Clinical Trial Results:
A Double-blind, Randomized, Placebo-controlled, Multicenter, Parallel-group Study with an Open-label Extension Phase to Evaluate the Efficacy and Safety of Adjunctive Perampanel in Primary Generalized Tonic-Clonic Seizures
Summary
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EudraCT number |
2011-000265-12 |
Trial protocol |
HU DE LV GR AT CZ NL PL LT |
Global end of trial date |
13 Nov 2015
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Results information
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Results version number |
v2(current) |
This version publication date |
10 Nov 2016
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First version publication date |
22 Jun 2016
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
E2007-G000-332
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01393743 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Eisai
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Sponsor organisation address |
100 Tice Boulevard, Woodcliff Lake, United States, 07677
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Public contact |
Medical Information, Eisai Limited, 44 2086001400, LMedInfo@eisai.net
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Scientific contact |
Medical Information, Eisai Limited, 44 2086001400, LMedInfo@eisai.net
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
13 Nov 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 May 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
13 Nov 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To demonstrate the efficacy of adjunctive perampanel therapy, compared to placebo, on primary generalized tonic-clonic (PGTC) seizures
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Protection of trial subjects |
This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following:
- Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008)
- International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal
Products, Committee for Proprietary Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for Human Use
- Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312
- European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states.
- Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Jul 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 6
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Country: Number of subjects enrolled |
Austria: 1
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Country: Number of subjects enrolled |
Czech Republic: 5
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Greece: 2
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Country: Number of subjects enrolled |
Latvia: 8
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Country: Number of subjects enrolled |
Lithuania: 4
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Country: Number of subjects enrolled |
Australia: 17
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Country: Number of subjects enrolled |
China: 36
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Country: Number of subjects enrolled |
India: 13
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Country: Number of subjects enrolled |
Israel: 3
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Country: Number of subjects enrolled |
Japan: 11
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Country: Number of subjects enrolled |
Korea, Republic of: 7
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Country: Number of subjects enrolled |
Serbia: 2
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Country: Number of subjects enrolled |
United States: 39
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Worldwide total number of subjects |
163
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EEA total number of subjects |
35
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
22
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Adults (18-64 years) |
140
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
Out of 138 participants who entered the extension phase, 78 participants completed and 60 participants discontinued the extension phase. Reasons for participant discontinuation was as follows: adverse event (12); lost to follow-up (2); participant choice (16); lack of efficacy (7); withdrawal of consent (8); pregnancy (1); and not specified (14). | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Of the 307 participants who were screened, 143 participants were screen failures and 164 participants were eligible to continue in the study but 1 participant withdrew from the perampanel group prior to receiving treatment. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Core Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||
Blinding implementation details |
Everyone in the Core Study took a total of 6 tablets of study drug, (combination of placebo alone or active drug plus placebo) in order to maintain the blind during the open-label Extension Blinded Conversion Period, which allowed participants to titrate a total daily dose of 12 mg (2 mg x 6 tablets). Participants whose dose was reduced due to intolerable adverse events was allocated a different kit that contained more placebo tablets in order to maintain the same total number of tablets (n=6).
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo (Core Study) | ||||||||||||||||||||||||
Arm description |
Participants received 6 tablets of perampanel matched placebo, once a day, before bedtime and with food. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received 6 tablets of perampanel-matched placebo, once a day, before bedtime and with food.
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Arm title
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Perampanel (Core Study) | ||||||||||||||||||||||||
Arm description |
Participants received 6 tablets (initially,1 tablet of 2 mg perampanel plus 5 tablets of perampanel matched placebo) and up-titrated weekly in 2 mg increments to a target dose range of 8 mg per day maintaining the blind with administration of 6 tablets per day of either perampanel/perampanel matched placebo. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Perampanel
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Investigational medicinal product code |
E2007
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received 6 tablets (initially ,1 tablet of 2 mg perampanel plus 5 tablets of perampanel matched placebo) and up-titrated weekly in 2 mg increments to a target dose range of 8 mg per day maintaining the blind with administration of 6 tablets per day of either perampanel/perampanel matched placebo.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo (Core Study)
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Reporting group description |
Participants received 6 tablets of perampanel matched placebo, once a day, before bedtime and with food. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Perampanel (Core Study)
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Reporting group description |
Participants received 6 tablets (initially,1 tablet of 2 mg perampanel plus 5 tablets of perampanel matched placebo) and up-titrated weekly in 2 mg increments to a target dose range of 8 mg per day maintaining the blind with administration of 6 tablets per day of either perampanel/perampanel matched placebo. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Perampanel Extension Phase
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Eligible participants from the Core Study had the option of entering into the Extension Phase. A total of 138 participants entered into the Extension Phase, 70 participants from the placebo arm of the Core Study and 68 participants from the perampanel arm of the Core Study. The Extension Phase Full Analysis Set (FAS) included all participants who were eligible to participate in the Extension Phase, received at least 1 dose of study drug in this phase, and had baseline seizure frequency data and at least 1 observation of valid seizure diary data during study drug treatment duration.
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Subject analysis set title |
Perampanel Extension Phase PGTC Seizures
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The median percent change from the Pre-perampanel baseline in PGTC seizure frequency per 28 days by 13-week intervals through greater than or equal to Week 144.
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Subject analysis set title |
Perampanel Extension Phase All Seizures
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The median percent change from the Pre-perampanel baseline in the seizure frequency per 28 days of all seizures by 13-week intervals through greater than or equal to Week 144.
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End points reporting groups
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Reporting group title |
Placebo (Core Study)
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Reporting group description |
Participants received 6 tablets of perampanel matched placebo, once a day, before bedtime and with food. | ||
Reporting group title |
Perampanel (Core Study)
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Reporting group description |
Participants received 6 tablets (initially,1 tablet of 2 mg perampanel plus 5 tablets of perampanel matched placebo) and up-titrated weekly in 2 mg increments to a target dose range of 8 mg per day maintaining the blind with administration of 6 tablets per day of either perampanel/perampanel matched placebo. | ||
Subject analysis set title |
Perampanel Extension Phase
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Eligible participants from the Core Study had the option of entering into the Extension Phase. A total of 138 participants entered into the Extension Phase, 70 participants from the placebo arm of the Core Study and 68 participants from the perampanel arm of the Core Study. The Extension Phase Full Analysis Set (FAS) included all participants who were eligible to participate in the Extension Phase, received at least 1 dose of study drug in this phase, and had baseline seizure frequency data and at least 1 observation of valid seizure diary data during study drug treatment duration.
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Subject analysis set title |
Perampanel Extension Phase PGTC Seizures
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The median percent change from the Pre-perampanel baseline in PGTC seizure frequency per 28 days by 13-week intervals through greater than or equal to Week 144.
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Subject analysis set title |
Perampanel Extension Phase All Seizures
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The median percent change from the Pre-perampanel baseline in the seizure frequency per 28 days of all seizures by 13-week intervals through greater than or equal to Week 144.
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End point title |
Median Percent Change in Primary Generalized Tonic Clonic Seizure Frequency (PGTC) Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | ||||||||||||
End point description |
Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days (as determined from participant diaries) was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change from baseline in PGTC seizure was analyzed over the Titration and Maintenance Periods combined, while baseline was defined as seizure frequency per 28 days based on all valid diary data during the Prerandomization Phase.
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End point type |
Primary
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End point timeframe |
Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
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Statistical analysis title |
Median Difference to Placebo | ||||||||||||
Statistical analysis description |
The median difference to placebo and the 95% confidence interval are based on the Hodges-Lehmann method.
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Comparison groups |
Placebo (Core Study) v Perampanel (Core Study)
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Number of subjects included in analysis |
162
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [1] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
-30.81
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-45.49 | ||||||||||||
upper limit |
-15.244 | ||||||||||||
Notes [1] - The P-value is based on a rank analysis of covariance with treatment and pooled country as factors, and prerandomization seizure frequency as a covariate. |
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End point title |
50% Responder Rate for Primary Generalized Tonic Clonic Seizure During Maintenance-LOCF - (for Core Study) | ||||||||||||
End point description |
A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance-last observation carried forward (LOCF) from prerandomization. The data was presented as the percentage of participants.
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End point type |
Primary
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End point timeframe |
Baseline (4 or 8 weeks) and Maintenance (13 weeks)
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Statistical analysis title |
P Value Compared to Placebo | ||||||||||||
Statistical analysis description |
The P value is based on non-missing values and is from a Cochran-Mantel-Haenszel test stratified by pooled country.
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Comparison groups |
Perampanel (Core Study) v Placebo (Core Study)
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Number of subjects included in analysis |
162
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0019 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
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End point title |
50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency per 28 days Relative to the Core Study Prerandomization Phase – (for Extension Phase) [2] | ||||||||||||||||||||||||||||
End point description |
Responder rate was defined as the percentage of participants who experienced a 50% or greater reduction in PGTC and total seizure frequency during treatment per 28 days relative to baseline (responder). Week 1 began on the date of first dose of the perampanel treatment regardless of whether it occurred in the Core Study or Extension Phase and continued to and included the date of the last dose of perampanel in the Extension Phase. For any given analysis window and seizure type(s), a 50% response from Core Study Prerandomization is a participant whose seizure frequency per 28 days for that seizure type(s) during that analysis window is 50% to 100% lower than his or her Core Study Prerandomization baseline seizure frequency per 28 days for that same seizure type(s). In Part B of the Extension Phase (after Visit 15), the seizure diary is only completed for days on which a seizure occurred and missing days were imputed as non-seizure days.
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End point type |
Primary
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End point timeframe |
Week 1 of perampanel treatment to date of last dose of perampanel in the Extension Phase
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistics were not calculated for this endpoint. |
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No statistical analyses for this end point |
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End point title |
50% Responder Rate for All Seizures During Maintenance-LOCF - (for Core Study) | ||||||||||||
End point description |
All seizures included PGTC, myoclonic, absence and all other seizures that occur during the study. A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance- LOCF from prerandomization. The data was presented as percentage of participants.
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End point type |
Secondary
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End point timeframe |
Baseline (4 or 8 weeks) and Maintenance (13 weeks)
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Statistical analysis title |
P value compared to placebo | ||||||||||||
Statistical analysis description |
The P value is based on non-missing values and is from a Cochran-Mantel-Haenszel test stratified by pooled country.
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Comparison groups |
Placebo (Core Study) v Perampanel (Core Study)
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Number of subjects included in analysis |
162
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1826 | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Confidence interval |
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End point title |
Median Percent Change in all Seizure Frequency per 28 days during the Titration and Maintenance Periods (combined) Relative to Baseline (Prerandomization) - (for Core Study) | ||||||||||||
End point description |
Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change in seizure frequency relative to baseline (prerandomization) for all seizures (PGTC, myoclonic, absence and all other seizures that occur during the study) per 28 days during the Titration and Maintenance Periods combined was analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
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Statistical analysis title |
Median Difference to Placebo | ||||||||||||
Statistical analysis description |
The median difference to placebo and the 95% confidence interval are based on the Hodges-Lehmann method.
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Comparison groups |
Perampanel (Core Study) v Placebo (Core Study)
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Number of subjects included in analysis |
162
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0018 [3] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
-23.45
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-40.668 | ||||||||||||
upper limit |
-8.518 | ||||||||||||
Notes [3] - The P value is based on a rank analysis of covariance with treatment and pooled country as factors, and prerandomization seizure frequency as a covariate. |
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End point title |
Median Percent Change in Primary Generalized Seizure Subtype Frequency per 28 days during the Titration and Maintenance Periods (combined) Relative to Baseline (Prerandomization) - (for Core Study) | ||||||||||||||||||
End point description |
Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change in seizure frequency relative to baseline (prerandomization) for primary generalized seizure subtype (myoclonic and absence) per 28 days during the Titration and Maintenance Periods combined was analyzed.
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End point type |
Secondary
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End point timeframe |
Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
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Statistical analysis title |
Median Difference to Placebo for Absence Seizures | ||||||||||||||||||
Statistical analysis description |
The median difference to placebo and the 95% confidence interval are based on the Hodges-Lehmann method.
