Electrical Status Epilepticus in Sleep: Response of Neuropsychological Deficits and Epileptiform Activity to Clobazam Treatment

NCT ID: NCT02127918

Last Updated: 2015-07-30

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 17 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2015-07-31

Brief Summary

Electrical status epilepticus in sleep (ESES) is a pattern of abnormal discharges in the electroencephalogram (EEG). Children who have this pattern present seizures and neuropsychological regression. There are no studies that systematically evaluate the response of abnormal discharges in the EEG, seizures and neuropsychological regression to different antiepileptic treatments. Therefore, treatment strategies in ESES are not based on scientific evidence. High-dose benzodiazepines such as diazepam (valium) have been reported to improve the severe EEG abnormalities of patients with ESES in the short-term. But the long-term response of seizures and neuropsychological regression has not been systematically studied. Clobazam is a benzodiazepine derivative with antiepileptic properties. The pharmacologic properties of clobazam make of this drug a particularly useful option in ESES: in patients with ESES the alpha-2 subunit of the GABA receptor is preferentially up-regulated and clobazam may have a higher affinity for this particular subunit, so investigators expect a higher effect of this drug on ESES patients than with other benzodiazepines (Loddenkemper et al, in preparation). The aim of our study is to objectively evaluate the response to clobazam treatment of neuropsychological deficits, seizures and abnormal discharges in the EEG in patients with ESES. Clobazam treatment is used in routine clinical practice and investigators will objectively quantify its effect.

Our working hypothesis is that high-dose clobazam treatment may control the abnormal epileptiform discharges in the EEG in patients with ESES. The reduction in abnormal epileptiform discharges may lead to an improvement in neuropsychological deficits and seizures. The predicted improvement in seizures and neuropsychological function would lead to a better quality of life in these patients.

Detailed Description

• A. RESEARCH METHODS

Study design. Investigators will perform a prospective descriptive cohort study with historical controls.

Participating institutions. Children's Hospital Boston (PI: Tobias Loddenkemper) and Children's Hospital Colorado (PI: Kevin Chapman).

Patients. Investigators will enroll patients with ESES studied at our centers and treated with high-dose clobazam treatment as decided by the clinical epileptologist.

The diagnosis of ESES will be confirmed based on neuropsychological regression in at least one domain of development, the presence of seizures that appear in an age-related manner and the presence in the EEG of the ESES pattern (Loddenkemper, et al. 2011a).

Contact with the patients. Once that the potential candidate is recognized (patient with ESES, a change in medication regimen is decided that includes initiation of clobazam), the research team will contact the primary epileptologist. The primary epileptologist will contact the patient in order to check whether the family and/or patient would like to be contacted for this research protocol. If the patient agrees to be contacted, the research team will contact the patient in order to propose them to participate in the study.

EEG assessment. Investigators will assess the epileptiform activity in the long-term monitoring unit before and after treatment for every patient.Assessment of clinical data. The clinical charts of the patients included in the study will be collected reviewed for relevant clinical information. This information will be updated and complemented with the patient and/or the family during the admissions for long-term monitoring. Assessment of neuropsychological data: A battery of neuropsychological tests will be performed by board-certified clinical neuropsychologists to obtain information regarding cognitive abilities.

Safety measures. Investigators will continuously monitor patients for adverse effects during hospitalization and provide them with contact information for continuous report of possible adverse effects. Potential risk to subjects. As subjects will be using a FDA-approved drug for the treatment of epilepsy their risk will be the same as in routine clinical care. There will not be risks associated with the specific use of clobazam as it is routinely used for clinical care and the decision to use it or not will depend on the primary provider and not on the research team. Other potential risks are related with the loss of privacy and confidentiality. Investigators will develop mechanisms to ensure protection of patients' privacy and confidentiality.

Quality control method. Investigators will perform quality control measures every 5 collected patients at Children's Hospital Boston. Additionally, independent medical monitoring will be implemented.

• B. STATISTICAL ANALYSIS

Calculation of the sample size. Our previous study with diazepam treatment (Sánchez Fernández, et al. in press-a) found that the difference in epileptiform activity before and after treatment was of around 30%. There are no other data available on the quantification of the response of epileptiform activity to antiepileptic treatment.

• C. PLANS FOR MISSING DATA

Recruitment of patients. Patients with ESES frequently belong to the category of patients that are not able to understand the study protocol both because of their age and because of neuropsychological regression. Their families and/or caretakers will decide in most cases about study enrollment and the patient consent/assent will be looked for when developmentally possible. Although studies with patients with severe developmental delays pose significant challenges, the burden of participating in the study will not be significantly different from the burden of normal clinical care. Additionally this study will be performed at centers that are familiar with the care of patients with severe developmental delay.

Sample size. Power calculation for the proposed study is challenging due to the novel approach. Our preliminary data, however, strongly favor feasibility and completion.

Conditions

Electrical Status Epilepticus in Sleep

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

ESES treated with clobazam

The patients that will participate in the protocol will be those that are administered for clinical reasons oral clobazam.

ESES treated with clobazam

Intervention Type: DRUG

The patients that will participate in the protocol will be those that are administered for clinical reasons oral clobazam.

Interventions

ESES treated with clobazam

The patients that will participate in the protocol will be those that are administered for clinical reasons oral clobazam.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• A change in treatment regimen is required because of very active epileptiform activity during sleep and neuropsychological regression. This means that only patients with very active epileptiform activity and, therefore, with a need for a change in treatment regimen as clinically indicated will be potentially eligible. Additionally, a prior clinical decision to use clobazam should have been made by the primary epileptologist in order to participate in the study.
• Availability for clinical, neuropsychological and EEG follow-up.

Exclusion Criteria

• Electro-clinical evolution that does not require a change in medication regimen or changes in medication regimen that do not include clobazam.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Lundbeck LLC

INDUSTRY

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Tobias Loddenkemper

Associate Professor of Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tobias Loddenkemper, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Locations

Children's Hospital Colorado

Aurora, Colorado, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Countries

United States

References

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Reference Type: BACKGROUND

PMID: 23163318 (View on PubMed)

Chavakula V, Sanchez Fernandez I, Peters JM, Popli G, Bosl W, Rakhade S, Rotenberg A, Loddenkemper T. Automated quantification of spikes. Epilepsy Behav. 2013 Feb;26(2):143-52. doi: 10.1016/j.yebeh.2012.11.048. Epub 2013 Jan 3.

Reference Type: BACKGROUND

PMID: 23291250 (View on PubMed)

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Reference Type: BACKGROUND

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Other Identifiers

IND 117060

Identifier Type: -

Identifier Source: secondary_id

BCH-P00003255

Identifier Type: -

Identifier Source: org_study_id