P-glycoprotein Inhibition as Adjunct Treatment for Medically Refractory Epilepsy.

• Status: Terminated
• Trial end date: 2010-10-01
• Target enrollment: 0
• Participant gender: All

Summary

In up to 1 out of 3 patients with epilepsy, seizures continue to occur despite the use of one or more antiepileptic medications. Patients also have significant problems with side-effects of these medications as doses are increased.

Our body naturally generates miniature pumps located on the surfaces of many organs to get rid of toxic substances, and antiepileptic medications can be considered by the cells of the body to be a toxin. Research with epileptic brain regions have shown an increase in the amount of drug pumps, therefore getting rid of antiepileptic drugs. One of these pumps is called p-glycoprotein (P-gp for short). Medications may be unable to penetrate and stay within the parts of the brain that need them them most. This may mean that the amount of drug is actually lower in the parts of the brain that cause seizures, and higher in the rest of the brain, which may be why patients may still feel side-effects when seizures are still occurring.

Research in animals has shown that blocking the P-gp pumps can improve how bad, and how many seizures occur as well as the length of seizures. Blockage of the pumps can be done using a different type of medication. Some medications that are used for common problems have been discovered to also block P-gp pumps. One of these, carvedilol, is used to treat heart failure and high blood pressure. It has been found to be very safe in these patients, and does not have a lot of side-effects. We plan to add this medication in addition to patient's anti-seizure medications to see if it will improve epileptic seizures.

The reason why some patients have high amounts of P-gp pumps and others do not may be related to their genetics. A simple blood test can be used to determine a person's potential to produce high quantities of the pumps. This study will also attempt to show that the genetics will affect how well the P-gp blocking will work.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Columbia University
• Collaborators: American Epilepsy Society; GlaxoSmithKline; Milken Family Foundation
• Treatments: Carvedilol; Krestin

Criteria

Inclusion Criteria:

• probable or definite localization-related, primary generalized or symptomatic generalized epilepsy that is medically-refractory, as defined by treatment failure of at least 2 anti-epilepsy drugs at standard doses, despite medication compliance as determined by the treating neurologist

• at least 3 seizures/month in the 3-month period prior to randomization. Seizures that will be considered include generalized tonic clonic, complex partial, myoclonic and absence seizures. Simple partial seizures must have an observable motor component or have been otherwise been documented by videoEEG to be a definite seizure.

• Patients with prior epilepsy brain surgery or vagal nerve stimulator implantation will be allowed if medication and seizure frequency has been stable for the prior 3 months.

• Ages between 10 and 75 years will be eligible for inclusion. Elderly patients without a history or symptoms of cardiovascular disease may be eligible on a case-by-case basis. No patients older than 75 will be included due to the possible cardiovascular side-effects.

• Pre-menopausal women must be utilizing two reliable forms of birth control or abstinence

• ability of the patient to understand the concept of a clinical trial by answering the following questions appropriately: o will your seizures get better, worse or stay the same? Response in the spirit of: Any of the 3 could happen.

Exclusion Criteria:

• pregnancy or breast-feeding

• systolic blood pressure <100mmHg

• resting heart rate < 55 bpm

• concurrent calcium channel, beta-blocker or digoxin therapy

• Known hypersensitivity to carvedilol or any component of the formulation

• Decompensated cardiac failure requiring intravenous inotropic therapy

• Coronary artery disease with history of angina or Any cause of unstable angina

• Second- or third-degree AV block or sick sinus syndrome

• Bronchial asthma or related bronchospastic conditions

• Severe hepatic or renal impairment

• Active drug or alcohol dependence, that, in the opinion of a study investigator, would interfere with adherence to study requirements

• Any acute medical or psychiatric illness requiring inpatient admission; exceptions are elective epilepsy monitoring or elective procedures