Clinical Trial Results:
An International, Double-blind, Randomized, Multi-center, Parallel Group, Historical-control Conversion to Monotherapy Study to Evaluate the Efficacy and Safety of Brivaracetam in Subjects (≥ 16 to 75 Years Old) With Partial Onset Seizures With or Without Secondary Generalization
Summary
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EudraCT number |
2008-000144-14 |
Trial protocol |
BE CZ DE SE |
Global end of trial date |
15 Feb 2010
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Dec 2016
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First version publication date |
07 Dec 2016
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Other versions |
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 |
N01276
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00698581 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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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 4815 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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Oct 2010
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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 |
15 Feb 2010
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of N01276 was to evaluate the efficacy of Brivaracetam (BRV) in the conversion to monotherapy at the doses of 50 and 100 mg/day (administered in 2 equal doses per day) in subjects with Partial Onset Seizures (POS) when compared to a historical pseudo-Placebo control group. This objective was based on the White Paper on Alternative Monotherapy Design in the Treatment of Epilepsy (French et al, 2005).
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Protection of trial subjects |
Standard measures to minimize pain and stress.
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Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
25 Aug 2008
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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 |
7 Years | ||
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 |
Australia: 8
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Country: Number of subjects enrolled |
Belgium: 4
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Country: Number of subjects enrolled |
Canada: 13
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Country: Number of subjects enrolled |
Czech Republic: 11
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Sweden: 12
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Country: Number of subjects enrolled |
United States: 34
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Worldwide total number of subjects |
88
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EEA total number of subjects |
33
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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) |
1
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Adults (18-64 years) |
84
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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 |
This study started to enroll patients in August 2008 and concluded in February 2010. | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
The Participant Flow refers to the Randomized Set (RS). Subjects withdrawn due to meeting an exit criterion are included in the count of early discontinuations with a reason of “Adverse Event” or “Lack of efficacy” as reported by the Investigator. | |||||||||||||||||||||||||||||||||
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 |
Carer, Investigator, Subject | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Brivaracetam 50 mg/day | |||||||||||||||||||||||||||||||||
Arm description |
Brivaracetam: 25 mg tablet - 50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study) | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Brivaracetam
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Investigational medicinal product code |
ucb 34714
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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 |
10 mg and 25 mg oral tablets of Brivaracetam.
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Arm title
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Brivaracetam 100 mg/day | |||||||||||||||||||||||||||||||||
Arm description |
Brivaracetam: 25 mg tablet - 100 mg daily for 17 weeks (or 21 weeks if down-titrated (100 mg > 50 mg > 20 mg) for subjects not participating in the follow-up study) | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Brivaracetam
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Investigational medicinal product code |
ucb 34714
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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 |
10 mg and 25 mg oral tablets of Brivaracetam.
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Baseline characteristics reporting groups
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Reporting group title |
Brivaracetam 50 mg/day
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Reporting group description |
Brivaracetam: 25 mg tablet - 50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study) | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Brivaracetam 100 mg/day
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Reporting group description |
Brivaracetam: 25 mg tablet - 100 mg daily for 17 weeks (or 21 weeks if down-titrated (100 mg > 50 mg > 20 mg) for subjects not participating in the follow-up study) | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Brivaracetam 50 mg/day
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Reporting group description |
Brivaracetam: 25 mg tablet - 50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study) | ||
Reporting group title |
Brivaracetam 100 mg/day
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Reporting group description |
Brivaracetam: 25 mg tablet - 100 mg daily for 17 weeks (or 21 weeks if down-titrated (100 mg > 50 mg > 20 mg) for subjects not participating in the follow-up study) | ||
Subject analysis set title |
Efficacy Analysis Set (BRV 50 mg/day treated subjects)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The Efficacy Analysis Set (EFF) consists of all randomized subjects with at least one intake of study medication who also entered into the Baseline antiepileptic drug (AED) Tapering Period and started the withdrawal of Baseline AEDs.
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End point title |
The cumulative exit rate at 112 days after the beginning of the Baseline Antiepileptic Drug (AED) Tapering Phase [1] | ||||||||||
End point description |
The cumulative exit rate was estimated using Kaplan-Meier methods and was based on the duration between start of the Evaluation Period (EP) and the earliest date the first exit criterion was met for each subject. Subjects completing the EP without meeting an exit criterion were censored on Day 112. The primary comparison was BRV 50 mg/day vs a historical control. The upper limit of the 2-sided 95 % Confidence Interval for the estimate was compared to the historical lower bound estimate of 0.722.
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End point type |
Primary
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End point timeframe |
From Week 1 up to Week 17
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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: Values presented below are from the statistical analysis of this Primary Endpoint. The upper limit of the two-sided 95% CI for the estimate of the exit rate at Day 112 for the BRV 50 mg/day arm, 0.626, was lower than the historical control exit rate of 0.772. Therefore the BRV 50 mg/day arm was considered statistically superior to historical control. |
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No statistical analyses for this end point |
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End point title |
The Number of patients reporting at least one Treatment-Emergent Adverse Event (TEAE) during the course of the study | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline through Re-conversion (approximately 31 weeks)
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No statistical analyses for this end point |
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End point title |
The number of patient withdrawal due to Adverse Events (AEs) during the course of the study | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline through Re-conversion (approximately 31 weeks)
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No statistical analyses for this end point |
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End point title |
The number of patients reporting at least one Serious Adverse Event (SAE) during the course of the study | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline through Re-conversion (approximately 31 weeks)
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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 |
Adverse Events (AEs) were collected from Visit 1 (Week -8) over the BRV Add-On Period and Evaluation Period up to the end of the Re-conversion Follow-up Period (Week 23).
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Adverse event reporting additional description |
Adverse Events refer to the Intention-to-Treat (ITT) Set consisting of all randomized subjects with at least one intake of study medication.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13.0
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Reporting groups
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Reporting group title |
Brivaracetam 50 mg/day
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Reporting group description |
Brivaracetam: 25 mg tablet - 50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Brivaracetam 100 mg/day
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Reporting group description |
Brivaracetam: 25 mg tablet - 100 mg daily for 17 weeks (or 21 weeks if down-titrated (100 mg > 50 mg > 20 mg) for subjects not participating in the follow-up study) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 2008 |
Protocol Amendment 1 was finalized on 04 Apr 2008, before any subjects were enrolled, and resulted in the following:
• Replacement of the option for enrollment in N01199 and N01125 with the option of enrollment in N01315. This change was based on feedback received from ethics committees and regulatory authorities in some European countries.
• Revision of the methods for handling missing data in acknowledgement of the fact that no details were known regarding the way missing data were handled, if at all, in the historical-control studies. Thus, the application of any imputation rule for the assessment of Exit Criterion 2 during the study (and implemented in the study EDC system) leading to subjects being prematurely or incorrectly exited from the study was avoided. Final sensitivity analyses were to include these revised methods. The possibility for the Investigator exiting subjects on the basis of Exit Criterion 4 was considered an adequate safeguard against subjects remaining too long in the study if missing data interfered with the assessment of Exit Criterion 1 or 2. |
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04 Apr 2008 |
Protocol Amendment 1 was finalized on 04 Apr 2008, before any subjects were enrolled, and resulted in the following:
• Addition of text describing randomization stratification by region to provide clarity with regard to the percentage of the subjects anticipated for enrollment in the US.
• Clarification that the total duration of the Baseline Period was 8 weeks +/-1 week.
• Replacement of exclusion criteria referring to “clusters” of seizures with “seizure patterns being too frequent or indistinctively separated to reliably be counted” in order to more clearly define the term “clusters.”
• Addition of a recommendation for the sites to call subjects weekly to promote good completion of the subject diary. Text referring to this recommendation was added to the Informed Consent.
• Replacement of the interactive voice response system (IVRS) with EDC for screening subjects. This change was made in accordance with recommendations of the IVRS and Seizure Frequency EDC system provider.
• Replacement of the subject’s daily record card (DRC) with the CRF as the location for recording the “Investigator Seizure Assessment.”
• Correction of typographical errors. |
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02 Nov 2009 |
Protocol Amendment 2 was finalized on 02 Nov 2009, and resulted in the following:
• Addition of a recruitment hold and interim analysis. This change was motivated by ongoing monitoring that suggested a higher than expected number of subjects discontinuing either for predefined exit criteria or other reasons. The interim analysis was to include efficacy information for all subjects who had an opportunity to complete 112 days of treatment after initiation of concomitant AED tapering by the time of the defined clinical cut-off date.
• Establishment of an IDMC to review primary efficacy, sensitivity, and safety data for the purpose of making a recommendation to the Sponsor regarding study continuation.
• Elimination of the requirement for restricted database access of the study team before approval of the final Statistical Analysis Plan (SAP) in accordance UCB Standard Operating Procedures (SOPs) revised subsequent to study initiation. Due to this change and because the primary efficacy analysis was fully specified in the original and amended protocols, this requirement was eliminated from this protocol.
• Updates of UCB study personnel and the List of Abbreviations.
Following the recruitment hold, a decision was made to require subjects who were in the Baseline Period, the BRV Add-On Period, and the AED Tapering Phase to terminate the study. Subjects who had already progressed to the Monotherapy Phase were permitted to remain in the study. |
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16 Nov 2009 |
Protocol Amendment 3 was finalized on 16 Nov 2009 (after the recruitment hold) and resulted in the following:
• Provision for enrollment in N01315 for subjects discontinued from the BRV Add-On Period or the Baseline AED Tapering Phase due to recruitment hold and interim analysis. This enrollment option was made available to provide continued treatment with BRV to these subjects as deemed beneficial by both subjects and Investigators.
• Correction of an error in Amendment 2 that placed information pertaining to database access and SAP finalization in an incorrect section of the protocol. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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 |