Comparison Between Lorazepam, Clonazepam and Clonazepam + Fosphenytoin for the Treatment of Out-of-hospital Generalized Status Epilepticus (LORACLOFT)

Comparison Between Lorazepam, Clonazepam and Clonazepam + Fosphenytoin for the Treatment of Out-of-hospital Generalized Status Epilepticus in Adults Patients

The main purpose of this study is to know on one hand if lorazepam is more (effective) than clonazepam and on the other hand if lorazepam is also effective as the association clonazepam + fosphenytoin in out-of-hospital treatment of the generalized convulsive status epilepticus in adult patients.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Status Epilepticus
• Intervention / Treatment: Drug: Placebo; Drug: Lorazepam; Drug: Clonazepam; Drug: Fosphenytoin

Detailed Description

Background: Early and rapid termination of status epilepticus with intravenous administration of benzodiazepines only or its association with other antiepileptic drug improves outcomes. Our out-of-hospital study aims to demonstrate on one hand the superiority of lorazepam compared with clonazepam and on the other hand the efficacy at least equivalent of lorazepam in comparison with the association clonazepam + fosphenytoin. If these hypotheses are demonstrated, the out-of-hospital treatment of the status epilepticus by lorazepam in monotherapy would then be strongly recommended, considering its efficacy and the simplicity of administration in the context of the pre-hospital emergency.Objective: To compare the efficacy of Lorazepam with that of Clonazepam and its association with Fosphenytoin for the treatment of out-of-hospital status epilepticus.

Participating centers: 41 prehospital emergency services employing mobile intensive care units and located in urban areas in France participated in this study. In France, the management of out-of-hospital medical emergencies is under the responsibility of the Service d'Aide Medicale Urgente (SAMU). Mobile intensive care units are staffed by an attending emergency physician or anesthesiologist, a nurse, and an ambulance driver. The study is coordinated by the prehospital emergency service of Lariboisiere Hospital, University Paris 7 (Paris, France)

Number of patients: 522 patients; 174 patients by group.

Duration of the study: The total duration planned is of 48 months Intermediate analysis: An intermediate analysis is planned while 261 patients will be included (50 % of the inclusions).Duration of participation of every patient: 24 hours Data collection: prehospital data recording during the 60 min period of the study, and intrahospital data recording by the medical report of hospitalization.

Methodology: Multicenter, randomized, double-blind trial with 3 arms.

Main criteria of evaluation: the cessation of the status epilepticus and the absence of recurrence from T20 minutes until T60 minutes after the beginning of the treatment.

The cessation of the status epilepticus is defined by the stop of any motor activity and any seizures or convulsive movements. The absence of recurrence is defined by the not occurrence of a new seizures after a period of cessation.

• Study Type: Interventional
• Enrollment (Actual): 434
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75010
    • Département d'Anesthésie - Réanimation - SMUR - Hôpital Lariboisière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients aged 18 years or older
• Out-of-hospital management

• presenting one of the criteria below noticed by the physician of the mobile intensive care unit:

  1. convulsive seizures at the time of treatment and were reported by reliable witnesses to have been continuously convulsing for longer than 5 minutes, without regaining consciousness, or
  2. if they were having more than 2 repeated convulsive seizures at the time of treatment without regaining consciousness

Exclusion Criteria:

• Patient having been already included in the study during a previous episode of status epilepticus
• Patient having already received before the arrival of the mobile intensive care unit one of theses studied drugs (lorazepam, clonazepam or fosphenytoin or phenytoin)
• Latent status epilepticus in deep coma
• Cerebral anoxia (post cardio respiratory arrest)
• Severe head trauma
• Patient presenting convulsive seizures of psychogenic origin
• Lennox Gastaut's syndrome
• Decision of urgent intubation
• Patients of more than 110 kg ( estimated weight
• Heart rate < 60 bpm or > 150 bpm
• Systolic Blood Pressure < 90 mmHg
• Atrioventricular block of 2nd or 3rd degree
• Ventricular tachycardia or ventricular fibrillation
• Sensibility known about benzodiazepines, fosphenytoin, phenytoin, other hydantoins, or barbiturate
• Contraindication known about benzodiazepines (severe respiratory failure, severe acute hepatic failure, myasthenia, syndrome of sleep apnea, glaucoma with closed angle
• Contraindication known about fosphenytoin (intermittent acute porphyry)
• Contraindication known about barbiturate (porphyry, severe respiratory failure, current treatment by saquinavir, ifosfamide and voriconazole, in association with millepertuis)
• Person unaffiliated in a National Social Security Insurance
• Pregnant or breast-feeding Woman
• Impossibility to put an intravenous or intra-osseous catheter for the treatment injection
• Absence of nurse in the mobile intensive care unit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1: Lorazepam + Placebo; [ L + P ] = lorazepam 0,1mg/kg by intravenous injection over a period of 2 to 3 minutes) + placebo 20 mg/kg by intravenous infusion over a period of 15 minutes	Drug: Placebo; placebo 20 mg/kg by intravenous infusion over a period of 15 minutes; Drug: Lorazepam; lorazepam 0,1mg/kg by intravenous injection over a period of 2 to 3 minutes)
Active Comparator: 2: Clonazepam + Placebo; [ C + P ] = clonazepam 0,015 mg/kg by intravenous injection over a period of 2 to 3 minutes + placebo 20 mg/kg by intravenous infusion over a period of 2 15 minutes	Drug: Placebo; placebo 20 mg/kg by intravenous infusion over a period of 15 minutes; Drug: Clonazepam; clonazepam 0,015 mg/kg
Active Comparator: 3: Clonazepam + Fosphenytoin; [ C + F ] = clonazepam 0,015 mg/kg by intravenous injection over a period of 2 to 3 minutes + fosphenytoin 20 mg/kg Equivalent Phenytoin (EP) by intravenous infusion over a period of 15 minutes	Drug: Clonazepam; clonazepam 0,015 mg/kg; Drug: Fosphenytoin; fosphenytoin 20 mg/kg Equivalent Phenytoin (EP) by intravenous infusion over a period of 15 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patient with a cessation of seizures and absence of recurrence	Percentage of patient with a cessation of seizures and absence of recurrence from 20 minutes until 60 minutes after the beginning of the treatment	between 20 and 60 minutes after the beginning of the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration between the first cessation and the recurrence of seizures	Duration between the first cessation and the recurrence of seizures	up to 60 minutes
Percentage of patients having had a second injection of benzodiazepine	Percentage of patients having had a second injection of benzodiazepine	up to 60 minutes
Percentage of patients having had an injection of the second line treatment	Percentage of patients having had an injection of the second line treatment (i.e. Fosphenytoin or barbiturate)	up to 60 minutes
Percentage of patients having a general anesthesia for refractory status epilepticus	Percentage of patients having a general anesthesia for refractory status epilepticus	up to 60 minutes
Percentage of patients having had a side effect	Percentage of patients having had a side effect (low blood pressure, arrhythmias)	up to 60 minutes
Percentage of patients having been mechanically ventilated	Percentage of patients having been mechanically ventilated in pre-hospital setting	up to 60 minutes
Glasgow Coma Scale	Glasgow Coma Scale on arrival at the hospital	60 minutes
Mortality	Mortality in pre-hospital setting	up to 60 minutes
Mortality	Mortality in hospital until J30 (if the patient still hospitalized)	up to Day 30
Length of stay in Intensive Care Unit	Length of stay in Intensive Care Unit	up to Day 30
Length of stay in hospital	Length of stay in hospital	up to Day 30

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Papa GUEYE, MD, PhD, Assistance Publique - Hôpitaux de Paris; Principal Investigator: François CONCINA, MD, CHU toulouse - Hôpital Purpan

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2013
• Primary Completion (Actual): February 23, 2018
• Study Completion (Actual): February 23, 2018

Study Registration Dates

• First Submitted: June 3, 2013
• First Submitted That Met QC Criteria: June 3, 2013
• First Posted (Estimate): June 5, 2013

Study Record Updates

• Last Update Posted (Actual): October 11, 2018
• Last Update Submitted That Met QC Criteria: October 10, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: epilepsy; benzodiazepines; seizures; convulsions; status epilepticus; anticonvulsants; convulsive seizures
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Seizures; Epilepsy; Status Epilepticus; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Sodium Channel Blockers; Lorazepam; Clonazepam; Fosphenytoin
• Other Study ID Numbers: P110123; 2012-003795-39 (EudraCT Number)