A Study Of The Safety And Efficacy Of Levetiracetam (Keppra®) (Ucb L059) In Children With Epilepsy

Phase 3

Completed

Conditions: Epilepsy, Partial

Interventions: Drug: Levetiracetam

Registration Number: NCT00150709

Lead Sponsor: UCB Pharma

Brief Summary: Open-label study to allow pediatric patients who have participated in prior Levetiracetam (Keppra®) studies to continue their treatment with adequate monitoring and standardized follow-up care until Levetiracetam (Keppra®) is approved for use in children or until the completion of the development program for pediatrics.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 223

Inclusion Criteria

Have completed Study N151, or any other applicable pediatric trials of Levetiracetam (Keppra®)
Be a patient for whom the treatment of Levetiracetam (Keppra®) would be of potential benefit such that the patient/parent(s)/legal guardian and the Investigator agree to continue treatment.

Exclusion Criteria

Not be on a ketogenic diet (during the course of this study).
Not have seizures too close together to accurately count (i.e., the patient's seizures must be countable).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
N159 PBO/LEV	Levetiracetam	Subjects had previously participated in study N159 in which they had received Placebo (PBO).
N01052 LEV/LEV	Levetiracetam	Subjects had previously participated in study N01052 in which they had received Levetiracetam (LEV).
N159 LEV/LEV	Levetiracetam	Subjects had previously participated in study N159 in which they had received Levetiracetam (LEV).
N01010+N151 LEV/LEV	Levetiracetam	Subjects had previously participated in study N01010 or study N151 in which they had received Levetiracetam (LEV).

Primary Outcome Measures

Name	Time	Method
Percentage Change From Baseline in Partial Onset (Type I) Seizure Frequency Per Week Over Time During the Treatment Period	During the Treatment Period (an average of 2 years), compared to Baseline	Percentage change from Baseline of partial onset (Type I) seizure frequency over the Treatment Period standardized to 1 week Period. According to the ILAE 1981 classification, seizures can be classified into one of the following three groups: Type I (partial onset seizures), Type II (generalized seizures) and Type III (unclassified seizures). Negative values indicate an improvement from Baseline.
Percentage Change From Baseline in Total (Type I, II, III) Seizure Frequency Per Week Over Time During the Treatment Period	During the Treatment Period (an average of 2 years), compared to Baseline	Percentage change from Baseline in total (type I, II, III) seizure frequency over the Treatment Period standardized to 1 week Period. Seizures were categorized in Type I (partial onset seizures), Type II (generalized seizures) and Type III (unclassified seizures) according to the ILAE 1981 classification. Negative values indicate an improvement from Baseline.

