Clinical Trial Results:
A Long Term Extension Study of E2080 in Patients with Lennox-Gastaut Syndrome
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Summary
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EudraCT number |
2016-004953-34 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
09 Aug 2013
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Results information
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Results version number |
v2(current) |
This version publication date |
15 Apr 2018
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First version publication date |
15 Mar 2018
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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 |
E2080-J081-305
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01151540 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Eisai Medical Research Inc.
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Sponsor organisation address |
4-6-10 Koishikawa, Bunkyo-Ku, Tokyo, Japan,
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Public contact |
Customer Joy Department. EJ, Eisai Co., Ltd., 81 33817-3700,
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Scientific contact |
Customer Joy Department. EJ, Eisai Co., Ltd., 81 33817-3700,
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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 |
25 Oct 2013
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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 |
09 Aug 2013
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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 investigate the safety of long term administration of E2080 in the participants with Lennox-Gastaut syndrome (LSG) who completed the E2080-J081-304 study.
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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 Council 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 Council for Harmonisation of
Technical Requirements for Registration 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 |
19 Nov 2010
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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 |
Japan: 54
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Worldwide total number of subjects |
54
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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) |
22
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Adolescents (12-17 years) |
11
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Adults (18-64 years) |
21
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||
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Pre-assignment
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Screening details |
Participants who successfully completed Study 304 were enrolled into this study. | ||||||||||||||
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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 |
Not blinded | ||||||||||||||
Blinding implementation details |
Initially participants were blinded, then changed over to open-label for the remainder of the study as follows; 1) Pre-conversion Period - designed to avoid breaking the blindness in the preceding Study 304 and to prevent any data obtained in the open-label treatment in Study 305 from affecting the evaluation in the Study 304, and 2) Conversion Period - participants on placebo were titrated to the appropriate dose of rufinamide (the Study Drug B) within 2 weeks under double-blind conditions.
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Arms
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Arm title
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Rufinamide | ||||||||||||||
Arm description |
Ralfinamide was administered orally twice daily after breakfast and dinner. Participants on placebo in Study 304 were titrated over to rufinamide within 2 weeks during the Conversion Period. As a general rule, the dose of rufinamide at the end of the Conversion Period was maintained throughout the Maintenance Period. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Rufinamide
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Investigational medicinal product code |
E2080
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Other name |
BANZEL
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ralfinamide was administered orally twice daily after breakfast and dinner.
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Baseline characteristics reporting groups
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Reporting group title |
Rufinamide
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Reporting group description |
Ralfinamide was administered orally twice daily after breakfast and dinner. Participants on placebo in Study 304 were titrated over to rufinamide within 2 weeks during the Conversion Period. As a general rule, the dose of rufinamide at the end of the Conversion Period was maintained throughout the Maintenance Period. | ||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Efficacy Analysis Set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Efficacy Analysis Set included 46 participants. 8 participants who had no evaluable efficacy data were excluded.
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End points reporting groups
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Reporting group title |
Rufinamide
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Reporting group description |
Ralfinamide was administered orally twice daily after breakfast and dinner. Participants on placebo in Study 304 were titrated over to rufinamide within 2 weeks during the Conversion Period. As a general rule, the dose of rufinamide at the end of the Conversion Period was maintained throughout the Maintenance Period. | ||
Subject analysis set title |
Efficacy Analysis Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The Efficacy Analysis Set included 46 participants. 8 participants who had no evaluable efficacy data were excluded.
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End point title |
Number of Participants with Adverse Events as a Measure of Safety and Tolerability of Rufinamide [1] | ||||||||||||||||||||
End point description |
Safety was assessed by monitoring and recording all adverse events (AEs), serious adverse events (SAEs), clinical laboratory tests, blood pressure, pulse rate, physical examination, and 12-lead electrocardiogram (ECG). Treatment-emergent adverse events (TEAEs) were defined as AEs that started on or after the date and time of administration of first dose of test drug, but not later than 30 days after discontinuation from the study, or if the AE was present prior to the administration of the first dose of test drug and increased in National Cancer Institute Common Toxicity Criteria (NCI CTC version 3.0) grade during the study or 30 days after discontinuation from the study. AEs were considered serious if it resulted in; death, was life-threatening, hospitalization/prolonged hospitalization, persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Safety analysis set included all treated participants.
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End point type |
Primary
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End point timeframe |
From date of first dose up to 30 days after the last dose of study treatment, up to approximately 2 years 10 months
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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: Statistical analysis was not performed on this data set. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Percent Change in Tonic-Atonic Seizure Frequency From Baseline (Per 28 Days) | ||||||||||||||||||||||
End point description |
The sum of the frequencies of tonic seizures and atonic seizures was defined as the “tonic-atonic seizure frequency”. The percent change in tonic-atonic seizure frequency was calculated using the tonic-atonic seizure frequency per 28 days of the Observation Period in Study 304 as the baseline and the tonic-atonic seizure frequency at Weeks 12, 24, 32, 40, 52 and Week 52 Last Observation Carried Forward (LOCF) as the post-treatment value. Percentage change in tonic - atonic seizure frequency was calculated as follows: [100 x (post-treatment value - baseline)/ baseline].
