Trial Outcomes & Findings for Study of Rufinamide in Pediatric Subjects 1 to Less Than 4 Years of Age With Lennox-Gastaut Syndrome Inadequately Controlled With Other Anti-epileptic Drugs (NCT NCT01405053)

Last Updated: 2019-08-06

Results Overview

CBCL: 99-item questionnaire measures specific behavioral problems or developmental delays, answered by a parent/legal guardian or suitable caregiver. Each item were rated using 3-point scale (0=Not True, 1=Somewhat/Sometimes True, 2=Very True/ Often True) to indicate how often or typical the behavior was. The 99 items were combined to yield scores for 8 problem area scales (emotionally reactive, anxious/depressed, somatic complaints, withdrawn, sleep problems, attention problems, aggressive behavior, and other problems) and 3 summary scores (internalizing, externalizing, and total problems). Total Problem score was sum of all the problem areas plus 1 additional item, ranging from 0 to 198. Total raw scores are converted to t-scores with mean of 50 and standard deviation (SD) of 10. T-scores were standardized test scores that indicate same degree of elevation in problems relative to the normative sample of peers. Higher scores were indicative of more problems.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

37 participants

Primary outcome timeframe

End of Treatment Period (up to approximately Week 106)

Results posted on

2019-08-06

Participant Flow

Participants took part in the study at 19 investigative sites in the United States, Canada, France, Greece, Italy, and Poland from 16 June 2011 to 02 November 2015.

A total of 43 participants were screened, out of which 37 participants were randomized and treated in the study.

Participant milestones

Participant milestones
Measure	Rufinamide Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 Antiepileptic Drugs (AEDs). Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 milligram per kilogram per day (mg/kg/day) in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Overall Study STARTED	25	12
Overall Study COMPLETED	15	4
Overall Study NOT COMPLETED	10	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Rufinamide Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 Antiepileptic Drugs (AEDs). Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 milligram per kilogram per day (mg/kg/day) in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Overall Study Adverse Event	3	0
Overall Study Lost to Follow-up	0	1
Overall Study Participant choice	2	1
Overall Study Inadequate therapeutic effect	2	1
Overall Study Withdrawal by Subject	3	4
Overall Study Other	0	1

Baseline Characteristics

Study of Rufinamide in Pediatric Subjects 1 to Less Than 4 Years of Age With Lennox-Gastaut Syndrome Inadequately Controlled With Other Anti-epileptic Drugs

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rufinamide n=25 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=12 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.	Total n=37 Participants Total of all reporting groups
Age, Continuous	28.3 months STANDARD_DEVIATION 9.99 • n=93 Participants	29.8 months STANDARD_DEVIATION 9.85 • n=4 Participants	28.8 months STANDARD_DEVIATION 9.83 • n=27 Participants
Sex: Female, Male Female	11 Participants n=93 Participants	2 Participants n=4 Participants	13 Participants n=27 Participants
Sex: Female, Male Male	14 Participants n=93 Participants	10 Participants n=4 Participants	24 Participants n=27 Participants

PRIMARY outcome

Timeframe: End of Treatment Period (up to approximately Week 106)

Population: The full analysis set for primary efficacy variable included randomized participants who received rufinamide or any other approved add-on AED of the investigator's choice and had baseline and at least 1 postdose cognition measurement. Participants who were evaluable for this outcome measure at given time period were included for assessment.

Outcome measures

Outcome measures
Measure	Rufinamide n=15 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=4 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Child Behavior Checklist (CBCL) Total Problem T-scores at the End of 2-year Treatment Period	55.7 score on a scale Standard Deviation 15.81	54.8 score on a scale Standard Deviation 4.50

PRIMARY outcome

Timeframe: Baseline and End of Treatment Period (up to approximately Week 106)

Outcome measures

Outcome measures
Measure	Rufinamide n=24 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=9 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Change From Baseline in CBCL Total Problem T-Scores at End of 2-year Treatment Period Baseline	56.6 score on a scale Standard Deviation 11.27	62.8 score on a scale Standard Deviation 13.07
Change From Baseline in CBCL Total Problem T-Scores at End of 2-year Treatment Period Change at Week 106	-0.3 score on a scale Standard Deviation 15.72	-6.7 score on a scale Standard Deviation 0.58

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to the End of the Treatment Period (up to approximately Week 106)

Population: The full analysis set for other efficacy variable included randomized participants who received rufinamide or any other add-on AED of the investigator's choice and had a baseline efficacy assessment and at least 1 post baseline efficacy assessment. Participants who were evaluable at a given time point were included for this assessment.

Withdrawal from either rufinamide or other AED was due to the occurrence of an adverse event or for lack of efficacy. Data was obtained till Week 106 and was extrapolated using Kaplan-Meier method to determine the overall survival time (in weeks) to withdrawal from treatment (excluding taper) due to an adverse event or lack efficacy.

Outcome measures

Outcome measures
Measure	Rufinamide n=2 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=2 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Time to Withdrawal From Treatment Due to an Adverse Event or Lack of Efficacy	142.0 weeks NA: Lower and upper limits of 95% Confidence Interval could not be calculated since insufficient number of participants had withdrawal from treatment due to adverse event or lack of efficacy.	28.0 weeks Interval 17.7 to NA: Lower and upper limits of 95% Confidence Interval could not be calculated since insufficient number of participants had withdrawal from treatment due to adverse event or lack of efficacy.

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to End of the Treatment Period (up to approximately Week 106)

Population: The full analysis set for other efficacy variable included randomized participants who received rufinamide or any other add-on AED of the investigator's choice and had a baseline efficacy assessment and at least 1 postbaseline efficacy assessment. Participants evaluable for this outcome measure at given time period were included for assessment.

The frequency per 28 days was defined as (S/D)\*28 where, S was equal to the sum of the seizures reported in the participant seizure diary during the specified time interval and D was equal to the number of days with non-missing data in the participant seizure diary for the specified study phase. The number of seizures was assessed and recorded by the participant's parent(s)/caregiver(s) in the participant seizure diary.

Outcome measures

Outcome measures
Measure	Rufinamide n=24 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=8 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Percent Change in Total Seizure Frequency Per 28 Days	-7.05 percent change in seizure frequency Interval -79.2 to 3644.1	-20.15 percent change in seizure frequency Interval -83.3 to 143.1

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to End of Treatment Period (up to approximately Week 106)

Population: The full analysis set for other efficacy variable included randomized participants who received rufinamide or any other add-on AED of the investigator's choice and had a baseline efficacy assessment and at least 1 postbaseline efficacy assessment. Participants evaluable for this outcome measure at given time period were included for assessment.

Outcome measures

Outcome measures
Measure	Rufinamide n=24 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=9 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days Partial seizures	-39.8 percent change in seizure frequency Interval -100.0 to 52281.9	-57.65 percent change in seizure frequency Interval -98.1 to -17.2
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days Absence seizures	-23.6 percent change in seizure frequency Interval -100.0 to 86.8	-49.70 percent change in seizure frequency Interval -98.9 to 1846.7
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days Atypical absence seizures	-70.95 percent change in seizure frequency Interval -100.0 to 16825.4	4.90 percent change in seizure frequency Interval -90.9 to 1189.7
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days Myoclonic seizures	-24.60 percent change in seizure frequency Interval -73.3 to 11462.4	-27.90 percent change in seizure frequency Interval -60.9 to 130.2
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days Clonic seizures	-60.85 percent change in seizure frequency Interval -100.0 to 140.4	-48.35 percent change in seizure frequency Interval -54.2 to -42.5
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days Tonic-atonic seizures	-35.20 percent change in seizure frequency Interval -100.0 to 1250.6	-31.80 percent change in seizure frequency Interval -81.9 to -4.0
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days Primary generalized tonic-clonic seizures	-97.80 percent change in seizure frequency Interval -100.0 to 37.6	-96.60 percent change in seizure frequency Interval -96.6 to -96.6
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days Other seizures	-90.65 percent change in seizure frequency Interval -100.0 to 183.8	-100.00 percent change in seizure frequency Interval -100.0 to -54.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to End of Treatment Period (up to approximately Week 106)

Worsening of seizures was summarized by the incidence of participants with doubling in total seizure frequency, doubling in frequency of major seizures (generalized tonic-clonic, drop attacks), or occurrence of new seizure type during each successive 3 to 4 month visit interval of the Maintenance Period relative to baseline.

Outcome measures

Outcome measures
Measure	Rufinamide n=24 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=9 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Incidence of Worsening of Seizures Doubling in total seizure frequency	4 Participants	1 Participants
Incidence of Worsening of Seizures Doubling in frequency of major seizures	5 Participants	1 Participants
Incidence of Worsening of Seizures Occurrence of a new seizure type	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 106

Population: The full analysis set for other efficacy variable included randomized participants who received rufinamide or any other approved add-on AED of the investigator's choice and had a baseline efficacy and at least 1 postbaseline efficacy assessment. Participants evaluable for this outcome measure at given time period were included for assessment.

CBCL: 99-item questionnaire, measures behavioral problems/developmental delays, answered by parent/guardian/caregiver. Each item rated on 3-point scale (0=Not True,1=Somewhat/Sometimes True, 2=Very/Often True). 99 items were combined to give scores for 8 problem area scales, where 1 for each 8 syndrome (emotionally reactive, anxious/depressed, somatic, withdrawn, sleep, attention, aggressive behavior, and other problems) were calculated, range: 0 (normal) to 16 (clinical behavior) and 3 summary scores (internalizing, externalizing, and total problems). All 3 summary scores reported scaled to T-scores. Total Problem score was sum of all the problem areas plus 1 additional item, ranging from 0 to 198. Total raw score were converted to t-scores with mean of 50 and SD of 10. T-scores were standardized test scores that indicate same degree of elevation in problems relative to normative sample of peers. Higher scores were indicative of more problems.

Outcome measures

Outcome measures
Measure	Rufinamide n=24 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=9 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total emotional reactive scores	59.0 score on a scale Standard Deviation 8.13	60.9 score on a scale Standard Deviation 8.64
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week 106:Total emotional reactive scores	-1.1 score on a scale Standard Deviation 9.30	-1.3 score on a scale Standard Deviation 6.11
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total anxious/depression scores	56.4 score on a scale Standard Deviation 7.48	54.6 score on a scale Standard Deviation 6.67
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week 106:Total anxious/depression scores	0.5 score on a scale Standard Deviation 8.87	0.7 score on a scale Standard Deviation 1.15
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total Somatic Complaints Scores	59.4 score on a scale Standard Deviation 8.13	54.9 score on a scale Standard Deviation 4.70
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week 106:Total Somatic Complaints Scores	0.1 score on a scale Standard Deviation 11.24	-1.7 score on a scale Standard Deviation 2.89
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total withdrawn scores	71.5 score on a scale Standard Deviation 11.72	72.1 score on a scale Standard Deviation 11.03
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week 106:Total withdrawn scores	-2.2 score on a scale Standard Deviation 13.22	-7.0 score on a scale Standard Deviation 9.54
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total Sleep Problems Scores	57.8 score on a scale Standard Deviation 10.72	62.4 score on a scale Standard Deviation 8.57
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week 106:Total sleep problem scores	-1.9 score on a scale Standard Deviation 12.30	-5.7 score on a scale Standard Deviation 7.57
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total attention problems scores	59.3 score on a scale Standard Deviation 9.17	65.9 score on a scale Standard Deviation 10.72
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week 106:Total attention problems scores	-1.1 score on a scale Standard Deviation 4.65	-7.7 score on a scale Standard Deviation 2.52
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total Aggressive Behavior Scores	52.5 score on a scale Standard Deviation 5.01	58.6 score on a scale Standard Deviation 12.07
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week106:Total aggressive behavior scores	3.2 score on a scale Standard Deviation 6.26	-0.3 score on a scale Standard Deviation 2.89
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total internalizing scores	61.6 score on a scale Standard Deviation 10.78	60.6 score on a scale Standard Deviation 9.71
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week 106:Total internalizing scores	-1.5 score on a scale Standard Deviation 13.73	-2.7 score on a scale Standard Deviation 1.53
Change From Baseline in CBCL Sub Scores at Week 106 Baseline: Total externalizing scores	47.5 score on a scale Standard Deviation 11.22	58.1 score on a scale Standard Deviation 15.92
Change From Baseline in CBCL Sub Scores at Week 106 Change at Week 106:Total externalizing scores	4.7 score on a scale Standard Deviation 10.07	-3.7 score on a scale Standard Deviation 3.51

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline, Weeks 24, 56, 88, and 106

