EpilepsyPhase 4NCT00610532
Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
A Phase 4 study testing phenytoin and phenytoin and probenecid in people with Epilepsy, run by Jim McAuley at 1 site in United States.
Trial summary
The study is being done to understand why some patients with epilepsy (disease of recurrence of seizures) do not respond very well to drug treatment with anticonvulsants. Despite the availability of many anticonvulsants, about 30% of patients with epilepsy are resistant to them. Read more about this study
- Who is it for?
- Ages 18 to 65 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Epilepsy
- What is being tested?
- phenytoin and phenytoin and probenecid
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- Mar 2006to Jun 2011
- Phase
- Phase 4
- 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 18 to 65 years
- Men only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Men with pharmacoresistant partial epilepsy defined as failure of two or more AEDs at a reasonable therapeutic dose
- Patient is able to understand and sign a consent form and able to keep a seizure calendar
- Patient is older than 18 years of age
- Patient is otherwise healthy by laboratory and physical examination
Who cannot join
- Patient is currently taking phenytoin
- Patient has a history of an adverse reaction to phenytoin
- Patient has a history of gout disease, peptic ulcer disease, blood dyscrasias, or uric acid kidney stones
- Patient has an allergy to sulfa drugs or probenecid
- Patient has been exposed to probenecid or another known transporter inhibitor (verapamil, progesterone, etc) in the three months prior to enrollment
- Patient has a history of renal impairment (creatinine clearance < 50 ml/min)
- Patient has a history of diabetes and is taking oral sulfonylurea agents
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Evaluating Transporter Protein Inhibitors in Patients With Epilepsy
The study is being done to understand why some patients with epilepsy (disease of recurrence of seizures) do not respond very well to drug treatment with anticonvulsants.
Despite the availability of many anticonvulsants, about 30% of patients with epilepsy are resistant to them. The cause of the resistance is not clear, but one of the reasons could be an increased amount of proteins in the cells of the body called transporter proteins.
Read more
Transporter proteins are a group of proteins that help to defend the body against toxins, including drugs, by pumping them out of the cells. Studies have shown that the number of transporter proteins is higher in the parts of the brain that trigger seizures when compared to other parts of the brain.
Studies in animals have shown that taking an anticonvulsant with an inhibitor (meaning "to stop" or "to reduce") of a transporter protein can increase the concentration of that anticonvulsant inside the brain cells. The main purpose of the study is to determine if taking an anticonvulsant and a transporter protein inhibitor will change the brain concentration of the anticonvulsant.
In this study, a single dose of phenytoin (Dilantin® is a brand name anticonvulsant which has phenytoin as its active ingredient), a commonly used anticonvulsant, will be given once by itself, and then will be given a separate time with a single (i.e. one time only) dose of probenecid. Probenecid, a medicine used commonly to treat gout (a disease of increased uric acid), is known to be an inhibitor of transporter proteins. The study will use electroencephalogram or EEG (recording of brain wave activities) to determine if the EEG pattern when probenecid is given, will be different from the EEG pattern when phenytoin is given alone. This will suggest that probenecid has affected the brain concentration of phenytoin.
Read the detailed description
About 30% of patients with epilepsy are refractory to medical treatment (pharmacoresistant epilepsy). The cause of which is multifactorial. Multidrug resistance (MDR) causes decreased uptake of medicines in tissues. MDR occurs because of overexpression of a family of transporter proteins that act as a physiological defense mechanism that pumps toxins out of cells. Two groups of transporters, P-glycoprotein (PGP) and multidrug resistance-associated proteins (MRP), are important gatekeepers in the blood brain barrier. PGP and MRP are overexpressed in the brain tissue of pharmacoresistant patients with partial epilepsy and many antiepileptic drugs (AEDs) are substrates for PGP, MRP or both.
It is logical to try to apply these observations to clinical practice. We hope that through co-administration of an inhibitor of transporter proteins, we can increase the CNS concentrations of AEDs, and subsequently improve seizure control. However, before this, it is critical to demonstrate that a transporter protein inhibitor can increase the concentration of AEDs in human brain.
Probenecid is an MRP inhibitor while phenytoin is an MRP substrate. Evaluating whether probenecid can increase the CNS concentration of PHT can potentially be achieved noninvasively by using pharmaco-EEG.
We plan to estimate the effect of probenecid (a transporter protein inhibitor) on the quantitative EEG recordings when it is administered to patients with pharmacoresistant epilepsy and in normal healthy volunteers.
We plan to recruit two groups of 10 subjects each, normal volunteers and patients with pharmacoresistant epilepsy. They will undergo two treatment regimens; EEG recording after administration of intravenous phenytoin only and again after pre-dosing them with probenecid.
