Clobazam in Patients With Lennox-Gastaut Syndrome

Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Clobazam in Patients With Lennox-Gastaut Syndrome

The purpose of this study is to evaluate the safety and efficacy of clobazam as adjunctive therapy in the treatment of seizures which lead to drop attacks (drop seizures) in patients 2 to 60 years of age with Lennox-Gastaut Syndrome (LGS). Patients will be enrolled at approximately 65 sites in the U.S. and ex-US for up to 23 weeks. Patients will be randomly assigned to either a low, medium or high dose, or placebo. The study will include a baseline period, a titration period and a maintenance period. After the maintenance period, patients will either continue into an open-label extension study or enter the taper period with a final visit 1 week after the last dose.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Epilepsy, Generalized; Seizures
• Intervention / Treatment: Drug: Clobazam Low Dose; Drug: Clobazam Medium Dose; Drug: Clobazam High Dose; Drug: Placebo

Detailed Description

LGS poses a significant treatment challenge. No single antiepileptic drug (AED) provides satisfactory relief for all or most patients with LGS and a combination of treatments is often required. Even with combination therapy, many LGS patients show resistance to treatment. Adjunctive therapy with newer anticonvulsant medications has demonstrated efficacy for some patients, although polytherapy and high medication doses are often associated with unfavorable adverse event profiles.

More effective and better-tolerated treatment options are needed for this population of medically intractable epilepsy patients. Clobazam may provide an improved safety profile compared to other AEDs currently approved for the treatment of LGS and may have less hypotonia and drooling effects than other benzodiazepines.

• Study Type: Interventional
• Enrollment (Actual): 238
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Chatswood, New South Wales, Australia, 2067
      • Strategic Health Evaluators
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital Department of Neurology
    • Melbourne, Victoria, Australia, 3081
      • Austin & Repatriation Hospital (Austin Health) Epilepsy Research Centre
• Belarus
  • Vitebsk, Belarus, 210023
    • Vitebsk Regional Diagnostic Center
• India
  • Mumbai, India, 400016
    • P.D. Hinduja National Hospital Medical Research Centre
  • Delhi
    • New Delhi, Delhi, India, 110002
      • Maulana Azad Medical College and Associated Lok Nayak Govind Ballabh Pant Hospitals and Guru Nanak Eye centre
  • Gujarat
    • Ahmedabad, Gujarat, India, 380006
      • Neurology Center
  • Karnataka
    • Bangalore, Karnataka, India, 560034
      • St. John's Medical College Hospital
    • Mangalore, Karnataka, India, 575002
      • Malikatta Neuro Center
    • Mangalore, Karnataka, India, 575018
      • K. S. Hedge Medical Academy
  • Maharashtra
    • Mumbai, Maharashtra, India, 400026
      • Jaslok Hospital & Research Centre
    • Pune, Maharashtra, India, 411 011
      • KEM Hospital & Research Centre
  • New Delhi
    • Delhi, New Delhi, India, 110095
      • Institute of Human Behaviour and Allied Sciences
  • Pune
    • Erandawane, Pune, India, 411004
      • Deenanath Mangeshkar Hospital and Research Center
  • Punjab
    • Ludhiana, Punjab, India, 1410108
      • Christian Medical College
  • Tamilnadu
    • Chennai, Tamilnadu, India, 600 100
      • Dr. Kamakshi Memorial Hospital
  • Uttra Pradesh
    • Lucknow, Uttra Pradesh, India, 226 003
      • Chhatrapati Sahu Ji Maharaj Medical University
  • West Bengal
    • Kolkata, West Bengal, India, 700054
      • Apollo Gleneagles Hospitals
• Lithuania
  • Kaunas, Lithuania, LT 50009
    • Kaunas University of Medicine Hospital
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35081
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital and Medical Center
    • Phoenix, Arizona, United States, 85216
      • Phoenix Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Loxahatchee, Florida, United States, 33470
      • Pediatric Neurology and Epilepsy Center
    • Pensacola, Florida, United States, 32504
      • Child Neurology Center of NW FL
    • Tampa, Florida, United States, 33606
      • University of South Florida
    • Tampa, Florida, United States, 33609
      • Pediatric Epilepsy & Neurology Specialists
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia
  • Idaho
    • Boise, Idaho, United States, 83712
      • Pediatric Neurology of Idaho Children's Specialty Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Chicago, Illinois, United States, 61516
      • Children's Memorial Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0284
      • University of Kentucky, Kentucky Clinic, Department of Neurology
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • LSU Health Sciences Center
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Mid-Atlantic Epilepsy and Sleep Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • St. Paul, Minnesota, United States, 55012
      • Minnesota Epilepsy Group
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • The Comprehensive Epilepsy Care Center for Children and Adults
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson University Hospital
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Regional Medical Center
    • Voorhees, New Jersey, United States, 08043
      • Clinical Research Center of New Jersey (CRCNJ)
  • New York
    • Rochester, New York, United States, 14450
      • University of Rochester Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University Neurology, Inc.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson Epilepsy Center
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • UTMG Pediatric Neurology
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center at UT Southwestern-Dallas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Health Care System
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine Pediatric Neurology
  • Virginia
    • Richmond, Virginia, United States, 23298-0211
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 60 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient must have been <11 years of age at the onset of LGS.
• Patient must have LGS.
• Patient must be on at least 1 AED.
• Parent or caregiver must be able to keep an accurate seizure diary.

Exclusion Criteria:

• Etiology of patient's seizures is a progressive neurologic disease. Patients with tuberous sclerosis will not be excluded from study participation, unless there is a progressive tumor.
• Patient has had an episode of status epilepticus within 12 weeks of baseline.
• Patient has had an anoxic episode requiring resuscitation within 6 months of screening.
• Patient has a clinically significant history of an allergic reaction or significant sensitivity to benzodiazepines.
• Patient is taking more than 3 concurrent AEDs.
• Patient has been on the ketogenic diet for less than 30 days prior to screening or suffers from frequent stooling.
• If the patient has a Vagal Nerve Stimulator (VNS), the settings have not been stable for at least 30 days prior to screening.
• Patient has taken corticotropins in the 6 months prior to screening.
• Patient is currently taking long-term systemic steroids (excluding inhaled mediation for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception will be made of prophylactic medication, for example, for idiopathic nephrotic syndrome or asthma.
• If the patient is taking felbamate, has been taking it for less than 1 year prior to screening.

Other protocol-defined inclusion and exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; tablets; orally; daily for 15-18 weeks
EXPERIMENTAL: Clobazam Low Dose	Drug: Clobazam Low Dose; 0.25 mg/kg/day; tablets; orally; for 15-18 weeks; Other Names: Onfi™
EXPERIMENTAL: Clobazam Medium Dose	Drug: Clobazam Medium Dose; 0.5 mg/kg/day; tablets; orally; for 15-18 weeks; Other Names: Onfi™
EXPERIMENTAL: Clobazam High Dose	Drug: Clobazam High Dose; 1.0 mg/kg/day; tablets; orally; for 15-18 weeks; Other Names: Onfi™

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Reduction in Number of Drop Seizures (12-week Maintenance Period).	Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.	4-week baseline period and 12-week maintenance period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Reduction in Number of Drop Seizures (First 4 Weeks of the 12-week Maintenance Period).	Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.	4-week baseline period and the first 4 weeks of the 12-week maintenance period
Percent Reduction in Number of Drop Seizures (Middle 4 Weeks of the 12-week Maintenance Period).	Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.	4-week baseline period and the middle 4 weeks of the 12-week maintenance period
Percent Reduction in Number of Drop Seizures (Last 4 Weeks of the 12-week Maintenance Period).	Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.	4-week baseline period and the last 4 weeks of the 12-week maintenance period
Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (12-week Maintenance Period).	Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.	4-week baseline period and the 12-week maintenance period
Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (First 4 Weeks of the 12-week Maintenance Period).	Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.	4-week baseline period and the first 4 weeks of the 12-week maintenance period
Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (Middle 4 Weeks of the 12-week Maintenance Period).	Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.	4-week baseline period and the middle 4 weeks of the 12-week maintenance period
Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (Last 4 Weeks of the 12-week Maintenance Period).	Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.	4-week baseline period and the last 4 weeks of the 12-week maintenance period
Tolerance	Study responders who have ≥50% reduction in their drop seizure rate during the first 4 or first 8 weeks of maintenance compared to the 4 week baseline period.	4-week baseline period and first 4/first 8 weeks of the maintenance period
Investigator Global Evaluations of the Patient's Overall Change in Symptoms.	The physician was asked to rate the patient's overall change in symptoms and overall change in seizure activity and Quality of Life since the beginning of clobazam treatment by checking "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse".	Week 15
Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms.	The parent/caregiver was asked to rate the patient's overall change in symptoms and overall change in seizure activity and Quality of Life since the beginning of clobazam treatment by checking "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse".	Week 15

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Reduction in the Number of Non-drop Seizures.	This outcome measure evaluated the percent reduction (average per week) in non-drop Seizures. Non-drop seizures were other seizures not meeting the drop seizure definition. Drop seizures were defined as a drop attack or spell (atonic, tonic or myoclonic) involving the entire body, trunk, or head that led to a fall, injury, slumping in chair, or head hitting surface or that could have led to a fall or injury, depending on the position of the patient at the time of the attack or spell.	4-week baseline period and the 12-week maintenance period
Percent Reduction of Total (Drop and Non-Drop) Seizures.	This outcome measure evaluated the percent reduction in average weekly rate in total (drop and non-drop) seizures. Drop seizures were defined as a drop attack or spell (atonic, tonic or myoclonic) involving the entire body, trunk, or head that led to a fall, injury, slumping in chair, or head hitting surface or that could have led to a fall or injury, depending on the position of the patient at the time of the attack or spell. Non-drop seizures were other seizures not meeting the drop seizure definition.	4-week baseline period and 12-week maintenance period

Collaborators and Investigators

• Sponsor: Lundbeck LLC

Publications and helpful links

General Publications

• Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011 Oct 11;77(15):1473-81. doi: 10.1212/WNL.0b013e318232de76. Epub 2011 Sep 28.
• Brigo F, Jones K, Eltze C, Matricardi S. Anti-seizure medications for Lennox-Gastaut syndrome. Cochrane Database Syst Rev. 2021 Apr 7;4(4):CD003277. doi: 10.1002/14651858.CD003277.pub4.
• Gidal BE, Wechsler RT, Sankar R, Montouris GD, White HS, Cloyd JC, Kane MC, Peng G, Tworek DM, Shen V, Isojarvi J. Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study. Neurology. 2016 Oct 25;87(17):1806-1812. doi: 10.1212/WNL.0000000000003253. Epub 2016 Sep 28.

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (ACTUAL): December 1, 2009
• Study Completion (ACTUAL): April 1, 2010

Study Registration Dates

• First Submitted: August 20, 2007
• First Submitted That Met QC Criteria: August 20, 2007
• First Posted (ESTIMATE): August 21, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2012
• Last Update Submitted That Met QC Criteria: January 6, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Epilepsy; Clobazam; Lennox-Gastaut Syndrome; Drop seizures
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes; Neurologic Manifestations; Genetic Diseases, Inborn; Epilepsy; Seizures; Epilepsy, Generalized; Lennox Gastaut Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Anti-Anxiety Agents; GABA Agents; Anticonvulsants; GABA-A Receptor Agonists; GABA Agonists; Clobazam
• Other Study ID Numbers: 13110A; OV1012 (OTHER: Former study ID)