E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048816 |
E.1.2 | Term | Lennox-Gastaut syndrome |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To determine the efficacy of clobazam (CLB) in the reduction of drop seizures at three dose levels when compared to baseline during 12 weeks maintenance dosing in a placebo controlled trial in patients with Lennox-Gastaut Syndrome (LGS). 2. To determine the safety of CLB when administered for up to 18 weeks at three different dose levels in patients with LGS. |
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E.2.2 | Secondary objectives of the trial |
1. To determine the efficacy of CLB as determined by responder rates and global evaluation of patient symptoms. 2. To determine population pharmacokinetic (PPK) parameters of CLB and its active metabolite N-desmethylclobazam (N-CLB) at steady-state dosing of CLB in patients with LGS and to describe sources of inter-patient variability (co-variates) including patient demographics, concomitant antiepileptic drug (AED) medications and genotype. 3. To evaluate the development of tolerance during treatment for up to 12 weeks. 4. To determine the effect of CLB on behavior utilizing the Child Behavior Checklist (CBCL). 5. To determine the impact of CLB on behavioral, cognitive and physical/neurologic disability through use of the Impact of Childhood Neurologic Disability Scale (ICNDS). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The patient or patients legally authorized representative (LAR) must sign and date the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form (ICF)/Health Insurance Portability and Accountability Act (HIPAA) Authorization (if required) prior to study participation. If appropriate, the patient will sign an Assent Form. 2. Male or female patients between 2 and 60 years of age (inclusive). 3. Patient must have been <11 years of age at the onset of LGS. 4. Patient must weigh ≥12.5 kg. 5. If female: a. Patient 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 30 days prior to randomization and for 30 days following completion of the study. b. Patient is not breastfeeding. c. Patients of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test performed on Study Day -1. 6. Patients with LGS as evidenced by: a. Greater than 1 type of generalized seizures, including drop seizures (atonic, tonic or myoclonic) for at least 6 months. b. Written documentation of having met the electroencephalogram (EEG) diagnostic criteria for a diagnosis of LGS at some point in their history (must have abnormal background activity accompanied by slow spike and wave pattern <2.5 Hz). 7. Patient must have experienced ≥2 drop seizures per week during the 4-week baseline period. 8. Patient must be on at least 1 AED. Patient must be on a stable AED dosing regimen for at least 30 days prior to screening. Neither a Vagal Nerve Stimulator (VNS) nor the ketogenic diet will count as an AED. 9. Patients must not have been on any benzodiazepines chronically (for any indication) for a period of at least 30 days prior to screening. Patients will be allowed to enter the study if they have used benzodiazepines as a rescue therapy within the 30 days prior to screening with a limit of 1 rescue per day up to an average of once per week. 10. In the investigators opinion, parent or caregiver must be able to keep an accurate seizure diary. 11. In the investigators and parent/caregivers opinions, the patient is able to take study drug. |
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E.4 | Principal exclusion criteria |
1. Etiology of patients seizures is a progressive neurologic disease. Patients with tuberous sclerosis will not be excluded from study participation, unless there is a progressive tumor. 2. Patient has had an episode of status epilepticus within 12 weeks of baseline. 3. Patient has had an anoxic episode requiring resuscitation within 6 months of screening. 4. Patient has a clinically significant history of an allergic reaction or significant sensitivity to benzodiazepines or to any of the other ingredients in clobazam tablets. 5. Patient is taking more than 3 concurrent AEDs. NOTE: VNS or ketogenic diet is allowed and will not be counted in the three allowed AEDs. 6. Patient has been on the ketogenic diet for less than 30 days prior to screening or suffers from frequent stooling. 7. If the patient has a VNS, the settings have not been stable for at least 30 days prior to screening. 8. Patient has previously been treated with CLB. 9. Patient has taken corticotropins in the 6 months prior to screening. 10. Patient 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. 11. If the patient is taking felbamate, he/she has been taking it for less than 1 year prior to screening. 12. Patient has experienced a clinically significant unresolved idiosyncratic reaction to an AED, e.g., topiramate with resulting metabolic acidosis, felbamate with resulting aplastic anemia or hepatic failure, or lamotrigine with resulting skin irritation and/or rash. 13. Patient 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). 14. If the patient is on any chronic medication, the dose has not been stable for at least 30 days prior to screening. 15. Patient has taken or used any investigational drug or device in the 30 days prior to screening. 16. Patient has a clinically significant unstable hepatic, hematological, renal, cardiovascular, gastrointestinal, or pulmonary disease or ongoing malignancy. 17. Patient has a diagnosis of sleep apnea. 18. Patient has compromised respiratory function or severe respiratory insufficiency. 19. Patient has a clinically significant abnormal laboratory value. 20. Patient has familial long QT syndrome, QT/QTc >500msec or a history of polymorphic ventricular tachycardia. 21. Patient has a progressive CNS lesion confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan. 22. Patient has a history of drug or alcohol abuse. 23. Patient has a history of poor compliance on past antiepileptic therapy. 24. Patient has inadequate supervision by parent or guardian. 25. For any reason, the patient is considered by the investigator to be an unsuitable candidate for the study. 26. Patient has a history of severe muscle weakness, including myasthenia gravis. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent reduction in number of drop seizures (average per week) from the 4-week baseline period compared to the 12-week maintenance period. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Planned number of patients: To be enrolled worldwide (enter baseline period): Approx. 240 To be randomized: Approx. 216 Patients completed [modifiedintent-to-treat (MITT) population]: Approx. 184
The IDMC will advise the Sponsor (Ovation) on whether to continue, modify or discontinue the study. If, in the judgment of the Sponsor, the continued exposure to the investigational product represents a significant risk to patients, the study will be stopped and the sites will be notified. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |