Clinical trial NCT00621478: 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
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Status Epilepticus
Lead sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sponsor class: NIH
First posted: 2008-02-22
Enrollment: 259
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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;

Primary outcomes:
measure: 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.
timeFrame: 30 minutes
Secondary outcomes:
measure: To determine population pharmacokinetics (PK) of lorazepam using sparse sampling.
timeFrame: 24 hr
measure: feasibility of identifying patients for informed consent prior to arrival in status epilepticus for a randomized controlled trial
timeFrame: 2 years
measure: the experience of community consultation and public disclosure
timeFrame: 2 years
measure: feasibility of enrolling pediatric patients under an exception from informed consent
timeFrame: 2 years
measure: determine patients' and parents' attitudes and reactions to an exception from informed consent approach
timeFrame: 2 years
measure: severe or life-threatening respiratory depression
timeFrame: 4 hours
Other outcomes:
Locations:
city: Davis
country: United States
facility: University of California- Davis Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington DC
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Baltimore
country: United States
facility: University of Maryland Hospital for Children
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Emergency Medicine Research
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Buffalo
country: United States
facility: Children's Hospital of Buffalo
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Pediatric Emergency Medicine
state: Utah
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Children's Corporate Center
state: Wisconsin
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
Study officials:
affiliation: Children's National Research Institute
name: James Chamberlain, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.