Efficacy and Safety of Diazepam in the Management of Refractory Epilepsy in Selected Patients Who Require Intermittent Medical Intervention for Acute Repetitive Seizures.

A Phase 3, Randomized, Double-blind, Parallel, Placebo-controlled, Multicenter Study, With Optional Open-label Continuation, Of The Efficacy And Safety Of Vanquix(tm) Auto-injector (Diazepam Injection) For The Management Of Selected, Refractory, Patients With Epilepsy Who Require Intermittent Medical Intervention To Control Episodes Of Acute Repetitive Seizures

To evaluate the efficacy and safety of diazepam in the management of refractory epilepsy in selected patients who require intermittent medical intervention for the control of episodes of acute repetitive seizures. In addition, to assess the support provided by caregivers who are not themselves or not under the direct supervision of health care professionals at the time of administration.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Epilepsy, Generalized; Seizures; Epilepsies, Partial; Epilepsy, Complex Partial
• Intervention / Treatment: Drug: Placebo; Drug: Vanquix Auto-Injector (Diazepam Injection)

• Study Type: Interventional
• Enrollment (Actual): 234
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Northport, Alabama, United States, 35476
      • Neurology Clinic, PC
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Clinical Trials, Inc
  • California
    • Irvine, California, United States, 92606
      • Stein Life Child Neurology Medical Specialists Inc.
    • Long Beach, California, United States, 90806
      • Collaborative Neuroscience Network, LLC
    • Newport Beach, California, United States, 92658
      • HOAG Memorial Hospital Presbyterian
    • Newport Beach, California, United States, 92663
      • Brain and Spine Surgeons of Orange County
    • Sacramento, California, United States, 95816
      • Sutter Institute for Medical Research
    • Sacramento, California, United States, 95816
      • Drug Shipment
    • Sacramento, California, United States, 95816
      • Sacramento Comprehensive Epilepsy Program
    • Sacramento, California, United States, 95816
      • Sutter Cancer Center Specialty Clinic
    • Sacramento, California, United States, 95819
      • Northern California Cardiology
  • Florida
    • Bradenton, Florida, United States, 34205
      • Bradenton Research Center, Inc.
    • Clearwater, Florida, United States, 33756
      • Morton Plant Hospital Epilepsy Clinic
    • Clearwater, Florida, United States, 33756
      • Morton Plant Hospital Pharmacy
    • Gulf Breeze, Florida, United States, 32561
      • Northwest Florida Clinical Research Group, LLC
    • Gulf Breeze, Florida, United States, 32561
      • Child Neurology Center of Northwest Florida
    • Lighthouse Point, Florida, United States, 33064
      • Emery Neuroscience Center
    • Loxahatchee, Florida, United States, 33470
      • Pediatric Neurology and Epilepsy Center
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Orlando, Florida, United States, 32819
      • Pediatric Neurology, PA
    • Orlando, Florida, United States, 32806
      • EKG only
    • Tallahassee, Florida, United States, 32308
      • Tallahassee Neurological Clinic
    • Tallahassee, Florida, United States, 32308
      • AMO Corp
    • Tampa, Florida, United States, 33609
      • Pediatric Epilepsy & Neurology Specialists
    • Tampa, Florida, United States, 33613
      • Willsey Research Inc
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Child Neurology Associates, PC
    • Savannah, Georgia, United States, 31405
      • Savannah Neurology, PC
  • Idaho
    • Boise, Idaho, United States, 83702
      • Consultants in Epilepsy and Neurology, PLLC
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Comer Children's Hospital
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center (UCMC)
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospital Pharmacy
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center (UCMC) Center for Advanced Medicine (CAM)
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Clinical Trials Unit
    • Louisville, Kentucky, United States, 40202
      • University Neurologists PSC Pediatric Division
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Ambulatory Care Building Clinic
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Medical Center
  • Minnesota
    • St Cloud, Minnesota, United States, 56303
      • Neurology Clinic of St Cloud
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • The Comprehensive Epilepsy Care Center for Children and Adults
    • Kansas City, Missouri, United States, 64111
      • St Luke's Hospital
