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

Epilepsy, Partial Clinical Trial

Official title:

A Multi-Center, Open-Label, Long-Term, Follow-Up Study Of The Safety And Efficacy Of Levetiracetam (Ucb L059) In Children With Epilepsy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00150709
• Other study ID #: N157
• Status: Completed
• Phase: Phase 3
• Start date: January 26, 1998
• Est. completion date: January 25, 2006

Study information

• Verified date: June 2023
• Source: UCB Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 223
• Est. completion date: January 25, 2006
• Est. primary completion date: January 25, 2006
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 16 Years

Eligibility

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).

Related Conditions & MeSH terms

• Epilepsies, Partial
• Epilepsy
• Epilepsy, Partial

Intervention

Drug:
• Levetiracetam
Pharmaceutical form: Oral tablets and oral solution Route of administration: Oral use

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
UCB Pharma

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage Change From Baseline in Partial Onset (Type I) Seizure Frequency Per Week Over Time During the Treatment Period	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.	During the Treatment Period (an average of 2 years), compared to Baseline
Primary	Percentage Change From Baseline in Total (Type I, II, III) Seizure Frequency Per Week Over Time During the Treatment Period	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.	During the Treatment Period (an average of 2 years), compared to Baseline
Secondary	Absolute Change From Baseline in Partial Onset (Type I) Seizure Frequency Over Time During the Treatment Period	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.	During the Treatment Period (an average of 2 years), compared to Baseline
Secondary	Absolute Change From Baseline in Total (Type I, II, III) Seizure Frequency Per Week Over Time During the Treatment Period	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.	During the Treatment Period (an average of 2 years), compared to Baseline
Secondary	At Least 50% Responder Rate in Partial Onset (Type I) Seizure Frequency From Baseline Per Week During the Treatment Period	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).	During the Treatment Period (an average of 2 years), compared to Baseline
Secondary	At Least 50% Responder Rate in Total (Type I, II, III) Seizure Frequency From Baseline Per Week During the Treatment Period	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.	During the Treatment Period (an average of 2 years), compared to Baseline
Secondary	Number of Subjects Who Are Seizure-free for at Least 7 Days During the Treatment Period	A day was considered seizure-free if no seizures were reported for 24 hours.	During the Treatment Period (an average of 2 years)
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (Day 0)	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.	Day 0 (beginning day of the maintenance phase)
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (Day 1 - <= 2 Months)	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.	Day 1 - <= 2 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 2 Months - <= 4 Months)	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.	> 2 months - <= 4 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 4 Months - <= 6 Months)	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.	> 4 months - <= 6 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 6 Months - <= 8 Months)	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.	> 6 months - <= 8 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 8 Months - <= 10 Months)	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.	> 8 months - <= 10 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 10 Months - <= 12 Months)	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.	> 10 months - <= 12 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 12 Months - <= 14 Months)	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.	> 12 months - <= 14 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 14 Months - <= 16 Months)	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.	> 14 months - <= 16 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 16 Months - <= 18 Months)	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.	> 16 months - <= 18 months of the Maintenance Phase
Secondary	Cumulative Percentage of Subjects Who Are Continuously Seizure Free by Time Interval (> 18 Months - <= 20 Months)	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.	> 18 months - <= 20 months of the Maintenance Phase
Secondary	Number of Seizures by Type During the Treatment Period	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	During the Treatment Period (an average of 2 years)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 1	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.	Visit 1 (Screening Visit (Week 0))
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 1	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).	Titration Visit 1 (Week 2)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 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).	Titration Visit 2 (Week 4)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 3	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).	Titration Visit 3 (Week 6)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 2 (Month 2)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 3	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).	Visit 3 (Month 4)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 4 (Month 6)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 5	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).	Visit 5 (Month 9)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 6 (Month 12)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 7	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).	Visit 7 (Month 15)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 8	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).	Visit 8 (Month 18)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 9 (Month 21)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 10	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).	Visit 10 (Month 24)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 11	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).	Visit 11 (Month 27)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 12 (Month 30)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 13	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).	Visit 13 (Month 33)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 14	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).	Visit 14 (Month 36)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 15 (Month 39)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 16	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).	Visit 16 (Month 42)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 17	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).	Visit 17 (Month 45)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 18 (Month 48)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 19	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).	Visit 19 (Month 51)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 20	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).	Visit 20 (Month 54)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 21 (Month 57)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 22	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).	Visit 22 (Month 60)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 23	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).	Visit 23 (Month 63)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 24 (Month 66)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 25	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).	Visit 25 (Month 69)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 26	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).	Visit 26 (Month 72)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 27 (Month 75)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 28	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).	Visit 28 (Month 78)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 29	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).	Visit 29 (Month 81)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 30 (Month 84)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 31	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).	Visit 31 (Month 87)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Withdrawal Visit	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).	Withdrawal visit (up to Month 90)
Secondary	Percentage of Subjects in Categories of Investigator's Rating of Change to Previous Visit in Global Evaluation Scale at Final Visit	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).	Final visit (up to Month 90)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 1	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.	Visit 1 (Screening Visit (Week 0))
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 1	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).	Titration Visit 1 (Week 2)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 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).	Titration Visit 2 (Week 4)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Titration Visit 3	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).	Titration Visit 3 (Week 6)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 2 (Month 2)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 3	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).	Visit 3 (Month 4)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 4 (Month 6)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 5	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).	Visit 5 (Month 9)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 6 (Month 12)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 7	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).	Visit 7 (Month 15)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 8	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).	Visit 8 (Month 18)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 9 (Month 21)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 10	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).	Visit 10 (Month 24)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 11	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).	Visit 11 (Month 27)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 12 (Month 30)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 13	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).	Visit 13 (Month 33)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 14	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).	Visit 14 (Month 36)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 15 (Month 39)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 16	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).	Visit 16 (Month 42)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 17	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).	Visit 17 (Month 45)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 18 (Month 48)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 19	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).	Visit 19 (Month 51)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 20	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).	Visit 20 (Month 54)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 21 (Month 57)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 22	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).	Visit 22 (Month 60)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 23	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).	Visit 23 (Month 63)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 24 (Month 66)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 25	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).	Visit 25 (Month 69)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 26	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).	Visit 26 (Month 72)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 27 (Month 75)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 28	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).	Visit 28 (Month 78)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 29	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).	Visit 29 (Month 81)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 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).	Visit 30 (Month 84)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Visit 31	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).	Visit 31 (Month 87)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Withdrawal Visit	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).	Withdrawal visit (up to Month 90)
Secondary	Percentage of Subjects in Categories of Parent/Legal Guardian's Rating of Change to Previous Visit in Global Evaluation Scale at Final Visit	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).	Final visit (up to Month 90)

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