Secondary Outcome Measures

Name	Time	Method
Absolute Change From Baseline in Partial Onset (Type I) Seizure Frequency Over Time During the Treatment Period	During the Treatment Period (an average of 2 years), compared to Baseline	Absolute change from Baseline of Partial onset (Type I) seizure frequency over the Treatment Period standardized to 1 week Period. According to the ILAE 1981 classification, seizures can be classified into one of the following three groups: Type I (partial onset seizures), Type II (generalized seizures) and Type III (unclassified seizures). Negative values indicate an improvement from Baseline.
At Least 50% Responder Rate in Partial Onset (Type I) Seizure Frequency From Baseline Per Week During the Treatment Period	During the Treatment Period (an average of 2 years), compared to Baseline	At least 50% responder rate in Partial Onset (Type I) Seizure Frequency per Week over the Treatment Period is defined as the percentage of subjects with a reduction from baseline in Partial Onset (Type I) seizure frequency of at least 50%. According to the ILAE 1981 classification, seizures can be classified into one of the following three groups: Type I (partial onset seizures), Type II (generalized seizures) and Type III (unclassified seizures).
Number of Subjects Who Are Seizure-free for at Least 7 Days During the Treatment Period	During the Treatment Period (an average of 2 years)	A day was considered seizure-free if no seizures were reported for 24 hours.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (Day 0)	Day 0 (beginning day of the maintenance phase)	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Absolute Change From Baseline in Total (Type I, II, III) Seizure Frequency Per Week Over Time During the Treatment Period	During the Treatment Period (an average of 2 years), compared to Baseline	Absolute change from Baseline in total (type I, II, III) seizure frequency over the Treatment Period standardized to 1 week period. Seizures were categorized in Type I (partial onset seizures), Type II (generalized seizures) and Type III (unclassified seizures) according to the ILAE 1981 classification. Negative values indicate improvement from Baseline.
At Least 50% Responder Rate in Total (Type I, II, III) Seizure Frequency From Baseline Per Week During the Treatment Period	During the Treatment Period (an average of 2 years), compared to Baseline	At least 50% responder rate in total (Type I, II, III) Seizure Frequency per Week over the Treatment Period is defined as the percentage of subjects with a reduction from baseline in total (Type I, II, III) seizure frequency of at least 50%. Seizures were categorized in Type I (partial onset seizures), Type II (generalized seizures) and Type III (unclassified seizures) according to the ILAE 1981 classification.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (Day 1 - <= 2 Months)	Day 1 - <= 2 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 4 Months - <= 6 Months)	> 4 months - <= 6 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 6 Months - <= 8 Months)	> 6 months - <= 8 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 2 Months - <= 4 Months)	> 2 months - <= 4 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 14 Months - <= 16 Months)	> 14 months - <= 16 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 3	Titration Visit 3 (Week 6)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 6	Visit 6 (Month 12)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 13	Visit 13 (Month 33)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 14	Visit 14 (Month 36)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 16	Visit 16 (Month 42)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 21	Visit 21 (Month 57)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 28	Visit 28 (Month 78)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 8 Months - <= 10 Months)	> 8 months - <= 10 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 10 Months - <= 12 Months)	> 10 months - <= 12 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 16 Months - <= 18 Months)	> 16 months - <= 18 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 18 Months - <= 20 Months)	> 18 months - <= 20 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 1	Titration Visit 1 (Week 2)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The Global Evaluation Scale (GES) is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 5	Visit 5 (Month 9)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 12 Months - <= 14 Months)	> 12 months - <= 14 months of the Maintenance Phase	A time interval was considered seizure-free if no seizures were reported in that time interval. The Treatment Period consisted of a 6-week Titration Phase and a Maintenance Phase lasting until market approval or completion of development of levetiracetam for the pediatric indication.
Number of Seizures by Type During the Treatment Period	During the Treatment Period (an average of 2 years)	Number of following seizure types were assessed: Total seizures (Type I, II, III), Total Type I seizures, Total Type II seizures, Total Type III seizures
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 1	Visit 1 (Screening Visit (Week 0))	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The Global Evaluation Scale (GES) is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit). The reference time point for Visit 1 is in the respective feeder study of the participant.
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 2	Titration Visit 2 (Week 4)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 2	Visit 2 (Month 2)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 3	Visit 3 (Month 4)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 4	Visit 4 (Month 6)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 7	Visit 7 (Month 15)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 8	Visit 8 (Month 18)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 18	Visit 18 (Month 48)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 19	Visit 19 (Month 51)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 20	Visit 20 (Month 54)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 22	Visit 22 (Month 60)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 24	Visit 24 (Month 66)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 26	Visit 26 (Month 72)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 9	Visit 9 (Month 21)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 12	Visit 12 (Month 30)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 10	Visit 10 (Month 24)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 11	Visit 11 (Month 27)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 15	Visit 15 (Month 39)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 17	Visit 17 (Month 45)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 23	Visit 23 (Month 63)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 25	Visit 25 (Month 69)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 30	Visit 30 (Month 84)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Final Visit	Final visit (up to Month 90)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 1	Visit 1 (Screening Visit (Week 0))	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit). The reference time point for Visit 1 is in the respective feeder study of the participant.
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 3	Visit 3 (Month 4)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 17	Visit 17 (Month 45)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 22	Visit 22 (Month 60)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 27	Visit 27 (Month 75)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Withdrawal Visit	Withdrawal visit (up to Month 90)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 2	Titration Visit 2 (Week 4)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 3	Titration Visit 3 (Week 6)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 6	Visit 6 (Month 12)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 29	Visit 29 (Month 81)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 31	Visit 31 (Month 87)	Disease evolution compared to the last visit was evaluated by the investigator applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 1	Titration Visit 1 (Week 2)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 2	Visit 2 (Month 2)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 5	Visit 5 (Month 9)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 8	Visit 8 (Month 18)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 13	Visit 13 (Month 33)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 14	Visit 14 (Month 36)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 4	Visit 4 (Month 6)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 7	Visit 7 (Month 15)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 9	Visit 9 (Month 21)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 11	Visit 11 (Month 27)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 20	Visit 20 (Month 54)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 10	Visit 10 (Month 24)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 19	Visit 19 (Month 51)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Withdrawal Visit	Withdrawal visit (up to Month 90)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 12	Visit 12 (Month 30)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 15	Visit 15 (Month 39)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 16	Visit 16 (Month 42)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 18	Visit 18 (Month 48)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 21	Visit 21 (Month 57)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 26	Visit 26 (Month 72)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 28	Visit 28 (Month 78)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 23	Visit 23 (Month 63)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 27	Visit 27 (Month 75)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 31	Visit 31 (Month 87)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 24	Visit 24 (Month 66)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 25	Visit 25 (Month 69)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 29	Visit 29 (Month 81)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 30	Visit 30 (Month 84)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).
Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Final Visit	Final visit (up to Month 90)	Disease evolution compared to the last visit was evaluated by the parent/legal guardian applying following categories: Marked improvement, moderate improvement, slight improvement, no change, slight worsening, moderate worsening, marked worsening, not done. The GES is a 7-point scale wherein 7 categories are ranked from 1 (marked improvement from previous visit) to 7 (marked worsening from previous visit).