    • Kansas City, Missouri, United States, 64111
      • MRI Location
    • Kansas City, Missouri, United States, 64111
      • St Luke's Hospital Neurological Consultants
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Gibbsboro, New Jersey, United States, 08026
      • Clinical Research Center Of New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical Group
    • New Brunswick,, New Jersey, United States, 08901
      • University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School
  • New York
    • Buffalo, New York, United States, 14222
      • Women and Children's Hospital of Buffalo
    • Buffalo, New York, United States, 14207
      • Elmwood Clinic
    • Buffalo, New York, United States, 14209
      • Millard Fillmore Gates Hospital/Comprehensive Epilepsy Center
    • New York, New York, United States, 10016
      • NYU Medical Center, Comprehensive Epilepsy Center
    • Rochester, New York, United States, 14642
      • Strong Memorial Hospital
    • Rochester, New York, United States, 14642
      • University of Rochester, Strong Epilepsy Center
  • North Carolina
    • Greensboro, North Carolina, United States, 27405
      • Guilford Neurologic Associates
    • Greensboro, North Carolina, United States, 27401
      • Cone Health Child Neurology
    • Raleigh, North Carolina, United States, 27607
      • Raleigh Neurology Associates, PA
  • Ohio
    • Cleveland, Ohio, United States, 44195-5102
      • The Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44195-5102
      • The Cleveland Clinic Health Systems
    • Columbus, Ohio, United States, 43210
      • Ohio State University
    • Columbus, Ohio, United States, 43210
      • Ohio State University Neurology Clinic
    • Columbus, Ohio, United States, 43210
      • Ohio State University University Hospital
  • Oregon
    • Portland, Oregon, United States, 97210
      • North Pacific Epilepsy Research/The Northrup Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19134-1095
      • St. Christopher's Hospital for Children
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Hospital for Children
    • York, Pennsylvania, United States, 17402
      • Wellspan Neurosciences
    • York, Pennsylvania, United States, 17403
      • Apple Hill Medical Center (EKG & Lab Draw)
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina Hospitals and Clinics
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina/Department of Pharmacy Service
    • Orangeburg, South Carolina, United States, 29118
      • The Neurology and Pain Clinic
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Mid-South Physicians Group, PLLC
    • Memphis, Tennessee, United States, 38103
      • University of Tennessee Lebonheur Pediatric Specialists Inc.
    • Nashville, Tennessee, United States, 37232-2551
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Epilepsy Clinic
    • Nashville, Tennessee, United States, 37203
      • Access Clinical Trial, Inc.
    • Nashville, Tennessee, United States, 37203
      • CMC - Physician's Park
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Hospital Pharmacy
  • Texas
    • Dallas, Texas, United States, 75230
      • Neurological Clinic of Texas, PA
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Physcian Network
    • Ft Worth, Texas, United States, 76104
      • Cook Children's Medical Center Office of Grants and Research
    • San Antonio, Texas, United States, 78258
      • Alamo City Clinical Research, LLC
  • Virginia
    • Richmond, Virginia, United States, 23298-0042
      • Virginia Commonwealth University Health System
    • Richmond, Virginia, United States, 23298-0211
      • Virginia Commonwealth University Division of Child Neurology
    • Richmond, Virginia, United States, 23298-0599
      • Virginia Commonwealth University Ambulatory Care Center/Department of Neurology
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98104
      • University of Washington Regional Epilepsy Center, Harborview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria

For Patient:

• Older than 2 years of age and between 6 and 136 kg body weight
• Recipient of clinical diagnosis of epilepsy, taking a stable antiepileptic drug regimen for at least 2 weeks, and requiring intermittent medical intervention to control episodes of acute repetitive seizures (ARS)
• Experienced at least 2 episodes of ARS in previous year, one of which occurred in previous 6 months
• Has episodes of ARS that include complex partial or generalized seizures
• Has a responsible caregiver available to participate
• Is not pregnant or lactating and is practicing an acceptable method of birth control.

For Caregiver:

• Age of 18 years or older and has demonstrated responsibility as a caregiver through training to:

  • Recognize an episode of repetitive seizures for which the injection was intended,
  • Administer study drug
  • Count and record seizures and respiratory rate in the patient diary,
  • Monitor the patient and record observations in the patient diary for 12 hours following study drug treatment
  • Recognize the need for immediate medical attention.

Key Exclusion Criteria

For Patient:

• Petit mal status or petit mal variant status
• History of ARS consistently progressing to status epilepticus
• History of failure to respond to benzodiazepine treatment
• Hypersensitivity to diazepam
• Acute narrow angle glaucoma
• Alcohol and/or other substance abuse
• Has taken another investigational drug in previous 30 days
• Acute or progressive neurologic or severe psychiatric disease or severe mental abnormality.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; During the Double-blind Period, participants received a single, age- and weight-appropriate dose of placebo solution as a deep intramuscular injection in the mid to outer thigh. Drug was administered by a caregiver using a spring-driven, pressure-activated, prefilled autoinjector at the onset of an episode of acute repetitive seizures (ARS).	Drug: Placebo; Intramuscular autoinjector; administered at onset of an episode
EXPERIMENTAL: Diazepam; During the Double-blind Period, participants received a single, age- and weight-appropriate dose of diazepam solution, ranging from 0.2 to 0.5 mg/kg, as a deep intramuscular injection in the mid to outer thigh. Additional doses were permissible during the Open-label Period. Drug was administered by a caregiver using a spring-driven, pressure-activated, prefilled autoinjector at the onset of an episode of ARS.	Drug: Vanquix Auto-Injector (Diazepam Injection); Intramuscular autoinjector: 5, 10, 15, or 20 mg (based on participant's age and weight); administered at the onset of an episode

