| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Generalised Tonic Clonic Seizures |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 17.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10018101 |
| E.1.2 | Term | Generalised tonic-clonic seizures |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 |
To demonstrate superior efficacy of pregabalin compared to placebo for treatment of PGTC seizures as measured by the 28 day seizure rate.
Safety objective:
To assess the safety and tolerability of pregabalin relative to placebo in pediatric and adult subjects with PGTC seizures.
|
|
| E.2.2 | Secondary objectives of the trial |
| To demonstrate superior efficacy of pregabalin compared to placebo for PGTC seizures as determined by responder rate. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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/caregiver/legal representative/ has been informed of all pertinent aspects of the study. When there are 2 parents or 2 legal representatives/caregivers, consent should be obtained from both of the child’s parents/legal representatives/caregivers 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 caregiver(s) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male and female subjects 5 to 65 years of age inclusive on the date of the screening visit.
4. Diagnosis of epilepsy with seizures classified as PGTC seizures according to the International League Against Epilepsy (ILAE 2010) 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. Therefore, results should be sent to the Pfizer designated independent reviewer at least one week prior to randomization. Results must be consistent with the diagnosis of generalized epilepsy and must demonstrate that no abnormality is likely to be progressive.
- Confirmation of diagnosis by the Pfizer designated independent reviewer before randomization. All required diagnostic information should be sent to the reviewer as soon as possible, but no later than one week prior to randomization.
5. Must have at least 1 PGTC seizure in the 8 weeks prior to screening. Must have a minimum of 3 PGTC seizures during the 8-week baseline phase and at least 1 PGTC in each 4-week period of the baseline phase.
6. Currently receiving adequate and stable dosage of 1 to 3 anti-epileptic treatments (stable within 28 days of screening). Benzodiazepine medication used on a regular basis at a stable dosage will be considered 1 of the concurrent anti-epileptic treatments. A previously implanted vagus nerve stimulator (VNS) for the treatment of epilepsy is allowed and considered 1 of the 3 anti-epileptic treatments. A ketogenic diet is also allowed given that the diet is adhered to for the duration of the study but is not considered one of the three treatments.
7. A 12-lead ECG at screening without significant abnormal findings as determined by the investigator and confirmed by a central ECG reader.
8. Subjects and caregivers must be thought to be compliant in anticipation of study procedures and requirements and able to follow the investigator’s instructions. They must be able to visit the clinic on schedule and be both cooperative and reliable. Subjects and caregivers must be considered willing and able to monitor seizure rate and complete daily seizure and dosing diaries.
9. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 30 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
10. Female subjects who are considered not of childbearing potential must meet one of the following criteria:
1. Have undergone hysterectomy or bilateral oophorectomy;
2. Have medically confirmed ovarian failure; or
3. Are medically confirmed to be post-menopausal (ie, cessation of regular menses for at least 12 consecutive months
with no alternative pathological or physiological cause; laboratory confirmation (eg, FSH level) may be indicated when cessation of menses has been less than one year. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. A current diagnosis of febrile seizures, or seizures related to an ongoing acute medical illness. Exacerbation of PGTC’s due to fever is allowed; fever must have ended at least 60 days prior to Screening Visit.
2. Seizures classified as focal seizures (simple partial, complex partial, or partial becoming secondarily generalized). Note that the ILAE (ILAE 2010) proposed replacing the expression ‘‘secondarily generalized seizure’’ with “evolving to a bilateral, convulsive seizure (involving tonic, clonic, or tonic and clonic components).”
3. Status Epilepticus within 1 year prior to screening.
4. Lennox-Gastaut syndrome, infantile spasms, Benign Epilepsy with Centrotemporal Spikes (BECTS) and Dravet syndrome.
5. Seizures related to drugs, alcohol, or acute medical illness.
6. Any change in anti-epileptic treatment regimen (type of medication or dose; VNS alteration) within 28 days of the screening visit or during the baseline phase.
