| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Partial Onset Epilepsy and other Seizures |
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| MedDRA Classification |
| 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 |
The primary objective of the study is:
• To compare the effectiveness of topiramate 5, 15, or 25 mg/kg/day (administered as either sprinkle capsules or oral liquid formulation) with that of placebo as an adjunct to concurrent anticonvulsant therapy in reducing POS seizure rates in infants (1 to 23 months of age, inclusive) with POS after 20 days of double-blind treatment
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of topiramate oral liquid and sprinkle formulations in infants with epilepsy at dosages up to 5, 15, and 25 mg/kg/day (in 20 days of double-blind treatment) and up to 60 mg/kg/day (in up to 1 year of open-label treatment)
Pharmacokinetic assessments will be conducted to supplement data from other studies, for further characterization of the pharmacokinetics of topiramate and to evaluate the effects of covariates on the pharmacokinetics of topiramate in infants with epilepsy.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
• Subjects must be male or female infants between 1 and 23 months of age, inclusive, at screening.
• Subjects must be at least 41 weeks of gestational age at screening.
• Subjects must be receiving regular enteral feeding (solid food; bottle- or cup-fed; or using gastrostomy, jejunostomy, or nasogastric tube), with or without breast-feeding.
• Subjects must weigh > or =3.5 kg and <15.5 kg at screening; length using an infant measuring table (heel to crown) must be > or =49 cm. There must be evidence of continued weight and height gain prior to the first day of screening.
• Parents (or their legally acceptable representatives) of subjects must have signed an informed consent/permission document indicating that they understand the purpose of and procedures required for the study and are willing to give permission for their child to participate in the study.
• Subjects must have clinical or EEG evidence of POS (simple or complex), with or without secondary generalization, at least 1 month prior to the first day of screening in subjects >6 months of age, or at least 2 weeks prior to the first day of screening in subjects < or =6 months of age. Subjects may have multiple seizure types as long as POS is present. Acceptable evidence of POS includes 1 of the following:
- Documented recurrent clinical seizures with asymmetric motor features or characteristic behavioral alterations. The interictal EEGs may be negative or inconclusive, provided that the clinical criterion for POS is met.
- A routine EEG or vEEG showing focal or asymmetric EEG findings (epileptiform discharges, focal slowing, focal attenuation, or a combination), with or without secondary generalization. Clinical seizures with symmetric or behavioral features are acceptable in the presence of EEG evidence of an asymmetric origin.
• Subjects must have been receiving 1 or 2 concurrent marketed AEDs for > or =1 month for subjects >6 months of age and for >2 weeks for subjects < or =6 months of age; this regimen must remain unchanged throughout the screening and double-blind treatment phases.
• As documented on the worksheet for inadequacy of treatment, the regimen of AEDs at entry:
- Must be considered to be optimized (including, if clinically appropriate, recent demonstration of adequate blood levels) in the opinion of the investigator
- Must be considered inadequate in controlling seizures in the opinion of the investigator, as shown in part by a retrospective history of at least 1 seizure in the 4 weeks prior to the first day of screening
- Must have been unchanged for at least 5 half-lives prior to the first day of screening, as described in Section 8.1 and Attachment 2
• Caregivers (parents or their legally acceptable representatives) of the subjects must be able to accurately maintain the subject take-home record, including items of general health.
• Subjects must have had a computerized tomography or magnetic resonance imaging scan to confirm the absence of a progressive lesion, such as a tumor, with the exception of lesions of tuberous sclerosis and Sturge-Weber syndrome, which are allowed.
• Subjects must have an ECG at screening with no abnormal, clinically significant interpretations by the central reader.
Subjects who meet all previous inclusion criteria, and meet the following additional inclusion criterion, will be eligible for the baseline 48-hour vEEG:
• Subjects must have a retrospective history of at least 7 seizures in the 2 weeks before the first day of screening.
Subjects who meet all previous inclusion criteria, and meet the following additional inclusion criterion, will be eligible to enter the double-blind treatment phase:
• Subjects must have evidence of > or =2 electroclinical POS seizures, as defined in Section 9.3.1, during the 48-hour baseline vEEG examination.
