Effect of Valproic Acid Concentration on Photic Response

This study has been completed.
Sponsor:
Collaborator:
Abbott
Information provided by:
Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00609245
First received: February 1, 2008
Last updated: March 21, 2011
Last verified: March 2011
  Purpose

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.


Condition Intervention
Photosensitive Epilepsy
Drug: Valproic Acid
Drug: placebo

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Effect of Small Changes in Plasma Valproic Acid Concentration on the Photoparoxysmal Response

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Analysis of total change in SPR from baseline to highest VPA conc., for each patient, averaged across patients, determines overall efficacy of VPA. [ Time Frame: At the start of EEG monitoring/drug infusion, and also on an hourly basis thereafter ] [ Designated as safety issue: No ]

Enrollment: 13
Study Start Date: December 2007
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: VPA Drug: 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 Na VPA dose predictions will be based upon population VPA pharmacokinetic parameters (Dutta 2003).
Other Name: Depakote
Placebo Comparator: placebo Drug: placebo
Each patient will have a placebo-infusion (with 0.9% NS or D5W) of 12-hour duration at visit 2.

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.

  Eligibility

Ages Eligible for Study:   15 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00609245

Locations
United States, Missouri
The Comprehensive Epilepsy Care Center for Children & Adults
Chesterfield, Missouri, United States, 63017
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Abbott
Investigators
Principal Investigator: Bassel Abou-Khalil, MD Vanderbilt University
Principal Investigator: William Rosenfeld, MD The Comprehensive Epilepsy Care Center for Children & Adults
Principal Investigator: Dorothee Kasteleijn-Nolst Trenite, MD, PhD The Comprehensive Epilepsy Care Center for Children & Adults
  More Information

No publications provided

Responsible Party: Bassel Abou-Khalil, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00609245     History of Changes
Other Study ID Numbers: IRB# 070849
Study First Received: February 1, 2008
Last Updated: March 21, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
epilepsy
photosensitive
valproic acid

Additional relevant MeSH terms:
Epilepsy
Epilepsy, Reflex
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Valproic Acid
Anticonvulsants
Antimanic Agents
Central Nervous System Agents
Central Nervous System Depressants
Enzyme Inhibitors
GABA Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on October 22, 2014