7. Progressive or potentially progressive structural CNS lesion or a progressive encephalopathy.
8. Progressive inborn errors of metabolism.
9. Subjects with a history of life-threatening neoplasms within 5 years prior to study entry, other than carcinoma in situ of the cervix or basal cell carcinoma of the skin.
10. Known or suspected chronic hematologic, hepatic or renal disease (AST and ALT above 3 times the upper limit of normal); or bilirubin, BUN, or creatinine above 2 times the upper limit of normal.
11. Estimated creatinine clearance (CLcr) <60 mL/min for subjects >= 17 years of age and <80 mL/min/1.73m2 (using age appropriate equations) for subjects <17 years of age.
12. Other severe acute or chronic medical or psychiatric conditions (e.g., major depressive disorder; bipolar disorder; schizophrenia or other psychoses) or laboratory abnormality that may increase the risk associated with trial participation or
investigational product 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 females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to use a highly effective method of contraceptionfor at least 30 days after the last dose of investigational product.
14. Taking any non-antiepileptic (non-AED) medication that would be anticipated to alter the effectiveness of the subject’s investigational product, response, seizure rate, or seizure characteristics. Medications to treat ADHD (eg, amphetamine,
methylphenidate, guanfacine, clonidine, and atomoxetine) will be allowed if the dose is stable and remains stable throughout the duration of the study.
15. Concomitant use of gabapentin, felbamate or vigabatrin is prohibited during the study.
16. Taking or have taken any other investigational drug within the last 30 days prior to screening.
17. Participation in any other studies within 30 days before the current study begins and/or during study participation.
18. Use of cocaine, phencyclidine (PCP), marijuana, or other illegal or illicit drugs is prohibited. Use of amphetamines, barbiturates, opiates, or benzodiazepines without a valid current prescription is prohibited.
19. Alcohol or substance abuse or dependence within the previous year.
20. History of lack of efficacy for treatment of epilepsy with pregabalin at presumed efficacious doses.
21. Known allergy or intolerance to pregabalin or its excipients or other alpha2-delta ligands (eg, gabapentin).
22. Prior participation in a pregabalin clinical trial for epilepsy.
23. Treatment with pregabalin for any reason within 60 days prior to screening.
24. Unwilling or unable to comply with the Life Style Guidelines.
25. Not reasonably expected to complete the trial.
26. Any subjects who are considered at risk of suicide or self-harm based upon any of the rating scale results (eg, PHQ-8, MINI KID, C-SSRS or the clinical judgment of the Investigator.
27. Subjects unable to tolerate oral medication.
28. Subjects whose parent(s)/legal representative(s)/caregiver(s) are investigational site staff members or subjects whose relatives are Pfizer employees directly involved in the conduct of the trial. |
|
| 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 PGTC seizures collected during the double-blind assessment phase. Results will be reported as “percent reduction in seizures” relative to placebo. The 28-day seizure rate will be calculated as follows for the double-blind assessment phase:
28-day seizure rate = # of seizures in the double-blind assessment phase of study/[# of days in period - # of missing diary days in period] x 28
When the log-transformation is used, the quantity “1” is added to the 28-day seizure rate for all subjects to account for any possible "0" seizure incidence. This will result in the following primary efficacy endpoint: loge (28-day seizure rate + 1).
The 28-day seizure rate for the baseline phase will be calculated similarly.
Safety Endpoints:
The evaluation of safety will include adverse event (AE) data (occurrence, nature, intensity, and relationship to study drug), suicidality assessments (as age appropriate), body weight, clinical laboratory data, and the results of physical examinations, vital
signs, neurological examinations, and electrocardiograms (ECGs).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Responder rate, defined as the proportion of subjects who had at least a 50% reduction in 28-day PGTC seizure rate during the double-blind assessment phase, as measured from baseline (data collected during the 8-week baseline phase). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 75 |
| 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 |
| China |
| Croatia |
| Czech Republic |
| Estonia |
| France |
| Greece |
| Hungary |
| India |
| Korea, Republic of |
| Lithuania |
| Malaysia |
| Netherlands |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| Completion of the taper phase of the last patient (LPLV) |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
Print
