EpilepsyPhase 1/2NCT02899611
A Dose Ranging Pilot Study for Intracerebroventricular (ICV) Delivery of Valproate in Subjects With Temporal Seizures
A Phase 1/2 study testing Valproate in people with Epilepsy, run by Cerebral Therapeutics LLC at 1 site in Australia.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Epilepsy
- What is being tested?
- Valproate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteAustralia
- Study dates
- Aug 2016to 1 Jun 2021
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
- Medically refractory for more than one year.
- Needs be literate in English or native language of the country of the study enrollment to complete neuropsychological testing.
- Subject can be reasonably expected to maintain a seizure diary alone or with the assistance of a competent individual.
- Women of childbearing potential must be using a medically accepted method of contraception and have a negative qualitative β-human chorionic growth hormone (β-HCG) pregnancy test result from a urine or blood sample collected at Screening.
- Non-childbearing potential is defined as any female who is post menopausal since the last 1 year or has had hysterectomy or bilateral oophorectomy or is surgically sterilized.
- Medically accepted forms of birth control include:
- Intrauterine device in place for at least 3 months
- Adequate barrier methods (e.g., diaphragm and foam), or an oral contraceptive in combination with another method (e.g., spermicidal cream). An oral contraceptive alone is not considered adequate for this study.
- If on hepatic inducing AEDs which could lower serum hormone levels (phenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine, topiramate, zonisamide, rufinamide, lacosamide) then an oral contraceptive must have minimum dosage equivalent to 50 µg daily of ethinyl estradiol.
Who cannot join
- 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.
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- 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.
- Subject has uncontrolled Type I or Type II diabetes, hypercoagulability. Controlled diabetics for >12 months as evidenced by HbA1C <8% can be included in study based on Investigators assessment.
- Subject has history or evidence of congestive heart failure, clinically significant peripheral edema, or anemia with a hematocrit <30%.
- Subject has liver function tests aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at Screening ≥ 3 times the upper limit of normal, or clinically significant renal disease or insufficiency.
- Subject has elevated (clinically significant thrombocytosis) or decreased (< 175/μL) platelet count. Subjects should not be taking aspirin or nonsteroidal anti-inflammatory drugs within the week before and week after implantation of catheter and pump.
- Subject has abnormal prothrombin time or INR (> 14 seconds) or partial thromboplastin time (> 50 seconds).
- Subject has, after 3 minutes in the supine position, systolic blood pressure < 90 or > 180 or pulse outside the range of 50-100 beats per minute.
- Subject has had cancer within 3 years prior to Screening with the exception of squamous and basal cell carcinomas of the skin, and in situ carcinoma of the breast or cervix.
- Subject is on chronic anticoagulants or, in the opinion of the Investigator, is not a suitable candidate for cranial surgery for any reason.
- Subject has known HIV infection or known or suspected prion disease.
- Subject has known allergies to drugs or excipients.
- Subject is breastfeeding.
- In the opinion of the investigator, the subject has a clinically significant or unstable medical condition (including alcohol and/or drug abuse) or a progressive CNS disease
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Dose Ranging Pilot Study to Assess Intracerebroventricular (ICV) Delivery of Valproate in Subjects With Focal Seizures, With Temporal Lobe Onset With or Without Secondary Generalization
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). .
Read the detailed description
Epilepsy patients that are refractory to oral anti-epileptic drug (AED) treatment have significantly higher mortality, higher morbidity, higher economic costs and diminished quality of life compared to those who suffer from epilepsy that can be adequately controlled with medical management. Current options for refractory patients include neurosurgical brain resection, responsive neurostimulation, and vagal nerve stimulation. None of these options is satisfactory due to the low applicability of surgery for patients with poorly localized or multifocal seizures and the limited success of currently available alternative treatment options.
In this study, patients with medically refractory focal epilepsy will be treated with intracerebroventricular (ICV) administration of valproate using an implantable drug pump system. This is a dose ranging study, with a randomized, double-blind dose escalation component, to establish the dose range of ICV valproate delivery. Clinical assessments, adverse events (AEs), seizure diaries, concomitant medications, blood samples and cerebrospinal fluid (CSF) will be collected and reviewed at designated time points. Magnetic resonance imaging (MRI) and electroencephalography (EEG) will also be performed. Subjects will have their surgery, dose changes and pharmacokinetics performed in an inpatient setting.
The ICV Valproate dose will be escalated stepwise from 3 mg/day to 60 mg/day through Day 64 if tolerated, or stopped earlier upon establishment of a subject's maximum tolerated dose (MTD). The MTD for each subject will be determined based on the highest dose tolerated without experiencing a dose-limiting adverse event (AE). After establishing a subject's MTD, delivery of ICV Valproate will continue at the MTD through Day 64 of the blinded evaluation period. Subjects and assessing physicians will remain blinded to the treatment dose during the blinded evaluation period. Subjects can continue in the open-label evaluation period (non-blinded) for 52 weeks following the blinded evaluation period.
- Conditions
- Epilepsy
- Being tested
- Valproate
- Keywords
- Epilepsy
- Medical subject headings
- Epilepsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ValproateDrug
Also called Valproic acid, Depacon, Epilim
ICV Valproate is a dilution of the commercially available Epilim product, which is a sterile intravenous (IV) formulation of Sodium Valproate.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Valproate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 14 months
Changes in the Number of Seizures
Seizure diaries will be collected, monitored and reviewed at designated time points.
Measured: 14 months
Secondary outcomes (3)
Pharmacokinetic Parameters
Peak Plasma Concentration (Cmax) will be measured for plasma and cerebrospinal fluid levels of valproate for each subject.
Measured: 20 months
Pharmacokinetic Parameters 2
Area Under Curve will be measured for plasma and cerebrospinal fluid levels of valproate for each subject.
Measured: 20 months
Pharmacokinetic Parameters 3
Half Life will be measured for plasma and cerebrospinal fluid levels of valproate for each subject.
Measured: 20 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Sep 2016 (estimated)
- Study startAug 2016
- Primary completion1 Jun 2021
- Study completion1 Jun 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for EpilepsyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cerebral Therapeutics LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Neuroscience Trials Australia
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02899611
- Sponsor's protocol ID
- DA071976
- Status last verified
- Mar 2023
- First submitted
- 3 Sep 2016
- Last updated
- 16 Mar 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 32395709
Study at a glance
From the registry record, last updated by the sponsor on 16 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Dose Ranging Pilot Study to Assess Intracerebroventricular (ICV) Delivery of Valproate in Subjects With Focal Seizures, With Temporal Lobe Onset With or Without Secondary Generalization
- ClinicalTrials.gov ID
- NCT02899611
- Acronym / sponsor ID
- DA071976
- Conditions
- Epilepsy
- Keywords
- Epilepsy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Cerebral Therapeutics LLCIndustry (pharma, biotech, devices)
- Collaborators
- Neuroscience Trials Australia
- Study start
- Aug 2016 (actual)
- Primary completion
- 1 Jun 2021 (actual)
- Study completion
- 1 Jun 2021 (actual)
- First posted
- 14 Sep 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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). .
Detailed description
Epilepsy patients that are refractory to oral anti-epileptic drug (AED) treatment have significantly higher mortality, higher morbidity, higher economic costs and diminished quality of life compared to those who suffer from epilepsy that can be adequately controlled with medical management. Current options for refractory patients include neurosurgical brain resection, responsive neurostimulation, and vagal nerve stimulation. None of these options is satisfactory due to the low applicability of surgery for patients with poorly localized or multifocal seizures and the limited success of currently available alternative treatment options.
In this study, patients with medically refractory focal epilepsy will be treated with intracerebroventricular (ICV) administration of valproate using an implantable drug pump system. This is a dose ranging study, with a randomized, double-blind dose escalation component, to establish the dose range of ICV valproate delivery. Clinical assessments, adverse events (AEs), seizure diaries, concomitant medications, blood samples and cerebrospinal fluid (CSF) will be collected and reviewed at designated time points. Magnetic resonance imaging (MRI) and electroencephalography (EEG) will also be performed. Subjects will have their surgery, dose changes and pharmacokinetics performed in an inpatient setting.
The ICV Valproate dose will be escalated stepwise from 3 mg/day to 60 mg/day through Day 64 if tolerated, or stopped earlier upon establishment of a subject's maximum tolerated dose (MTD). The MTD for each subject will be determined based on the highest dose tolerated without experiencing a dose-limiting adverse event (AE). After establishing a subject's MTD, delivery of ICV Valproate will continue at the MTD through Day 64 of the blinded evaluation period. Subjects and assessing physicians will remain blinded to the treatment dose during the blinded evaluation period. Subjects can continue in the open-label evaluation period (non-blinded) for 52 weeks following the blinded evaluation period.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| ICV Valproate | Experimental | Drug: ValproatePatients 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- 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).
Key exclusion criteria (27 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ValproateAlso: Valproic acid, Depacon, EpilimICV Valproate is a dilution of the commercially available Epilim product, which is a sterile intravenous (IV) formulation of Sodium Valproate. | Drug | ICV Valproate |
Primary outcome
Maximum Tolerated Dose (MTD)
Time frame: 2 months
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.
Safety: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time frame: 14 months
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.
Changes in the Number of Seizures
Time frame: 14 months
Seizure diaries will be collected, monitored and reviewed at designated time points.
3 secondary outcomes
Pharmacokinetic Parameters
Time frame: 20 months
Pharmacokinetic Parameters 2
Time frame: 20 months
Pharmacokinetic Parameters 3
Time frame: 20 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Mar 2023.
- Derived from this study: PubMed 32395709Cook 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Valproate in people with Epilepsy, run by Cerebral Therapeutics LLC at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) (time frame: 2 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02899611, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Mar 2023.