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

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.

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.