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Comparison groups |
Placebo (Core Study) v Perampanel (Core Study)
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Number of subjects included in analysis |
162
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.3478 [4] | ||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||||
Point estimate |
-12.25
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-53.054 | ||||||||||||||||||
upper limit |
26.989 | ||||||||||||||||||
Notes [4] - The P value is based on a rank analysis of covariance with treatment and pooled country as factors, and prerandomization seizure frequency as a covariate. |
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Statistical analysis title |
Median Difference to Placebo for Myoclonic Seizure | ||||||||||||||||||
Statistical analysis description |
The median difference to placebo and the 95% confidence interval are based on the Hodges-Lehmann method.
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Comparison groups |
Placebo (Core Study) v Perampanel (Core Study)
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Number of subjects included in analysis |
162
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.61 | ||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||||
Point estimate |
24.87
|
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Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
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lower limit |
-15.338 | ||||||||||||||||||
upper limit |
59.938 |
|
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End point title |
50% Responder Rate for Primary Generalized Seizure Subtype During Maintenance - LOCF - (for Core Study) | ||||||||||||||||||
End point description |
Primary generalized seizure subtype included absence and myoclonic seizures. A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance - (last observation carried forward LOCF) from prerandomization. The data was presented as the percentage of participants.
|
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End point type |
Secondary
|
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End point timeframe |
Baseline (4 or 8 weeks) and Maintenance (13 weeks)
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|
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Statistical analysis title |
P Value Compared to Placebo for Absence Seizures | ||||||||||||||||||
Statistical analysis description |
The P value is based on non-missing values and is from a Cochran-Mantel-Haenszel test stratified by pooled country.
|
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Comparison groups |
Placebo (Core Study) v Perampanel (Core Study)
|
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Number of subjects included in analysis |
162
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
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Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.4653 | ||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||
Confidence interval |
|||||||||||||||||||
Statistical analysis title |
P Value Compared to Placebo for Myoclonic Seizures | ||||||||||||||||||
Statistical analysis description |
The P value is based on non-missing values and is from a Cochran-Mantel-Haenszel test stratified by pooled country.
|
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Comparison groups |
Placebo (Core Study) v Perampanel (Core Study)
|
||||||||||||||||||
Number of subjects included in analysis |
162
|
||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||
P-value |
= 0.3694 | ||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||
Confidence interval |
|
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End point title |
Percent Change from Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency per 28 Days - (for Extension Phase) | ||||||||||||||||||||||||||||||
End point description |
Week 1 began on the date of first dose of the perampanel treatment regardless of whether it occurred in the Core Study or Extension Phase and continued to and included the date of the last dose of perampanel in the Extension Phase. For any given analysis window and seizure type(s), a 50% responder from Core Study Randomization is a participant whose seizure frequency per 28 days for that seizure type(s) during that analysis window is 50% to 100% lower than his or her Core Study Prerandomization baseline seizure frequency per 28 days for that same seizure type(s). In Part B of the Extension Phase (after Visit 15), the seizure diary is only completed for days on which a seizure occurred and missing days were imputed as non-seizure days.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Date of first dose of study drug to date of last dose of study drug in the Extension Phase
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
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End point title |
Summary of Percent Change from Pre-Perampanel Baseline in Seizure Frequency per 28 Days - (for Extension Phase) | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Efficacy assessments included seizure counts from participant diaries. The percent change in seizure frequency was assessed during the perampanel treatment duration, with the pre-perampanel baseline being used for evaluating the change. The pre-perampanel baseline was defined as follows: 1) for all participants who had been assigned to placebo treatment in the Core Study, the pre-perampanel baseline was computed from all valid seizure diary data during the Core Study, and 2) for participants who had been assigned to perampanel in the Core Study, the pre-perampanel baseline was computed from all valid seizure diary data during the Prerandomization Phase plus the 4 weeks prior to the Prerandomization Phase of the Core Study. The perampanel treatment duration consisted of: 1) the Randomization Phase of the Core Study plus the Extension Phase for participants assigned to perampanel in the Core Study, and 2) the Extension Phase for participants assigned to placebo in the Core Study.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Weeks: 1 to 13, 14 to 26, 27 to 39, 40 to 52, 53 to 65, 66 to 78, 79 to 91, 92 to 104, 105 to 117, 118 to 130, 131 to 143, greater than or equal to 144
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Number of Participants with Treatment Emergent Adverse events and serious adverse events as a measure of safety and tolerability of perampanel in subjects with inadequately controlled PGTC seizures - (for Core Study) | ||||||||||||||||||
End point description |
An Adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered an investigational product. A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening (i.e., the subject was at immediate risk of death from the AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect (in the child of a subject who was exposed to the study drug). In this study, treatment emergent adverse events (TEAEs) (defined as an AE that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication) were assessed.
