Safety and efficacy of memantine add on in Lennox-Gastaut Syndrome: A randomized double blind placebo- controlled trial

Lennox-Gastaut syndrome (LGS) is a severe childhood epileptic encephalopathy characterized by classical triad of 1). Multiple types of seizure, 2). Cognitive impairment and 3). Diffuse slow spike and slow wave discharges on EEG. In this study, we propose to evaluate the Safety and efficacy of memantine add on compared to placebo in Lennox-Gastaut Syndrome. We will also evaluate the effect of memantine on the cognitive function in patient with LGS by the use of six item Pediatric Quality of Life Inventory (PedsQL) Cognitive Functioning Scale, effect on the EEG changes and effect on the Clinical Global Impression Improvement Scale (CGI-I) compared to those who will receive placebo. Children aged 2 to 18 years having LG syndrome who are using 1-5 ASM for 1 month will be included. After the eligibility checking, patients will be in 1 month screening period during which caregiver will be advised to maintain a diary recording of daily seizure frequency, type of seizure and drop attacks. The demographic details including age, gender duration of illness and developmental milestones will be enquired. Height, weight and BMI will be noted. Any history of antenatal, perinatal and postnatal events will be recorded. Their baseline blood counts, hemoglobin, serum chemistry including liver function test, kidney function test, sodium, potassium, calcium alkaline phosphatase and thyroid stimulating hormone, vitamin B12 and folic acid will be done. Genetic study will be considered in affording patients. Cranial MRI scan findings will be noted. After a 4-week of baseline screening period for recoding of seizure frequency, patients will be randomized to memantine or placebo using simple 1:1 randomization after obtaining inform consent. The sample size is calculated and Memantine will be given orally in a dose of 5 mg per day in first week, followed by 5 mg twice a day (10 mg/day) in second week and finally continue at a dose of 5 mg morning and 10 mg evening (15 mg/day) from third week onwards. There after dose will be maintained till 12 weeks. The placebo arm will receive similar dose of saccharine. In addition to adverse event recording throughout the study, the routine safety assessments include a physical and a neurological evaluation will be performed at each study visit. Study visits will be scheduled monthly till 3 months, or any time if any medical emergency situation arise. Clinical laboratory tests (biochemistry, hematology, urine analysis) will be conducted at the time of entry into the study, at the end the study or in the situation with adverse event. EEG will be performed at baseline and at the end of the study. Brain magnetic resonance imaging (MRI) evaluations will also baseline. The primary end point will the percentage change from baseline in drop attacks in memantine group compared to the placebo group. The secondary end points will be the percentage change from baseline in frequency of different types of seizures (generalized convulsive seizures, secondary generalized convulsive seizure, focal to bilateral tonic-clonic, tonic, atonic, or tonic or atonic). A 50% or greater reduction in seizure, number of seizure free days, improvement in PedsQL Cognitive Functioning Scale and on the Clinical Global Impression-Improvement (CGI-I) scale in both the groups. Additional secondary outcomes are improvement in EEG and adverse events. The primary and secondary outcome parameter will be analyzed using parametric or nonparametric tests depending on the data. Intension to treat and per protocol analysis of the primary outcome will be done.