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

Primary Purpose

Status Epilepticus

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
lorazepam or diazepam
Sponsored by
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Status Epilepticus

Eligibility Criteria

3 Months - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 3 months to less than 18 years;

  2. 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:

  1. Pregnancy;
  2. Shock prior to study drug (sustained hypotension requiring inotropic therapy);
  3. Significant dysrhythmia prior to study drug (other than sinus tachycardia);
  4. Need for emergent surgical intervention and general anesthesia for a condition present prior to study drug;
  5. Known sensitivity to benzodiazepines or known contraindication to benzodiazepine use; or
  6. 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:

  1. Pregnancy;
  2. Use of a benzodiazepine within 1 week of presentation.
  3. Parent/guardian refusal to give informed consent by the methods described;
  4. 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;

Sites / Locations

  • University of California- Davis Medical Center
  • Children's Hospital Colorado
  • Children's National Medical Center
  • University of Maryland Hospital for Children
  • University of Michigan Emergency Medicine Research
  • Children's Hospital of Michigan
  • Children's Hospital of Buffalo
  • Children's Hospital of Philadelphia
  • Children's Medical Center Dallas
  • Texas Children's Hospital
  • University of Utah Pediatric Emergency Medicine
  • Medical College of Wisconsin Children's Corporate Center
  • Alberta Children's Hospital
  • Children's Hospital of Eastern Ontario

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Cohort 1

Cohort 2

Arm Description

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

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

Outcomes

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.

Secondary Outcome Measures

To determine population pharmacokinetics (PK) of lorazepam using sparse sampling.
feasibility of identifying patients for informed consent prior to arrival in status epilepticus for a randomized controlled trial
the experience of community consultation and public disclosure
feasibility of enrolling pediatric patients under an exception from informed consent
determine patients' and parents' attitudes and reactions to an exception from informed consent approach
severe or life-threatening respiratory depression

Full Information

First Posted
February 20, 2008
Last Updated
December 14, 2012
Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT00621478
Brief Title
Efficacy and Safety Study Comparing Lorazepam and Diazepam for Children in the Emergency Department With Seizures (Status 2)
Official Title
Use Of Lorazepam For The Treatment Of Pediatric Status Epilepticus: A Randomized, Double-Blinded Trial Of Lorazepam And Diazepam
Study Type
Interventional

2. Study Status

Record Verification Date
July 2012
Overall Recruitment Status
Completed
Study Start Date
February 2008 (undefined)
Primary Completion Date
May 2012 (Actual)
Study Completion Date
May 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Status Epilepticus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
259 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Active Comparator
Arm Description
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
Arm Title
Cohort 2
Arm Type
Active Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
lorazepam or diazepam
Other Intervention Name(s)
Ativan, Valium
Intervention Description
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.
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
To determine population pharmacokinetics (PK) of lorazepam using sparse sampling.
Time Frame
24 hr
Title
feasibility of identifying patients for informed consent prior to arrival in status epilepticus for a randomized controlled trial
Time Frame
2 years
Title
the experience of community consultation and public disclosure
Time Frame
2 years
Title
feasibility of enrolling pediatric patients under an exception from informed consent
Time Frame
2 years
Title
determine patients' and parents' attitudes and reactions to an exception from informed consent approach
Time Frame
2 years
Title
severe or life-threatening respiratory depression
Time Frame
4 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Months
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 3 months to less than 18 years; Generalized tonic clonic status epilepticus, defined as: 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 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 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;
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James Chamberlain, MD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California- Davis Medical Center
City
Davis
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington DC
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
University of Maryland Hospital for Children
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
University of Michigan Emergency Medicine Research
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48106
Country
United States
Facility Name
Children's Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Children's Hospital of Buffalo
City
Buffalo
State/Province
New York
ZIP/Postal Code
14222
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Medical Center Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390-9063
Country
United States
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah Pediatric Emergency Medicine
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84158
Country
United States
Facility Name
Medical College of Wisconsin Children's Corporate Center
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T3B6A8
Country
Canada
Facility Name
Children's Hospital of Eastern Ontario
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H8L1
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
27993298
Citation
Chamberlain DB, Chamberlain JM. Making Sense of a Negative Clinical Trial Result: A Bayesian Analysis of a Clinical Trial of Lorazepam and Diazepam for Pediatric Status Epilepticus. Ann Emerg Med. 2017 Jan;69(1):117-124. doi: 10.1016/j.annemergmed.2016.08.449.
Results Reference
derived
PubMed Identifier
24756515
Citation
Chamberlain JM, Okada P, Holsti M, Mahajan P, Brown KM, Vance C, Gonzalez V, Lichenstein R, Stanley R, Brousseau DC, Grubenhoff J, Zemek R, Johnson DW, Clemons TE, Baren J; Pediatric Emergency Care Applied Research Network (PECARN). Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. JAMA. 2014 Apr 23-30;311(16):1652-60. doi: 10.1001/jama.2014.2625.
Results Reference
derived

Learn more about this trial

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

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