| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adjunctive (add on) therapy for adult subjects with partial onset seizures with or without secondary generalization. |
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| E.1.1.1 | Medical condition in easily understood language |
| Adult subjects with partial onset seizures |
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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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048674 |
| E.1.2 | Term | Partial seizures with secondary generalization |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
| To evaluate the efficacy of pregabalin CR administered once daily as compared to placebo as adjunctive treatment in reducing the frequency of seizures in partial onset epilepsy, utilizing the endpoint of Log transformed 28 day partial seizure rate, in adult subjects with partial onset seizures. |
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| E.2.2 | Secondary objectives of the trial |
•To characterize the efficacy of pregabalin CR vs. placebo on the frequency of partial seizures as determined by responder rate, and percentage change from baseline on 28 day partial seizure rates.
•To characterize the effects pregabalin CR vs. placebo on measures of anxiety, sleep disturbance, and treatment satisfaction.
•To assess the safety and tolerability of pregabalin CR in adult subjects with partial onset seizures.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of and agrees to all pertinent aspects of the study. 2.Otherwise healthy men or non-pregnant, non-lactating women aged 18 years or older. Men and women must use an acceptable method of contraception as detailed in the lifestyle guidelines section. Women must have a confirmed negative pregnancy test prior to enrollment. 3.Diagnosis of epilepsy with partial onset seizures (as defined in the International League Against Epilepsy Classification of Seizures 1997, 2010, Appendix 3). Partial onset seizures may be simple or complex, with or without evolution into a bilateral, convulsive seizure (previously termed secondary generalization). In addition to this, for determination of eligibility the following definitions cross from the ILAE of 1997 to those of 2010. Seizures without impairment of consciousness or awareness must have an observable motor component and are termed "simple partial seizures". When there is impairment in consciousness or awareness, the 1997 term "complex partial seizures" is applied. Diagnosis must be established by subject’s history (eg, the phenomenology (description) of the seizures, excluding confounding disorders such as pseudo-seizures, syncopes, etc.), family history, neurological examination, the results of EEG testing done within 2 years prior to study participation and the results of brain imaging (if none available, must be obtained during the 8 week screening
pre-randomization period and be available at V3). Results must be consistent with
the diagnosis of focal-onset epilepsy. Simple partial seizures without a visible motor
component (ie, lacking visible movements during the seizure) are not counted toward
eligibility. 4.Subjects must have a minimum of 3 partial seizures during the 1 month (28 days) prior to the screening visit for entry into baseline observation phase and at least 6 partial seizures during the 8 week baseline observation phase with no 28 day period free of partial seizures. A caregiver or witness must be with the Subject for a sufficient duration to accurately chronicle the occurrence of seizures, if appropriate given the subject's seizure types. These seizures must be documented properly in the subject's seizure diary. Simple partial seizures without a visible motor component (ie, lacking visible movements during the seizure) will be recorded, but are not counted toward eligibility. 5.Subjects who currently take 1 to 3 AEDs that are at stable dosages, within clinically acceptable therapeutic range or within the range of tolerability of the subject, and who have taken at least 2 prior (or ongoing) AEDs. For two weeks prior to screening and during study participation subjects must remain on stable dosages (same dosage throughout the study: at screening, the baseline observation period, and the double blind maintenance period) of 1 to 3 AEDs concomitantly throughout the trial. Other AEDs must be discontinued completely at least 2 weeks prior to screening (this does not include rescue medication). 6.No progressive structural abnormality on a head CT scan (with contrast) or MRI within 2 years prior to study participation (if none available, must be obtained and evaluated prior to randomization). 7.Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Subjects (or primary caregiver/guardian) must be thought to be able to document the occurrence of seizures, along with a record of study drug doses taken, in a daily diary. |
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1.A progressive cause of seizures or a reversible cause of seizures 2.Subjects who only experience simple partial seizures without a motor component in the 8 week baseline seizure record phase. 3.Primary generalized seizures (including in setting of co-existing partial-onset epilepsy), which include for example: Clonic, tonic & tonic clonic seizures (secondarily generalized seizures are permitted); Absence seizures; Myoclonic, Myoclonic atonic, Myoclonic tonic seizures; Reflex epilepsies. 4.Lennox Gastaut Syndrome. 5.Status epilepticus within 1 year prior to screening. 6.Subjects with other neurologic illness that could impair endpoint assessment. 7.A significant psychiatric disorder, recurrent episodes of severe depression (any pharmacologic treatment or hospitalization for illness within 1 year prior to Screening) or subjects with serious suicidal risk. Subjects with mild, chronic depression without recent hospitalization who are being maintained on a stable dose of single antidepressant are acceptable. 8.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality (including, for example, platelet count <100 x 10 to the power of 9/L; white blood cell (WBC) count <2.5 x 10 to the power of 9/L; neutrophil count <1.5 x 10 to the power of 9/L) that may increase risk associated with study participation or investigational product administration or may interfere with interpretation of study results and, in the judgment of investigator, would make the subject inappropriate for entry into this study.9.Subjects with any clinically unstable medical conditions including: cardiovascular, hematological, autoimmune, endocrine, renal, hepatic, retinal & gastrointestinal disease. 10.Any subjects who are considered at risk of suicide based on Sheehan Suicidality Tracking Scale or PHQ 8 or likely to self harm, based on clinical judgment. Based on judgment of the investigator, a subject should be excluded or a risk assessment should be done by a qualified mental health professional if the subject has had suicidal ideation in past 6 months, suicidal behaviors or attempts in the past year, or current major psychiatric disorders that are not explicitly permitted in inclusion/exclusion criteria. 11.Screening 12 lead ECG with clinically significant abnormalities prior to andomization.12.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. 13.Subjects with active gastrointestinal (GI) disease including any GI surgery that in the opinion of the investigator or Sponsor would interfere with absorption of study medication. 14.Subjects with difficulties swallowing tablets or unable to tolerate oral medication.
15.Estimated creatinine clearance (CLcr) <60 mL/min (using Cockcroft Gault equation).Subjects who have estimated CLcr <60 mL/min by this screening method may have their CLcr measured, at investigator’s discretion, with a 24 hour urine collection performed at the central laboratory. If this 24 hour urine CLcr is >60 mL/min, the subject is not excluded. 16.Alcohol or substance abuse or dependence within the previous year. 17.Use of prohibited medications as listed in protocol in absence of an washout phase, or likelihood of requiring treatment during study period with medications not permitted by the protocol.18.Subjects who are not suitable to be treated with pregabalin according to respective local labeling. 19.Participation in any clinical trial within 30 days prior to screening and/or during study participation. 20.History of lack of efficacy for treatment of epilepsy with pregabalin.21. Hyper-sensitivity or intolerance to pregabalin or other α2δ ligands (eg, gabapentin). 22.Prior participation in pregabalin clinical trial for epilepsy. 23.Treatment with pregabalin for any reason in 60 days prior to screening or during the trial. 24.Any concomitant medication that could alter effectiveness of study drug 25.Clinically significant liver disease which may prevent subject from completing the study or an elevation in either bilirubin, aspartate aminotransferase or alanine aminotransferase of greater than 3 times the maximum value of laboratory assay normal range.Laboratory assays may be repeated once during baseline observation period, to confirm acceptability /unacceptability of any subject. 26.Female subjects who are pregnant, nursing or intend to become pregnant during course of the study. Men & women of reproductive potential who are unwilling or unable to use adequate contraception to prevent pregnancy during treatment and for 30 days after discontinuing study treatment. 27.Use of cocaine, phencyclidine or other illegal or illicit drugs is prohibited. Use of amphetamines, barbiturates, opiates or benzodiazepines, without a valid current prescription is prohibited. |
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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 double-blind maintenance treatment phase. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Timepoints are Visit 1 (Week - 8) to Visit 7 (Week 14), where seizure information is captured daily on a diary. |
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| E.5.2 | Secondary end point(s) |
- Responder rate (proportion of subjects who have a 50% reduction in partial seizure rate from baseline during the double-blind maintenance treatment phase compared to the 8-week baseline (screening) seizure period).
- The percentage change from baseline in 28-day partial seizure rates during the double-blind maintenance treatment phase.
- Frequency of secondary generalized tonic-clonic seizures (SGTC).
- Log-transformed 28-day SGTC rate for all SGTCs collected during the double-blind maintenance treatment phase.
- SGTC responder rate.
- Changes from baseline in the anxiety and depression scores of the Hospital Anxiety and Depression Scale (HADS) scores.
- Change from baseline in Medical Outcomes Study-Sleep Scale (MOS-Sleep Scale) domain scores.
- Global scores on the patient-rated Benefit, Satisfaction, and Willingness to Continue Measure (BSW). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints utilize the seizure diary and thus the same timepoints as the primary endpoint. Timepoints are Visit 1 (Week - 8) to Visit 7 (Week 14), where seizure information is captured daily on a diary. |
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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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Bosnia and Herzegovina |
| Bulgaria |
| China |
| Croatia |
| Czech Republic |
| Estonia |
| Finland |
| Germany |
| Hong Kong |
| Hungary |
| India |
| Malaysia |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Singapore |
| South Africa |
| Thailand |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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