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|NCT02899611 : A Dose Ranging Pilot Study to Assess Intracerebroventricular (ICV) Delivery of Valproate in Subjects With Temporal Seizures|
|Phase||Phase 1/Phase 2|
|Ages||Min: 18 Years Max: 65 Years|
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
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
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
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
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 ?-human chorionic growth hormone
(?-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.
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
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/?L)
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
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
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