| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Partial onset seizures
Crisis Epilépticas Parciales |
|
| 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 | 10034091 |
| E.1.2 | Term | Partial seizures, simple |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to demonstrate the long-term retention rate of CRS versus TPM and LEV when given adjunctively to subjects with partial onset seizures over a 6-month period. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to determine characteristics of the
study medications that might influence retention rate; specifically:
- The cognitive and neuropsychiatric side effect index (composite adverse event rates) to compare the tolerability of the study medications
- Reasons for discontinuation from the study
- Seizure rate comparisons among the treatment arms
- Cognitive changes relative to baseline (computerized cognitive test battery)
- Subject-reported mood states and behavioral and cognitive side effect changes (patient- and observer-reported) relative to baseline
- Genes/genotypes that may be related to the response to, or metabolism of CRS may also be evaluated |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female aged 16 years or older
2. Subjects must weigh at least 45 kg (~100lbs)
3. Established diagnosis, for at least 3 months prior to screening, of partial onset seizures, including simple partial motor, complex partial, or secondarily generalized seizures
4. At least 1 partial onset seizure during the 3-month retrospective baseline period prior to screening
5. History of AED failure (due to lack of efficacy or tolerability) to at least 1 but not more than 4 AEDs in the past. The occasional use of rescue medication is not considered prior AED use
6. Current treatment with at least 1 and no more than 2 AEDs given at stable dosage(s) 30 days prior to screening. Additional infrequent (less than 3 days during the 3 month baseline) and occasional use of sedatives or benzodiazepines to prevent breakthrough seizures is permitted
7. Females must be postmenopausal for at least 2 years, surgically sterile, abstinent, or, if sexually active, practicing an acceptable method of birth control (eg, intrauterine device, double-barrier method, male partner sterilization) before entry and throughout the study. Females must have a negative serum beta chorionic gonadotropin pregnancy test result at screening/randomization
8. Negative urine drug screen (except for prescription benzodiazepines, prescription barbiturates, or prescription narcotics) at screening
9. Willing to adhere to the prohibitions and restrictions as specified in Section 4.4, Prohibitions and Restrictions
10. Must have signed an informed consent form document (subjects or their legally acceptable representatives) indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. Assent is also required of adolescents as described in Section 16.2.3, Informed Consent. (Assent applies to adolescents only. Adults not competent to consent will not be allowed into the study.)
11. For adolescents (as defined by local regulations), a responsible person must be available to accompany the subject to the study center at each visit, to provide reliable information for the safety and efficacy evaluations, and to accurately and reliably dispense the study drug as directed, if in the opinion of the investigator, the subject cannot otherwise be compliant with study procedures and study drug
|
|
| E.4 | Principal exclusion criteria |
1. Have a generalized epileptic syndrome
2. Have primary generalized seizures
3. Have atonic seizures
4. Have typical or atypical absence seizures
5. Have only simple partial type seizures with manifestations other than motor symptoms (ie, simple partial sensory)
6. History of unprovoked status epilepticus in the last 6 months prior to screening
7. History of Lennox-Gastaut Syndrome
8. Failed, in the judgment of the investigator, an adequate treatment attempt (dose and duration) with TPM or LEV due to lack of efficacy or tolerability (or other medications with equivalent international nonproprietary names)
9. Currently (within the past 30 days prior to screening) taking TPM or LEV (or other medications with equivalent international non-proprietary names)
10. More than 3 days of sedative or benzodiazepine use for seizures in the 3 months prior to screening
11. Diagnosis of psychotic disorder, bipolar disease, or major depression or other neurologic conditions, serious or medically unstable systemic disease, suicidal ideation or attempts, or homicide attempts at any time in the past 2 years
12. History of nephrolithiasis with symptomatic renal stones within the last 2 years prior to screening
13. Diagnosis of autism and/or pervasive developmental disability not otherwise specified (NOS) and/or mental retardation or evidence of an intelligence quotient (IQ) ≤70
14. ALT greater than 1.5 times the ULN or total bilirubin above the ULN at screening
15. History of drug-induced liver injury (ie, history of ALT elevation 3 times ULN from prior drug exposure) or severe drug-induced, hypersensitivity reactions
16. History of any medical conditions that could potentially disqualify the subject for medical or safety reasons (e.g., renal insufficiency; vascular, pulmonary, gastrointestinal, endocrine, hematologic, or metabolic disturbances)
17. Diagnosis of any form of chronic liver disease, cirrhosis, or liver cancer. Examples of chronic liver disease include autoimmune hepatitis, hemochromatosis, Wilson’s disease, primary biliary cirrhosis, sclerosing cholangitis
18. Positive hepatitis serology as determined by multiantigen enzyme immunoassay (EIA): includes Anti-HCV, HBsAg, Anti-HBc, HepBCoreM, and Anti-HBs. Subjects with positive Anti-HCV test results will be excluded from the study. Criteria for excluding subjects based on hepatitis B results are provided in Attachment 1
19. Known to be positive for human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS). Note: HIV testing is not required for this study
20. Clinically relevant abnormalities for laboratory test values at screening
21. History of experimental drug or medical device use within the 30 days prior to screening
22. History of prior exposure to CRS
23. Current treatment with a vagal nerve stimulator (VNS) or ketogenic diet
24. Planned epilepsy surgery within the next 12 months
25. Subjects who have a test score of less than 7 on the Non-Verbal Reasoning Test (NVRT) during visit 2, prior to randomization. Note: Such subjects may be retested once after 7 days if the investigator believes that the subject can read and comprehend instruction, is able to operate a computer mouse and a keyboard, and is assumed to have an IQ above 70.
26. Subjects with clinical evidence of significant cardiac disease, including unstable angina, myocardial infarction within the past 2 years, uncontrolled heart failure, congenital short QT syndrome, Brugada syndrome, major arrhythmias, or significant shortening or lengthening of QTcF intervals (<330 ms or >500 ms) should be excluded from the study
27. Females who are pregnant or breast-feeding
28. Unable to meet or perform study requirements (eg, recording of subject diary information), inability to read and comprehend instructions or to use a computer and its peripherals (mouse, keyboard), known or suspected inability to comply with the study protocol
29. Unable to swallow solid oral dosage forms whole with the aid of water (subjects may not chew, divide, dissolve, or crush the study drug)
30. Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the discretion of the investigator or study center, including family members of the employees or the investigator
In addition, subjects should be excluded if in the opinion of the investigator they should not be enrolled in the study because of the precautions, warnings or contraindications outlined in the local Topamax® (topiramate) and/or local Keppra® (levetiracetam) package insert.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is time to discontinuation (all cause) over the 6-month core double-blind phase. This primary endpoint is a clinically meaningful composite measure of efficacy, safety and tolerability over time, reflecting the therapeutic effectiveness of antiepileptic drugs (AEDs). |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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) | 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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.8.5.1 | Number of sites anticipated in the EEA | 82 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Last visit of last patient. |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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