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Next Seizure or Rescue Medication During the Double-blind Period (Kaplan-Meier 50th Percentile)	An event was defined as an episode of or required rescue medication for an episode of acute repetitive seizures (ARS) within 15 minutes to 12 hours following study drug administration. Patients without an ARS event were censored at 12 hours. Diaries were provided; if no diary was returned, or the diary did not provide answers to questions about seizures and rescue during the 12-hour follow-up period, the patient was considered censored as of 15 minutes past the treatment time, unless another contact was documented. If seizure control following study drug administration was inadequate, diazepam rectal gel was provided as a rescue medication, given only in the first 4 hours after study drug administration and only if the caregiver was directed to do so by the Investigator or designee at the time of the ARS episode. Patients and their caregivers were trained to recognize the onset of an episode of ARS and when and how to administer study drug.	From 15 minutes to 12 hours after study drug administration for an episode of ARS during the Double-blind Period
Percentage of Participants With an Event (Next Seizure or Rescue Medication) During the Open-label Period	An event was defined as an episode of or required rescue medication for an episode of acute repetitive seizures (ARS) within 15 minutes to 12 hours following study drug administration. Patients without an ARS event were censored at 12 hours. Diaries were provided; if no diary was returned, or the diary did not provide answers to questions about seizures and rescue during the 12-hour follow-up period, the patient was considered censored as of 15 minutes past the treatment time, unless another contact was documented. If seizure control following study drug administration was inadequate, diazepam rectal gel was provided as a rescue medication, given only in the first 4 hours after study drug administration and only if the caregiver was directed to do so by the Investigator or designee at the time of the ARS episode. Patients and their caregivers were trained to recognize the onset of an episode of ARS and when and how to administer study drug.	From 15 minutes to 12 hours after study drug administration for an episode of ARS during the Double-blind Period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Requiring Rescue Medication During the Double-blind Period	If seizure control following study drug administration was inadequate, diazepam rectal gel was provided as a rescue medication, given only in the first 4 hours after study drug administration and only if the caregiver was directed to do so by the Investigator or designee at the time of the acute repetitive seizure (ARS) episode. Each patient's specific criteria for seizure and an episode of ARS were determined by the Investigator. Patients and their caregivers were trained to use these criteria to recognize the onset of an episode of ARS and when and how to administer study drug. An episode of ARS was defined as an episode of multiple complex, partial, or generalized seizures occurring over a brief period (minutes to 12 hours) with the patient regaining consciousness between seizures, which were readily recognizable by the patient or a trained caregiver. ARS includes seizures sometimes referred to as serial, cluster, crescendo, or stuttering prolonged.	From 15 minutes to 12 hours following study drug administration for an episode of ARS during the Double-blind Period
Number of Participants Requiring Emergency Department Visits During the Double-blind Period	Any use of emergency treatment (such as an emergency room visit) was recorded in the patient's diary, along with the date, time, and reason for the emergency treatment. Emergency department visits required some type of rescue action taken, other than the visit itself. An episode of acute repetitive seizures (ARS) was defined as an episode of multiple complex, partial, or generalized seizures occurring over a brief period (minutes to 12 hours) with the patient regaining consciousness between seizures, which were readily recognizable by the patient or a trained caregiver. ARS includes seizures sometimes referred to as serial, cluster, crescendo, or stuttering prolonged.	From 15 minutes to 12 hours following study drug administration for onset of an episode of ARS during the Double-blind Period
Number of Participants Requiring Rescue Medical Care Other Than Rescue Medication or Emergency Department Visits During the Double-blind Period	Other rescue medical care consisted of care other than rescue medication or emergency department visits. Each patient's specific criteria for seizure and an episode of acute repetitive seizure (ARS) were determined by the Investigator. Patients and their caregivers were trained to use these criteria to recognize the onset of an episode of ARS and when and how to administer study drug. An episode of ARS was defined as an episode of multiple complex, partial, or generalized seizures occurring over a brief period (minutes to 12 hours) with the patient regaining consciousness between seizures, which were readily recognizable by the patient or a trained caregiver. ARS includes seizures sometimes referred to as serial, cluster, crescendo, or stuttering prolonged.	From 15 minutes to 12 hours following study drug administration for an episode of ARS during the Double-blind Period
Mean Score on Caregiver Global Treatment Assessment During the Double-blind Period	Caregiver global evaluation is based on seizure frequency, severity, and overall outcome compared with previous episodes and is rated on a 10-cm visual analogue scale, where 0=much worse and 10=much better. A higher score indicates greater improvement. An episode of acute repetitive seizures (ARS) is defined as an episode of multiple complex, partial, or generalized seizures occurring over a brief period (minutes to 12 hours) with the patient regaining consciousness between seizures, which were readily recognizable by the patient or a trained caregiver. ARS includes seizures sometimes referred to as serial, cluster, crescendo, or stuttering prolonged.	Assessments completed at the end of each treated episode of ARS in the Double-blind Period
