede Haaksbergerstraat 55 Netherlands 7513 ER
    4 University Medical Center Groningen Groningen Hanzeplein 1 Netherlands 9700 RB
    5 St. Antonius Hospital Nieuwegein Koekoekslaan 1 Netherlands 3430 EM
    6 Academic Medical Center Amsterdam Meibergdreef 9 Netherlands 1105 AZ
    7 VieCuri Medical Centre Venlo Tegelseweg 210 Netherlands 5912 BL
    8 Rijnstate Hospital Arnhem Wagnerlaan 55 Netherlands 6815 AD
    9 Maasstad Hospital Rotterdam Zuid-Holland Netherlands 3079 DZ
    10 Maastricht UMC+ Maastricht Netherlands
    11 Canisius-Wilhelmina Hospital Nijmegen Netherlands

    Sponsors and Collaborators

    • University of Twente
    • Rijnstate Hospital
    • Medisch Spectrum Twente
    • Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
    • Radboud University Medical Center
    • University Medical Center Groningen
    • St. Antonius Hospital
    • VieCuri Medical Centre
    • Université Libre de Bruxelles
    • Maasstad Hospital
    • Maastricht University Medical Center
    • Canisius-Wilhelmina Hospital

    Investigators

    • Principal Investigator: Jeannette Hofmeijer, MD PhD, Rijnstate Hospital and University of Twente
    • Principal Investigator: Michel van Putten, MD PhD, Medisch Spectrum Twente and University of Twente
    • Principal Investigator: Janneke Horn, MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
    • Study Director: Barry Ruijter, MD, University of Twente

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Jeannette Hofmeijer, MD PhD, University of Twente
    ClinicalTrials.gov Identifier:
    NCT02056236
    Other Study ID Numbers:
    • NEF-14-18
    • NL46296.044.13
    First Posted:
    Feb 5, 2014
    Last Update Posted:
    Feb 21, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Jeannette Hofmeijer, MD PhD, University of Twente
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Feb 21, 2022