Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy

Study Overview
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Brief Summary
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Epilepsy is one of the most common and frequently encountered neurological conditions that impose a huge burden on the healthcare systems. Despite the abundance of antiepileptic drugs (AEDs) available, 30% of people continue to have seizures even after long-term therapy of 6-8 years. This group of people requires a more aggressive treatment since monotherapy, the first choice scheme, is not sufficient to control seizure and its complications, multiple drug therapy or polytherapy often results in the culmination of unwanted effects. The need for an add-on AEDs with a good safety profile is of utmost importance.The beneficial effects of melatonin on sleep, its wide safety window, and its ability to cross the blood-brain barrier have the potential to improve the quality of life in seizure patients. Various animal studies have suggested that melatonin receptors are the potential targets for anticonvulsant drug development. In animal studies, melatonin was found to suppress generalized seizure and seizure susceptibility and it also has neuroprotection and synapse modulating properties. Some clinical trials mostly on paediatric population also found that melatonin can improve the clinical outcome in epilepsy. Therefore, we have planned to conduct a randomized, add-on placebo-controlled clinical trial on the effect of melatonin on seizure outcome, neuronal damage and quality of life in adult patients with generalized seizure.

Detailed Description
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Epilepsy is a chronic disabling neurologic condition which often leads to numerous adverse long-term neurologic complications, such as behavioural and cognitive deficits, increased susceptibility to recurrent seizures, and neuronal injury or death. Cognitive dysfunction, depression, anxiety and sleep disorders are some of the highly prevalent and most debilitating complications of epilepsy. Despite the abundance of antiepileptic drugs (AEDs), even after long-term treatment of 6-8 years, 30% of patients continue having seizures. This group of patients requires a more aggressive treatment, since monotherapy fails to control seizures, considering the fact that the number of seizures is the single most important predictive factor for both early and long-term remission of seizures. Nevertheless, polytherapy often results in a number of adverse effects. The need for better-tolerated add-on therapy is the need of the hour to overcome this therapeutic hurdle. Melatonin, an endogenous hormone, acting through MT1 and MT2 receptors exert a depressive effect on brain excitability and have been shown to exert an anticonvulsant activity in various animal models. In some clinical trials also it has been found that add-on melatonin therapy improves the clinical outcome. Uberoset al evaluated the sleep-wake pattern, plasma melatonin levels and the urinary excretion of its metabolite among children with severe epileptic disorders, before and after a therapeutic trial with melatonin. They found sleep efficiency was significantly higher and better controls of convulsive episodes were achieved with among patients who received melatonin. Goldberg-Stern et aland Elkhayat et al concluded that melatonin could be effective and safe for decreasing seizure frequency and severity in patients with intractable epilepsy. Gupta et al found that melatonin has the potential to improve quality of life in pediatric epilepsy because of its beneficial effects on sleep, its wide safety window, and its ability to cross the blood-brain barrier. In another study by Jain SV et al melatonin resulted in a statistically significant decrease in sleep onset latency and wakefulness after sleep onset. Guptaet al also concluded that add-on melatonin can be of promise in the pharmacotherapy of pediatric epilepsy and as an adjunct, can be a putative neuroprotector in conditions involving oxidative stress like epilepsies. Dabak et al and Brazil et measured melatonin in febrile seizure and temporal lobe epilepsy and found to be lower in epilepsy in comparison to the controls. Our literature review reveals that till date most of the clinical studies on the effect of melatonin in epilepsy have been conducted in the pediatric population and there is no clinical trial done on its effect on seizure outcome, neuroprotective effect, sleep and circadian rhythm and quality of life in adult patients with epilepsy. So the present randomized clinical trial has been designed to fill the knowledge gap and evaluate the effect of add-on melatonin on seizure severity, neuronal damage and sleep quality in adult patients suffering from a generalized seizure.

Official Title
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Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy: A Randomized, add-on Placebo-controlled Clinical Trial

Conditions
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Generalized Epilepsy

Intervention / Treatment
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* Drug: Melatonin 3 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients with the clinical diagnosis of generalized epilepsy with generalised onset motor seizure (ILAE 2017) with a history of an episode of seizure within 72 hours of presentation. Patients aged 18-60 years, of either sex. Treatment-naive patients or patients who had not taken any treatment for at least 4 weeks before inclusion. Exclusion Criteria: History of any recent traumatic brain injury, cerebral ischemia/TIA/stroke. Patients with neuroendocrinal tumors. History of any invasive neurosurgical/non-invasive neuropsychiatric procedure. Patients who are already under treatment for the presenting conditions. Medication history of psychoactive or central nervous system depressant drugs. Pregnant and nursing women. Patients with a history of allergy to valproate, melatonin or other melatonin agonists. Patients with drug/alcohol abuse. Patients with any hepatic dysfunction.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control Arm<br>The patients in Control Arm will receive placebo with valproate (20 mg/kg). | Other: Placebo<br>* Placebo with Valproate<br>|
| Experimental: Melatonin Arm<br>The Experimental Arm will receive tablet melatonin as an add-on to valproate. Melatonin will be prescribed 3 mg/day to the patients and will be advised to take 30 minutes before bedtime. | Drug: Melatonin 3 mg<br>* Melatonin 3 mg/ day with Valproate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Responder Rate from baseline | Responder rate is defined as percentage of patients having ≥50% reduction in seizure frequency. | Baseline, 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in seizure severity from baseline | The change in seizure severity in terms of change in Chalfont-National Hospital seizure severity scale (NHS3) | Baseline , 8 weeks | 
| Change in neuronal damage from baseline | The change in neuronal damage in terms of change in serum NSE (Neuron-specific Enolase) level | Baseline, 8 weeks | 
| Change in sleep quality from the baseline | The change in sleep quality in terms of change in Pittsburgh sleep quality index (PSQI) score | Baseline, 8 weeks | 
| Change in day time sleepiness from the baseline | The change in daytime sleepiness in terms of change in Epworth sleepiness scale | Baseline, 8 weeks | 
| Change in antioxidant property from the baseline | The change in antioxidant property in terms of change in serum glutathione reductase | Baseline, 8 weeks | 
| Change in the quality of life from the baseline | The change in the quality of life in terms of change in Quality of Life in Epilepsy Inventory (QOLIE-31) | Baseline, 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melatonin, Neuron-specific Enolase, Responder rate