The frequency of epileptic seizures was recorded in the seizure diary by the recorder. Seizure frequency was counted based on the classification established by the International League Against Epilepsy (ILAE). The diary recorder monitored the participant and recorded the seizure diary in a consistent manner, and continued these practices throughout the study period. The Efficacy Analysis Set was used.
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End point type |
Secondary
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End point timeframe |
Baseline (Observation period in Study 304), Week 12, Week 24, Week 32, Week 40, Week 52 and Week 52 LOCF
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Percent Change in the Total Seizure Frequency From Baseline (Per 28 Days) | ||||||||||||||||||||||
End point description |
Percent change in the total seizure frequency (per 28 days) was calculated using the total seizure frequency per 28 days of the Observation Period of Study 304 as the baseline and the total seizure frequency per 28 days at Weeks 12, 24, 32, 40, 52 and Week 52 LOCF as the post-treatment value. Percentage change in total seizure frequency was calculated as follows: [100 x (post-treatment value - baseline)/ baseline].
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End point type |
Secondary
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End point timeframe |
Baseline (Observation period in Study 304), Week 12, Week 24, Week 32, Week 40, Week 52 and Week 52 LOCF
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Percent change in the Frequency of Seizures Other than Tonic-Atonic Seizures | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Percent change in the frequency of seizures other than tonic-atonic seizures (per 28 days) was calculated using the total seizure frequency per 28 days of the Observation Period as the baseline and the total seizure frequency per 28 days of the Weeks, 12, 24, 32, 40, 52 and 52 LOCF as the post-treatment value. Percentage change in total seizure frequency was calculated as follows: [100 x (post-treatment value - baseline)/ baseline].
Seizures analyzed other than tonic-atonic seizures included: Partial seizure frequency, Absence seizure, Atypical absence seizure, Myoclonic seizure, Tonic seizure, Tonic-clonic seizure, Atonic seizure, and Unclassified epileptic seizure. This data was based on the diary data collected for 7 days after each visit. Seizure frequency was counted based on the classification established by the ILAE. The diary recorder monitored the participant and recorded the seizure diary in a consistent manner. The Efficacy Analysis Set was used.
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End point type |
Secondary
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End point timeframe |
Baseline (Observation period in Study 304), Week 12, Week 24, Week 32, Week 40, Week 52 and Week 52 LOCF
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants who Achieved 100%, 75%, 50% or 25% reduction in Tonic-Atonic Seizure Frequency (Responders) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Categorized percent change in Tonic-atonic seizure frequency per 28 Days by visit relative to the baseline (Observation Phase in Study 304) was determined based on the diary data collected for 7 days after each visit. The Efficacy Analysis Set was used.
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End point type |
Secondary
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End point timeframe |
Week 12, Week 24, Week 32, Week 40, Week 52 and Week 52 LOCF
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants With An Increase In Tonic-Atonic Seizure Frequency | ||||||||||||||||||||||||||||||||
End point description |
Number of participants with an increase in Tonic-atonic seizure frequency per 28 Days by visit relative to the baseline (Observation Phase in Study 304) was determined based on the diary data collected for 7 days after each visit. The Efficacy Analysis Set was used.
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End point type |
Secondary
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End point timeframe |
Week 12, Week 24, Week 32, Week 40, Week 52 and Week 52 LOCF
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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 |
From date of first dose up to 15 days after the last dose of study treatment, up to approximately 2 year and 10 months
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
Rufinamide
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Reporting group description |
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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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12 May 2010 |
• Description of the method for examining concomitant drugs was modified.
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05 Jul 2010 |
• Clarified the administrations of study treatment during the Conversion Period.
• Clarified the dose reduction procedure during the Conversion Period.
• Changes made to the clinical trial plan on how blood pressure is taken. |
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13 Oct 2010 |
• Phenobarbital (suppository) was added to rescue drugs for status epilepticus.
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11 Apr 2011 |
• Newly approved levetiracetam was added to the concomitant antiepileptic drugs which can be used in this study.
• Levetiracetam was added to the prohibited antiepileptic drugs for participants under 15 years old, since the drug had not been allowed for patients with <15 years old.
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31 Oct 2011 |
• Gabapentin was deleted from the prohibited antiepileptic drugs for participants under 15 years old, since the drug was approved for children. |
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03 Apr 2012 |
• Emergency treatment for epilepticus status was revised to include intravenous hyphenytoin as a rescue medication.
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24 Oct 2012 |
• Revisions made to the Study Design etc. in response to future approval and marketing of the study drug.
• Clinical trial was to be considered a post-marketing trial after approval and marketing of the study drug.
• End date of the study was defined as the date at which the study drug is on the market and can be prescribed
• Assessments at the end of the study are clarified.
• Clarified the tapering and end-of-study-assessments those not required for the participants who can continuously use rufinamide after completion of this study.
• Instructions were given on how marketed study drug should be handled and delivered to medical institutions for the participants.
• Clarification was given on the follow-up of adverse events and serious adverse events.
• List of surveys and evaluations the investigators should conduct as the end of the trial.
• Clarified the report of pregnancy after use of marketed study drug.
• Compliance with Good Post-marketing Study Practice (GPSP) was included. |
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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 | |||
