Clinical Study of Lamotrigine to Treat Newly Diagnosed Typical Absence Seizure in Children and Adolescents

A Multi-center, Uncontrolled, Open-label, Evaluation of Lamotrigine Monotherapy on Newly Diagnosed Typical Absence Seizures in Children and Adolescents

This is a multi-center, uncontrolled, open-label study to evaluate the efficacy and safety of lamotrigine monotherapy on newly diagnosed typical absence seizure in children and adolescents in Japan and South Korea.

The study period is composed the baseline, fixed escalation phase, escalation phase, maintenance phase, taper phase, and post study examination. During the fixed escalation phase, the investigational product is administered at 0.3 mg/kg/day for 2 weeks (Week 1 to 2), followed by 0.6 mg/kg/day for 2 weeks (Week 3 to 4). Subjects thereafter visit the clinic once every 1 to 2 weeks during the escalation phase to increase the dose by 0.6 mg/kg/day up to a maximum of 10.2 mg/kg/day or 400 mg/day (whichever was less) until patients are confirmed to be seizure-free by HV tests for clinical signs. After seizure free is confirmed by HV-clinical signs, the dose is increased by one level and HV-EEG (electroencephalography) test (first test) is assessed at the next visit. If seizure free is observed by HV-EEG, the same dose is administered. Thereafter, HV-EEG (second test) is assessed at the next visit and if seizure free is confirmed again, the subjects enter the 12-week maintenance phase. During the maintenance phase, patients visit the clinic once every 4 weeks. The dose can be adjusted as necessary within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day (whichever was less) taking into account the status of seizures and the safety. The investigational product is administered once daily (in the evening). However, if the number of tablets is large, twice-daily administration (in the morning and evening) is also allowed. After the completion of maintenance phase, subjects who have responded to lamotrigine without tolerability issues are eligible to enter the extension phase of the study if clinically indicated.

Inclusion Criteria:

1. Target disease: Subjects with newly diagnosed and untreated typical absence seizure which is classifiable by the International Classification of Seizures.

2. Diagnosis of typical absence seizures is established by at least one of two 4-minute hyperventilation tests as supported by clinical signs and EEG findings.

   The following criteria will be used to define a typical absence seizure on the EEG: a discharge of generalized spike-and-wave or multiple spike-and-wave activity lasting ≥3 seconds during the awake state. The frequency of the spike-and-wave should be between 2.5-4.5 Hz.

3. Age (at the time of obtaining consent):

   • 2 to 15 years of age in Japan
   • 2 to 12 years of age in South Korea

4. Subjects must weigh at least 7 kg

5. Outpatients

6. Parent/guardian must have given written informed consent. Subjects who are intellectually able to understand the concepts and procedures of the protocol must give assent by also signing the consent.

7. Gender: Male or female

8. QTc<450 millisecond (msec) or <480msec for subjects with Bundle Branch Block - values based on either single ECG values or triplicate ECG averaged QTc values obtained over a brief recording period.

Exclusion Criteria:

1. Subjects with partial seizure or generalized seizures other than typical absence.
2. Subjects with a history of rash associated with other treatment.
3. Subjects with any clinically significant chronic cardiac, renal, or hepatic medical condition. Any patient with these conditions will be excluded from the study even if these conditions are being controlled with chronic therapy.
4. Subjects with an acute or chronic illness likely to impair drug absorption, distribution, metabolism or excretion or with any unstable physical symptoms likely to require hospitalization during participation in the study.
5. Subjects with a psychiatric disorder requiring medication, or who had psychiatric conditions in the past that was both judged to be severe and required hospitalization.
6. Subjects with an acute or progressive neurological disorder or an organic disease.
7. Subjects with currently taking any psychoactive drugs to treat hyperactivity disorder or attention deficit disorder.
8. Subjects with an unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
9. Female subjects who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study.
10. Children in foster care: A child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. This can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The definition of a child in care does not include a child who is adopted or who has an appointed legal guardian.
11. Subjects taking inducers of lamotrigine glucuronidation (i.e., rifampicin, lopinavir/ritonavir), atazanavir/ritonavir, risperidone, oral contraceptives or hormone drug which includes estrogen.
12. Subjects having participated in other clinical study in the past 3 months before the start of investigational product.
13. Subjects who have active suicidal plan/intent or have had active suicidal thoughts in the past 3 months before the start of investigational product or who have history of suicide attempt in the last 1 year before the start of investigational product or more than 1 lifetime suicide attempt.
14. Subjects whom the investigator (or subinvestigator) considers ineligible for the study.