Clinical Trial Results:
Open-label, 2-dose level trial to evaluate pharmacokinetics, safety, and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in infants with refractory epilepsy with partial-onset seizures aged from 1 month to <2 years
Summary
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EudraCT number |
2012-001091-11 |
Trial protocol |
CZ PT IT HR RO |
Global end of trial date |
03 Apr 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Jan 2021
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First version publication date |
28 Jan 2021
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Other versions |
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Summary report(s) |
Synopsis |
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 |
BIA-2093-211
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
BIAL - Portela & CA, S.A.
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Sponsor organisation address |
À Av. Siderurgia Nacional, Coronado, Portugal, 4745-457
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Public contact |
André Garrido, BIAL - Portela & Cª, S.A., 00351 229866100, andre.garrido@bial.com
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Scientific contact |
Joana Moreira, BIAL - Portela & Cª, S.A., 00351 229866100, joana.moreira@bial.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000696-PIP02-10 | ||
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 |
11 Sep 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Apr 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Apr 2020
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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 |
Primary: To evaluate the steady state pharmacokinetic (PK) profile of ESL.
Secondary: To assess the safety and tolerability of ESL in the defined patient population at the doses used and to perform exploratory analyses of efficacy.
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Protection of trial subjects |
This study was conducted in compliance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good
Clinical Practice, including the archiving of essential documents.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Apr 2018
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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 |
Russian Federation: 7
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Country: Number of subjects enrolled |
Serbia: 2
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Country: Number of subjects enrolled |
Ukraine: 11
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Country: Number of subjects enrolled |
Czechia: 3
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Worldwide total number of subjects |
23
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EEA total number of subjects |
3
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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) |
23
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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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 |
The patient recruitment period lasted approximately 66 months. The actual overall study duration or patient recruitment period may vary. | |||||||||||||||
Pre-assignment
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Screening details |
Subjects who met all the inclusion criteria and none of the exclusion criteria. 23 subjects were enrolled to the trial and 1 subject experienced an SAE of status epilepticus during the Screening Period that led to study discontinuation (recorded as a screen failure). | |||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
23 | |||||||||||||||
Number of subjects completed |
23 | |||||||||||||||
Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Overall - Group 1 - Age Cohort A | |||||||||||||||
Arm description |
Age ≥1 to <6 months Subjects in Group 1 Age cohort A had 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5). | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Eslicarbazepine acetate
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Investigational medicinal product code |
BIA 2‑093
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Other name |
Zebinix
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Pharmaceutical forms |
Oral suspension, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
After a Screening Period of up to 3 weeks, Group 1 began treatment. For Age cohort A, there was no titration and subjects were treated with 5 mg/kg once daily (QD) for 5 days in a 6-day Evaluation Period.
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Arm title
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Overall - Group 1 - Age Cohort B | |||||||||||||||
Arm description |
Age ≥6 to <24 months Subjects in Group 1 Age cohort B had up to 15 days of treatment: a 5-day Up-titration Period (from Visit 1a through Visit 1e [Day -5 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a 5-day Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Eslicarbazepine acetate
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Investigational medicinal product code |
BIA 2‑093
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Other name |
Zebinix
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Pharmaceutical forms |
Tablet, Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
After a Screening Period of up to 3 weeks, Group 1 began treatment. For Age cohort B, subjects had a 5-day Up-titration Period at 5 mg/kg QD before increasing to 10 mg/kg QD for the Evaluation Period and a 5-day Down-titration Period if subjects did not continue in the extension study or discontinued the study early.
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Arm title
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Overall - Group 2 - Age Cohort A | |||||||||||||||
Arm description |
Age ≥1 to <6 months Subjects in Group 2 Age cohort A had up to 20 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a one 5-day step Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Eslicarbazepine acetate
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Investigational medicinal product code |
BIA 2‑093
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Other name |
Zebinix
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Pharmaceutical forms |
Tablet, Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
After a Screening Period of up to 3 weeks, subjects in Group 2 began a 5-day Up-titration Period at 5 mg/kg QD, followed by a second 5-day Up-titration Period at 12.5 mg/kg QD, before proceeding to the evaluation dose at 20 mg/kg QD for 5 days in a 6-day Evaluation Period. If subjects did not continue in the subsequent extension study or discontinued the study early, down-titration was to occur as follows: one 5-day down-titration step at 12.5 mg/kg QD.
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Arm title
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Overall - Group 2 - Age Cohort B | |||||||||||||||
Arm description |
Age ≥6 to <24 months Subjects in Group 2 Age cohort B had up to 25 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a Down-titration Period in two 5-day steps (Day 6 through Day 15) if subjects did not continue in the extension study. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Eslicarbazepine acetate
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Investigational medicinal product code |
BIA 2‑093
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Other name |
Zebinix
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Pharmaceutical forms |
Tablet, Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
After a Screening Period of up to 3 weeks, subjects in Group 2 began a 5-day Up-titration Period at 5 mg/kg QD, followed by a second 5-day Up-titration Period at 12.5 mg/kg QD, before proceeding to the evaluation dose at 20 mg/kg QD for 5 days in a 6-day Evaluation Period. If subjects did not continue in the subsequent extension study or discontinued the study early, down-titration was to occur as follows: two 5-day down-titration steps, starting at 12.5 mg/kg QD followed by 5 mg/kg QD.
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Baseline characteristics reporting groups
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Reporting group title |
Overall - Group 1 - Age Cohort A
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Reporting group description |
Age ≥1 to <6 months Subjects in Group 1 Age cohort A had 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall - Group 1 - Age Cohort B
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Reporting group description |
Age ≥6 to <24 months Subjects in Group 1 Age cohort B had up to 15 days of treatment: a 5-day Up-titration Period (from Visit 1a through Visit 1e [Day -5 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a 5-day Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall - Group 2 - Age Cohort A
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Reporting group description |
Age ≥1 to <6 months Subjects in Group 2 Age cohort A had up to 20 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a one 5-day step Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall - Group 2 - Age Cohort B
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Reporting group description |
Age ≥6 to <24 months Subjects in Group 2 Age cohort B had up to 25 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a Down-titration Period in two 5-day steps (Day 6 through Day 15) if subjects did not continue in the extension study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Overall - Group 1 - Age Cohort A
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Reporting group description |
Age ≥1 to <6 months Subjects in Group 1 Age cohort A had 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5). | ||
Reporting group title |
Overall - Group 1 - Age Cohort B
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Reporting group description |
Age ≥6 to <24 months Subjects in Group 1 Age cohort B had up to 15 days of treatment: a 5-day Up-titration Period (from Visit 1a through Visit 1e [Day -5 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a 5-day Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study. | ||
Reporting group title |
Overall - Group 2 - Age Cohort A
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Reporting group description |
Age ≥1 to <6 months Subjects in Group 2 Age cohort A had up to 20 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a one 5-day step Down-titration Period (Day 6 through Day 10) if subjects did not continue in the extension study. | ||
Reporting group title |
Overall - Group 2 - Age Cohort B
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Reporting group description |
Age ≥6 to <24 months Subjects in Group 2 Age cohort B had up to 25 days of treatment: an Up-titration Period in two 5-day steps (from Visit 1a through Visit 1j [Day -10 through Day -1]), 5 days of treatment during a 6-day Evaluation Period (Day 1 through Day 5), and a Down-titration Period in two 5-day steps (Day 6 through Day 15) if subjects did not continue in the extension study. | ||
Subject analysis set title |
Group 1 - Age Cohort A x Safety Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who received at least 1 dose of IMP
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Subject analysis set title |
Group 1 - Age Cohort B x Safety Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who received at least 1 dose of IMP
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Subject analysis set title |
Group 2 - Age Cohort A x Safety Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who received at least 1 dose of IMP
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Subject analysis set title |
Group 2 - Age Cohort B x Safety Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who received at least 1 dose of IMP
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Subject analysis set title |
Group 1 - Age Cohort A x PK Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The pharmacokinetics set is defined as all safety set subjects that had adequate eslicarbazepine plasma concentration data
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Subject analysis set title |
Group 1 - Age Cohort B x PK Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The pharmacokinetics set is defined as all safety set subjects that had adequate eslicarbazepine plasma concentration data
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Subject analysis set title |
Group 2 - Age Cohort A x PK Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The pharmacokinetics set is defined as all safety set subjects that had adequate eslicarbazepine plasma concentration data
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Subject analysis set title |
Group 2 - Age Cohort B x PK Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The pharmacokinetics set is defined as all safety set subjects that had adequate eslicarbazepine plasma concentration data
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End point title |
Steady state PK profile of ESL - Cmax [1] | |||||||||||||||||||||||||
End point description |
Cmax, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
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End point type |
Primary
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End point timeframe |
6 day Evaluation Period
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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: please refer to synopsis |
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No statistical analyses for this end point |
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End point title |
Steady state PK profile of ESL - Cmax/dose [2] | |||||||||||||||||||||||||
End point description |
Dose-normalised Cmax, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
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End point type |
Primary
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End point timeframe |
6 day Evaluation Period
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: please refer to synopsis |
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No statistical analyses for this end point |
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End point title |
Steady state PK profile of ESL - tmax [3] | |||||||||||||||||||||||||
End point description |
tmax, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
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End point type |
Primary
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End point timeframe |
6 day Evaluation Period
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Notes [3] - 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: please refer to synopsis |
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No statistical analyses for this end point |
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End point title |
Steady state PK profile of ESL - AUCτ [4] | |||||||||||||||||||||||||
End point description |
AUCτ, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
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End point type |
Primary
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End point timeframe |
6 day Evaluation Period
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Notes [4] - 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: please refer to synopsis |
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No statistical analyses for this end point |
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End point title |
Steady state PK profile of ESL - AUCτ/dose [5] | |||||||||||||||||||||||||
End point description |
Dose-normalised AUCτ, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
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End point type |
Primary
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End point timeframe |
6 day Evaluation Period
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Notes [5] - 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: please refer to synopsis |
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No statistical analyses for this end point |
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End point title |
Steady state PK profile of ESL - t1/2 [6] | |||||||||||||||||||||||||
End point description |
t1/2, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
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End point type |
Primary
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End point timeframe |
6 day Evaluation Period
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Notes [6] - 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: please refer to synopsis |
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No statistical analyses for this end point |
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End point title |
Steady state PK profile of ESL - CL/F [7] | |||||||||||||||||||||||||
End point description |
CL/F, derived by non-compartmental analysis from the plasma drug concentration versus time profiles
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End point type |
Primary
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End point timeframe |
6 day Evaluation Period
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Notes [7] - 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: please refer to synopsis |
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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 informed consent until the date of the EOT visit/EDV.
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Adverse event reporting additional description |
From informed consent until EOT visit/EDV. This period was extended to follow-up on all ongoing AEs after the EOT visit/EDV until the AE was finally resolved or it was medically justifiable to stop further follow up (e.g. a chronic condition is reached). In case of death, AE(s) that were ongoing and did not cause death could be left ongoing.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Group 1 - Age Cohort A x Safety Set
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Reporting group description |
Subjects in the Safety Set treated with ESL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 1 - Age Cohort B x Safety Set
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Reporting group description |
Subjects in the Safety Set treated with ESL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2 - Age Cohort A x Safety Set
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Reporting group description |
Subjects in the Safety Set treated with ESL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2 - Age Cohort B x Safety Set
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Reporting group description |
Subjects in the Safety Set treated with ESL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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26 May 2017 |
Local Amendment#1, Czech Republic
This protocol amendment amends Protocol Final Version No. 2.0 (21-DEC-2016).
It was prepared in order to comply with the requirements issued by the Czech State Institute
for Drug Control dated 20.03.2017.
• The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European ancestry. Thus, although there are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine or chemically-related compounds treatment, and the use of carbamazepine or chemicallyrelated compounds may be considered if the benefits are thought to exceed the risks, subjects who are known to be positive for HLA-A*3101 allele are not considered eligible due to safety reasons [1,2]. A new exclusion criterion was added.
• Due to safety reasons, subjects with worsening of liver function must be withdrawn from the trial.
• If an overnight stay/hospitalisation is required due to the subject’s study participation, one parent will have the opportunity to stay together with his/her child as required. The resulting accommodation costs will be covered by the sponsor. |
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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 |