Clinical Trial Results:
A multi-center, double-blind, historical control, randomized conversion to monotherapy study with Keppra XR for treatment of partial onset seizures
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Summary
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EudraCT number |
2007-000897-21 |
Trial protocol |
PL |
Global end of trial date |
14 Sep 2009
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Jun 2016
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First version publication date |
02 Aug 2015
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Other versions |
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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 |
N01280
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00419094 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
UCB Pharma, S.A.
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Sponsor organisation address |
Chemin du Foriest, Braine-l’ Alleud, Belgium, 1420
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Public contact |
Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
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Scientific contact |
Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
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Sponsor organisation name |
UCB, Inc.
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Sponsor organisation address |
1950 Lake Park Drive, Smyrna, United States, 30080
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Public contact |
Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
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Scientific contact |
Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.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 Nov 2009
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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 |
14 Sep 2009
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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 primary objective of this study was to assess the efficacy of Keppra extended release (XR) compared with a historical control, in the conversion to monotherapy treatment of partial onset seizures.
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Protection of trial subjects |
Not applicable
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Background therapy |
Standard antiepileptic drug (AED) therapy | ||
Evidence for comparator |
Other AEDs based on historical control | ||
Actual start date of recruitment |
06 Aug 2007
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
3 Years | ||
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 |
Mexico: 60
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Country: Number of subjects enrolled |
Poland: 67
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Country: Number of subjects enrolled |
Russian Federation: 64
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Country: Number of subjects enrolled |
United States: 37
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Worldwide total number of subjects |
228
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EEA total number of subjects |
67
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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) |
31
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Adults (18-64 years) |
194
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
The Efficacy (EFF) population is defined as all subjects in the Intent-to-Treat (ITT) population who enter into the Previous Antiepileptic (AED) Discontinuation (D/C) Phase. The Per Protocol (PP) population consists of all subjects in the EFF population who have no important protocol deviations related to efficacy. | |||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects are to be randomized into treatment with either Keppra XR 2000 mg/day or Keppra XR 1000 mg/day in a 3:1 ratio. 303 subjects were screened/enrolled and 228 randomized. | |||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall 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, Carer | |||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Keppra XR 1000 mg/day | |||||||||||||||||||||||||||||||||||||||
Arm description |
1000 mg/day once daily for 18 weeks (administered as two Keppra XR tablets and two placebo tablets once daily). | |||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Keppra XR
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Investigational medicinal product code |
Levetriacetam XR
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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 |
Keppra XR 1000 mg/day: administered as two Keppra XR tablets and two Placebo tablets once daily
Keppra XR 2000 mg/day: administered as four Keppra XR tablets once daily
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
Placebo
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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 |
Matching Placebo Tablet
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Arm title
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Keppra XR 2000 mg/day | |||||||||||||||||||||||||||||||||||||||
Arm description |
2000 mg/day once daily for 18 weeks (administered as four Keppra XR tablets once daily). | |||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Keppra XR
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Investigational medicinal product code |
Levetriacetam XR
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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 |
Keppra XR 1000 mg/day: administered as two Keppra XR tablets and two Placebo tablets once daily
Keppra XR 2000 mg/day: administered as four Keppra XR tablets once daily
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Baseline characteristics reporting groups
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Reporting group title |
Keppra XR 1000 mg/day
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Reporting group description |
1000 mg/day once daily for 18 weeks (administered as two Keppra XR tablets and two placebo tablets once daily). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Keppra XR 2000 mg/day
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Reporting group description |
2000 mg/day once daily for 18 weeks (administered as four Keppra XR tablets once daily). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Keppra XR 1000 mg/day
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Reporting group description |
1000 mg/day once daily for 18 weeks (administered as two Keppra XR tablets and two placebo tablets once daily). | ||
Reporting group title |
Keppra XR 2000 mg/day
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Reporting group description |
2000 mg/day once daily for 18 weeks (administered as four Keppra XR tablets once daily). | ||
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End point title |
The cumulative exit rate at 112 days after the beginning of the previous antiepileptic drug (AED) tapering phase [1] | |||||||||||||||
End point description |
Cumulative exit rate at day 112, based on the duration between start date of previous AED tapering to the earliest date exit criterion was met; calculated using Kaplan Meier Methods. Subjects prematurely discontinued for reasons unrelated to exit criteria were censored as of last dose of study drug. Subjects who completed without meeting exit criteria were censored at Day 112. Exit criteria include increase in seizure frequency, severity, duration, status epilepticus, or new generalized seizure. Upper 95% 2-sided confidence limit for exit rate is compared to the historical control rate: 0.678.
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End point type |
Primary
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End point timeframe |
112 days
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| Notes [1] - 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: Due to system limitations with studies using an external control, the stat. analysis results could not be entered in this section. The stat. analysis for the prim. and sec. efficacy variable was based on a comparison btw the historical control exit rate (0.678) to the upper limit of the 2-sided 95 % CI for the estimated event rate. If the upper limit of the 95 % CI for the estimate of the event rate for the Keppra arm was less than 0.678, the analysis was positive in favor of the Keppra arm. |
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| Notes [2] - Primary Efficacy analysis was conducted for the Keppra XR 2000 mg/day group only. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
The cumulative rate of exit events, which include discontinuation due to exit criteria, withdrawal due to adverse events (AE) and withdrawal due to lack of efficacy, at 112 days after the beginning of previous antiepileptic drug (AED) tapering phase | |||||||||||||||
End point description |
The cumulative exit event rate at Day 112 was calculated using Kaplan Meier methods. The exit event rate estimate was based on the duration between the start date of previous AED tapering to the earliest date an exit event occured. Subjects who prematurely discontinued for reasons unrelated to exit criteria, adverse event, or lack of efficacy were censored as of the last dose of study medication. Subjects who completed the study without having an exit event were censored as of Day 112.
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End point type |
Secondary
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End point timeframe |
112 days
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| Notes [3] - Evaluated for Keppra XR 2000 mg/day only. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
The cumulative rate of exit events due to any reasons at 112 days after the beginning of previous antiepileptic drug (AED) tapering phase | |||||||||||||||
End point description |
The cumulative exit event rate at Day 112 was calculated using Kaplan Meier methods. The exit event rate estimate was based on the duration between the start date of previous AED tapering to the earliest date an exit event occured. Subjects who completed the study without having an exit event were censored as of Day 112.
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End point type |
Secondary
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End point timeframe |
112 days
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| Notes [4] - Evaluated for Keppra XR 2000 mg/day only. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
The Cumulative Exit Rate at 112 days for the Keppra XR 1000 mg group After the Beginning of the Previous Antiepileptic Drug (AED) Tapering Phase | |||||||||||||||
End point description |
Keppra XR 1000 mg arm was not intended for inferential analysis (planned 3 to 1 randomization, Keppra XR 2000 mg: 1000 mg). The Exit Rate was based on the duration between the start date of previous AED tapering to the earliest date an exit crterion was met. Subjects who prematurely discontinued for reasons unrelated to exit criteria were censored as of the last dose of study medication. Subjects who completed the study without meeting an exit criterion were censored as of Day 112.
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End point type |
Secondary
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End point timeframe |
112 days
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| Notes [5] - Evaluated for Keppra XR 1000 mg/day only. |
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| No statistical analyses for this end point | ||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to 29 weeks
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
9.0
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Reporting groups
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Reporting group title |
Keppra XR 2000 mg/day
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Reporting group description |
2000 mg/day once daily for 18 weeks (administered as four Keppra XR tablets once daily) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Keppra XR 1000 mg/day
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Reporting group description |
1000 mg/day once daily for 18 weeks (administered as two Keppra XR tablets and two placebo tablets once daily) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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04 Apr 2007 |
Protocol Amendment 1 (dated 04 Apr 2007) provided for administrative changes, Content changes, and changes to the study design. This amendment was implemented before any subjects were screened for the study.
• The content changes tightened the inclusion/exclusion criteria and were reflective of the criteria indicated in the historical control White Paper or Alternative Monotherapy Design in the Treatment of Epilepsy
• The inclusion criterion regarding baseline AED use was modified to 'If taking 2 AEDs, 1 of the baseline AEDs should be taken at less than or equal to 50% of the minimum recommended dose.'
• The exclusion criteria were modified as follows:
• New criterion added: Seizures that are uncountable due to clustering during the 8-week period prior to Screening (Visit 1) and during the 8-week Baseline Period |
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04 Apr 2007 |
• Benzodiazepine use. (Original text: Regular use of benzodiazepines or intake of benzodiazepines on more than an occasional basis [more than average once per week])
• Use of an investigational drug or device in the 4 months preceding randomization
• A sensitivity analysis was added to satisfy anticipated requirements from FDA
• Additionally, changes were made to the study design. Rather than utilizing a randomization ratio of 1:1, a ratio of 3:1 was used. This changed the planned sample size to 223 subjects (167 in the 2000 mg/day group and 56 in the 1000 mg/day group). The anticipated number of subjects to be screened was changed to 279. For the statistical analysis, only the 2000 mg/day group was planned to be tested against the historical control. The dose of 2000 mg/day was 90% powered |
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14 Apr 2008 |
Protocol Amendment 2 (dated 14 Apr 2008) provided administrative changes, changes to the Inclusion and Exclusion Criteria section, and changes to the Permitted Concomitant Treatments section due to specific wording inadvertently omitted or documented incorrectly on the previous protocol amendment. This amendment was implemented after 64 subjects had been screened for participation in the study.
The change to the inclusion criteria was a modification of the amount of baseline AEDs allowed. Amendment 2 allowed 1 of the baseline AEDs to have been taken at less than or equal to 50% of the minimum recommended dose.
The wording for the administration of concomitant antiepileptic medications allowed for tapering off to start at Visit 4 because the visit number was incorrectly documented in original protocol.
The CRF page entitled “Subject Eligibility (Inclusion Criteria)” was amended to include additional language noted in this amendment. |
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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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/22516508 |
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