|
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End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
For each participant, from the first treatment dose till 30 days after the last dose or up to 21 weeks for core study and 142 weeks for extension phase.
|
||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
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Adverse events information
|
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Timeframe for reporting adverse events |
From the date of first dose of perampanel up to 30 days after the last dose, or up to approximately 163 weeks total.
|
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Adverse event reporting additional description |
Treatment-emergent Adverse Events (TEAEs) included AEs that occurred from the first dose of perampanel (in Core Study or Extension Phase) to 30 days after the last dose of perampanel, or that were present before the first day of perampanel administration but worsened in severity during the study. TEAEs are reported in the Safety Section.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
|
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Reporting group title |
Placebo (Core Study)
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Reporting group description |
Participants received 6 tablets of perampanel matched placebo, once a day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Perampanel (Extension Phase)
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Reporting group description |
The Extension Phase had two parts: Part A (6-week blinded Conversion Period plus a 32-week Maintenance Period) and Part B (maximum of 104-week Maintenance Period). Part A: Participants who received placebo in the Core Study were started on blinded oral perampanel (2 mg/day) and were up-titrated weekly in 2-mg increments to the optimal dose per investigator's discretion. Participants who were assigned to the perampanel arm in the Core Study continued to receive blinded perampanel once daily at the dose received during the Maintenance Period of the Core Study. Conversion Period: dose adjustments could be made at the investigator’s discretion. Part B: Participants were unblinded to study treatment and remained on the optimal perampanel dose established during the blinded Conversion Period (Part A). Dose adjustment in 2-mg increments (upwards or downwards) was allowed at the investigator's discretion. The maximum dose of perampanel allowed during the Extension Phase was 12 mg/day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Perampanel (Core Study)
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Reporting group description |
Participants received 6 tablets (initially ,1 tablet of 2 mg perampanel plus 5 tablets of perampanel matched placebo) and up-titrated weekly in 2 mg increments to a target dose range of 8 mg per day maintaining the blind with administration of 6 tablets per day of either perampanel/perampanel matched placebo. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
27 Oct 2011 |
• Clarified age level per health authority request to postpone recruitment of adolescent
subjects until safety data are available from the ongoing pediatric study.
• Evidence of active hepatic disease was added as an exclusion criterion per health
authority request.
• The Conversion Period was extended to eliminate potential unblinding.
• Increased the number of PGTC seizures (from ≥2 to ≥3) required during the 8-week
Baseline Period.
• Added prohibited medications to exclusion criteria to meet health authority requirements. |
||
12 Apr 2012 |
• Study duration was extended by 52 weeks to provide subjects the option to continue
accessing perampanel treatment if they are benefiting from the study drug; Extension
Phase was split into Part A and Part B.
• To guarantee uninterrupted treatment to those subjects who benefit from perampanel,
stipulated treatment until perampanel became commercially available.
• Increased the maximum number of AEDs allowed to 3 to align with patient population
targeted by this protocol, based on feedback from Key Opinion Leaders.
• Exclusion of subjects aged ≥65 years for India per the request of the Drug Controller
General of India.
• Increased the number of sites changed to 95 to ensure target recruitment was met in a
timely fashion.
• Addition of QOLIE-31-P and HCRU to demonstrate that improving the seizure frequency
impacts quality of life of these subjects, including visits to hospitals. |
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15 Nov 2013 |
• Extension Phase Part B extended by 52 weeks to provide continued treatment until
efficacy and safety results in this indication become available.
• Specified an end of treatment visit for subjects who had at least 52 weeks of treatment in
the Extension Phase.
• Stipulated explicitly, the termination of the Extension Phase upon commercial
availability of perampanel or if a positive risk-benefit assessment in this indication was
not demonstrated.
• Added decision points for subjects’ continued participation after completion of Extension
Part A. As an added safety measure a total of 52 weeks exposure to perampanel was to
be achieved before extended treatment is initiated. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |