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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02899611




Registration number
NCT02899611
Ethics application status
Date submitted
3/09/2016
Date registered
14/09/2016
Date last updated
5/11/2019

Titles & IDs
Public title
A Dose Ranging Pilot Study for Intracerebroventricular (ICV) Delivery of Valproate in Subjects With Temporal Seizures
Scientific 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
Secondary ID [1] 0 0
DA071976
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 0 0
Condition category
Condition code
Neurological 0 0 0 0
Epilepsy
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Valproate

Experimental: ICV Valproate - 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.


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

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
2 months
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
14 months
Primary outcome [3] 0 0
Changes in the Number of Seizures - Seizure diaries will be collected, monitored and reviewed at designated time points.
Timepoint [3] 0 0
14 months
Secondary outcome [1] 0 0
Pharmacokinetic Parameters - Peak Plasma Concentration (Cmax) will be measured for plasma and cerebrospinal fluid levels of valproate for each subject.
Timepoint [1] 0 0
20 months
Secondary outcome [2] 0 0
Pharmacokinetic Parameters 2 - Area Under Curve will be measured for plasma and cerebrospinal fluid levels of valproate for each subject.
Timepoint [2] 0 0
20 months
Secondary outcome [3] 0 0
Pharmacokinetic Parameters 3 - Half Life will be measured for plasma and cerebrospinal fluid levels of valproate for each subject.
Timepoint [3] 0 0
20 months

Eligibility
Key inclusion criteria
1. Subject is 18 to 65 years old.

2. Subject does not have coagulopathy, ventricular anatomic distortion or abnormally low
brain weight or significant volume loss etc. and is approved to have surgery.

3. 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.

4. 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.

5. 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).

6. 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.

7. Subject has had a CT or MRI of the brain to rule out progressive structural lesions.

8. 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)

9. Subject has previously failed at least 3 AEDs in single or combination use.

10. 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.

11. Subject has completed all investigations necessary to satisfy the PI that noninvasive
therapies are not likely to be satisfactorily successful.

12. 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.

13. Subject has seizures that are distinct, stereotypical events that can be reliably
counted, in the opinion of the Investigator, by the subject or caregiver.

14. 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.

15. Subject understands study procedures and has voluntarily provided signed, informed
consent in accordance with institutional and local regulatory requirements.

16. Medically refractory for more than one year.

17. Needs be literate in English or native language of the country of the study enrollment
to complete neuropsychological testing.

18. Subject can be reasonably expected to maintain a seizure diary alone or with the
assistance of a competent individual.

19. Women of childbearing potential must be using a medically accepted method of
contraception and have a negative qualitative ß-human chorionic growth hormone (ß-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:

1. Intrauterine device in place for at least 3 months

2. 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.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subject has any significant neurologic disease other than epilepsy.

2. Subject has history, within 12 months prior to Screening, of repetitive seizures that
cannot be counted.

3. 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.

4. Subject has been diagnosed with partial motor, primarily generalized seizures or has
been diagnosed with psychogenic or nonepileptic seizures in the preceding year.

5. Subject has had status epilepticus refractory to benzodiazepines and phenytoin within
one year prior to Screening

6. Subject is currently taking neuroleptic medication for behavior control.

7. 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.

8. Subject is currently implanted with an activated DBS, or RNS device used for treatment
of a neurologic or psychiatric condition.

9. 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.

10. Subject is currently taking oral valproic acid or sodium divalproex.

11. Subject has refractory motor seizures.

12. Subject has had more than 10 seizures in one day or more than 300 seizures in one
month within the last year.

13. Subject has known allergy to valproic acid, divalproex sodium, Epilim, or Depacon.

14. 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.

15. Subject has had alcohol or substance abuse within the past 5 years.

16. 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.

17. Subject has history or evidence of congestive heart failure, clinically significant
peripheral edema, or anemia with a hematocrit <30%.

18. 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.

19. 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.

20. Subject has abnormal prothrombin time or INR (> 14 seconds) or partial thromboplastin
time (> 50 seconds).

21. 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.

22. 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.

23. Subject is on chronic anticoagulants or, in the opinion of the Investigator, is not a
suitable candidate for cranial surgery for any reason.

24. Subject has known HIV infection or known or suspected prion disease.

25. Subject has known allergies to drugs or excipients.

26. Subject is breastfeeding.

27. 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

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
St. Vincent Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
3010 - Melbourne

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Cerebral Therapeutics LLC
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Neuroscience Trials Australia
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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). .
Trial website
https://clinicaltrials.gov/show/NCT02899611
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications