Clinical Trial Results:
A Double-blind Trial Comparing the Efficacy, Tolerability and Safety of Monotherapy Topiramate Versus Phenytoin in Subjects With Seizures Indicative of New Onset Epilepsy
Due to a system error, the data reported in v1 is not correct and has been removed from public view.
Summary
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EudraCT number |
2015-001222-42 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
06 Aug 2007
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Results information
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Results version number |
v2(current) |
This version publication date |
15 Jul 2016
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First version publication date |
31 Jul 2015
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Other versions |
v1 (removed from public view) |
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 |
CAPSS-272
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00210782 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Johnson & Johnson Pharmaceutical Research and Development
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Sponsor organisation address |
Archimedesweg 29, Leiden, Netherlands, 2333CM
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Public contact |
Clinical Registry Group-JB BV, Johnson & Johnson Pharmaceutical Research and Development, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group-JB BV, Johnson & Johnson Pharmaceutical Research and Development, ClinicalTrialsEU@its.jnj.com
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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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Aug 2007
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Aug 2007
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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 |
The objective of this study was to compare the effectiveness and safety of two treatment regimens, topiramate as compared to phenytoin, in preventing seizures in subjects with new-onset epilepsy who require rapid initiation of antiepileptic drug therapy. The purpose of the Open-Label Extension Phase of the study was to evaluate the efficacy, tolerability, and safety of monotherapy topiramate during the 12-week Open-Label Extension Phase in subjects who completed the Double-Blind Phase of the study or who exited the Double-Blind Phase of the study due to seizure.
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Protection of trial subjects |
Safety evaluations for this study included monitoring of adverse events, clinical laboratory tests (hematology, serum chemistry and urinalysis), vital sign measurements, physical and neurological examination.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
28 Jun 2004
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United States: 261
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Worldwide total number of subjects |
261
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EEA total number of subjects |
0
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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) |
29
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Adults (18-64 years) |
221
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From 65 to 84 years |
11
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Of the 261 subjects who were randomized into the study 133 subjects received topiramate and 128 received phenytoin. Overall, 217 subjects (83.1%) completed the Double-Blind Phase of the study. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Baseline 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 |
Investigator, Subject | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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Topiramate | |||||||||||||||||||||||||||
Arm description |
The initiation dose on Day 1 for topiramate-randomized subjects was 100 milligram (mg), administered orally as an initial dose of 50 mg of topiramate, followed by two successive doses of 25 mg each administered at 2-hour intervals. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
TOPAMAX
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Investigational medicinal product code |
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Other name |
TOPIRAMATE
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The initiation dose on Day 1 for topiramate-randomized subjects was 100 milligram (mg), administered orally as an initial dose of 50 mg of topiramate, followed by two successive doses of 25 mg each administered at 2-hour intervals.
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Arm title
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Phenytoin | |||||||||||||||||||||||||||
Arm description |
The initiation dose on Day 1 for phenytoin-randomized subjects was 1,000 mg, administered orally as an initial dose of 400 mg of phenytoin, followed by two successive doses of 300 mg each administered at 2-hour intervals. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
PHENYTEK
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Investigational medicinal product code |
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Other name |
PHENYTOIN SODIUM
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
The initiation dose on Day 1 for phenytoin-randomized subjects was 1,000 mg, administered orally as an initial dose of 400 mg of phenytoin, followed by two successive doses of 300 mg each administered at 2-hour intervals.
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Period 2
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Period 2 title |
Double Blind
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Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Investigator, Subject | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Topiramate | |||||||||||||||||||||||||||
Arm description |
The initiation dose on Day 1 for topiramate-randomized subjects was 100 milligram (mg), administered orally as an initial dose of 50 mg of topiramate, followed by two successive doses of 25 mg each administered at 2-hour intervals. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
TOPAMAX
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Investigational medicinal product code |
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Other name |
TOPIRAMATE
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The initiation dose on Day 1 for topiramate-randomized subjects was 100 milligram (mg), administered orally as an initial dose of 50 mg of topiramate, followed by two successive doses of 25 mg each administered at 2-hour intervals.
