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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified April 2011 by Columbia University.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborators:
American Epilepsy Society
Milken Family Foundation
GlaxoSmithKline
Information provided by:
Columbia University
ClinicalTrials.gov Identifier:
NCT00524134
First received: August 31, 2007
Last updated: April 22, 2011
Last verified: April 2011
  Purpose

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.


Condition Intervention Phase
Epilepsy
Drug: Carvedilol-CR
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label Pilot Study Using Carvedilol-CR as a P-glycoprotein Inhibitor as Adjunct Therapy in the Treatment of Medically-refractory Epilepsy

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • The proportion of each treatment arm with ≥50% reduction in seizures [ Time Frame: 12 weeks at highest tolerated dose ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Percent change in total seizure count between treatment arms. [ Time Frame: 12 weeks at highest tolerated dose ] [ Designated as safety issue: No ]
  • Seizure Freedom [ Time Frame: 12 weeks at highest tolerated dose ] [ Designated as safety issue: No ]
  • Medication retention/treatment failure [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Sub-analysis by seizure type [ Time Frame: 12 months at highest tolerated dose ] [ Designated as safety issue: No ]

Estimated Enrollment: 33
Study Start Date: December 2008
Estimated Study Completion Date: April 2011
Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Carvedilol-CR up to 80mg daily, used as a P-glycoprotein inhibitor to increase drug concentrations in specific regions of the brain.
Drug: Carvedilol-CR
Week 1: 20mg capsule once daily Week 2-3: 40mg capsule once daily Week 4-15: 80mg once daily Week 16: tapering (40mg/day x 4d, then 20mg/day x 3d), unless the patient wishes to continue receiving the medication.
Other Name: Coreg-CR

Detailed Description:

The Center for Disease Control reports that epilepsy afflicts 2.7 million Americans with annual costs of $15.5 billion. They estimate that 3% of Americans will have a diagnosis of epilepsy by age 80, and decided in 1997 to focus on treatment, with a motto of "no seizures, no side effects".

Antiepileptic drugs (AED) can fail, despite being structurally unrelated and acting on different parts of the nervous system. This refractory state constitutes up to 35% of the epilepsy population, and may be due to pharmacoresistance. Efflux transporters, such as P-glycoprotein (Pgp), are present at the bloodbrain barrier and serve to pump out structurally unrelated compounds, likely serving as a method for the removal of toxins (and drugs). Upregulation of efflux transporters such as Pgp by tumor cells are thought to contribute to chemotherapy resistant cancer tumors, but Pgp has also been found focally at seizure foci. Its overexpression was also noted in blood vessel endothelial cells following temporal lobe resection for intractable epilepsy. Case series have shown mRNA for MDR1, the gene encoding Pgp, to be 10x greater in the medial temporal lobes of patients with temporal lobe epilepsy, as compared to those without epilepsy. Pathological examination following surgical resections have found that epilepsy causing lesions such as cortical dysplasias, encephalitis, tuberculous leptomeningitis, tuberous sclerosis and astrocytomas express Pgp in neurons and/or glia, whereas normal brain parenchyma does not. In animal and cell research, upregulation has been seen following seizure induction and status epilepticus. Many AEDs are validated substrates to Pgp in animal studies. Delivery of these medications to the brain is likely associated with Pgp and in some cases, presence of the substrate may upregulate Pgp.

When Pgp inhibitors were added to animal models of drug resistant epilepsy, there were significant improvements in seizure frequency, duration and severity, providing proof-of-concept at the animal level. Carvedilol and verapamil, among other medications, have been found to be potent Pgp inhibitors. Verapamil and dexverapamil, either oral or intravenous, has been used as Pgp-inhibitors in clinical trials, with success as an adjuvant in malignant lymphoma and a phase III study as an adjunct in chemorefractory, metastatic breast carcinoma. There have been no clinical trials published using Pgp-inhibition in epilepsy.

  Eligibility

Ages Eligible for Study:   10 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  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: NCT00524134

Locations
United States, New York
Columbia Comprehensive Epilepsy Center
New York, New York, United States, 10032
Sponsors and Collaborators
Columbia University
American Epilepsy Society
Milken Family Foundation
GlaxoSmithKline
Investigators
Principal Investigator: Derek Chong, MD, MSc Columbia University
  More Information

No publications provided

Responsible Party: Derek Chong, MD MSc FRCPC, Columbia University
ClinicalTrials.gov Identifier: NCT00524134     History of Changes
Other Study ID Numbers: AAAC3821
Study First Received: August 31, 2007
Last Updated: April 22, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Columbia University:
Epilepsy
Seizure
p-glycoprotein

Additional relevant MeSH terms:
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Carvedilol
Krestin
Adjuvants, Immunologic
Adrenergic Agents
Adrenergic Antagonists
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic beta-Antagonists
Anti-Infective Agents
Antibiotics, Antineoplastic
Antihypertensive Agents
Antineoplastic Agents
Antiviral Agents
Cardiovascular Agents
Immunologic Factors
Interferon Inducers
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Radiation-Protective Agents
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on November 24, 2014