A Study of the Efficacy and Safety of Pregabalin as Add-On Therapy for Partial Onset Seizures in Children Ages 4-16 Years

All partial onset seizures experienced during baseline phase were recorded by the participants or their parents/legal guardian, in a daily seizure diary. 28-day seizure rate for all partial onset seizures = ([number of seizures in the baseline phase] divided by [number of days in baseline phase minus {-} number of missing diary days in baseline phase])*28. For log-transformation, the quantity 1 was added to the 28-day seizure rate for all participants to account for any possible "0" seizure incidence. This resulted in final calculation as: log transformed (28-day seizure rate +1).

All partial onset seizures experienced during treatment phase were recorded by the participants or their parents/legal guardian in a daily seizure diary. 28-day seizure rate for all partial onset seizures = ([number of seizures in the treatment phase] divided by [number of days in treatment phase minus {-} number of missing diary days in treatment phase])*28. For log-transformation, the quantity 1 was added to the 28-day seizure rate for all participants to account for any possible "0" seizure incidence. This resulted in final calculation as: log transformed (28-day seizure rate +1).

Percentage of participants with 50 percent (%) or greater reduction from baseline in 28-day seizure rate during the 12 week treatment phase were reported. 28-day seizure rate for all partial onset seizures = ([number of seizures in the treatment phase] divided by [number of days in treatment phase minus {-} number of missing diary days in treatment phase])*28.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 7 days after last dose of study drug (up to 13 weeks) that were absent before treatment or that worsened relative to pre- treatment state. AEs included both serious and non-serious adverse events.

Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 7 days after last dose of study drug (up to 13 weeks) that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to drug was assessed by the investigator. AEs included both serious and non-serious adverse events.

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. AEs were classified according to the severity in 3 categories a) mild: AEs does not interfere with participant's usual function b) moderate: AEs interferes to some extent with participant's usual function c) severe: AEs interferes significantly with participant's usual function.

The C-SSRS (mapped to C-CASA) is a participant-rated questionnaire to assess suicidal ideation and suicidal behavior. For suicidal ideation and behaviour, data from C-SSRS was mapped to C-CASA codes 1, 2, 3, 4 and 7. C-SSRS assessed whether participant experienced the following: completed suicide (C-CASA code 1); suicide attempt (response of "Yes" on "actual attempt") (C-CASA code 2); preparatory acts toward imminent suicidal behavior (ISB) ("Yes" on "preparatory acts or behavior")(C-CASA code 3); suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent) (C-CASA code 4); any self-injurious behavior with no suicidal intent (C-CASA code 7). In this outcome, number of participants with positive response (response of "yes") to C-SSRS (mapped to C-CASA categories 2, 3, 4 and 7) at baseline were reported.

C-SSRS (mapped to C-CASA):participant-rated questionnaire to assess suicidal ideation and suicidal behavior. For suicidal ideation and behaviour, data from C-SSRS was mapped to C-CASA codes 1, 2, 3, 4 and 7. C-SSRS assessed whether participant experienced the following: completed suicide (C-CASA code 1); suicide attempt (response of "Yes" on "actual attempt") (C-CASA code 2); preparatory acts toward imminent suicidal behavior (ISB) ("Yes" on "preparatory acts or behavior")(C-CASA code 3); suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent) (C-CASA code 4); any self-injurious behavior with no suicidal intent (C-CASA code 7). Number of participants with positive response (response of "yes") to C-SSRS (mapped to C-CASA categories 1, 2, 3, 4 and 7) during post baseline time period (Day 1 up to Week 13) were reported

CBCL assessed suicidal behavior in children below 6 years. It is 100-item questionnaire completed by parent/legal guardian, based on participant's behavior in past 2 months. All 100 items rated on 3-point scale: 0=not true for that child; 1=sometimes true; 2=very/often true. Total CBCL score ranges from 0 (not true) to 200 (very/often true). Higher scores=higher levels of problematic behaviors or dysfunction. Scores from all items were used to calculate 3 subscale scores: Withdrawn subscale scores, Internalizing problems subscale scores and total problem subscale scores. All subscale scores reported scaled to T Scores. Higher scores for each CBCL subscales indicated higher levels of problematic behaviors or dysfunction. In this study, a cut-off of >=68 on the T-scores was used for all 3 subscales. If a participant T Score was >=68 in any of the sub-scales, the participant was referred for Mental Health Risk Assessment that included assessment of participant continuation to the study.

CBCL assessed suicidal behavior in children below 6 years. It is 100-item questionnaire completed by parent/legal guardian, based on participant's behavior in past 2 months. All 100 items rated on 3-point scale: 0=not true for that child; 1=sometimes true; 2=very/often true. Total CBCL score ranges from 0 (not true) to 200 (very/often true). Higher scores=higher levels of problematic behaviors or dysfunction. Scores from all items were used to calculate 3 subscale scores: Withdrawn subscale scores, Internalizing problems subscale scores and total problem subscale scores. All subscale scores reported scaled to T Scores. Higher scores for each CBCL subscales indicated higher levels of problematic behaviors or dysfunction. In this study, a cut-off of >=68 on the T-scores was used for all 3 subscales. If a participant T Score was >=68 in any of the sub-scales, the participant was referred for Mental Health Risk Assessment that included assessment of participant continuation to the study

CBCL assessed suicidal behavior in children below 6 years. It is 100-item questionnaire completed by parent/legal guardian, based on participant's behavior in past 2 months. All 100 items rated on 3-point scale: 0=not true for that child; 1=sometimes true; 2=very/often true. Total CBCL score ranges from 0 (not true) to 200 (very/often true). Higher scores=higher levels of problematic behaviors or dysfunction. Scores from all items were used to calculate 3 subscale scores: Withdrawn subscale scores, Internalizing problems subscale scores and total problem subscale scores. All subscale scores reported scaled to T Scores. Higher scores for each CBCL subscales indicated higher levels of problematic behaviors or dysfunction. In this study, a cut-off of >=68 on the T-scores was used for all 3 subscales. If a participant T Score was >=68 in any of the sub-scales, the participant was referred for Mental Health Risk Assessment that included assessment of participant continuation to the study

CogState battery:computerized test battery used to assess cognitive domains through cognition tests/tasks. The test battery was presented on computer with external response buttons. In this study, Cogstate battery consisted of 2 tasks which measured psychomotor function (detection task) and attention (paediatric identification task). Detection task was a measure of simple reaction time and provided a valid assessment of psychomotor function in participants. In this task, a playing card turning face up was presented in the center of the computer screen. As soon as this happened, the participant was to press the 'Yes' response key. There was no minimum or maximum scores since it was a time-based assessment. The software measured the speed of accurate responses to each event. In this outcome measure, speed of performance of participants (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Lower scores indicated better performance.

CogState battery: computerized test battery used to assess cognitive domains through cognition tests/tasks. The test battery was presented on computer with external response buttons. Paediatric identification task: a measure of choice reaction time and valid assessment of visual attention. In this task, a playing card turning face up was presented in center of the computer screen. As soon as this happened, participant had to decide whether color of card was black or not. If color was black, participants was to press "Yes" response key, otherwise "no". There was no minimum/maximum scores since it was a time-based assessment. The software measured speed of accurate responses (correct identification of color) to each event. In this outcome measure, speed of performance of participants to correctly identify the color (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Lower scores indicated better performance.

Criteria for abnormality: hematology (hemoglobin, hematocrit, red blood cells count:<]0.8*lower limit of normal [LLN],platelets:<0.5*LLN/greater than [>]1.75*upper limit of normal [ULN],leukocytes:<0.6*LLN or>1.5*ULN, lymphocytes, total neutrophils:<0.8*LLN or >1.2*ULN, basophils, eosinophil, monocytes:>1.2*ULN); Liver Function(aspartate aminotransferase ,alanine aminotransferase, alkaline phosphatase, Gamma glutamyl transferase:>0.3*ULN, total protein, albumin:<0.8*LLN or >1.2*ULN); bilirubin:>1.5*ULN; renal function(blood urea nitrogen, creatinine:>1.3*ULN); Electrolytes(sodium:<0.95*LLN or>1.05*ULN, potassium, chloride, calcium, bicarbonate:<0.9*LLN or >1.1*ULN); Lipids(cholesterol, triglycerides >1.3*ULN); creatine kinase:>2.0*ULN; glucose fasting:<0.6*LLN or >1.5*ULN, urine white blood corpuscles and RBC:>= 20/High Power Field [HPF];urine casts: >1/Low Power Field(LPF);urine bacteria:>20/HPF. Hormones (tetraiodothyronine and thyroid stimulating hormone:<0.8*LLN or >1.2*ULN).

Criteria for abnormalities in vital signs included: sitting systolic blood pressure (SBP) values: maximum increase and decrease of >=30 millimeter of mercury (mmHg) from baseline; sitting diastolic blood pressure (DBP) value: maximum increase and decrease of >=20 mmHg from baseline.

Neurological examinations included: level of consciousness, mental status, cranial nerve assessment, muscle strength and tone, reflexes, pin prick and vibratory sensation (the latter using a 128-Hertz tuning fork), coordination and gait. Clinical significance was based on investigator's discretion.

Criteria for abnormalities in ECG findings: 1) Time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS complex): >=140 milliseconds (msec); 2) The interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization (PR interval): >=200 msec; 3) Time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula (QTCF interval): absolute value 450 to <480 msec, 480 to <500 msec, >=500 msec; 4) Maximum QT interval: >=500 msec; 5) Maximum QTCB interval (Bazett's correction): 450 to< 480 msec, 480 to <500 msec, >=500 msec. Only those categories of ECG abnormalities in which participants were found abnormal, were reported in this outcome measure.

Physical examinations evaluated the following body systems/organs: general appearance; dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; abdominal; genitourinary (optional); lymphatic; musculoskeletal/extremities; and neurological. Clinical significance was determined by the investigator.