Efficacy and Safety Study Comparing Lorazepam and Diazepam for Children in the Emergency Department With Seizures (Status 2) - Full Text View

Sponsor:	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:	NCT00621478

Purpose

Children with seizures are frequently seen in the emergency department. The drug lorazepam, which is commonly used, is not labeled by the US Food and Drug Administration for children for this use. The FDA, under the Best Pharmaceuticals for Children Act, has requested that a study comparing diazepam, a drug that is labeled by the FDA for this indication, with lorazepam be performed. The study will show whether one drug is more effective and safe than the other.

Condition	Intervention	Phase
Status Epilepticus	Drug: lorazepam or diazepam	Phase 2 Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Use Of Lorazepam For The Treatment Of Pediatric Status Epilepticus: A Randomized, Double-Blinded Trial Of Lorazepam And Diazepam

Resource links provided by NLM:

MedlinePlus related topics: Seizures

Drug Information available for: Diazepam Lorazepam

U.S. FDA Resources

Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

Primary Outcome Measures:

cessation of convulsions within 10 minutes of the initial administration of the study drug and a sustained absence of convulsions for 30 minutes from the initial administration of the study drug. [ Time Frame: 30 minutes ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To determine population pharmacokinetics (PK) of lorazepam using sparse sampling. [ Time Frame: 24 hr ] [ Designated as safety issue: No ]
feasibility of identifying patients for informed consent prior to arrival in status epilepticus for a randomized controlled trial [ Time Frame: 2 years ] [ Designated as safety issue: No ]
the experience of community consultation and public disclosure [ Time Frame: 2 years ] [ Designated as safety issue: No ]
feasibility of enrolling pediatric patients under an exception from informed consent [ Time Frame: 2 years ] [ Designated as safety issue: No ]
determine patients' and parents' attitudes and reactions to an exception from informed consent approach [ Time Frame: 2 years ] [ Designated as safety issue: No ]
severe or life-threatening respiratory depression [ Time Frame: 4 hours ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	262
Study Start Date:	February 2008
Estimated Study Completion Date:	September 2012
Estimated Primary Completion Date:	September 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Cohort 1 Cohort 1 (preconsented) patients will involve obtaining informed consent from the legally authorized representative of a potential study subject before they present to the ED in SE. Patient assent will be obtained for patients as per local IRB rules. The consent document (enclosed in this application) will inform parents that if their child comes to the ED and qualifies for the study based on study inclusion/exclusion criteria, they will be enrolled. Patients who cannot be contacted to confirm consent will be enrolled in Cohort 2 (EFIC) as detailed below. Patients in Cohort 1 will be randomized in a blinded fashion to either lorazepam 0.1 mg/kg or diazepam 0.2 mg/kg	Drug: lorazepam or diazepam Administration instructions will ask to deliver 0.04 ml per kilogram of child's weight of the study medication up to a maximum of 1.6 ml. 0.04 ml/kg (maximum dose 1.6 ml) will deliver 0.1 mg/kg of lorazepam (maximum dose 4 mg) and 0.2 mg/kg of diazepam (maximum dose 8 mg). Half of this dose can be repeated in 5 minutes if the patient is still convulsing. The medication will be administered as a slow IV push. Other Names: Ativan Valium
Active Comparator: Cohort 2 Cohort 2 (EFIC) will include patients who appear in the ED with SE and qualify for the study but have not given prior consent. These patients will be enrolled under the EFIC regulations. The parent/guardian will be given the opportunity to object to participation or ask additional questions. The child will be enrolled (dosed) with study medication under an EFIC. Once the child is stabilized, a research staff member will approach the parent or LAR to obtain informed consent to continue the child's participation in the study. If a parent or LAR refuses continued participation, then no further study procedures will be performed. Safety and data will be collected in accordance with federal regulations. Cohort 2 will be randomized, like Cohort 1, to either lorazepam 0.1 mg/kg or diazepam 0.2 mg/kg	Drug: lorazepam or diazepam Administration instructions will ask to deliver 0.04 ml per kilogram of child's weight of the study medication up to a maximum of 1.6 ml. 0.04 ml/kg (maximum dose 1.6 ml) will deliver 0.1 mg/kg of lorazepam (maximum dose 4 mg) and 0.2 mg/kg of diazepam (maximum dose 8 mg). Half of this dose can be repeated in 5 minutes if the patient is still convulsing. The medication will be administered as a slow IV push. Other Names: Ativan Valium

Arms

Assigned Interventions

Active Comparator: Cohort 1

Cohort 1 (preconsented) patients will involve obtaining informed consent from the legally authorized representative of a potential study subject before they present to the ED in SE. Patient assent will be obtained for patients as per local IRB rules. The consent document (enclosed in this application) will inform parents that if their child comes to the ED and qualifies for the study based on study inclusion/exclusion criteria, they will be enrolled.

Patients who cannot be contacted to confirm consent will be enrolled in Cohort 2 (EFIC) as detailed below.

Patients in Cohort 1 will be randomized in a blinded fashion to either lorazepam 0.1 mg/kg or diazepam 0.2 mg/kg

Drug: lorazepam or diazepam

Administration instructions will ask to deliver 0.04 ml per kilogram of child's weight of the study medication up to a maximum of 1.6 ml. 0.04 ml/kg (maximum dose 1.6 ml) will deliver 0.1 mg/kg of lorazepam (maximum dose 4 mg) and 0.2 mg/kg of diazepam (maximum dose 8 mg). Half of this dose can be repeated in 5 minutes if the patient is still convulsing.

The medication will be administered as a slow IV push.

Other Names:

Ativan
Valium

Active Comparator: Cohort 2

Cohort 2 (EFIC) will include patients who appear in the ED with SE and qualify for the study but have not given prior consent. These patients will be enrolled under the EFIC regulations. The parent/guardian will be given the opportunity to object to participation or ask additional questions.

The child will be enrolled (dosed) with study medication under an EFIC. Once the child is stabilized, a research staff member will approach the parent or LAR to obtain informed consent to continue the child's participation in the study. If a parent or LAR refuses continued participation, then no further study procedures will be performed. Safety and data will be collected in accordance with federal regulations.

Cohort 2 will be randomized, like Cohort 1, to either lorazepam 0.1 mg/kg or diazepam 0.2 mg/kg

Drug: lorazepam or diazepam

Administration instructions will ask to deliver 0.04 ml per kilogram of child's weight of the study medication up to a maximum of 1.6 ml. 0.04 ml/kg (maximum dose 1.6 ml) will deliver 0.1 mg/kg of lorazepam (maximum dose 4 mg) and 0.2 mg/kg of diazepam (maximum dose 8 mg). Half of this dose can be repeated in 5 minutes if the patient is still convulsing.

The medication will be administered as a slow IV push.

Other Names:

Ativan
Valium

Detailed Description:

Textbooks and expert opinion recommend both diazepam and lorazepam as initial therapy for children in status epilepticus (SE) and provide recommended doses that are commonly used. However, unlike diazepam, lorazepam is only FDA-approved for treatment for SE in patients over 18 years of age. Despite this fact, many experts support the use of lorazepam over diazepam in pediatric SE. Increased duration of action, increased effectiveness in terminating SE, and a lower incidence of respiratory depression have been cited as potential advantages of lorazepam over diazepam. However, data to support firm recommendations for one medication over another are lacking. Thus, either diazepam (FDA-approved) or lorazepam can be considered first-line agents for pediatric SE, and the physician's choice of agent depends on local practice patterns and individual treatment styles. In the prehospital (Emergency Medical Services) setting, diazepam is commonly chosen because of a longer shelf life without refrigeration.

The purpose of this study is to determine the differences in efficacy and safety between these two commonly used benzodiazepines, as requested by the FDA under the Best Pharmaceuticals for Children Act, using the Exception from Informed Consent provided by the FDA.

Eligibility

Ages Eligible for Study:	3 Months to 18 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age 3 months to less than 18 years;
Generalized tonic clonic status epilepticus, defined as:
1. Three or more generalized tonic clonic seizures within the last hour and currently experiencing a convulsion (i.e. the current convulsion may be the third convulsion within one hour); or
2. Two or more generalized tonic clonic seizures in succession with no recovery of consciousness between seizures and currently experiencing a convulsion (i.e. the current convulsion may be the second convulsion without recovery of consciousness after the first convulsion); or
3. A seizure that lasts at least 5 minutes that is either generalized tonic clonic in its entirety or starts focal and then generalizes. The seizure must be associated with loss of consciousness

Exclusion Criteria:

Pregnancy;
Shock prior to study drug (sustained hypotension requiring inotropic therapy);
Significant dysrhythmia prior to study drug (other than sinus tachycardia);
Need for emergent surgical intervention and general anesthesia for a condition present prior to study drug;
Known sensitivity to benzodiazepines or known contraindication to benzodiazepine use; or
Use of a benzodiazepine within 1 week of presentation.

Certain exclusion criteria may not be known at the time of drug administration due to the need for emergent treatment. Thus patients will be terminated from the study (early terminators) if the investigators discover any of the following conditions after administration of study drug:

Pregnancy;
Use of a benzodiazepine within 1 week of presentation.
Parent/guardian refusal to give informed consent by the methods described;
Patient's refusal to assent (for patients ≥ 7 yrs old and mentally competent to understand study procedures) by the methods described, or as required by the local IRB;

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00621478

Contacts

Contact: James Chamberlain, MD

202-476-3253

jchamber@cnmc.org

Locations

United States, California
University of California- Davis Medical Center	Recruiting
Davis, California, United States, 95817
Contact: Shari Nichols 916-734-7596 shari.nichols@ucdmc.ucdavis.edu
Principal Investigator: Cheryl Vance, MD
United States, Colorado
Children's Hospital Colorado	Recruiting
Aurora, Colorado, United States, 80045
Contact: Kendra Kocher 303-724-2592 Kendra.Kocher@childrenscolorado.org
Principal Investigator: Joseph Grubenhoff, MD
United States, District of Columbia
Children's National Medical Center	Recruiting
Washington DC, District of Columbia, United States, 20010
Contact: Jim Chamberlain, MD 202-476-3253 jchamber@cnmc.org
Children's National Medical Center	Recruiting
Washington DC, District of Columbia, United States, 20010
Contact: Ebony Parham 202-476-3718 eparham@cnmc.org
Principal Investigator: Kathleen Brown, MD
United States, Maryland
University of Maryland Hospital for Children	Recruiting
Baltimore, Maryland, United States, 21201
Contact: Bahiyyah Jackson 410-706-0204 bjackson@peds.umaryland.edu
Principal Investigator: Richard Lichenstein, MD
United States, Michigan
University of Michigan Emergency Medicine Research	Recruiting
Ann Arbor, Michigan, United States, 48106
Contact: Philip Villanueva 734-615-8981 pvillanu@med.umich.edu
Principal Investigator: Rachel Stanley, MD
Children's Hospital of Michigan	Recruiting
Detroit, Michigan, United States, 48201
Contact: Amy Stolinski 313-745-1332 astolins@med.wayne.edu
Principal Investigator: Prashant Mahajan, MD
United States, New York
Children's Hospital of Buffalo	Completed
Buffalo, New York, United States, 14222
United States, Pennsylvania
Children's Hospital of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Joseph Mechak 267-426-7932 MECHAKJ@email.chop.edu
Principal Investigator: Jill Baren, MD
United States, Texas
Children's Medical Center Dallas	Recruiting
Dallas, Texas, United States, 75390-9063
Contact: Anne-Marie Jones 214-456-8436 annemarie.jones@childrens.com
Principal Investigator: Pam Okada, MD
Texas Children's Hospital	Recruiting
Houston, Texas, United States, 77030
Contact: Victor Gonzalez, MD 832-824-5977 vmgonza1@texaschildrens.org
Principal Investigator: Charles Macias, MD, MPH
United States, Utah
University of Utah Pediatric Emergency Medicine	Recruiting
Salt Lake City, Utah, United States, 84158
Contact: Kammy Jacobsen 801-599-6403 kammy.jacobsen@hsc.utah.edu
Principal Investigator: Maija Holsti, MD, MPH
United States, Wisconsin
Medical College of Wisconsin Children's Corporate Center	Completed
Milwaukee, Wisconsin, United States, 53226
Canada, Alberta
Alberta Children's Hospital	Not yet recruiting
Calgary, Alberta, Canada, T3B6A8
Contact: Janielee Williamson, RN 403-955-3186 Janie.Williamson@albertahealthservices.ca
Principal Investigator: David Johnson, MD
Canada, Ontario
Children's Hospital of Eastern Ontario	Recruiting
Ottawa, Ontario, Canada, K1H8L1
Contact: Candice McGahern 613-737-7600 ext 4111 CMcGahern@cheo.on.ca
Principal Investigator: Roger Zemek, MD

Sponsors and Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Principal Investigator:

James Chamberlain, MD

Children's Research Institute

More Information

No publications provided

Responsible Party:	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:	NCT00621478 History of Changes
Other Study ID Numbers:	N01HD043393, 275200403393C
Study First Received:	February 20, 2008
Last Updated:	February 10, 2012
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Status Epilepticus
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Diazepam
Lorazepam
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs

Gastrointestinal Agents
Hypnotics and Sedatives
Central Nervous System Depressants
Muscle Relaxants, Central
Neuromuscular Agents
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 22, 2012