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Arm title
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Phenytoin | |||||||||||||||||||||||||||
Arm description |
The initiation dose on Day 1 for phenytoin-randomized subjects was 1,000 mg, administered orally as an initial dose of 400 mg of phenytoin, followed by two successive doses of 300 mg each administered at 2-hour intervals. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
PHENYTEK
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Investigational medicinal product code |
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Other name |
PHENYTOIN SODIUM
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
The initiation dose on Day 1 for phenytoin-randomized subjects was 1,000 mg, administered orally as an initial dose of 400 mg of phenytoin, followed by two successive doses of 300 mg each administered at 2-hour intervals.
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Baseline characteristics reporting groups [1]
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Reporting group title |
Topiramate
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Reporting group description |
The initiation dose on Day 1 for topiramate-randomized subjects was 100 milligram (mg), administered orally as an initial dose of 50 mg of topiramate, followed by two successive doses of 25 mg each administered at 2-hour intervals. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phenytoin
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Reporting group description |
The initiation dose on Day 1 for phenytoin-randomized subjects was 1,000 mg, administered orally as an initial dose of 400 mg of phenytoin, followed by two successive doses of 300 mg each administered at 2-hour intervals. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: Not all the enrolled subjects were treated with study drugs. As baseline only included treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period |
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Subject analysis sets
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Subject analysis set title |
Double Blind ITT (Intent-to-treat) Analysis Set - Topiramate
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
ITT Population is defined as all randomized subjects who received at least one dose of study drug and had at least one post-randomization efficacy measurement.
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Subject analysis set title |
Double Blind ITT (Intent-to-treat) Analysis Set - Phenytoin
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
ITT Population is defined as all randomized subjects who received at least one dose of study drug and had at least one post-randomization efficacy measurement.
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End points reporting groups
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Reporting group title |
Topiramate
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Reporting group description |
The initiation dose on Day 1 for topiramate-randomized subjects was 100 milligram (mg), administered orally as an initial dose of 50 mg of topiramate, followed by two successive doses of 25 mg each administered at 2-hour intervals. | ||
Reporting group title |
Phenytoin
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Reporting group description |
The initiation dose on Day 1 for phenytoin-randomized subjects was 1,000 mg, administered orally as an initial dose of 400 mg of phenytoin, followed by two successive doses of 300 mg each administered at 2-hour intervals. | ||
Reporting group title |
Topiramate
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Reporting group description |
The initiation dose on Day 1 for topiramate-randomized subjects was 100 milligram (mg), administered orally as an initial dose of 50 mg of topiramate, followed by two successive doses of 25 mg each administered at 2-hour intervals. | ||
Reporting group title |
Phenytoin
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Reporting group description |
The initiation dose on Day 1 for phenytoin-randomized subjects was 1,000 mg, administered orally as an initial dose of 400 mg of phenytoin, followed by two successive doses of 300 mg each administered at 2-hour intervals. | ||
Subject analysis set title |
Double Blind ITT (Intent-to-treat) Analysis Set - Topiramate
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
ITT Population is defined as all randomized subjects who received at least one dose of study drug and had at least one post-randomization efficacy measurement.
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Subject analysis set title |
Double Blind ITT (Intent-to-treat) Analysis Set - Phenytoin
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
ITT Population is defined as all randomized subjects who received at least one dose of study drug and had at least one post-randomization efficacy measurement.
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End point title |
Time to First Seizure During The Double Blind Phase | ||||||||||||
End point description |
Efficacy analysis set included all ITT subjects who received at least 1 dose of study drug and had at least 1 post-randomization efficacy measurement.
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End point type |
Primary
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End point timeframe |
Day 1 up to Day 28
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Statistical analysis title |
Wald Chi square | ||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with time to first seizure.