LDS, a caregiver-administered survey consisted of 8-item questionnaire and vocabulary list of 310 words organized within 14 semantic categories. List contained high frequency words (e.g. more), less common words (e.g. hamburger), and lexical chunks (e.g. Sesame Street). Average LDS score, calculated by dividing total number of words across all valid phrases by number of phrases with greater than (\>) 0words; for participants with no words, average was 0. This value was compared to standardized chart to obtain percentile rating. LDS provided 2 scores: average phrase length (number of words/phrase) and number of endorsed vocabulary words. LDS phrase length was categorized into delay (less than or equal to \[\<=\] 20th percentile) and no delay (\>20th percentile). LDS vocabulary was categorized into delay(\<=15th percentile)and no delay(\>15th percentile). Both raw scores were used to provide 2 normative scores based on child's age in months. Higher scores indicated better language development.

Outcome measures

Outcome measures
Measure	Rufinamide n=24 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=9 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Baseline: LDS average phrase length	0.3 words Standard Deviation 0.87	0 words Standard Deviation 0.00
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Change at Week 24: LDS average phrase length	0.2 words Standard Deviation 1.11	0.7 words Standard Deviation 1.28
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Change at Week 56: LDS average phrase length	0.1 words Standard Deviation 1.02	0.0 words Standard Deviation 0.00
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Change at Week 88: LDS average phrase length	0.1 words Standard Deviation 1.03	0.0 words Standard Deviation 0.00
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Change at Week 106: LDS average phrase length	0.4 words Standard Deviation 1.12	0.0 words Standard Deviation 0.00
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Baseline:LDS Vocabulary Score	10.4 words Standard Deviation 37.72	0.6 words Standard Deviation 1.67
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Change at Week 24:LDS Vocabulary Score	7.1 words Standard Deviation 21.55	4.8 words Standard Deviation 8.22
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Change at Week 56:LDS Vocabulary Score	17.9 words Standard Deviation 39.24	-0.40 words Standard Deviation 2.15
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Change at Week 88:LDS Vocabulary Score	25.4 words Standard Deviation 49.87	0.0 words Standard Deviation 0.00
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period Change at Week 106:LDS Vocabulary Score	39.6 words Standard Deviation 75.62	1.0 words Standard Deviation 2.00

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 106

Population: The full analysis set for other efficacy variable included randomized participants who received rufinamide or any other add-on AED of the investigator's choice and had a baseline efficacy assessment and at least 1 postbaseline efficacy assessment. Participants evaluable for this outcome measure at given time period were included for assessment.

The QoLCE was a 76-item questionnaire designed specifically to measure quality of life in children with epilepsy. QOLCE consists of 16 quality of life subscales (14 multi-item and 2 single item). Each subscales had number of items or questions with responses as excellent, very good, good, fair, and poor. They were changed to 1, 2, 3, 4, and 5 as per instructions. Then changed on a scale of 100, where 1 is equal to (=) 0, 2=25, 3=50, 4=75, and 5=100. Items corresponding to each subscale were marked and there mean score was score of that subscale. The form was completed by a parent or caregiver who interacted with the child on a consistent, daily basis and took about 20 to 30 minutes to complete. The higher the score, the better the child's quality of life.

Outcome measures

Outcome measures
Measure	Rufinamide n=24 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=9 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Change From Baseline in Total Score of Quality of Life in Childhood Epilepsy (QoLCE) Scale Baseline	50.4 score on a scale Standard Deviation 10.05	49.6 score on a scale Standard Deviation 7.88
Change From Baseline in Total Score of Quality of Life in Childhood Epilepsy (QoLCE) Scale Week 106	-1.3 score on a scale Standard Deviation 8.49	1.5 score on a scale Standard Deviation 1.00

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 106

The QoLCE was a 76-item questionnaire designed specifically to measure quality of life in children with epilepsy. QOLCE consists of 16 quality of life subscales (14 multi-item and 2 single item). Each subscales had number of items or questions with responses as excellent, very good, good, fair, and poor. They were changed to 1, 2, 3, 4, and 5 as per instructions. Then changed on a scale of 100, where 1=0, 2=25, 3=50, 4=75, and 5=100. Items corresponding to each subscale were marked and there mean score was score of that subscale. The form was completed by a parent or caregiver who interacted with the child on a consistent, daily basis and took about 20 to 30 minutes to complete. The higher the score, the better the child's quality of life.

