EpilepsyPhase 2/3NCT00524134
P-glycoprotein Inhibition as Adjunct Treatment for Medically Refractory Epilepsy.
A Phase 2/3 study testing Carvedilol-CR in people with Epilepsy, run by Columbia University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 10 to 75 years
- Conditions the study is for
- Epilepsy
- What is being tested?
- Carvedilol-CR
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2008to Oct 2010
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 10 to 75 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Columbia Comprehensive Epilepsy Center
New York, New York, 10032
About this study
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
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.
Read more
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.
Read the 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.
- Conditions
- Epilepsy
- Being tested
- Carvedilol-CR
- Keywords
- Epilepsy, Seizure, p-glycoprotein
- Medical subject headings
- Epilepsy, Seizures
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Carvedilol-CRDrug
Also called Coreg-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.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Carvedilol-CR up to 80mg daily, used as a P-glycoprotein inhibitor to increase drug concentrations in specific regions of the brain. Receives: Drug: Carvedilol-CR |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of Each Treatment Arm With ≥50% Reduction in Seizures
Measured: 12 weeks at highest tolerated dose
Secondary outcomes (3)
Percent Change in Total Seizure Count Between Treatment Arms
Measured: 12 weeks at highest tolerated dose
Prevalence of Seizure Freedom
Measured: 12 weeks at highest tolerated dose
Prevalence of Medication Retention/Treatment Failure
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Sep 2007 (estimated)
- Study startDec 2008
- Primary completionOct 2010
- Study completionOct 2010
Why it stopped: PI left the institution.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for EpilepsyStudies of the same condition, open and under way.
- More trials run by Columbia UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Columbia University
- Sponsor type
- University, hospital or other
- Collaborators
- American Epilepsy Society, Milken Institute, GlaxoSmithKline
- Responsible party
- Sponsor
- Investigators
- Derek Chong, MD, MSc, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00524134
- Sponsor's protocol ID
- AAAC3821
- Status last verified
- Apr 2016
- First submitted
- 31 Aug 2007
- Last updated
- 23 May 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 23 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00524134
- Acronym / sponsor ID
- AAAC3821
- Conditions
- Epilepsy
- Keywords
- Epilepsy, Seizure, p-glycoprotein
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: PI left the institution.
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Columbia UniversityUniversity, hospital or other
- Collaborators
- American Epilepsy Society, Milken Institute, GlaxoSmithKline
- Study start
- Dec 2008
- Primary completion
- Oct 2010 (actual)
- Study completion
- Oct 2010 (actual)
- First posted
- 3 Sep 2007 (estimated)
- Results
- Posted 22 Apr 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Carvedilol-CRCarvedilol-CR up to 80mg daily, used as a P-glycoprotein inhibitor to increase drug concentrations in specific regions of the brain. |
Who may qualify
- Ages
- 10 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Carvedilol-CRAlso: Coreg-CRWeek 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. | Drug | 1 |
Primary outcome
Proportion of Each Treatment Arm With ≥50% Reduction in Seizures
Time frame: 12 weeks at highest tolerated dose
3 secondary outcomes
Percent Change in Total Seizure Count Between Treatment Arms
Time frame: 12 weeks at highest tolerated dose
Prevalence of Seizure Freedom
Time frame: 12 weeks at highest tolerated dose
Prevalence of Medication Retention/Treatment Failure
Time frame: 16 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 May 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Derek Chong, MD, MSc principal investigator
Columbia University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Carvedilol-CR in people with Epilepsy, run by Columbia University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 23 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Apr 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of Each Treatment Arm With ≥50% Reduction in Seizures (time frame: 12 weeks at highest tolerated dose). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 May 2016.