Lentiviral Gene Therapy for Epilepsy

Study Overview
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Brief Summary
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This is a phase I/IIa clinical trial investigating the safety of a lentiviral epilepsy gene therapy using an engineered potassium channel in patients with refractory epilepsy.

Detailed Description
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Epilepsy affects about 1% of the population. One third of affected individuals continue to have seizures despite optimal medication. The only realistic prospect of seizure freedom, feasible in very few cases, is surgery to remove the brain area where seizures arise. Patients with refractory neocortical epilepsy who are being evaluated for surgical resection of the seizure focus will be invited to join the trial. The non-integrating lentiviral vector, which has been engineered to deliver an engineered potassium channel, will be administered via intracerebral infusion to the area scheduled for resection. The primary objective in this study is to test the safety of the lentiviral gene therapy treatment, including the surgical procedures required for vector administration. Secondary objectives will look at delayed onset adverse events and indicators of efficacy.

Official Title
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Phase I/IIa, First-in-human, Open-label, Single-site Trial of In-vivo Lentiviral Engineered Potassium (K+) Channel (EKC) Gene Therapy for Refractory Epilepsy

Conditions
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Drug Resistant Epilepsy

Intervention / Treatment
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* Genetic: lentiviral gene therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SCREENING/PRE-CONSENT: Female and male patients with refractory focal epilepsy Aged ≥ 18 years (no upper age limit but deemed medically fit for surgery with a life expectancy of at least 5 years) Patient lives within 1 hour of transfer to an acute neurosurgical unit Being considered for resective brain surgery (to remove the epileptogenic focus) based on first-stage preoperative assessments carried out as part of routine clinical care within 2 years of registration, showing: 4.1. Absence of vascular brain lesions or vascular malformations and/or cancer in the resection area (as confirmed on MRI) 4.2. Absence of active, untreated psychiatric disease in the opinion of the treating clinician (as confirmed by neuropsychiatric assessment) 4.3. Patient requires second-stage intracranial EEG investigations to be carried out via burr hole surgery to further assess eligibility for resective brain surgery PRE-REGISTRATION: Patient deemed clinically suitable for resective brain surgery (i.e. a single region of seizure onset in the neocortex has been identified, and it does not overlap with areas necessary for critical functions such as language), as confirmed by intracranial EEG investigations Patients who are women of childbearing potential (WOCBP), or male patients with female partners who are WOCBP or pregnant must agree to use highly effective methods of contraception from the time consent is signed until three months after treatment. Men (if applicable), must also advise their female partners regarding contraceptive requirements as listed for female patients who are WOCBP or pregnant. Able and willing to give written informed consent to join trial Exclusion Criteria: Not deemed clinically suitable for resective brain surgery (e.g. because of failure to identify a single region of seizure onset in the neocortex, region is too extensive or the region overlaps with areas necessary for critical functions such as language), as confirmed by intracranial EEG investigations Vascular brain lesions or vascular malformations in area of planned resection Detection of active cancer or on systemic treatment for cancer Known or suspected HIV infection (confirmed by PCR test) and/or taking antiretroviral therapy Patient deemed medically unfit for anaesthesia and surgery Active, untreated psychiatric disease in the opinion of the treating clinician Concurrent and/or recent involvement in another clinical trial of an investigational medicinal product (within last 3 months) Females who are pregnant (confirmed by serum/urine ß-HCG) or actively breast-feeding Known allergies to excipients of lentiviral gene therapy Patient unlikely to cooperate with a 5-year follow-up; medical or psychological condition at the discretion of the investigator which would not permit compliance with the protocol or meaningful written informed consent Any other known condition which is assessed as an intolerable risk by the investigator upon inclusion in the trial

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lentiviral gene therapy treatment (Intervention Arm)<br>Patients will receive a single dose of lentiviral gene therapy treatment administered once intracranially | Genetic: lentiviral gene therapy<br>* lentiviral gene therapy to treat drug resistant epilepsy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety during the First Year (for adverse events related to lentiviral gene therapy only) | Number and severity of all adverse events (graded using CTCAE v5.0) in patients deemed causally related to lentiviral gene therapy | At 6 weeks, 3 months, 6 months and 12 months after trial treatment | 
| Safety during the First Year (for adverse events causally related to investigational surgical procedures only) | Number and severity of all adverse events (graded using CTCAE v5.0) deemed causally related to any of the investigational surgical trial procedures required for vector administration | At 6 weeks, 3 months, 6 months and 12 months after trial treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-Term Safety (for adverse events related to lentiviral gene therapy only) | Number of serious adverse events (graded using CTCAE v5.0) in patients related to the lentiviral gene therapy | From 1 to 5 years after treatment | 
| Long-Term Safety (for adverse events causally related to investigational surgical procedures only) | Number of serious adverse events (graded using CTCAE v5.0) in patients related to the investigational surgical procedures required for vector administration | From 1 to 5 years after treatment | 
| Clinical Indicators of Efficacy and Tolerability | Seizure frequency and severity over preceeding 4 weeks | Measured at 6 weeks, 3 months, 6 months, and 12 months/1 year after trial treatment | 
| Clinical Indicators of Efficacy and Tolerability | Seizure frequency and severity (using IALE outcomes scale) | Measured at 12 months/1 year, 2 years, 3 years, 4 years and 5 years after trial treatment | 
| Clinical Indicators of Efficacy and Tolerability | Proportion of patients who have had surgical resection | at 3, 6, or 12 months, or at 2, 3, 4, and 5 years after trial treatment | 
| Cortical excitability | Cortical excitability (assessed using TMS, EMG, and high-density EEG) | at 6 months after trial treatment (only for patients in TMS study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lentiviral gene therapy, brain, surgery, drug resistant epilepsy