TELSTAR: Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Twente
Sponsor:
Collaborators:
Rijnstate Hospital Arnhem
Medical Spectrum Twente Enschede
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Radboud University
Information provided by (Responsible Party):
Jeannette Hofmeijer, University of Twente
ClinicalTrials.gov Identifier:
NCT02056236
First received: February 4, 2014
Last updated: May 28, 2014
Last verified: May 2014
  Purpose

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 Intervention
Cardiac Arrest
Postanoxic Encephalopathy
Status Epilepticus
Drug: Anti-epileptic drugs
Other: No anti-epileptic drugs

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: TELSTAR: Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation

Resource links provided by NLM:


Further study details as provided by University of Twente:

Primary Outcome Measures:
  • Neurological outcome [ Time Frame: three months ] [ Designated as safety issue: No ]
    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 [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    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.



Estimated Enrollment: 172
Study Start Date: April 2014
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Anti-epileptic drugs

Step 1. Lorazepam 4 mg iv (initial dosage) titrated up to a maximum of 12 mg/24 hours OR midazolam 10 mg (initial dosage) up to 60 mg/24 hours (in steps of 5 mg/5 minutes) PLUS Fenytoine bolus i.v. 15-20 mg/kg in 30 minutes, followed by 150 mg 2 dd 1, adapted based on serum levels.

Step 2. Propofol infusion with a maximum 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. Serum levels should be measured, as the combination of fenytoin and valproic acid may result in a reduction of serum levels of fenytoin.

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 epileptic status match those from the "richtlijn epilepsie" from the Dutch guideline.

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.


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 perfrom 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 the recommendations for the treatment of status epilepticus by the "Nederlandse Vereninging voor Neurologie". The objective of the 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • Informed consent given by a legal representative
  • 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
  • Known allergic response to the treatment medication
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02056236

Contacts
Contact: Jeannette Hofmeijer, MD PhD 0031-88-0058877 jhofmeijer@rijnstate.nl
Contact: Michel J. van Putten, MD PhD Prof 0031-53-4872810 m.j.a.m.vanputten@utwente.nl

Locations
Netherlands
Medical Spectrum Twente Recruiting
Enschede, Haaksbergerstraat 55, Netherlands, 7513 ER
Contact: Michel J. van Putten, MD PhD Prof    0031-53-4872810    m.j.a.m.vanputten@utwente.nl   
Academical Medical Center Recruiting
Amsterdam, Meibergdreef 9, Netherlands, 1105 AZ
Contact: Janneke Horn, MD PhD    020 566 9111    j.horn@amc.uva.nl   
Rijnstate Hospital Recruiting
Arnhem, Wagnerlaan 55, Netherlands, 6815 AD
Contact: Jeannette Hofmeijer, MD PhD    0031-88-0058877    jhofmeijer@rijnstate.nl   
Radboud University Medical Center Recruiting
Nijmegen, Netherlands
Contact: Astrid Hoedemaekers, Dr    0031 (24) 3611111    Astrid.Hoedemaekers@radboudumc.nl   
Sponsors and Collaborators
University of Twente
Rijnstate Hospital Arnhem
Medical Spectrum Twente Enschede
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Radboud University
Investigators
Principal Investigator: Jeannette Hofmeijer, MD PhD Rijnstate Hospital and University of Twente
Principal Investigator: Michel J. van Putten, MD PhD Prof Medical Spectrum Twente and University of Twente
Principal Investigator: Janneke Horn, MD PhD Academical Medical Center
Study Director: Barry Ruijter, MSc University of Twente
  More Information

No publications provided

Responsible Party: Jeannette Hofmeijer, MD PhD, University of Twente
ClinicalTrials.gov Identifier: NCT02056236     History of Changes
Other Study ID Numbers: NEF-14-18, NL46296.044.13
Study First Received: February 4, 2014
Last Updated: May 28, 2014
Health Authority: the Netherlands: METC Twente

Keywords provided by University of Twente:
Cardiac arrest
Postanoxic encephalopathy
Electroencephalographic status epilepticus
EEG monitoring
Anti-epileptic drugs

Additional relevant MeSH terms:
Heart Arrest
Status Epilepticus
Heart Diseases
Cardiovascular Diseases
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Propofol
Anticonvulsants
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Anesthetics, Intravenous
Anesthetics, General
Anesthetics

ClinicalTrials.gov processed this record on September 18, 2014