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Safety and Effectiveness of Open-Label Clobazam in Subjects With Lennox-Gastaut Syndrome (LGS)

Primary Purpose

Lennox-Gastaut Syndrome

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Clobazam
Sponsored by
Lundbeck LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lennox-Gastaut Syndrome focused on measuring Lennox-Gastaut Syndrome (LGS), Epilepsy, Drop Seizures, Clobazam

Eligibility Criteria

2 Years - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • The subject or subject's legally authorized representative (LAR) must sign and date the institutional review board (IRB)/independent ethics committee (IEC) approved Informed Consent Form/Health Insurance Portability and Accountability Act (HIPAA) Authorization (if required) prior to study participation.
  • Previous participation in Lundbeck-sponsored LGS study.
  • Subject must weigh ≥12.5 kilograms.
  • Male or female subjects must have been between 2 and 60 years of age at the time of the enrollment in the Phase 3 double-blind study (13110A/OV1012/NCT00518713) or between 2 and 30 years of age at the time of the enrollment in the Phase 2 double-blind study (13108A/OV1002/NCT00162981) study.
  • If female:

    • Subject is either not of childbearing potential, defined as premenarchal, postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or if of childbearing potential, must comply with a method of birth control acceptable to the investigator during the study, for at least 4 weeks prior to study entry and for 4 weeks following completion of the study.
    • Subject is not breastfeeding.
    • Subjects of childbearing potential must have a negative serum pregnancy test at Study Day 1.
  • In the investigator's opinion, parent or caregiver must be able to keep an accurate seizure diary.

Exclusion Criteria:

  • Greater than 14 days have elapsed since the subject received his/her last dose of study medication in the previous Lundbeck-sponsored LGS study.
  • Subject had a serious or severe adverse event in the previous Lundbeck-sponsored LGS study that in the opinion of the investigator was probably or definitely related to clobazam use and precludes safe use of clobazam.
  • Subject has had an anoxic episode requiring resuscitation within 6 months of study entry.
  • Subject has a history of an allergic reaction or significant sensitivity to benzodiazepines or to any of the other ingredients in clobazam tablets.
  • Subject is taking more than 3 concurrent anti-epileptic drugs (AEDs). NOTE: Vagal Nerve Stimulator (VNS) or ketogenic diet is allowed and will not be counted in the three allowed AEDs.
  • Subject is currently taking long-term systemic steroids (excluding inhaled medication 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 subject is taking felbamate, has been taking it for less than 1 year prior to study entry or previous treatment with felbamate resulted in withdrawal due to liver or bone marrow adverse events.
  • Subject has experienced an idiosyncratic reaction to an AED, e.g., carbamazepine with resulting aplastic anemia or agranulocytosis, topiramate with resulting metabolic acidosis, felbamate with resulting aplastic anemia or hepatic failure, or lamotrigine with resulting skin irritation and/or rash.
  • Subject has shown any clinically significant history of hyper-sensitivity to central nervous system (CNS) active medications leading to neurobehavioral aberrations (e.g., increased biting, scratching, kicking, or hitting).
  • Subject has taken or used any investigational drug or device in the 30 days prior to screening, with the exception of clobazam in a Lundbeck-sponsored study.
  • Subject has a clinically significant unstable hepatic, hematological, renal, cardiovascular, gastrointestinal, or pulmonary disease or ongoing malignancy.
  • Subject has a diagnosis of sleep apnea.
  • Subject has a compromised respiratory function or severe respiratory insufficiency.
  • Subject has a history of severe muscle weakness, including myasthenia gravis.
  • Subject has a clinically significant abnormal laboratory value or electrocardiogram (ECG) abnormality.
  • Subject has progressive lesion confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan.
  • Subject has a history of drug or alcohol abuse.
  • Subject has a history of poor compliance on past antiepileptic therapy.
  • Subject has inadequate supervision by parent or guardian.
  • For any reason, the subject is considered by the investigator to be an unsuitable candidate for the study.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Clobazam

    Arm Description

    Outcomes

    Primary Outcome Measures

    Median Percent Reduction in Average Weekly Rate of Drop Seizures Based on the 7-day Assessment
    Number of drop seizures was obtained from seizure diaries
    Median Percent Reduction in Average Weekly Rate of Drop Seizures Based on the Last 30-day Assessment
    Number of drop seizures was obtained from seizure diaries

    Secondary Outcome Measures

    Percent of Patients Considered Treatment Responders Defined as Those With a ≥25%, ≥50%, ≥75%, 100% Reduction in Drop Seizures Based on the 7-day Assessment
    Number of drop seizures obtained from seizure diaries
    Percent of Patients Considered Treatment Responders Defined as Those With a ≥25%, ≥50%, ≥75%, 100% Reduction in Drop Seizures Based on the Last 30-day Assessment
    Number of drop seizures obtained from seizure diaries
    Investigator Global Evaluations of the Patient's Overall Change in Symptoms
    The physician was asked to rate the patient's overall change in symptoms 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".
    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 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".

    Full Information

    First Posted
    June 18, 2010
    Last Updated
    February 22, 2018
    Sponsor
    Lundbeck LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01160770
    Brief Title
    Safety and Effectiveness of Open-Label Clobazam in Subjects With Lennox-Gastaut Syndrome
    Acronym
    LGS
    Official Title
    Safety and Effectiveness of Open-Label Clobazam in Subjects With Lennox-Gastaut Syndrome
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    February 2018
    Overall Recruitment Status
    Completed
    Study Start Date
    December 2005 (undefined)
    Primary Completion Date
    February 2012 (Actual)
    Study Completion Date
    February 2012 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Lundbeck LLC

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The objective of this study is to evaluate the long-term safety and effectiveness of open-label clobazam in the treatment of drop seizures in subjects with LGS.
    Detailed Description
    This multi-center, open-label study is designed to evaluate the long-term safety and effectiveness of clobazam as adjunctive therapy in subjects with LGS. Subjects enrolled in Lundbeck LLC (formerly Ovation Pharmaceuticals, Inc.) sponsored studies 13108A/OV1002/NCT00162981 and 13110A/OV1012/NCT00518713 who either completed the study or who prematurely discontinued were offered the opportunity to rollover into this open-label study. Subjects will start at a common dose level of 0.5 mg/kg, not to exceed 40 mg/day, and must maintain the dose level for 48 hours. After 48 hours, investigators will be able to increase, decrease or maintain the subject's dose, up to a maximum target daily dose of 2.0 mg/kg (maximum dose of 80 mg/day). During the treatment period, seizures will be recorded during the week preceding each study visit or 30 days immediately following each study visit (dependent on Amendment approval). The subject or subject's caregiver will record daily counts of seizures, including drop seizures in the subject's seizure diary.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Lennox-Gastaut Syndrome
    Keywords
    Lennox-Gastaut Syndrome (LGS), Epilepsy, Drop Seizures, Clobazam

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    267 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Clobazam
    Arm Type
    Experimental
    Intervention Type
    Drug
    Intervention Name(s)
    Clobazam
    Other Intervention Name(s)
    Aedon, Antacastill, Castilium, Clarmyl, Frisium, Karidium, Mefrilan, Mystan, Noiafren, Onfi, Psiton, Psyton, Sentil, Seryl, Urbadan, Urbanil, Urbanol, Urbanyl.
    Intervention Description
    Clobazam will be provided in 5 mg, 10 mg and 20 mg tablets and will be dispensed in bottles as needed at each visit. Bottles may be dispensed between visits if necessary. Subjects will start at a common dose level of 0.5 mg/kg, not to exceed 40 mg/day, and must maintain the dose level for 48 hours. After the first 48 hours of the treatment period, investigators will be able to increase, decrease or maintain the subject's dose, up to an approximate maximum daily dose of 2.0 mg/kg (maximum dose of 80 mg/day).
    Primary Outcome Measure Information:
    Title
    Median Percent Reduction in Average Weekly Rate of Drop Seizures Based on the 7-day Assessment
    Description
    Number of drop seizures was obtained from seizure diaries
    Time Frame
    Baseline to month 36
    Title
    Median Percent Reduction in Average Weekly Rate of Drop Seizures Based on the Last 30-day Assessment
    Description
    Number of drop seizures was obtained from seizure diaries
    Time Frame
    Baseline to month 36
    Secondary Outcome Measure Information:
    Title
    Percent of Patients Considered Treatment Responders Defined as Those With a ≥25%, ≥50%, ≥75%, 100% Reduction in Drop Seizures Based on the 7-day Assessment
    Description
    Number of drop seizures obtained from seizure diaries
    Time Frame
    Baseline to month 36
    Title
    Percent of Patients Considered Treatment Responders Defined as Those With a ≥25%, ≥50%, ≥75%, 100% Reduction in Drop Seizures Based on the Last 30-day Assessment
    Description
    Number of drop seizures obtained from seizure diaries
    Time Frame
    Baseline to month 36
    Title
    Investigator Global Evaluations of the Patient's Overall Change in Symptoms
    Description
    The physician was asked to rate the patient's overall change in symptoms 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".
    Time Frame
    Baseline to month 36
    Title
    Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms
    Description
    The parent/caregiver was asked to rate the patient's overall change in symptoms 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".
    Time Frame
    Baseline to month 36

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    2 Years
    Maximum Age & Unit of Time
    60 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: The subject or subject's legally authorized representative (LAR) must sign and date the institutional review board (IRB)/independent ethics committee (IEC) approved Informed Consent Form/Health Insurance Portability and Accountability Act (HIPAA) Authorization (if required) prior to study participation. Previous participation in Lundbeck-sponsored LGS study. Subject must weigh ≥12.5 kilograms. Male or female subjects must have been between 2 and 60 years of age at the time of the enrollment in the Phase 3 double-blind study (13110A/OV1012/NCT00518713) or between 2 and 30 years of age at the time of the enrollment in the Phase 2 double-blind study (13108A/OV1002/NCT00162981) study. If female: Subject is either not of childbearing potential, defined as premenarchal, postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or if of childbearing potential, must comply with a method of birth control acceptable to the investigator during the study, for at least 4 weeks prior to study entry and for 4 weeks following completion of the study. Subject is not breastfeeding. Subjects of childbearing potential must have a negative serum pregnancy test at Study Day 1. In the investigator's opinion, parent or caregiver must be able to keep an accurate seizure diary. Exclusion Criteria: Greater than 14 days have elapsed since the subject received his/her last dose of study medication in the previous Lundbeck-sponsored LGS study. Subject had a serious or severe adverse event in the previous Lundbeck-sponsored LGS study that in the opinion of the investigator was probably or definitely related to clobazam use and precludes safe use of clobazam. Subject has had an anoxic episode requiring resuscitation within 6 months of study entry. Subject has a history of an allergic reaction or significant sensitivity to benzodiazepines or to any of the other ingredients in clobazam tablets. Subject is taking more than 3 concurrent anti-epileptic drugs (AEDs). NOTE: Vagal Nerve Stimulator (VNS) or ketogenic diet is allowed and will not be counted in the three allowed AEDs. Subject is currently taking long-term systemic steroids (excluding inhaled medication 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 subject is taking felbamate, has been taking it for less than 1 year prior to study entry or previous treatment with felbamate resulted in withdrawal due to liver or bone marrow adverse events. Subject has experienced an idiosyncratic reaction to an AED, e.g., carbamazepine with resulting aplastic anemia or agranulocytosis, topiramate with resulting metabolic acidosis, felbamate with resulting aplastic anemia or hepatic failure, or lamotrigine with resulting skin irritation and/or rash. Subject has shown any clinically significant history of hyper-sensitivity to central nervous system (CNS) active medications leading to neurobehavioral aberrations (e.g., increased biting, scratching, kicking, or hitting). Subject has taken or used any investigational drug or device in the 30 days prior to screening, with the exception of clobazam in a Lundbeck-sponsored study. Subject has a clinically significant unstable hepatic, hematological, renal, cardiovascular, gastrointestinal, or pulmonary disease or ongoing malignancy. Subject has a diagnosis of sleep apnea. Subject has a compromised respiratory function or severe respiratory insufficiency. Subject has a history of severe muscle weakness, including myasthenia gravis. Subject has a clinically significant abnormal laboratory value or electrocardiogram (ECG) abnormality. Subject has progressive lesion confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan. Subject has a history of drug or alcohol abuse. Subject has a history of poor compliance on past antiepileptic therapy. Subject has inadequate supervision by parent or guardian. For any reason, the subject is considered by the investigator to be an unsuitable candidate for the study.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Email contact via H. Lundbeck A/S
    Organizational Affiliation
    LundbeckClinicalTrials@lundbeck.com
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    23141144
    Citation
    Ng YT, Conry J, Paolicchi J, Kernitsky L, Mitchell W, Drummond R, Isojarvi J, Lee D, Owen R; OV-1004 study investigators. Long-term safety and efficacy of clobazam for Lennox-Gastaut syndrome: interim results of an open-label extension study. Epilepsy Behav. 2012 Dec;25(4):687-94. doi: 10.1016/j.yebeh.2012.09.039. Epub 2012 Nov 7.
    Results Reference
    result
    Citation
    Ng YT, Conry J, Kernitsky L, Mitchell W, Veidemanis R, Drummond R, Muniz R, Isojarvi J, Lee D, Paolicchi J. Long-Term Safety and Efficacy of Clobazam for Lennox-Gastaut Syndrome: Final Results of an Open-Label Extension Study. Late-Breaking Abstract #1.363 presented at the 66th annual meeting of the American Epilepsy Society, Nov. 30-Dec. 4, 2012, San Diego, California.
    Results Reference
    result
    PubMed Identifier
    27683846
    Citation
    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.
    Results Reference
    derived

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    Safety and Effectiveness of Open-Label Clobazam in Subjects With Lennox-Gastaut Syndrome

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