Subjects who meet all other inclusion and exclusion criteria but fail either of these last 2 may enter the open-label extension phase directly from the screening phase.
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| E.4 | Principal exclusion criteria |
Potential subjects who meet any of the following criteria will be excluded from participating in the study:
• Infants who are exclusively breast-fed and cannot take oral liquid medication
• Subjects with a surgically implanted and functioning vagus nerve stimulator
• Subjects with a history of febrile seizures or seizures due to an acute medical illness within 2 weeks prior to the first day of screening
• Subjects with a history of infantile seizures as a result of a correctable medical condition, such as metabolic disturbance, toxic exposure, neoplasm, or active infection within 2 weeks prior to the first day of screening
• Subjects with a history of nonepileptic seizures within 2 weeks prior to the first day of screening
• Subjects who have had epilepsy surgery within 3 months prior to the first day of screening
• Subjects with any progressive neurologic disorder, including malignancy, brain tumor, active central nervous system infection, demyelinating disease, or degenerative or progressive central nervous system disease, with the exception of tuberous sclerosis and Sturge Weber syndrome
• Subjects with any clinically significant uncontrolled medical illness, including hepatic or renal failure, ischemic cardiac disease, malignancy, or any disorder that, in the opinion of the investigator, places the subject at risk through participation in a clinical study
• Subjects with nephrocalcinosis, renal stones of any type, or hydronephrosis, as evidenced by medical history or screening examination
• Subjects with congenital glaucoma, abnormal slit-lamp examination (if previously performed), or known ocular deficits, or subjects receiving any ocular medications except lubricating eye drops or topical antibiotics
• Subjects with a known history of central hyperthermia, dysautonomia, or other disturbances of autonomic function
• Subjects with a known history of inborn errors of metabolism, mitochondrial dysfunction, or prior evidence of hyperammonemia
• Subjects with any clinically significant abnormality in laboratory tests at screening, including but not limited to:
- White blood cell (WBC) count <3,000/mL or absolute neutrophil count <1,000 /mL in the last 6 months for infants >6 months of age or at any time for those < or =6 months of age
- AST, ALT, or GGT > or =2 times the ULN
- Total bilirubin > or =1.5 mg/dL or conjugated bilirubin > or =20% of total
- Venous ammonia > or =2 times the ULN
- Creatinine clearance <70 mL/min per 1.73 m3 for infants > or =1 month to <6 months of age or <90 mL/min per 1.73 m3 for infants > or =6 months to <2 years of age; creatinine clearance at screening should be estimated using the Schwartz formula as follows:
• Subjects who are receiving 3 or more concurrent AEDs (including phenobarbital or benzodiazepines, regardless of the reason for prescription)
• Subjects being treated with furosemide, hydrochlorothiazide, vigabatrin, vitamin B6 therapy for epilepsy, monoamine oxidase (A or B) inhibitors, felbamate, zonisamide, or any other medication that is a potent carbonic anhydrase inhibitor (e.g., acetazolamide). Past treatment with furosemide for more than 2 weeks must be discussed with the sponsor.
• Subjects who have been treated with an investigational drug within 2 weeks prior to the first day of screening
• Subjects who have previously used topiramate or who have participated in a topiramate clinical study within 1 month prior to the first day of screening
• Subjects with a known allergy or hypersensitivity to topiramate sprinkle capsules or any of the ingredients of the oral liquid formulation or placebo formulations
• Subjects on a ketogenic diet to control epilepsy (e.g., the ketogenic diet, the Atkins diet, the South Beach diet, or another low-carbohydrate diet)
• • Subjects who are not reasonably expected to complete the study
• • Subjects who have had surgery for epilepsy within 3 months prior to the first day of screening
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable will be the percentage reduction in POS seizure rate from baseline to end point in the double-blind treatment phase as recorded on 48-hour vEEG and read by the central reader. |
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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 | No |
| 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 | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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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| The study is considered completed with the last visit of the last subject. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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