Lentiviral Gene Therapy for Epilepsy

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Drug Resistant Epilepsy
• Intervention / Treatment: Genetic: lentiviral gene therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Senior Clinical Project Manager; Phone Number: +44(0)2031088954; Email: ekctrial@ucl.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

SCREENING/PRE-CONSENT:

1. Female and male patients with refractory focal epilepsy
2. Aged ≥ 18 years (no upper age limit but deemed medically fit for surgery with a life expectancy of at least 5 years)
3. Patient lives within 1 hour of transfer to an acute neurosurgical unit

4. 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:

5. 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
6. 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.
7. Able and willing to give written informed consent to join trial

Exclusion Criteria:

1. 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
2. Vascular brain lesions or vascular malformations in area of planned resection
3. Detection of active cancer or on systemic treatment for cancer
4. Known or suspected HIV infection (confirmed by PCR test) and/or taking antiretroviral therapy
5. Patient deemed medically unfit for anaesthesia and surgery
6. Active, untreated psychiatric disease in the opinion of the treating clinician
7. Concurrent and/or recent involvement in another clinical trial of an investigational medicinal product (within last 3 months)
8. Females who are pregnant (confirmed by serum/urine ß-HCG) or actively breast-feeding
9. Known allergies to excipients of lentiviral gene therapy
10. 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
11. Any other known condition which is assessed as an intolerable risk by the investigator upon inclusion in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: Medical Research Council

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2024
• Primary Completion (Anticipated): September 1, 2028
• Study Completion (Anticipated): September 1, 2032

Study Registration Dates

• First Submitted: October 6, 2020
• First Submitted That Met QC Criteria: October 20, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Actual): May 15, 2023
• Last Update Submitted That Met QC Criteria: May 12, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: surgery; brain; lentiviral gene therapy; drug resistant epilepsy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Drug Resistant Epilepsy
• Other Study ID Numbers: 18/0202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data may be shared with other researchers who are working in the public and charitable sector (universities, research institutes) or commercial companies involved in health care research in the UK or overseas. Participant data will be fully anonymised prior to data sharing. This means there will be no way to link the data to the original data set, or to individual participants. Anonymisation will be done by the trial statistician. Data shared in this way will be protected by a contractual agreement put in place between UCL (the Sponsor) and any respective institution.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No