Mean Score on Physician Global Treatment Assessment During the Double-blind Period	Physician global evaluation is based on seizure frequency, severity, and overall outcome compared with previous episodes. The physician global evaluation is rated on a 10-cm visual analogue scale, where 0=much worse and 10=much better. A higher score indicates greater improvement. An episode of acute repetitive seizures (ARS) was defined as an episode of multiple complex, partial, or generalized seizures occurring over a brief period (minutes to 12 hours) with the patient regaining consciousness between seizures, which were readily recognizable by the patient or a trained caregiver. ARS includes seizures sometimes referred to as serial, cluster, crescendo, or stuttering prolonged.	At Visit 2 and subsequent visits in the Double-blind Period
Number of Participants Requiring Rescue Medication During the Open-label Period	Each patient's specific criteria for seizure and an episode of acute repetitive seizure (ARS) were determined by the Investigator. Patients and their caregivers were trained to use these criteria to recognize the onset of an episode of ARS and when and how to administer study drug. If seizure control following study drug administration was inadequate, diazepam rectal gel was provided as a rescue medication, given only in the first 4 hours after study drug administration and only if the caregiver was directed to do so by the Investigator or designee at the time of the ARS episode.	From 15 minutes to 12 hours after study drug administration during the Open-label Period
Number of Participants Requiring Emergency Department Visits During the Open-label Period	Any use of emergency treatment (such as an emergency room visit) was recorded in the patient's diary, along with the date, time, and reason for the emergency treatment. Emergency department visits required some type of rescue action taken, other than the visit itself.	From 15 minutes to 12 hours after study drug administration for onset of an episode of ARS during the Open-label Period
Number of Participants Requiring Rescue Medical Care Other Than Medication or Emergency Department Visits During the Open-label Period	Other rescue medical care consisted of care other than rescue medication or emergency department visits. Each patient's specific criteria for seizure and an episode of acute repetitive seizure (ARS) were determined by the Investigator. Patients and their caregivers were trained to use these criteria to recognize the onset of an episode of ARS and when and how to administer study drug.	From 15 minutes to 12 hours after study drug administration for onset of an episode of ARS during the Open-label Period
Mean Score on Caregiver Global Treatment Assessment During the Open-label Period	Caregiver global evaluation is based on seizure frequency, severity, and overall outcome compared with previous episodes and is rated on a 10-cm visual analogue scale, where 0=much worse and 10=much better. A higher score indicates greater improvement. An episode of acute repetitive seizures (ARS) is defined as an episode of multiple complex, partial, or generalized seizures occurring over a brief period (minutes to 12 hours) with the patient regaining consciousness between seizures, which were readily recognizable by the patient or a trained caregiver. ARS includes seizures sometimes referred to as serial, cluster, crescendo, or stuttering prolonged.	Assessments completed at the end of each treated episode of ARS in the Open-label Period
Mean Score on Physician Global Treatment Assessment During the Open-label Period	Physician global evaluation is based on seizure frequency, severity, and overall outcome compared with previous episodes and is rated on a 10-cm visual analogue scale, where 0=much worse and 10=much better. A higher score indicates greater improvement. An episode of acute repetitive seizures (ARS) is defined as an episode of multiple complex, partial, or generalized seizures occurring over a brief period (minutes to 12 hours) with the patient regaining consciousness between seizures, which were readily recognizable by the patient or a trained caregiver. ARS includes seizures sometimes referred to as serial, cluster, crescendo, or stuttering prolonged.	From Visit 2 and subsequent visits in the Open-label Period to discharge or study termination

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Abou-Khalil B, Wheless J, Rogin J, Wolter KD, Pixton GC, Shukla RB, Sherman NA, Sommerville K, Goli V, Roland CL. A double-blind, randomized, placebo-controlled trial of a diazepam auto-injector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures. Epilepsia. 2013 Nov;54(11):1968-76. doi: 10.1111/epi.12373. Epub 2013 Sep 20. Erratum In: Epilepsia. 2018 Dec;59(12):2344.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): July 1, 2014

Study Registration Dates

• First Submitted: April 27, 2006
• First Submitted That Met QC Criteria: April 27, 2006
• First Posted (ESTIMATE): April 27, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): September 23, 2016
• Last Update Submitted That Met QC Criteria: August 17, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Diazepam; Cluster Seizures; ARS; Acute Repetitive Seizures
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Complex Partial; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antiemetics; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anticonvulsants; Neuromuscular Agents; Muscle Relaxants, Central; Diazepam
• Other Study ID Numbers: K826-05-3001; B4511001 (OTHER: Alias Study Number)