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

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ClinicalTrials.gov Identifier: NCT03590197
Recruitment Status : Recruiting
First Posted : July 18, 2018
Last Update Posted : October 1, 2019
Sponsor:
Information provided by (Responsible Party):
RITUPARNA MAITI, All India Institute of Medical Sciences, Bhubaneswar

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Generalized Seizure Drug: Melatonin 3 mg Other: Placebo Phase 4

Detailed Description:

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: The recruited patients will be randomized by simple randomization into two treatment groups using computer-generated random codes. The random allocation code of the participants will be generated by PI who will not be involved in the patient recruitment. The codes will be assigned to a sequence of numbers and the numbered stickers will be pasted on the similar looking drug containers. The drug containers will be given to another investigator who will be responsible for patient recruitment. This process ensured allocation concealment.
Primary Purpose: Treatment
Official Title: Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Seizure: A Randomized, add-on Placebo-controlled Clinical Trial
Actual Study Start Date : August 6, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : March 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Seizures
Drug Information available for: Melatonin

Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Control Arm
The patients in Control Arm will receive placebo with valproate (20 mg/kg).
 Other: Placebo
Placebo with Valproate
Experimental: Melatonin Arm
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
Melatonin 3 mg/ day with Valproate


Outcome Measures
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Primary Outcome Measures :
  1. Change in Responder Rate from baseline [ Time Frame: Baseline, 8 weeks ]
    Responder rate is defined as percentage of patients having ≥50% reduction in seizure frequency.


Secondary Outcome Measures :
  1. Change in seizure severity from baseline [ Time Frame: Baseline , 8 weeks ]
    The change in seizure severity in terms of change in Chalfont-National Hospital seizure severity scale (NHS3)

  2. Change in neuronal damage from baseline [ Time Frame: Baseline, 8 weeks ]
    The change in neuronal damage in terms of change in serum NSE (Neuron-specific Enolase) level

  3. Change in sleep quality from the baseline [ Time Frame: Baseline, 8 weeks ]
    The change in sleep quality in terms of change in Pittsburgh sleep quality index (PSQI) score

  4. Change in day time sleepiness from the baseline [ Time Frame: Baseline, 8 weeks ]
    The change in daytime sleepiness in terms of change in Epworth sleepiness scale

  5. Change in antioxidant property from the baseline [ Time Frame: Baseline, 8 weeks ]
    The change in antioxidant property in terms of change in serum glutathione reductase

  6. Change in the quality of life from the baseline [ Time Frame: Baseline, 8 weeks ]
    The change in the quality of life in terms of change in Quality of Life in Epilepsy Inventory (QOLIE-31)


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All patients with the clinical diagnosis of generalized motor seizure (ILAE 2017)23 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 3 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03590197


Contacts
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Contact: Rituparna Maiti, M.D 9438884191 rituparnamaiti@gmail.com
Contact: Biswa R Mishra, M.D 9438884202 brm1678@gmail.com

Locations
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India
All India Institute of Medical Sciences (AIIMS) Recruiting
Bhubaneswar, Odisha, India, 751019
Contact: RITUPARNA MAITI, MD    9438884191    rituparnamaiti@gmail.com   
Contact: BISWA R MISHRA, MD       brm1678@gmail.com   
Sponsors and Collaborators
All India Institute of Medical Sciences, Bhubaneswar
Investigators
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Study Chair: Debasish Hota, D.M AIIMS, Bhubaneswar
More Information
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Publications of Results:

Other Publications:

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Responsible Party: RITUPARNA MAITI, Additional professor, All India Institute of Medical Sciences, Bhubaneswar
ClinicalTrials.gov Identifier: NCT03590197     History of Changes
Other Study ID Numbers: IEC/AIIMSBBSR/PGTh/18-19/02
First Posted: July 18, 2018    Key Record Dates
Last Update Posted: October 1, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by RITUPARNA MAITI, All India Institute of Medical Sciences, Bhubaneswar:
Melatonin
Neuron-specific Enolase
Responder rate
Additional relevant MeSH terms:
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Seizures
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Valproic Acid
Melatonin
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
 Physiological Effects of Drugs
Central Nervous System Depressants
Anticonvulsants
Enzyme Inhibitors
GABA Agents
Neurotransmitter Agents
Antimanic Agents
Tranquilizing Agents
Psychotropic Drugs