A Dose Ranging Pilot Study for Intracerebroventricular (ICV) Delivery of Valproate in Subjects With Temporal Seizures

NCT02899611 | Completed Phase 1

• 1 other identifier: DA071976
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with medically refractory epilepsy will be treated by intracerebroventricular (ICV) delivery of valproate using an implantable drug pump system. The dose of valproate will be escalated weekly during a blinded-evaluation period through Day 64 to determine the maximum tolerated dose (MTD). After Day 64, patients can continue for 52 weeks in the open-label evaluation period (non-blinded). .

Conditions

Epilepsy

Keywords

Epilepsy

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD)

  The ICV Valproate dose will be escalated stepwise through Day 64, if tolerated, or stopped earlier upon establishment of a subject's MTD. The MTD for each subject will be determined based on the highest dose tolerated without experiencing a dose-limiting AE.

  2 months

• Safety: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  Safety will be evaluated by monitoring for adverse events (AEs) and serious adverse events (SAEs). This will be monitored using various metrics including: clinical assessments, seizure diaries, concomitant medications, blood and CSF sampling. MRI Scan, EEG and ECG will also be performed and monitored to evaluate safety.

  14 months

• Changes in the Number of Seizures

  Seizure diaries will be collected, monitored and reviewed at designated time points.

  14 months

Secondary Outcomes (3)

• Pharmacokinetic Parameters

  20 months

• Pharmacokinetic Parameters 2

  20 months

• Pharmacokinetic Parameters 3

  20 months

Study Arms (1)

ICV Valproate

EXPERIMENTAL

Patients receive a daily dose of ICV Valproate that increases from 3 mg to 60 mg (or MTD) over 8 weeks. A placebo week is randomly inserted in the dose escalation. During the placebo week, the patient receives normal saline.

Drug: Valproate

Interventions

Valproate DRUG

ICV Valproate is a dilution of the commercially available Epilim product, which is a sterile intravenous (IV) formulation of Sodium Valproate.

Also known as: Valproic acid, Depacon, Epilim

ICV Valproate

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject is 18 to 65 years old.
• Subject does not have coagulopathy, ventricular anatomic distortion or abnormally low brain weight or significant volume loss etc. and is approved to have surgery.
• Subject had onset of epilepsy after age 5, had normal brain development up to age 5, and has full scale IQ \> 70 by testing or functional assessment.
• Subject has brain volume which is not noted to be abnormally small due to atrophy by either the radiologist reading on MRI scan or the treating clinicians (the neurosurgeon) review of the MRI scan.
• Subject has had confirmed epilepsy for a minimum of 1 year, with diagnosis of focal seizures with temporal lobe onset, with or without secondarily generalized seizures, as defined by the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures (1981).
• In the opinion of the investigator, subject has disabling seizures. Disabling refers to seizures that are severe enough to cause injuries, or significantly impair functional ability in domains including employment, psychosocial education and mobility.
• Subject has had a CT or MRI of the brain to rule out progressive structural lesions.
• Subject has had an EEG or video EEG or invasive monitoring within the past 3 yrs consistent with partial seizures (a normal interictal EEG is consistent with partial seizures)
• Subject has previously failed at least 3 AEDs in single or combination use.
• Subject is taking currently approved AED medication(s) (but is not on valproate or divalproex sodium) and has been on a stable dosing regimen for 1 month prior to Screening.
• Subject has completed all investigations necessary to satisfy the PI that noninvasive therapies are not likely to be satisfactorily successful.
• For the 3 months before informed consent an average of four or more clinically significant focal seizures of temporal lobe onset, with or without secondary generalization, per month. Only seizures with objectively visible manifestations should be counted. The subject should have no period longer than 30 days in the 3 months prior to enrollment with less than 2 seizures. Seizures of hippocampal origin are preferred if the seizure origin is known or determined from imaging and seizure localization.
• Subject has seizures that are distinct, stereotypical events that can be reliably counted, in the opinion of the Investigator, by the subject or caregiver.
• Subject has hearing, vision, and physical abilities adequate to perform assessments, with or without corrective aids, including keeping a seizure and medication diary during study follow-up.
• Subject understands study procedures and has voluntarily provided signed, informed consent in accordance with institutional and local regulatory requirements.

You may not qualify if:

• Subject has any significant neurologic disease other than epilepsy.
• Subject has history, within 12 months prior to Screening, of repetitive seizures that cannot be counted.
• Subject has pseudoseizures or seizures secondary to illicit drug or alcohol use, neoplasia, active CNS infection, demyelinating disease, degenerative neurological disease, progressive central nervous system disease or metabolic illness.
• Subject has been diagnosed with partial motor, primarily generalized seizures or has been diagnosed with psychogenic or nonepileptic seizures in the preceding year.
• Subject has had status epilepticus refractory to benzodiazepines and phenytoin within one year prior to Screening
• Subject is currently taking neuroleptic medication for behavior control.
• Subject is taking scheduled doses of benzodiazepines or has required, in the 3 months prior to Screening, benzodiazepine use more than 4 times per month for seizure control. One use is defined as taking up to 3 doses in a 24 hour period.
• Subject is currently implanted with an activated DBS, or RNS device used for treatment of a neurologic or psychiatric condition.
• Subject has VNS and the VNS stimulation parameters are not stable. Stable shall be defined such that the stimulation parameters have been changed in the last 4 months or the patient/designee is able to report "magnet swipe" during the same time period.
• Subject is currently taking oral valproic acid or sodium divalproex.
• Subject has refractory motor seizures.
• Subject has had more than 10 seizures in one day or more than 300 seizures in one month within the last year.
• Subject has known allergy to valproic acid, divalproex sodium, Epilim, or Depacon.
• Subject has unstable depression being treated with more than 1 anti-depressant medication, or has current evidence of or history within the past 2 years of DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, and prior suicide attempt within five years. Also excluded are subjects with a history of postictal psychosis or psychosis or depression secondary to a discontinued AED.
• Subject has had alcohol or substance abuse within the past 5 years.

Sponsors & Collaborators

• Cerebral Therapeutics LLC: lead
• Neuroscience Trials Australia: collaborator

Study Sites (1)

St. Vincent Hospital

Melbourne, Victoria, 3010, Australia

Location

Related Publications (1)

• Cook M, Murphy M, Bulluss K, D'Souza W, Plummer C, Priest E, Williams C, Sharan A, Fisher R, Pincus S, Distad E, Anchordoquy T, Abrams D. Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: A first-in-man study. EClinicalMedicine. 2020 May 3;22:100326. doi: 10.1016/j.eclinm.2020.100326. eCollection 2020 May.

  PMID: 32395709 DERIVED

MeSH Terms

Conditions

Epilepsy

Interventions

Valproic Acid; Epilim

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2016
• First Posted: September 14, 2016
• Study Start: August 1, 2016
• Primary Completion: June 1, 2021
• Study Completion: June 1, 2021
• Last Updated: March 16, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)