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

April 21, 2016 updated by: Columbia University

An Open-label Pilot Study Using Carvedilol-CR as a P-glycoprotein Inhibitor as Adjunct Therapy in the Treatment of Medically-refractory Epilepsy

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
6

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10032
        • Columbia Comprehensive Epilepsy Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

10 years to 75 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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 Names:
  • Coreg-CR

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Proportion of Each Treatment Arm With ≥50% Reduction in Seizures
Time Frame: 12 weeks at highest tolerated dose
12 weeks at highest tolerated dose

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Percent Change in Total Seizure Count Between Treatment Arms
Time Frame: 12 weeks at highest tolerated dose
12 weeks at highest tolerated dose
Prevalence of Seizure Freedom
Time Frame: 12 weeks at highest tolerated dose
12 weeks at highest tolerated dose
Prevalence of Medication Retention/Treatment Failure
Time Frame: 16 weeks
16 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Columbia University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
GlaxoSmithKline
American Epilepsy Society
Milken Institute

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Derek Chong, MD, MSc, Columbia University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2008

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 1, 2010

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2010

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 31, 2007

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 31, 2007

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 3, 2007

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 23, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 21, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • AAAC3821

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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