Effect of Valproic Acid Concentration on Photic Response

NCT ID: NCT00609245

Last Updated: 2017-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-12-31
• Study Completion Date: 2008-12-31

Brief Summary

We are trying to learn if small changes in the amount of a valproate in the blood (given through an IV) will change the way the brain reacts to flashing lights.

Detailed Description

Photosensitive epilepsy is a form of epilepsy that is considered to have a genetic basis in most instances. It is a reflex type of epilepsy. Patients with this condition exhibit epileptic activity patterns (called photoparoxysmal response-PPR) on their EEG during intermittent photic stimulation with certain flash frequencies.

Specific Aims

1. To determine the extent of the pharmacodynamic effect of small changes in total and free VPA concentration via constant infusion of intravenous sodium valproate within the same photosensitive epilepsy patient.

2. To determine the change in total and free VPA concentration required to achieve maximal effect on PPR in patients with photosensitive epilepsy.

Hypothesis

1. Valproic acid (VPA) demonstrates differential pharmacodynamic effect on PPR with small changes in VPA concentration (5-20 mg/L changes in total, or 0.5 to 2 mg/L changes in free VPA) within the same patient. In essence, the VPA concentration-response curve in patients with photosensitive epilepsy is relatively steep.

2. Intravenously-administered VPA will demonstrate a reduction in standard photosensitive range (SPR) or abolition of PPR for at least 80% of patients studied, when the entire range of free VPA concentrations is considered.

Photosensitivity, defined as a PPR on intermittent photic stimulation (IPS), is found in approximately 5% of all epileptic patients. Markedly photosensitive patients are usually sensitive to IPS within clearly defined limits of flash frequency (mostly between 10-30 Hz). This photosensitivity range, the difference between the highest and lowest flash rates that consistently elicit a photoparoxysmal response (PPR), can be used as a quantitative measure of photosensitivity.

Administration of some antiepileptic drugs (AEDS) can diminish or even abolish PPR. With a standard set of tested frequencies, a standard photosensitive range (SPR) can be used to measure drug effect on photosensitivity. Combined with blood level monitoring, the model offers information about actual pharmacodynamic effect as measured with IPS related to the changes in blood levels.

The standardized IPS procedure includes delivery of short (5 second-) trains of flashes. The stimulation starts with the lowest frequencies (which usually do not produce a PPR) only up to the limits of the photosensitivity range (the threshold frequencies for which the patient shows an epileptiform EEG response). After that the stimulation starts again with the highest frequencies (which also do not produce a PPR) down to the frequency that produces a definite PPR.

The photic stimulator will be manually controlled for all stimulations in order to abort the stimulation when a clear PPR is elicited. With all stimulations, there is simultaneous recording of the EEG and direct observation of the patient for clinical changes. With all the safety measures in place, the likelihood of provoking prominent clinical seizures is extremely low.

Conditions

Photosensitive Epilepsy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Placebo then Valproic Acid (VPA)

all patients will have placebo on day 1 and VPA infusion on day 2

Group Type: EXPERIMENTAL

Valproic Acid

Intervention Type: DRUG

The investigators will utilize intravenous sodium valproate at visit 3. Dosage will be individualized to each patient's body weight, age, and hepatic-enzyme-inducing status. Intravenous VPA dose predictions will be based upon population VPA pharmacokinetic parameters (Dutta 2003).

Placebo

Intervention Type: DRUG

Each patient will have a placebo-infusion (with 0.9% NS or D5W) of 12-hour duration at visit 2.

Interventions

Valproic Acid

The investigators will utilize intravenous sodium valproate at visit 3. Dosage will be individualized to each patient's body weight, age, and hepatic-enzyme-inducing status. Intravenous VPA dose predictions will be based upon population VPA pharmacokinetic parameters (Dutta 2003).

Intervention Type: DRUG

Placebo

Each patient will have a placebo-infusion (with 0.9% NS or D5W) of 12-hour duration at visit 2.

Intervention Type: DRUG

Other Intervention Names

Depacon; Normal Saline (NS) and 5% Dextrose in water (D5W)

Eligibility Criteria

Inclusion Criteria

• Male or female patients
• Aged 15 to 65 years
• Patients with a diagnosis of epilepsy for which they are either taking up two AEDs, not including VPA/divalproex, or no AEDs
• Patients with a reproducible IPS-induced photo-paroxysmal responses of at least 7 SPR-EEG units as measured at two different time points in the day (pm screening Study Visit 1 and am of Visit 2).
• Are in good health (with the exception of epilepsy).
• Able and willing to provide written informed consent.

Exclusion Criteria

• Patients not exhibiting a photo-paroxysmal-EEG response
• Patients with active psychogenic seizures
• Women who are pregnant or lactating
• Women of reproductive potential who do not agree to use effective birth-control methods during the study and for one week after receiving study drug.
• Patients taking any dosage form of VPA/divalproex within 4 weeks prior to the study
• Patients taking more than two concomitant AEDs
• Patients with any clinically significant laboratory abnormality, which in the opinion of the investigator, will exclude the patient from the study
• Patients who are suffering from active liver disease indicated by abnormal liver function tests greater than three times the upper limit of normal (AST and ALT), patients with porphyria, or patients with a family history of severe hepatic dysfunction
• Patients with a history of alcoholism, drug abuse, or drug addiction (within the past 12 months)
• Patients with a history of sensitivity or allergic reaction to valproate / divalproex
• Patients who have a medical history which would contraindicate sodium valproate (VPA) administration
• Patients who have participated in any other trials involving an investigational product or device within 30 days of screening.
• Patients with clinically significant ECG abnormalities, as judged by the PI, at screening visit
• Patients with such poor intravenous access that the insertion of two intravenous catheters (one for sodium valproate infusion and one, in a contralateral arm vein, for serial blood sampling) for a 12-hour period is not possible.
• Patients who received benzodiazepines within one week of study initiation
• Status epilepticus within one year of screening
• Generalized tonic-clonic seizure within 24 hours of photic stimulation procedure

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Abbott

INDUSTRY

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Bassel Abou-Khalil

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bassel Abou-Khalil, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

William Rosenfeld, MD

Role: PRINCIPAL_INVESTIGATOR

The Comprehensive Epilepsy Care Center for Children & Adults

Dorothee Kasteleijn-Nolst Trenite, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

The Comprehensive Epilepsy Care Center for Children & Adults

Locations

The Comprehensive Epilepsy Care Center for Children & Adults

Chesterfield, Missouri, United States

Vanderbilt University

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

IRB# 070849

Identifier Type: -

Identifier Source: org_study_id