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.3661 | ||||||||||||
Method |
Wald Chi-squared | ||||||||||||
Confidence interval |
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End point title |
Effect of sex, age, Baseline Weight, Baseline Seizure Type, and Duration Since First Diagnosis of Epilepsy on the Time to Seizure | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Efficacy analysis set included all ITT subjects who received at least 1 dose of study drug and had at least 1 post-randomization efficacy measurement. No descriptive data was planned to be analyzed for this endpoint. Thus NA (Not applicable)= +/-9999
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End point type |
Secondary
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End point timeframe |
Day 1 up to Day 28
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Statistical analysis title |
Statistical Analysis 1: Wald Chi square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with sex.
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.8021 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 2: Wald Chi square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with age.
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.7616 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 3: Wald Chi square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with baseline weight
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.5147 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 4: Wald Chi square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with generalized tonic-clonic seizure.
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.9353 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 5: Wald Chi Square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with complex partial seizure.
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.063 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 6: Wald Chi Square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with simple partial seizure.
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.7094 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-square | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 7: Wald Chi Square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with absence seizure.
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.9899 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 8: Wald Chi Square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with myoclonic seizure.
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Comparison groups |
Topiramate v Phenytoin
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.5001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
Statistical Analysis 9: Wald Chi Square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with other seizure type.
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Comparison groups |
Topiramate v Phenytoin
|
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Number of subjects included in analysis |
254
|
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Analysis specification |
Pre-specified
|
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Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.9947 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 10: Wald Chi Square | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
Inferential Tests for treatment difference in time to first seizure by exiting seizure type during the double-blind phase was analyzed using Wald test from Cox proportional hazard model with duration since first diagnosis of epilepsy on the time to seizure.
|
||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
Topiramate v Phenytoin
|
||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
254
|
||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority | ||||||||||||||||||||||||||||||||||||||||||
P-value |
= 0.7131 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Wald Chi-squared | ||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|
||||||||||
End point title |
Proportion of Subjects who Were Seizure-Free at Day 28 | |||||||||
End point description |
Efficacy analysis set included all ITT subjects who received at least 1 dose of study drug and had at least 1 post-randomization efficacy measurement.
|
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End point type |
Secondary
|
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End point timeframe |
Day 28
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Time to First Seizure by Seizure Type | ||||||||||||||||||
End point description |
Time to first seizure by seizure type was calculated Kaplan-Meier estimates for the ITT Population for each treatment group. Efficacy analysis set included all ITT subjects who received at least 1 dose of study drug and had at least 1 post-randomization efficacy measurement.
|
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End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Day 1 up to Day 28
|
||||||||||||||||||
|
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Incidence of Seizures Observed During the Double Blind Phase | ||||||||||||||||||||||||
End point description |
The proportion of subjects who experienced GTC or complex partial seizures, GTC seizures, complex partial seizures and seizures of all types were observed during the double blind phase of the study. Efficacy analysis set included all ITT subjects who received at least 1 dose of study drug and had at least 1 post-randomization efficacy measurement.
|
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End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Day 1 up to Day 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
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Adverse events information
|
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Timeframe for reporting adverse events |
Day 1 up to Day 49
|
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
WHOART | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1992
|
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Reporting groups
|
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Reporting group title |
Topiramate
|
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Reporting group description |
Topiramate | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phenytoin
|
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Reporting group description |
Phenytoin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
27 Jun 2005 |
Amendment 1 provided specific criteria for acceptable benzodiazepine use, added text specifying visit windows, and provided details about follow-up for subjects who exited due to a complex partial or GTC seizure, about taper for subjects not entering the Open-Label Extension Phase, and about returned study drug. |
||
31 May 2006 |
Amendment 2 included the following changes: Change in the primary analysis model, allowing a decrease in the sample size from 310 subjects (155 per treatment group) to 262 subjects (131 per treatment group); change in primary efficacy analysis for the Double-Blind Phase from Kaplan-Meier estimates of the cumulative rate of time to the first seizure to a non-inferiority log-rank test for the equivalence of
2 seizure-free survival curves; allow subjects with a positive tetrahydrocannabinol (THC) at screening to enter the study, establishment of
independent data monitoring committee (IDMC), procedure to allow subjects to receive a prescription for topiramate at the end of the Open-Label Extension Phase, since topiramate had been approved for monotherapy. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |