Safety and Efficacy of Lacosamide as Additional Therapy in Patients Suffering From Epileptic Tonic-Clonic Seizures

AEs were considered treatment-emergent if event had onset on or after date of first study medication dose in EP0012 and within 30 days following last study medication dose or events whose intensity worsened on or after date of first study medication dose and within 30 days following date of last study medication administration. Adverse Events were reported spontaneously by the participant and/or caregiver or observed by the investigator.

AEs were considered treatment-emergent if event had onset on or after date of first study medication dose in EP0012 and within 30 days following last study medication dose or events whose intensity worsened on or after date of first study medication dose and within 30 days following date of last study medication administration. Adverse Events were reported spontaneously by the participant and/or caregiver or observed by the investigator.

The number of study participants with appearance of new absence and/or myoclonic seizure types experienced during the Treatment Period but who did not experience in Combined Baseline Period or in seizure classification history, before taking LCM were reported. To determine appearance of new seizure type, the Combined Baseline Period was used. Thus, the participants who directly enrolled into EP0012, the Baseline absence, and/or myoclonic seizure data from SP0982's 4-week Prospective Baseline Period were combined with any reported Baseline absence, and myoclonic seizure information in the daily seizure diary from EP0012 (reported before first dose in EP0012) to recalculate the study participant's Baseline variables such as days with absence, and/or myoclonic seizures per 28 days.

The number of participants experiencing an increase of up to 25% in the number of days with absence seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period (for those participants with absence seizure data reported in the 4-week Prospective Baseline Period in SP0982) were reported. This period started on the day of Visit 1 of SP0982 and ended the day before Visit 2 of SP0982. For the direct enrollers into EP0012, Prospective Baseline ended the day before Visit 1 (or prior to first dose) of EP0012.

The number of participants experiencing an increase of >25% to 50% in the number of days with absence seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period (for those participants with absence seizure data reported in the 4-week Prospective Baseline Period in SP0982) were reported. This period started on the day of Visit 1 of SP0982 and ended the day before Visit 2 of SP0982. For the direct enrollers into EP0012, Prospective Baseline ended the day before Visit 1 (or prior to first dose) of EP0012.

The number of participants experiencing an increase of >50% to 75% in the number of days with absence seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period (for those participants with absence seizure data reported in the 4-week Prospective Baseline Period in SP0982) were reported. This period started on the day of Visit 1 of SP0982 and ended the day before Visit 2 of SP0982. For the direct enrollers into EP0012, Prospective Baseline ended the day before Visit 1 (or prior to first dose) of EP0012.

The number of participants experiencing an increase of >75% in the number of days with absence seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period (for those participants with absence seizure data reported in the 4-week Prospective Baseline Period in SP0982) were reported. This period started on the day of Visit 1 of SP0982 and ended the day before Visit 2 of SP0982. For the direct enrollers into EP0012, Prospective Baseline ended the day before Visit 1 (or prior to first dose) of EP0012.

The number of participants experiencing an increase of up to 25% in the number of days with myoclonic seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period (for those participants with myoclonic seizure data reported in the 4-week Prospective Baseline Period in SP0982) were reported. This period started on the day of Visit 1 of SP0982 and ended the day before Visit 2 of SP0982. For the direct enrollers into EP0012, Prospective Baseline ended the day before Visit 1 (or prior to first dose) of EP0012.

The number of participants experiencing an increase of >25% to 50% in the number of days with myoclonic seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period (for those participants with myoclonic seizure data reported in the 4-week Prospective Baseline Period in SP0982) were reported. This period started on the day of Visit 1 of SP0982 and ended the day before Visit 2 of SP0982. For the direct enrollers into EP0012, Prospective Baseline ended the day before Visit 1 (or prior to first dose) of EP0012.

The number of participants experiencing an increase of >50% to 75% in the number of days with myoclonic seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period (for those participants with myoclonic seizure data reported in the 4-week Prospective Baseline Period in SP0982) were reported. This period started on the day of Visit 1 of SP0982 and ended the day before Visit 2 of SP0982. For the direct enrollers into EP0012, Prospective Baseline ended the day before Visit 1 (or prior to first dose) of EP0012.

The number of participants experiencing an increase of >75% in the number of days with myoclonic seizures per 28 days during the Treatment Period compared to the Prospective Baseline Period (for those participants with myoclonic seizure data reported in the 4-week Prospective Baseline Period in SP0982) were reported. This period started on the day of Visit 1 of SP0982 and ended the day before Visit 2 of SP0982. For the direct enrollers into EP0012, Prospective Baseline ended the day before Visit 1 (or prior to first dose) of EP0012.

Seizure worsening was defined as a participant experiencing >=50% increase in the number of days with absence seizures per 28 days from Prospective Baseline. Percentages for seizure worsening were based on those participants who have reported a history of or an occurrence of absence seizures in Prospective Baseline or the Treatment Period.

Seizure worsening was defined as a participant experiencing >=50% increase in the number of days with myoclonic seizures per 28 days from Prospective Baseline. Percentages for seizure worsening were based on those participants who have reported a history of or an occurrence of myoclonic seizures in Prospective Baseline or the Treatment Period.

TEMA values are defined in the Statistical Analysis Plan (SAP) as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Hematology parameter, Hemoglobin were those that were observed post-Baseline (BL) during the Treatment Period but not present at Baseline. For the age range, '2 years (y) to <17 years', the abnormality criteria were '<=95' grams/deciliter (g/dL) (Low) and '>160' g/dL (High). For age range, '>=17 years', the abnormality Criteria were '<=85% of lower limit of normal (LLN)' value (Low) and '>=115% of upper limit of normal (ULN)' value (High) of Hemoglobin in blood.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Hematocrit were those that were observed post-BL during the Treatment Period but not present at BL. For the age range, '2 years to <17 years', the abnormality criteria were '<=29%' (Low) and '>47%' (High) hematocrit values. For age range, '>=17 years', the abnormality criteria were '<=85% of LLN' (Low) and '>=115% of ULN' (High) of Hematocrit values in blood.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Platelet count were those that were observed post-BL during the Treatment Period but not present at BL. For the age range of '>1 month', the abnormality criteria were '<=100' 10^9/L and '>=600' 10^9/L of Platelets count value.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Erythrocytes parameter were those that were observed post-BL during the Treatment Period but not present at BL. For the age range, '>=2years', the abnormality criteria were '<3.5' 10^12/L of Erythrocytes value in blood. Early Termination Visit (TV) was last visit in the study (up to approximately 5 years).

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Leukocytes were those that were observed post-BL during the Treatment Period but not present at BL. For all age ranges, the abnormality criteria were '<=3.0' 10^9/L (Low) and '>= 16.0' 10^9/L (High) of Leukocytes values in blood.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Basophils Absolute were those that were observed post-BL during the Treatment Period but not present at BL. For the age range, '>1 month', the abnormality criteria were '>=0.4' 10^9/L of Basophils in blood.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Eosinophils Absolute were those that were observed post-BL during the Treatment Period but not present at BL. For the age range, '>1 month', the abnormality criteria were '>=1.0' 10^9/L of Eosinophils in the blood.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Lymphocytes Absolute were those that were observed post-Baseline (BL) during the Treatment Period but not present at Baseline. For the age range, '2 years - <6 years', the abnormality criteria were '<0.7' 10^9/L (Low) and '>6.9' 10^9/L (High). For age range, '>=6 years', the abnormality criteria were '<0.6' 10^9/L (Low) and '>5.0' 10^9/L (High) for Lymphocytes Absolute in the blood.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Monocytes Absolute were those that are observed post-BL during the Treatment Period but not present at BL. For the age range, '>1 month', the abnormality criteria was '>=2.0' 10^9/L of Monocytes in blood.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Neutrophils Absolute were those that were observed post-BL during the Treatment Period but not present at BL. For the age range, '>1 month', the abnormality criteria was '<1.5' 10^9/L of Neutrophils in blood.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Calcium were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '1 year -<17 years', the abnormality criteria were '<=1.85' millimoles per litre (mmol/L) and '>=2.95' mmol/L. For age range, '>=17 years', the abnormality criteria was '<=1.9 mmol/L' and '>=2.75 mmol/L' of serum Calcium.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Sodium were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '>1 month', the abnormality criteria were '<127' mmol/L (Low) and '>151' mmol/L (High) of serum Sodium.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Potassium were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '>=1 year', the abnormality criteria were '<= 3.0' mmol/L (Low) and '>= 6.0' mmol/L (High) of serum Potassium.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Chloride were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '>1 month', the abnormality criteria were '<=90' mmol/L (Low) and '>=112' mmol/L (High) of serum Chloride.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Bicarbonate were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '>1 month-<17 years', the abnormality criteria were '<15' mmol/L (Low) and '>38' mmol/L (High). For age range, '>=17 years', the abnormality criteria were '<18' mmol/L (Low) and '>38' mmol/L (High) of serum Bicarbonate.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Creatinine were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '1-<10 years', the abnormality criteria were '>106.8' micromole per litre (umol/L), for '10-<16 years', the abnormality criteria were '>159.12' umol/L and for '>=16 years', the abnormality criteria was '>=176.8' umol/L for serum Creatinine.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Aspartate Aminotransferase (AST) were those that were observed post- BL during the Treatment Period but not present at Baseline. For all ages, the abnormality criteria were specified as '≥3.0 units per litre (U/L) x ULN' (High A), '≥5.0 U/L x ULN' (High B), and '≥10.0 U/L x ULN' (High C) of serum AST.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Alanine Aminotransferase (ALT) were those that were observed post- BL during the Treatment Period but not present at Baseline. For all ages, the abnormality criteria were specified as '≥3.0 U/L x ULN' (High A), '≥5.0 U/L x ULN' (High B), and '≥10.0 U/L x ULN' (High C) of serum ALT.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Total Bilirubin were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '>1 month', the abnormality criteria was '≥34.208' umol/L of serum Bilirubin.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Alkaline Phosphatase were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '4 years -<10 years', the abnormality criteria was '>=834 U/L', for '10 years -<17 years', the abnormality criteria was '>=1761 U/L' and for '>=17 years', the abnormality criteria was '>=3.0 U/L x ULN' of serum alkaline phosphatase.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Gamma Glutamyl Transferase (GGT) were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '1 year-<13 years', the abnormality criteria was '>=66' U/L (High A), for '13 years-<17 years', the abnormality criteria was '>=126' U/L (High B) and for '>=17 years', the abnormality criteria was '>=3.0 U/L x ULN' (High C) of serum GGT.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Glucose were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '>1 month-<17 years', the abnormality criteria were from '<2.775' mmol/L (Low) and '>=9.99' mmol/L (High). For age range, '>=17 years', the abnormality criteria were '<2.775' mmol/L (Low) and '>=11.1' mmol/L (High) of serum Glucose.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Albumin were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '>=1 year to <17 years', the abnormality criteria were '<24' g/L and '>84' g/L and for age range, '>=17 years', the abnormality criteria was '<26' g/L of serum albumin.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Total Protein were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '1 year to <17 years', the abnormality criteria were '<43' g/L and '>120' g/L. For age range, '>=17 years', the abnormality criteria were '<43' g/L and '>130' g/L of serum protein.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA laboratory results of Phosphate were those that are observed post- BL during the Treatment Period but not present at Baseline. For the age range, '1 year-<17 years', the abnormality criteria were from '<0.5814' mmol/L (Low) and '>2.3902' mmol/L (High). For age range, '>=17 years', the abnormality Criteria were '<=0.646' mmol/L (Low) and '>=1.938' mmol/L (High) of serum phosphate.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA ECG results of QT interval parameter were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '1 month (m)-<12 years', the abnormality criteria were '>=500 milliseconds (ms)' (Abnormal (Abn) A). For age range, '>=12 years', the abnormality criteria were '>=500 ms' (Abn B) or '>=60 ms increase from Baseline' (Abn C). The abnormality in QT interval was observed at Week 0 as the participant was rolled over from SP0982 study and was constantly having abnormal ECG parameters while in SP0982 and EP0012.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA ECG results of QTc(F) interval were those that are observed post- BL during the Treatment Period but not present at Baseline. For the age range '3 years -<12 years' and '>=12 years- <17 years', the abnormality criteria were from '>440 ms' (Abn A) and '>15% increase from Baseline' value (Abn B). For age range, '>=17 years', the abnormality Criteria were '>450 ms' (Abn C), '>480 ms' (Abn D), '>500 ms' (Abn E) or '>=60 ms increase from Baseline' value (Abn F). The abnormality in QTc(F) interval was observed at Week 0 as the participant was rolled over from SP0982 study and was constantly having abnormal ECG parameters while in SP0982 and EP0012.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA ECG results of QTc(B) interval were those that are observed post- BL during the Treatment Period but not present at Baseline. For the age range '3 years -<12 years' and '>=12 years- <17 years', the abnormality criteria were '>450 ms' (Abn A) and '>15% increase from Baseline' value (Abn B). For age range, '>=17 years', the abnormality criteria were '>450 ms' (Abn C), '>480 ms' (Abn D), '>500 ms' (Abn E) or '>=60 ms increase from Baseline' value (Abn F). The abnormality in QTc(B) interval was observed at Week 0 as the participant was rolled over from SP0982 study and was constantly having abnormal ECG parameters while in SP0982 and EP0012.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA ECG results of PR interval were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '3 years -<12 years', the abnormality criteria were '>180 ms' (Abn A) and '>25% increase from Baseline' value (Abn B). For the age range, '>=12 years - <17 years', the abnormality criteria were '>200 ms' (Abn C) and '>25% increase from Baseline' value (Abn D). For age range, '>=17 years', the abnormality criteria were treatment-emergent values above '>200 ms' (Abn E), '>220 ms' (Abn F), or '>250 ms' (Abn G).

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA ECG results of QRS interval were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '3 years -<12 years', the abnormality criteria were '>100 ms' (Abn A) and '>25% increase from Baseline' value (Abn B). For the age range, '>=12 years - <17 years', the abnormality criteria were '>110 ms' (Abn C) and '>25% increase from Baseline' (Abn D). For age range, '>=17 years', the abnormality criteria were treatment-emergent values above '>100 ms' (Abn E), '>120 ms' (Abn F), or '>140 ms' (Abn G).

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA ECG results of Heart rate interval were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '3 years -<12 years', the abnormality criteria were '<60 beats per minute (bpm)' (Abn A) and '>130 bpm' (Abn B). For the age range, '>=12 years', the abnormality criteria were '<50 bpm' (Abn C) and '>120 bpm' (Abn D).

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA vital signs results of Pulse rate were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '3 years -<12 years', the abnormality criteria were '<60 bpm' (Low) and '>130 bpm' (High). For the age range, '12 years - <17 years', the abnormality criteria were '<=50 bpm' (Low) and '>=120 bpm' (High). For the age range, '>=17 years', the abnormality criteria were '<=50 bpm and a decrease from Baseline of >=15 bpm' (Low A), '>=120 bpm and an increase from Baseline of >=15 bpm' (High A), '<60 bpm' (Low B) and '>100 bpm' (High B). The Pulse rate was reported as per positions such as 'Supine 3 minute (Sup 3 min)', 'Standing 1 minute' (Std 1 min), and 'Standing 3 minute' (Std 3 min).

TEMA values of Systolic Blood Pressure (BP) results were those that were observed post- BL during the Treatment Period but not present at Baseline. For the age range, '3 years -<12 years', the abnormality criteria were '<80 millimeters of mercury (mmHg)' (Low) and '>140 mmHg' (High). For the age range, '>=12 years - <17 years', the abnormality criteria were '<90 mmHg' (Low) and '>160 mmHg' (High). For the age range, '>=17 years', the abnormality criteria were '<=90 mmHg and decrease from Baseline of >=20 mmHg' (Low A), '>=180 mmHg and increase from Baseline of >=20' mmHg (High A), '<90 mmHg' (Low B), '>140 mmHg (High B), and '>160 mmHg' (High C). Systolic BP were reported as per positions such as 'Sup 3 min', 'Std 1 min, and 'Std 3 min'.

TEMA values of Diastolic BP results were those that are observed post- BL during the Treatment Period but not present at Baseline. For the age range, '3 years -<12 years', the abnormality criteria were '<50 mmHg' (Low) and '>80 mmHg' (High), '>=12 years - <17 years', the abnormality criteria were '<=50 mmHg' (Low) and '>=105 mmHg' (High), and '>=17 years', the abnormality criteria were '<=50 mmHg and decrease from Baseline of >=15 mmHg' (Low A), '>=105 mmHg and increase from Baseline of >=15' mmHg (High A), '<50 mmHg' (Low B), '>90 mmHg' (High B), and '>100 mmHg' (High C). Diastolic BP were reported as per positions such as 'Sup 3 min', 'Std 1 min, and 'Std 3 min'.

TEMA values are defined in the SAP as significant deviations from the expected range of age-appropriate values. TEMA vital signs parameter results were those that are observed post- BL during the Treatment Period but not present at Baseline. For the age range, '1 month - <17 years', the abnormality criteria were '<3% of normal body weight' in Kilograms (kg) or '>97% of normal body weight' in kgs. Here, '<3% of normal' is presented as 'Low' and '>97% of normal' is presented as 'High'. For the age range '>=17 years', the abnormality criteria were 'Increase/decrease of >=10%' body weight in kgs (presented as Inc/Dec A) or 'Increase/decrease of >=7%' body weight in kgs (presented as Inc/Dec B).

The 28-day PGTCS frequency during the relative period was subtracted from the 28-day Combined Baseline PGTCS frequency and the result was divided by 28-day Combined Baseline PGTCS frequency and the result was then multiplied by 100 to get percent change in PGTCS frequency per 28 days from Combined Baseline Period (CB) to the appropriate analysis Period. The CB was defined as the combined 12-week Historical Baseline and 4-week Prospective Baseline periods immediately prior to randomization in the study SP0982 or prior to Visit 1 (first dose) if direct enrollers in EP0012.