Outcome measures

Outcome measures
Measure	Rufinamide n=24 Participants Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=9 Participants Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Change From Baseline in Sub-scores in QoLCE Baseline: Physical restriction	50.1 score on a scale Standard Deviation 10.33	49.9 score on a scale Standard Deviation 8.23
Change From Baseline in Sub-scores in QoLCE Baseline: Energy/Fatigue	51.6 score on a scale Standard Deviation 10.48	44.3 score on a scale Standard Deviation 4.55
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Energy/Fatigue	-3.1 score on a scale Standard Deviation 12.22	2.8 score on a scale Standard Deviation 4.11
Change From Baseline in Sub-scores in QoLCE Baseline: Attention/Concentration	49.9 score on a scale Standard Deviation 10.14	51.1 score on a scale Standard Deviation 9.05
Change From Baseline in Sub-scores in QoLCE Change at Week 106:Attention/Concentration	-2.1 score on a scale Standard Deviation 7.31	2.5 score on a scale Standard Deviation 6.24
Change From Baseline in Sub-scores in QoLCE Baseline: Memory	50.2 score on a scale Standard Deviation 9.54	52.6 score on a scale Standard Deviation 6.57
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Memory	-0.5 score on a scale Standard Deviation 12.18	0.5 score on a scale Standard Deviation 1.00
Change From Baseline in Sub-scores in QoLCE Baseline: Language	49.8 score on a scale Standard Deviation 10.42	53.1 score on a scale Standard Deviation 4.43
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Language	-0.5 score on a scale Standard Deviation 9.63	-0.5 score on a scale Standard Deviation 11.56
Change From Baseline in Sub-scores in QoLCE Baseline: Other cognitive	48.6 score on a scale Standard Deviation 10.32	53.1 score on a scale Standard Deviation 7.54
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Other cognitive	0.3 score on a scale Standard Deviation 6.19	-1.0 score on a scale Standard Deviation 4.00
Change From Baseline in Sub-scores in QoLCE Baseline: Depression	51.2 score on a scale Standard Deviation 9.27	45.3 score on a scale Standard Deviation 10.59
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Depression	-2.6 score on a scale Standard Deviation 11.64	2.3 score on a scale Standard Deviation 8.62
Change From Baseline in Sub-scores in QoLCE Baseline: Anxiety	50.1 score on a scale Standard Deviation 10.27	48.5 score on a scale Standard Deviation 12.29
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Anxiety	-0.1 score on a scale Standard Deviation 12.12	1.3 score on a scale Standard Deviation 6.90
Change From Baseline in Sub-scores in QoLCE Baseline: Control/Helplessness	50.7 score on a scale Standard Deviation 9.31	47.8 score on a scale Standard Deviation 12.27
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Control/Helplessness	0.2 score on a scale Standard Deviation 10.90	3.0 score on a scale Standard Deviation 11.52
Change From Baseline in Sub-scores in QoLCE Baseline: Self-esteem	50.1 score on a scale Standard Deviation 10.18	50.5 score on a scale Standard Deviation 10.98
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Self-esteem	-1.3 score on a scale Standard Deviation 9.48	-6.0 score on a scale Standard Deviation 8.08
Change From Baseline in Sub-scores in QoLCE Baseline: Social interactions	49.9 score on a scale Standard Deviation 10.56	50.5 score on a scale Standard Deviation 8.48
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Social interactions	-1.5 score on a scale Standard Deviation 11.64	4.0 score on a scale Standard Deviation 5.89
Change From Baseline in Sub-scores in QoLCE Baseline: Social activities	50.5 score on a scale Standard Deviation 10.50	46.6 score on a scale Standard Deviation 3.96
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Social activities	0.9 score on a scale Standard Deviation 11.30	3.5 score on a scale Standard Deviation 3.70
Change From Baseline in Sub-scores in QoLCE Baseline: Stigma	48.9 score on a scale Standard Deviation 11.06	50.7 score on a scale Standard Deviation 8.07
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Stigma	-0.1 score on a scale Standard Deviation 12.67	4.5 score on a scale Standard Deviation 10.25
Change From Baseline in Sub-scores in QoLCE Baseline: Behavior	51.4 score on a scale Standard Deviation 10.39	45.8 score on a scale Standard Deviation 9.33
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Behavior	0.2 score on a scale Standard Deviation 5.92	7.3 score on a scale Standard Deviation 6.55
Change From Baseline in Sub-scores in QoLCE Baseline: General-health	50.5 score on a scale Standard Deviation 10.02	49.0 score on a scale Standard Deviation 8.40
Change From Baseline in Sub-scores in QoLCE Change at Week 106: General health	-1.3 score on a scale Standard Deviation 10.98	-2.0 score on a scale Standard Deviation 10.86
Change From Baseline in Sub-scores in QoLCE Baseline: Quality-of-life	49.5 score on a scale Standard Deviation 9.71	50.7 score on a scale Standard Deviation 9.98
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Quality-of-life	1.1 score on a scale Standard Deviation 9.46	3.3 score on a scale Standard Deviation 12.28
Change From Baseline in Sub-scores in QoLCE Change at Week 106: Physical restriction	-1.0 score on a scale Standard Deviation 7.51	-6.8 score on a scale Standard Deviation 7.32

Adverse Events

Rufinamide

Serious events: 10 serious events

Other events: 21 other events

Deaths: 1 deaths

Any Other Approved Antiepileptic Drug

Serious events: 5 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Eisai Medical Services

Eisai Inc.

Phone: 1-888-422-4743

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Rufinamide n=25 participants at risk Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=12 participants at risk Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Eye disorders Blindness	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Bronchitis	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Bronchitis viral	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Bronchopneumonia	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Encephalitis	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Gastroenteritis	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Pneumonia	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Pneumonia influenzal	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Respiratory syncytial virus bronchiolitis	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Respiratory tract infection	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Viral infection	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Injury, poisoning and procedural complications Joint dislocation	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Metabolism and nutrition disorders Dehydration	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Nervous system disorders Generalized tonic-clonic seizure	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Nervous system disorders Lethargy	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Nervous system disorders Seizure	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	25.0% 3/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Nervous system disorders Status epilepticus	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Respiratory distress	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Skin and subcutaneous tissue disorders Rash	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)

Measure	Rufinamide n=25 participants at risk Participants received rufinamide oral suspension as an add-on therapy to the participant's existing regimen of 1 to 3 AEDs. Participants underwent a 2 week Titration Period during which rufinamide dose was increased from 10 mg/kg/day in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.	Any Other Approved Antiepileptic Drug n=12 participants at risk Participants received any other approved AEDs of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator's usual practice.
Investigations Weight decreased	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Metabolism and nutrition disorders Decreased appetite	12.0% 3/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Nervous system disorders Somnolence	20.0% 5/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Gastrointestinal disorders Constipation	12.0% 3/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Gastrointestinal disorders Diarrhoea	16.0% 4/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	25.0% 3/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Gastrointestinal disorders Nausea	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Gastrointestinal disorders Vomiting	28.0% 7/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
General disorders Gait disturbance	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
General disorders Pyrexia	16.0% 4/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	25.0% 3/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Bronchiolitis	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Bronchitis	12.0% 3/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Nasopharyngitis	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Otitis media	16.0% 4/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Pneumonia	16.0% 4/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Sinusitis	16.0% 4/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Upper respiratory tract infection	28.0% 7/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	33.3% 4/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Investigations Blood bicarbonate decreased	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Psychiatric disorders Irritability	12.0% 3/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Psychiatric disorders Sleep disorder	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Cough	16.0% 4/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	16.7% 2/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Lower respiratory tract congestion	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Nasal congestion	12.0% 3/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Respiratory tract congestion	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	0.00% 0/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Skin and subcutaneous tissue disorders Dermatitis diaper	4.0% 1/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Skin and subcutaneous tissue disorders Rash	8.0% 2/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Urinary tract infection	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Injury, poisoning and procedural complications Lip injury	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Injury, poisoning and procedural complications Post procedural complication	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Injury, poisoning and procedural complications Postoperative fever	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Injury, poisoning and procedural complications Procedural nausea	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Injury, poisoning and procedural complications Procedural pain	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Upper respiratory tract congestion	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Respiratory, thoracic and mediastinal disorders Stridor	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Nervous system disorders Circadian rhythm sleep disorder	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Nervous system disorders Cognitive disorder	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Surgical and medical procedures Strabismus correction	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Psychiatric disorders Aggression	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
Infections and infestations Pharyngitis streptococcal	0.00% 0/25 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)	8.3% 1/12 • From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)