Refractory Status Epilepticus Treatment Study

Refractory Status Epilepticus: Plasmatic Levels Monitorization Utility

Identify the most effective dose of valproic acid when used in combination with phenytoin for treatment of patients with refractory status epilepticus, which allow a better clinical course and prognosis of the disease.

Study Overview

• Status: Completed
• Conditions: Grand Mal Status Epilepticus; Non-convulsive Status Epilepticus
• Intervention / Treatment: Drug: valproic acid (VPA)

Detailed Description

Phase III Clinical trial, to identify the most effective dose of valproic acid (20mg/kg bolus, 1mg/kg/h maintenance vs 40mg/kg bolus, 2mg/kg/h maintenance) in combination with phenytoin, in patients with refractory status epilepticus.

Multicenter clinical trial, single-blind, prospective, randomized 1:1 assignment.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital Universitari de Bellvitge

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients ≥ 18 years of age who meet the diagnosis of EER seizure, and previously they have been treated according to the clinical protocol at our center status (Diazepam 10mg Clonazepam 1mg and Phenytoin or iv at a dose of 20mg/kg in case persistence of the clinic):

   -Present seizures for at least 30 minutes without regaining awareness among them.

2. Patients ≥ 18 years of age who meet the diagnosis of nonconvulsive EER, and previously they have been treated according to the clinical protocol at our center status (Diazepam 10mg Clonazepam 1mg and Phenytoin or iv at a dose of 20mg/kg in case persistence of the clinic):

   • After submitting an EER seizures that yield clinically performed an EEG that shows SE electricity.
   • Evidence of a non-convulsive SE to perform an EEG of a patient admitted for any cause, either by filing seizures, altered mental status, or any other cause, and to persist after the treatment administered previously discussed.
3. Patients in whom it has obtained the written informed consent by the representative and/or patient, as the case

Exclusion Criteria:

1. Patients with severe cerebral anoxia, when the first EEG evidences a pattern of flare-suppression.
2. Patients who registers PLEDs (periodic epileptic lateralaized Discharges) without clinical seizure activity association to register or without electrical crises.
3. Patients < 18 years of age.
4. Patients in whom there is diagnostic doubt (eg non-convulsive status among and encephalopathy).
5. Pregnant or breastfeeding.
6. Patients with allergy to phenytoin, hydantoin or hypersensitivity to sodium valproate
7. Patients with porphyria
8. Patients with severe liver disease or dysfunction.
9. Patients with heart block or second and third grade sinus bradycardia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 40mg/kg intial valproate bolus; Patient receives a 40mg/kg valproate bolus with a maintenance of 1mg/kg/h, after benzodiazepine + phenytoin administration	Drug: valproic acid (VPA); Best dosage at the initial bolus of VPA in patient with satatus epilepticus refractarius (after benzodiazepine + phenytoin treatment); Other Names: Valrpoic acid; Phenytoin; Benzodiazepines; Status Epilepticus Refractarius
Active Comparator: 20mg/Kg intial bolus valproate; Patient receives a 20mg/kg valproate bolus with a maintenance of 1mg/kg/h, after benzodiazepine + phenytoin administration	Drug: valproic acid (VPA); Best dosage at the initial bolus of VPA in patient with satatus epilepticus refractarius (after benzodiazepine + phenytoin treatment); Other Names: Valrpoic acid; Phenytoin; Benzodiazepines; Status Epilepticus Refractarius

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
status epilepticus resolution	After 48h treatment administration the status epilepticus has to be solved without any other antiepileptic medications	after 48h treatment administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimation of pharmacokinetic parameters of valproate (VPA) and phenytoin (PHT)	Estimation of pharmacokinetic parameters of VPA (Cl: clearance, Vd: volume of distribution) and PHT (Vmax: maximum speed of metabolism and Km: plasma concentration at which the rate of metabolism is half the maximum)	During 48h post valproate administration

Collaborators and Investigators

• Sponsor: Hospital Universitari de Bellvitge
• Collaborators: Hospital Clinic of Barcelona; Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta; Germans Trias i Pujol Hospital; Hospital Vall d'Hebron
• Investigators: Principal Investigator: Mercè Falip, MD, Hospital Universitari de Bellvitge

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: April 24, 2012
• First Submitted That Met QC Criteria: April 25, 2012
• First Posted (Estimate): April 26, 2012

Study Record Updates

• Last Update Posted (Estimate): March 12, 2013
• Last Update Submitted That Met QC Criteria: March 10, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: benzodiazepines; valproic acid; refractory status epilepticus; phenytoin; Valproic acid initial dosage in status treatment
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Status Epilepticus; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; GABA Agents; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Antimanic Agents; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Valproic Acid; Phenytoin
• Other Study ID Numbers: NEU-2009-01