| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034089 |
| E.1.2 | Term | Partial seizures NOS |
| E.1.2 | System Organ Class | 100000004852 |
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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 primary objective of this study is to evaluate the efficacy of 2 dose levels of pregabalin (Level 1: 2.5 mg/kg/day; maximum 150 mg day and Level 2: 10 mg/kg/day; maximum 600 mg day) compared to placebo as an adjunctive treatment in reducing the frequency of partial onset seizures in pediatric subjects 4 to 16 years of age. |
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| E.2.2 | Secondary objectives of the trial |
-To characterize the efficacy of pregabalin vs. placebo on the frequency of partial onset seizures as determined by responder rate in pediatric subjects 4 to 16 years of age.
-To assess the safety and tolerability of pregabalin in pediatric subjects 4 to 16 years
of age with partial onset seizures. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that the subject and/or parent/legally acceptable representative has been informed of all pertinent aspects of the study. When there are 2 parents or 2 legally acceptable representatives, consent should be obtained from both of the child’s parents/legal representatives if present at the meeting where the informed consent document is signed. Subject to local regulations whenever the minor is able to give assent, the minor’s assent must also be obtained.
2. Subjects and/or parent(s)/legally acceptable representative who are willing and able to
comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Subjects and/or parent(s)/legally acceptable representative must be considered willing and able to complete daily seizure diaries and monitor seizure frequency.
4. Male and female epilepsy subjects, 4 to 16 years of age inclusive on the date of the Screening Visit.
5. Diagnosis of epilepsy with partial onset seizures classified as simple partial, complex partial or partial becoming secondarily generalized, according to the International League Against Epilepsy (ILAE) Please see appendix 1 of the protocol for additional siezure type inclusions. Diagnosis must be established by:
- Subject’s history (eg, description of seizures excluding confounding disorders such as pseudoseizures, syncopes etc) family history and neurological exam.
- Subjects must have had a contrast enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain within 60 months of the Screening Visit and an EEG within 24 months of the screening visit. However, if clinical symptoms have emerged or a change in clinical status has
occurred such that an imaging study would be required, then a CT or MRI of the head should be performed regardless of the amount of time that has elapsed since the previous CT/MRI scan. Results must be available as soon as possible following screening and must be completed and reviewed prior to randomization. Imaging results must be consistent with the diagnosis of focal-onset epilepsy and must demonstrate that no abnormality is likely to be progressive
- Confirmation of diagnosis by independent reviewer before randomization.
6. Must have a partial onset seizure frequency of at least 3 seizures per 28-day period prior to screening. Must have a partial onset seizure frequency of ≥6 seizures and no
continuous 4 week seizure free period during the 8 week baseline phase prior to randomization.
7. Currently receiving a stable regimen of 1 to 3 antiepileptic treatments (stable within 28 days prior to screening). Benzodiazepine medication used on a regular basis at a stable dosage will be considered 1 of the concurrent antiepileptic treatments. A previously implanted Vagus Nerve Stimulator (VNS) for the treatment of epilepsy is allowed and will be considered one of the 3 antiepileptic treatments.
8. A 12-lead ECG at screening without significant abnormal findings as determined by
the investigator and confirmed by the Central ECG Reader. |
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| E.4 | Principal exclusion criteria |
1. Primary generalized seizures (including in the setting of co-existing partial onset seizures) which may include for example:
- Clonic, tonic and clonic-tonic seizures (note that partial onset seizures that become secondarily generalized are not exclusionary).
- Absence seizures.
- Infantile spasms.
- Myoclonic, myoclonic atonic, myoclonic tonic seizures.
2. Lennox-Gastaut syndrome, Benign Epilepsy with Centrotemporal Spikes (BECTS) and Dravet syndrome. 3. A current diagnosis of febrile seizures, or seizures related to an ongoing acute medical illness. 4. Exacerbation of POS due to fever occurring within 60 days of screening 5. Status epilepticus within 1 year prior to screening. 6. Seizures related to drugs, alcohol, or acute medical illness. 7. Any change in AED regimen (type of medication or dose) within 28 days of the Screening Visit or during the Baseline Phase. 8. Progressive structural CNS lesion or a progressive encephalopathy.
