Clinical Trial Results:
A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LACOSAMIDE AS ADJUNCTIVE THERAPY FOR UNCONTROLLED PRIMARY GENERALIZED TONIC-CLONIC SEIZURES IN SUBJECTS WITH IDIOPATHIC GENERALIZED EPILEPSY
Summary
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EudraCT number |
2011-003100-21 |
Trial protocol |
PT SK HU DE ES CZ BE IT PL FR BG RO Outside EU/EEA |
Global end of trial date |
05 Jun 2019
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Results information
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Results version number |
v1 |
This version publication date |
21 Dec 2019
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First version publication date |
21 Dec 2019
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Other versions |
v2 |
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 |
SP0982
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02408523 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
UCB BIOSCIENCES, Inc.
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Sponsor organisation address |
8010 Arco Corporate Drive, Raleigh, United States, NC 27617
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Public contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
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Scientific contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.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-000402-PIP03-17 | ||
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 |
21 Jun 2019
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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 |
05 Jun 2019
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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 demonstrate the efficacy of oral lacosamide (LCM) vs placebo as adjunctive therapy for uncontrolled primary generalized tonic-clonic (PGTC) seizures in subjects with idiopathic generalized epilepsy (IGE) currently taking 1 to 3 concomitant anti-epileptic drugs (AEDs) independent of the number of prior failed AEDs
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Protection of trial subjects |
During the conduct of the study all participants were closely monitored.
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Background therapy |
Background therapy as permitted in the protocol. | ||
Evidence for comparator |
Not Applicable | ||
Actual start date of recruitment |
23 Apr 2015
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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 |
5 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: 17
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Brazil: 15
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Country: Number of subjects enrolled |
Bulgaria: 13
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Country: Number of subjects enrolled |
China: 5
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Country: Number of subjects enrolled |
Czech Republic: 15
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Hungary: 13
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Country: Number of subjects enrolled |
Israel: 7
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Country: Number of subjects enrolled |
Italy: 2
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Country: Number of subjects enrolled |
Japan: 30
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Country: Number of subjects enrolled |
Mexico: 1
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Country: Number of subjects enrolled |
Poland: 16
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Country: Number of subjects enrolled |
Portugal: 1
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Country: Number of subjects enrolled |
Romania: 8
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Country: Number of subjects enrolled |
Russian Federation: 30
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Country: Number of subjects enrolled |
Slovakia: 11
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Country: Number of subjects enrolled |
Korea, Democratic People's Republic of: 6
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Country: Number of subjects enrolled |
Spain: 9
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Country: Number of subjects enrolled |
Taiwan: 2
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Country: Number of subjects enrolled |
United States: 30
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Worldwide total number of subjects |
242
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EEA total number of subjects |
99
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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) |
17
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Adolescents (12-17 years) |
32
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Adults (18-64 years) |
191
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
The study started to enroll patients in April 2015 and concluded in May 2019. | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
The study included a 12-week Historical Baseline, a 4-week Prospective Baseline Period, a 6-week (minimum) to 24-week (maximum) Treatment Period (including a 6-week titration) and a 4-week End of Study Period. Participant Flow refers to the Safety Set. | |||||||||||||||||||||||||||||||||
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 |
Investigator, Subject, Carer, Assessor | |||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||
Arm description |
Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). | |||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo tablet
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Investigational medicinal product code |
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Other name |
PBO
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg.
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Investigational medicinal product name |
Placebo oral solution
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Investigational medicinal product code |
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Other name |
PBO
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg or maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).
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Arm title
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Lacosamide | |||||||||||||||||||||||||||||||||
Arm description |
Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Lacosamide tablet
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Investigational medicinal product code |
SPM927
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Other name |
Vimpat
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg.
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Investigational medicinal product name |
Lacosamide oral solution
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Investigational medicinal product code |
SPM927
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Other name |
Vimpat
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg or maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Lacosamide
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Reporting group description |
Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). | ||
Reporting group title |
Lacosamide
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Reporting group description |
Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). | ||
Subject analysis set title |
Placebo (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg.
Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg).
Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).
Participants formed the Full Analysis Set (FAS).
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Subject analysis set title |
Lacosamide (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg).
Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg).
Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).
Participants formed the FAS.
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Subject analysis set title |
Placebo (SS)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg.
Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg).
Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).
Participants formed the Safety Set (SS).
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Subject analysis set title |
Lacosamide (SS)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg).
Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg).
Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).
Participants formed the SS.
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End point title |
Time to the second primary generalized tonic clonic (PGTC) seizure during the 24-week Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24) | |||||||||
End point description |
The primary efficacy variable was the time to the second primary generalized tonic clonic seizure (PGTCS) during the 24-week Treatment Period which was estimated using Kaplan-Meier (KM) methods.
Note: 1 patient from the Lacosamide (FAS) group was randomized after the 125th event and did not appear in this analysis.
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End point type |
Primary
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End point timeframe |
During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
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Statistical analysis title |
Statistical analysis 1 | |||||||||
Statistical analysis description |
Comparison of LCM versus Placebo was based on a Cox proportional hazards regression model with an effect for treatment, stratifying for the following combinations of study participants’ Baseline PGTCS frequency and Development from interactive response technology (IRT) (<= 2 per 28 days in the Combined Baseline Period and Pediatric, <= 2 per 28 days in the Combined Baseline Period and Adult, and > 2 per 28 days in the Combined Baseline Period). The reference group was Placebo.
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Comparison groups |
Placebo (FAS) v Lacosamide (FAS)
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Number of subjects included in analysis |
240
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.001 [1] | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
0.54
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.377 | |||||||||
upper limit |
0.774 | |||||||||
Notes [1] - Wald's method was used to calculate the p-value, Hazard Ratio (HR) and confidence intervals (CIs). |
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End point title |
Seizure freedom for primary generalized tonic clonic (PGTC) seizures during the 24-week Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24) | ||||||||||||
End point description |
A seizure-free day from primary generalized tonic clonic seizures (PGTCS) was defined as a day where no PGTCS were reported in the seizure diary and PGTCS were assessed, which was estimated using Kaplan-Meier (KM) methods.
Note: 1 patient from the Lacosamide (FAS) group was randomized after the 125th event and did not appear in this analysis.
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End point type |
Secondary
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End point timeframe |
During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
The key secondary efficacy variable was evaluated using an extended Mantel-Haenszel testing procedure. Baseline PGTCS Frequency from Combined Baseline and development (age from interactive response technology (IRT)) were calculated from IRT.
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Comparison groups |
Placebo (FAS) v Lacosamide (FAS)
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Number of subjects included in analysis |
239
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.011 [2] | ||||||||||||
Method |
Mantel-Haenszel | ||||||||||||
Parameter type |
KM seizure free of LCM vs Placebo | ||||||||||||
Point estimate |
14.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
3.2 | ||||||||||||
upper limit |
25.1 | ||||||||||||
Notes [2] - Superiority of LCM vs Placebo p-value was based on a chi-square test on 1 degree of freedom. |
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End point title |
Time to the first primary generalized tonic clonic (PGTC) seizure during the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24) | |||||||||
End point description |
The time to the first primary generalized tonic clonic seizure (PGTCS) during the 24-week Treatment Period was estimated using Kaplan-Meier (KM) methods.
Note: 1 patient from the Lacosamide (FAS) group was randomized after the 125th event and did not appear in this analysis.
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End point type |
Secondary
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End point timeframe |
During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
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Statistical analysis title |
Statistical analysis 1 | |||||||||
Statistical analysis description |
Comparison of LCM versus Placebo was based on a Cox proportional hazards regression model with an effect for treatment, stratifying for the following combinations of study participants’ Baseline PGTCS frequency and Development from interactive response technology (IRT) (<= 2 per 28 days in the Combined Baseline Period and Pediatric, <= 2 per 28 days in the Combined Baseline Period and Adult, and > 2 per 28 days in the Combined Baseline Period). The reference group was Placebo.
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Comparison groups |
Placebo (FAS) v Lacosamide (FAS)
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Number of subjects included in analysis |
239
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.012 [3] | |||||||||
Method |
Regression, Cox | |||||||||
Parameter type |
Hazard ratio (HR) | |||||||||
Point estimate |
0.683
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.507 | |||||||||
upper limit |
0.921 | |||||||||
Notes [3] - Wald's method was used to calculate the p-value, Hazard Ratio (HR) and confidence intervals (CIs). |
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End point title |
Percentage of participants with at least one adverse event (AE) as reported spontaneously by the subject and/or caregiver or observed by the investigator | ||||||||||||
End point description |
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product (IMP), whether or not related to the IMP.
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End point type |
Secondary
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End point timeframe |
From Visit 1 (Week -4) to End of Study Period (up to Week 36)
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No statistical analyses for this end point |
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End point title |
Plasma Concentrations of Lacosamide | |||||||||||||||||||||
End point description |
Lacosamide plasma concentration was expressed in micrograms per milliliter (μg/mL).
Means and standard deviation (SD) were only calculated if at least 2/3 of the concentrations were quantified at the respective timepoint. Values Below Limit of Quantification (BLQ) were replaced by value of 0 in calculations of means and SDs.
Note: 999 is a placeholder used for values that were not calculated.
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End point type |
Secondary
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End point timeframe |
During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
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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 were collected from Week 1 to End of Study Period (up to Week 36).
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Adverse event reporting additional description |
Only non-serious TEAEs occurring above the reporting threshold of 5% of participants in any treatment group are included in this summary.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Lacosamide (SS)
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Reporting group description |
Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the SS. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (SS)
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Reporting group description |
Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the Safety Set (SS). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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25 Sep 2012 |
Protocol Amendment 1, dated 25 Sep 2012, provided the following key changes.
The primary purpose of this substantial amendment was to identify significant changes to the study design including inclusion and exclusion criteria, as well as the addition of an independent data monitoring committee (IDMC). In addition, study secondary variables were changed to more accurately represent the study design.
• The protocol was updated to include randomization stratified by age at informed consent (≥12 to <18 years of age vs ≥18 years of age). This was in order to maintain balance within each treatment arm and within the existing baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the 16-week Combined Baseline Period prior to randomization) as well as to provide greater control for variability when analyzing the primary efficacy variable (time to second seizure).
• An inclusion criterion was added to include study participants of normal intelligence for age in the judgment of the investigator. Exclusion criteria were added or modified to further exclude study participants who had a diagnosis of developmental delay or mental retardation or a history of status epilepticus. The rationale for adding the inclusion/exclusion criteria was that study participants with developmental delay or mental retardation are more likely to have symptomatic rather than idiopathic seizures.
• The inclusion criterion regarding the lower limit body weight for male and female study participants ≥12 years of age was changed from ≥ 30kg to ≥ 50kg. This was based on the observations collected to date from pediatric PK/tolerability studies. |
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25 Sep 2012 |
- Continuation 1 -
• The text regarding the use of benzodiazepines was revised to clarify that up to 3 marketed antiepileptic drugs (AEDs) were allowed for study inclusion provided at least 1 of the 3 AEDs was a benzodiazepine regardless of indication. The intermittent use of a benzodiazepine was permitted for epilepsy indications only and limited to 2 doses per 28 days; intermittent use for non-epilepsy indications was prohibited. The rationale for this change was based on data from SP0961 in which approximately 20% of PGTCS study participants with idiopathic generalized epilepsy (IGE) used benzodiazepines. Study participants were not excluded from the study due to benzodiazepine use unless they were using benzodiazepines intermittently for indications other than epilepsy. This change was consistent with other PGTCS studies in regards to benzodiazepine use.
• The secondary efficacy endpoint time to first PGTCS during the 24-week Treatment Period was added as a key secondary endpoint as UCB considers that LCM will improve the rate of seizure freedom in this difficult-to-treat population. A gatekeeping strategy was used to control Type I error.
• For the assessment of the effect of LCM on quality of life in pediatric study participants, the SP0982 protocol was updated to include the Pediatric Quality of Life Inventory™ (PedsQL). The PedsQL is widely used in epilepsy and other therapeutic areas, and allows for comparison with other diseases. In addition, the PedsQL also allows for consistency across age groups and development programs, and is available in many languages for global clinical studies.
• For the assessment of neurobehavior and cognition in pediatric study participants, the SP0982 protocol was updated to include the Achenbach Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function® (BRIEF), respectively. The addition of these assessments also allows for consistency across age groups and development programs. |
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25 Sep 2012 |
- Continuation 2 -
• To ensure study participant safety, interim assessments for safety and futility were performed using an independent data monitoring committee (IDMC) due to the novel study design and primary endpoint in this patient population. Furthermore, a minority of study participants (~10%) in SP0961 showed an increase in absence seizures that, in this uncontrolled study, could not be distinguished between the drug vs the natural course of the disease and required additional examination in the current study.
• SP0982 was an event-driven study where the statistical properties were based upon the number of events, not the number of study participants as is typical in most epilepsy studies (the primary efficacy variable was time to second PGTCS). As a result, the protocol was amended to reflect this focus. Furthermore, a maximum sample size of 250 study participants was introduced if 125 events were not observed on or before the 200th study participant randomized. This is standard for event-driven studies and represents an approximate 25% increase from the projected sample size, in case the event rate was lower than anticipated. |
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11 Jul 2014 |
Protocol Amendment 2, dated 11 Jul 2014, provided the following key changes.
The primary purpose of this substantial amendment was to identify significant changes to the study design and the inclusion of pediatric study participants (≥4 to <12 years of age). In addition, the key study secondary efficacy variable was changed to more accurately represent the study design.
• The protocol was updated to include randomization stratified by age at informed consent for study participants ≥4 to <12 years of age. This was in order to maintain balance within each treatment arm and within the existing baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the 16-week Combined Baseline Period prior to randomization) as well as provide greater control for variability when analyzing the primary efficacy variable (time to second seizure).
• An inclusion criterion was modified to include study participants ≥4 years of age. Exclusion criteria were modified in regards to study participants who had a diagnosis of developmental delay or mental retardation or a history of status epilepticus. The rationale for modifying the exclusion criteria was that study participants with developmental delay or mental retardation are more likely to have symptomatic rather than idiopathic seizures. The rationale for modifying the exclusion criteria for study participants with a history of status epilepticus was to align with the withdrawal criteria (ie, a study participant may have been withdrawn from the study due to an episode of status epilepticus, a prolongation of seizure duration, a worsening of seizure frequency, or emergence of a new seizure type considered by the investigator to require intervention). |
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08 Jun 2016 |
Protocol Amendment 4, dated 08 Jun 2016, provided the following key changes.
The primary purpose of this substantial amendment was to clarify elements of the study design including inclusion and exclusion criteria, exit criteria, and withdrawal criteria, as well as the duration of the Baseline Period, procedure for dividing the daily dose for the tablet formulation without breaking tablets, permitted and prohibited concomitant medication, consent for prescreening electroencephalogram (EEG), seizure count, temperature for storage of plasma samples, and determination of sample size. The protocol was also updated according to the new UCB protocol template, for example, with the addition of text regarding potential drug-induced liver injury (PDILI). |
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07 Nov 2017 |
Protocol Amendment 5, dated 07 Nov 2017, provided the following key changes.
The primary purpose of this substantial amendment was to stop the study participants’ study participation once 125 events had been observed to avoid exposing study participants to Placebo unnecessarily and allow for flexible dosing of the treatment in the open-label follow-up study EP0012.
In addition, the following changes were made:
• The initial plan was to enroll 20% pediatric study participants out of a total sample size of approximately 200 study participants, which would have resulted in 40 pediatric study participants enrolled in the study. Due to a fluctuating event rate, the study was changed to enroll study participants until the 125th event occurred (an event was defined as the occurrence of the second PGTCS during the 24-week Treatment Period). Changing the number of pediatric study participants from 20% to 40 absolute ensured that at least 40 pediatric study participants were recruited while also limiting the number of required pediatric study participants in case more than 200 study participants were enrolled. This was considered appropriate in light of the extremely challenging recruitment of pediatric study participants in this study. Additionally, from the biostatistical point of view, increasing the number of pediatric study participants from 40 to 45 or 50 is very unlikely to yield significantly new or different safety information.
• To update the introduction with regulatory information on the marketing authorization of Vimpat and to provide an update on the LCM clinical program.
• To appropriately align the Inclusion Criterion 7.a with the examples given in the supportive table.
• To clarify that Visit 5 was the beginning of the Maintenance Period (18 weeks).
• To remove some blood sampling details from the protocol and refer to the laboratory manual. |
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07 Nov 2017 |
- Continuation -
• To clarify the potential drug-induced liver injury (PDILI) criteria requiring immediate and permanent discontinuation of the investigational medicinal product (IMP).
• To clarify that if the monitor had no direct access to the source electronic medical records, certified copies should have been generated by the investigator and verified by the monitor against the original medical record.
• To make a minor clarification to the sentence about pooling strategies for age strata for consistency with the Statistical Analysis Plan (SAP). |
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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 |