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TELSTAR: Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation (TELSTAR)

Primary Purpose

Cardiac Arrest, Anoxic Encephalopathy, Status Epilepticus

Status
Completed
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
Anti-epileptic drugs
No anti-epileptic drugs
Sponsored by
University of Twente
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cardiac Arrest focused on measuring Cardiac arrest, Postanoxic encephalopathy, Electroencephalographic status epilepticus, EEG monitoring, Anti-epileptic drugs

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hôpital Erasme - Université libre de Bruxelles
  • Radboud University Medical Center
  • Medisch Spectrum Twente
  • University Medical Center Groningen
  • St. Antonius Hospital
  • Academic Medical Center
  • VieCuri Medical Centre
  • Rijnstate Hospital
  • Maasstad Hospital
  • Maastricht UMC+
  • Canisius-Wilhelmina Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Anti-epileptic drugs

No anti-epileptic drugs

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Neurological outcome
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

Long term outcome
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.

Full Information

First Posted
February 4, 2014
Last Updated
February 3, 2022
Sponsor
University of Twente
Collaborators
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
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1. Study Identification

Unique Protocol Identification Number
NCT02056236
Brief Title
TELSTAR: Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation
Acronym
TELSTAR
Official Title
TELSTAR: Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
April 2014 (undefined)
Primary Completion Date
April 24, 2021 (Actual)
Study Completion Date
January 24, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Twente
Collaborators
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

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiac Arrest, Anoxic Encephalopathy, Status Epilepticus
Keywords
Cardiac arrest, Postanoxic encephalopathy, Electroencephalographic status epilepticus, EEG monitoring, Anti-epileptic drugs

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
172 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Anti-epileptic drugs
Arm Type
Experimental
Arm Description
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.
Arm Title
No anti-epileptic drugs
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Anti-epileptic drugs
Other Intervention Name(s)
Lorazepam, Midazolam, Fenytoin, Propofol, Levetiracetam, Valproate, Thiopental
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
No anti-epileptic drugs
Intervention Description
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.
Primary Outcome Measure Information:
Title
Neurological outcome
Description
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).
Time Frame
three months
Secondary Outcome Measure Information:
Title
Long term outcome
Description
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.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeannette Hofmeijer, MD PhD
Organizational Affiliation
Rijnstate Hospital and University of Twente
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Michel van Putten, MD PhD
Organizational Affiliation
Medisch Spectrum Twente and University of Twente
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Janneke Horn, MD PhD
Organizational Affiliation
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Barry Ruijter, MD
Organizational Affiliation
University of Twente
Official's Role
Study Director
Facility Information:
Facility Name
Hôpital Erasme - Université libre de Bruxelles
City
Brussels
State/Province
Lenniksebaan 808
ZIP/Postal Code
1070
Country
Belgium
Facility Name
Radboud University Medical Center
City
Nijmegen
State/Province
Geert Grooteplein-Zuid 10
ZIP/Postal Code
6525 GA
Country
Netherlands
Facility Name
Medisch Spectrum Twente
City
Enschede
State/Province
Haaksbergerstraat 55
ZIP/Postal Code
7513 ER
Country
Netherlands
Facility Name
University Medical Center Groningen
City
Groningen
State/Province
Hanzeplein 1
ZIP/Postal Code
9700 RB
Country
Netherlands
Facility Name
St. Antonius Hospital
City
Nieuwegein
State/Province
Koekoekslaan 1
ZIP/Postal Code
3430 EM
Country
Netherlands
Facility Name
Academic Medical Center
City
Amsterdam
State/Province
Meibergdreef 9
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
VieCuri Medical Centre
City
Venlo
State/Province
Tegelseweg 210
ZIP/Postal Code
5912 BL
Country
Netherlands
Facility Name
Rijnstate Hospital
City
Arnhem
State/Province
Wagnerlaan 55
ZIP/Postal Code
6815 AD
Country
Netherlands
Facility Name
Maasstad Hospital
City
Rotterdam
State/Province
Zuid-Holland
ZIP/Postal Code
3079 DZ
Country
Netherlands
Facility Name
Maastricht UMC+
City
Maastricht
Country
Netherlands
Facility Name
Canisius-Wilhelmina Hospital
City
Nijmegen
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
25377067
Citation
Ruijter BJ, van Putten MJ, Horn J, Blans MJ, Beishuizen A, van Rootselaar AF, Hofmeijer J; TELSTAR study group. Treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation (TELSTAR): study protocol for a randomized controlled trial. Trials. 2014 Nov 6;15:433. doi: 10.1186/1745-6215-15-433.
Results Reference
background
PubMed Identifier
35196426
Citation
Ruijter BJ, Keijzer HM, Tjepkema-Cloostermans MC, Blans MJ, Beishuizen A, Tromp SC, Scholten E, Horn J, van Rootselaar AF, Admiraal MM, van den Bergh WM, Elting JJ, Foudraine NA, Kornips FHM, van Kranen-Mastenbroek VHJM, Rouhl RPW, Thomeer EC, Moudrous W, Nijhuis FAP, Booij SJ, Hoedemaekers CWE, Doorduin J, Taccone FS, van der Palen J, van Putten MJAM, Hofmeijer J; TELSTAR Investigators. Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Feb 24;386(8):724-734. doi: 10.1056/NEJMoa2115998.
Results Reference
derived
PubMed Identifier
26971488
Citation
Hofmeijer J, van Putten MJ. EEG in postanoxic coma: Prognostic and diagnostic value. Clin Neurophysiol. 2016 Apr;127(4):2047-55. doi: 10.1016/j.clinph.2016.02.002. Epub 2016 Feb 11.
Results Reference
derived
PubMed Identifier
26384469
Citation
Ruijter BJ, van Putten MJ, Hofmeijer J. Generalized epileptiform discharges in postanoxic encephalopathy: Quantitative characterization in relation to outcome. Epilepsia. 2015 Nov;56(11):1845-54. doi: 10.1111/epi.13202. Epub 2015 Sep 19.
Results Reference
derived
Links:
URL
http://www.telstartrial.nl/en/
Description
TELSTAR trial website (English version)

Learn more about this trial

TELSTAR: Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation

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