9. Progressive errors of metabolism. 10. Known or suspected chronic hematologic, hepatic or renal disease (AST and ALT above 3 times the upper limit of normal (ULN); or bilirubin, BUN, or creatinine above 2 times the ULN within the previous 6 months prior to screening). 11. Estimated creatinine clearance (ClCR) <80 mL/min/1.73 m2. 12. Other severe acute or chronic medical or psychiatric condition (eg, current major depressive disorder; schizophrenia or other psychoses) or laboratory abnormality that may increase the risk associated with study participation or study medication administration or may interfere with the interpretation of the study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. 13. Pregnant or nursing females (females who are menarchal must have a negative pregnancy test); menarchal females of childbearing potential who are unwilling or unable to use an acceptable method of contraception from at least 14 days prior to the first dose of study medication until completion of the study.
14. Taking any non-antiepileptic (non-AED) medication that could alter the effectiveness of the subject’s medication, response, seizure frequency or characteristics. Medications for Attention Deficit/Hyperactivity Disorder will be permitted if medication doses are stable and remain so throughout the duration of study. A
ketogenic diet will also be allowed given that the diet is adhered to for the duration of the study. 15. The concomitant use of gabapentin is prohibited. 16. Use of cocaine, phencyclidine (PCP), or other illegal or illicit drugs is prohibited. Use of amphetamines, barbiturates, opiates, or benzodiazepines without a valid current prescription is prohibited.
17. History of lack of efficacy for treatment of epilepsy with pregabalin at presumed efficacious doses. 18. Known allergy or intolerance to pregabalin or its excipients, including lactose, or other α2δ ligands (eg, gabapentin). 19. Prior participation in a pregabalin clinical trial.
20. Treatment with pregabalin for any reason within 60 days prior to screening. 21. History of sensitivity to heparin or heparin induced thrombocytopenia. 22. Unwilling or unable to comply with the Life Style Guidelines. 23. Not reasonably expected to complete the trial.
24. Participation in other clinical studies within 30 days before the current study begins and/or during study participation. 25. Subjects whose parents/legally acceptable representatives are investigational site staff members or subjects whose parents / legally acceptable representative are Pfizer employees directly involved in the conduct of the trial. 26. Any subjects considered at risk of suicide based on the MINI-KID and C-SSRS Lifetime (subjects age ≥6 years) or CBCL (subjects <6 years) or likely to self harm based on clinical judgment. Based on the judgment of the investigator, a subject should be excluded or a risk assessment should be done by a qualified mental health
professional based on responses to assessment of suicidal ideation and behaviour and if the subject has had suicidal ideation in the last 6 months prior to screening, suicidal behaviors or attempts within the past year or current major psychiatric disorders that are not explicitly permitted in the inclusion/exclusion criteria. A risk assessment should also be performed in any child <6 years of age who has ever exhibited any potentially self-injurious or high-risk behaviors such as hurting himself or herself, or unusual behaviors such as running into traffic or using items as weapons (eg, knife, bat). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the log-transformed (loge) 28-day seizure rate for all partial onset seizures collected during the 12 week double-blind treatment phase. Data from the 1-week double blind taper phase will not be used in the efficacy analyses. Results will be reported as “percent reduction in seizures” relative to placebo. For calculation see protocol. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
| Responder Rate, defined as subjects who have a ≥50% reduction in partial seizure rate from baseline during the double-blind treatment phase. Subjects meeting this criterion will be considered a favorable outcome. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 44 |
| 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 | No |
| 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 |
| Austria |
| Belgium |
| Bulgaria |
| Croatia |
| Czech Republic |
| Estonia |
| Finland |
| France |
| Greece |
| Guatemala |
| Hungary |
| India |
| Italy |
| Korea, Republic of |
| Lithuania |
| Malaysia |
| Netherlands |
| Panama |
| Philippines |
| Poland |
| Romania |
| Singapore |
| Sweden |
| Turkey |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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