E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary generalised tonic-clonic seizures (PGTCS) in idiopathic generalised epilepsy (IGE) |
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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 | HLT |
E.1.2 | Classification code | 10018101 |
E.1.2 | Term | Generalised tonic-clonic seizures |
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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 objective of this study is to assess the efficacy of adjunctive zonisamide in idiopathic generalised epilepsy (IGE) in reducing the frequency of tonic-clonic seizures in subjects with continuing primary generalised tonic clonic seizures (PGTCS) despite treatment with one or two other anti-epileptic drugs (AEDs).
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of adjunctive zonisamide. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is male or female and aged 6-65 years.
2. Subject has ≥ 3 PGTCS over the two months before screening and during the eight weeks Baseline Period with at least one seizure in each one month period. PGTCS must occur in the context of IGE and may be accompanied by other primary generalised seizures, provided these are also consistent with a diagnosis of IGE.
3. Subject (or parent/caregiver, for subjects below the age of consent) is willing to sign an informed consent form. For subjects below the age of consent in their country, where appropriate they must be willing to give informed (written or verbal) assent. Subjects from the age specified in local regulations will be required to sign an appropriate informed consent form.
4. Subject is taking a stable regimen of one or two other AEDs for at least two weeks prior to Visit 1 (start of the Baseline Period).
5. Subject has a clinical diagnosis of any type of idiopathic generalised epilepsy which has PGTCS (and which may be accompanied by other generalised seizure types), according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures (1981) and the ILAE Classification of Epilepsies and Epileptic Syndromes (1989). Diagnosis should have been established by clinical history, electroencephalogram (EEG) and computed tomography/magnetic resonance imaging (CT/MRI) of the brain consistent with idiopathic generalised epilepsy. CT/MRI scan should have been performed within five years of the screening visit or, if not available from this period, should be performed in the Baseline Period.
6. EEG should have been performed within one year of the screening visit or, if not available from this period, should be performed in the Baseline Period.
7. Female subjects are pre-menarchal, or if of childbearing potential, are not pregnant or lactating or are post-menopausal.
8. Female subjects of childbearing potential must abide by the one of the following medically acceptable contraceptive measures: oral contraception pill, contraceptive injections, implants or patches, intrauterine device in place for at least three months or vasectomised partner or abstinence throughout the study.
9. Subject has a body weight ≥ 20 kg.
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E.4 | Principal exclusion criteria |
1. Subject has progressive or focal neurological disease (as determined by pre-existing brain imaging such as CT or MRI performed maximally five years before the screening visit), or clinically significant organic disease.
2. Subject has a history of, or results of clinical investigations (including EEG data) that are suggestive of partial seizures as defined by the ILAE, including generalised tonic clonic seizures which are suspected to be secondarily generalised.
3. Subjects with cryptogenic or symptomatic generalised epilepsy.
4. Subjects with psychogenic seizures.
5. Subject has a history of status epilepticus within a year of screening while complying with AEDs.
6. Subject has seizures that only occur in clustered patterns.
7. Subject has a history of renal calculi or renal insufficiency (above the upper normal limits of creatinine).
8. Subject has a known diagnosis of human immunodeficiency virus (HIV) or hepatitis B or C.
9. Subject had a predisposing condition that might interfere with absorption, distribution, or excretion of zonisamide.
10. Subject has a history of sensitivity to sulfonamide drugs or zonisamide and its excipients.
11. Subject has a recent history of excessive alcohol use or drug abuse.
12. Subject has a history of suicide attempt in the five years before the screening visit.
13. Subject has abnormal screening laboratory values that were clinically significant.
14. Subject has a history of demonstrated non-compliance with treatment or the subject or parent/caregiver can be reasonably expected not to be compliant with study procedures or to complete the study.
15. Subject has participated in a study of an investigational drug or device within 30 days prior to screening.
16. Subject has received previous treatment with zonisamide.
17. Subject is treated with ketogenic diet or vagus nerve stimulator.
18. Subject has a history of necessary treatment with rescue benzodiazepines which is foreseen to continue during the study. Rescue benzodiazepines will not be allowed in this study (stable dosing with a benzodiazepine as (one of the) baseline anti-epileptic drug(s) is allowed).
19. Current psychosis or moderate to severe depression, or use of anti-psychotic drugs, Monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, benzodiazepine or barbiturate treatment for disorders other than epilepsy, and stimulants (amphetamine derivatives) within 28 days before the screening visit.
20. Concomitant use of acetazolamide, carbonic anhydrase inhibitors such as topiramate and drugs with anticholinergic activity.
21. Concomitant use of felbamate or use of felbamate within two months prior to Visit 1.
22. Subject is not able to swallow capsules.
23. Subject is not in general good health as determined by medical history, physical exam and screening laboratory results.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy parameter is the proportion of responders assessed during the maintenance phase. A responder is defined as a subject with a decrease from baseline in PGTCS frequency of ≥ 50% (i.e. 28-day PGTC seizure frequency in period from Week 4 to the Week 16 visit compared to Week -8 to randomisation). |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 | 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
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Last visit of the last randomized patient |
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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 | 10 |
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 | 10 |