- Conditions
- Epilepsy
- Being tested
- phenytoin, phenytoin and probenecid
- Keywords
- pharmacoresistance, healthy volunteers
- Medical subject headings
- Epilepsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
phenytoinDrug
intravenous phenytoin (15 mg/kg) single dose
phenytoin and probenecidDrug
intravenous phenytoin (15 mg/kg) single dose and oral probenecid 2000 mg single dose
| Study group | Role | What they receive |
|---|---|---|
| A | Experimental | intravenous phenytoin alone Receives: Drug: phenytoin |
| B | Experimental | intravenous phenytoin plus probenecid Receives: Drug: phenytoin and probenecid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Quantitative EEG Recordings
Measured: end of each treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Feb 2008 (estimated)
- Study startMar 2006
- Primary completionJun 2011
- Study completionJun 2011
Why it stopped: Investigators decided not to continue
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.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jim McAuley
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Jim McAuley, Ohio State University
- Investigators
- James W McAuley, PhD, Principal investigator, Ohio State UniversityBassel F Shneker, MD, Principal investigator, Ohio State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00610532
- Sponsor's protocol ID
- 2005H0170
- Status last verified
- May 2013
- First submitted
- 28 Jan 2008
- Last updated
- 14 May 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 May 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluating Transporter Protein Inhibitors in Patients With Epilepsy
- ClinicalTrials.gov ID
- NCT00610532
- Acronym / sponsor ID
- 2005H0170
- Conditions
- Epilepsy
- Keywords
- pharmacoresistance, healthy volunteers
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Investigators decided not to continue
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Jim McAuleyUniversity, hospital or other
- Study start
- Mar 2006
- Primary completion
- Jun 2011 (actual)
- Study completion
- Jun 2011 (actual)
- First posted
- 8 Feb 2008 (estimated)
- Results
- Posted 14 May 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study is being done to understand why some patients with epilepsy (disease of recurrence of seizures) do not respond very well to drug treatment with anticonvulsants.
Despite the availability of many anticonvulsants, about 30% of patients with epilepsy are resistant to them. The cause of the resistance is not clear, but one of the reasons could be an increased amount of proteins in the cells of the body called transporter proteins.
Transporter proteins are a group of proteins that help to defend the body against toxins, including drugs, by pumping them out of the cells. Studies have shown that the number of transporter proteins is higher in the parts of the brain that trigger seizures when compared to other parts of the brain.
Studies in animals have shown that taking an anticonvulsant with an inhibitor (meaning "to stop" or "to reduce") of a transporter protein can increase the concentration of that anticonvulsant inside the brain cells. The main purpose of the study is to determine if taking an anticonvulsant and a transporter protein inhibitor will change the brain concentration of the anticonvulsant.
In this study, a single dose of phenytoin (Dilantin® is a brand name anticonvulsant which has phenytoin as its active ingredient), a commonly used anticonvulsant, will be given once by itself, and then will be given a separate time with a single (i.e. one time only) dose of probenecid. Probenecid, a medicine used commonly to treat gout (a disease of increased uric acid), is known to be an inhibitor of transporter proteins. The study will use electroencephalogram or EEG (recording of brain wave activities) to determine if the EEG pattern when probenecid is given, will be different from the EEG pattern when phenytoin is given alone. This will suggest that probenecid has affected the brain concentration of phenytoin.
Detailed description
About 30% of patients with epilepsy are refractory to medical treatment (pharmacoresistant epilepsy). The cause of which is multifactorial. Multidrug resistance (MDR) causes decreased uptake of medicines in tissues. MDR occurs because of overexpression of a family of transporter proteins that act as a physiological defense mechanism that pumps toxins out of cells. Two groups of transporters, P-glycoprotein (PGP) and multidrug resistance-associated proteins (MRP), are important gatekeepers in the blood brain barrier. PGP and MRP are overexpressed in the brain tissue of pharmacoresistant patients with partial epilepsy and many antiepileptic drugs (AEDs) are substrates for PGP, MRP or both.
It is logical to try to apply these observations to clinical practice. We hope that through co-administration of an inhibitor of transporter proteins, we can increase the CNS concentrations of AEDs, and subsequently improve seizure control. However, before this, it is critical to demonstrate that a transporter protein inhibitor can increase the concentration of AEDs in human brain.
Probenecid is an MRP inhibitor while phenytoin is an MRP substrate. Evaluating whether probenecid can increase the CNS concentration of PHT can potentially be achieved noninvasively by using pharmaco-EEG.
We plan to estimate the effect of probenecid (a transporter protein inhibitor) on the quantitative EEG recordings when it is administered to patients with pharmacoresistant epilepsy and in normal healthy volunteers.
We plan to recruit two groups of 10 subjects each, normal volunteers and patients with pharmacoresistant epilepsy. They will undergo two treatment regimens; EEG recording after administration of intravenous phenytoin only and again after pre-dosing them with probenecid.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | Experimental | Drug: phenytoinintravenous phenytoin alone |
| B | Experimental | Drug: phenytoin and probenecidintravenous phenytoin plus probenecid |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Men with pharmacoresistant partial epilepsy defined as failure of two or more AEDs at a reasonable therapeutic dose
- Patient is able to understand and sign a consent form and able to keep a seizure calendar
- Patient is older than 18 years of age
- Patient is otherwise healthy by laboratory and physical examination
Key exclusion criteria (7 listed)
- Patient is currently taking phenytoin
- Patient has a history of an adverse reaction to phenytoin
- Patient has a history of gout disease, peptic ulcer disease, blood dyscrasias, or uric acid kidney stones
- Patient has an allergy to sulfa drugs or probenecid
- Patient has been exposed to probenecid or another known transporter inhibitor (verapamil, progesterone, etc) in the three months prior to enrollment
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 |
|---|---|---|
| phenytoinintravenous phenytoin (15 mg/kg) single dose | Drug | A |
| phenytoin and probenecidintravenous phenytoin (15 mg/kg) single dose and oral probenecid 2000 mg single dose | Drug | B |
Primary outcome
Quantitative EEG Recordings
Time frame: end of each treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2013.
- 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.
James W McAuley, PhD principal investigator
Ohio State University
Bassel F Shneker, MD principal investigator
Ohio State University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing phenytoin and phenytoin and probenecid in people with Epilepsy, run by Jim McAuley 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 4 inclusion and 7 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 14 May 2013. 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 phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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 14 May 2013). 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?
Quantitative EEG Recordings (time frame: end of each treatment). 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 14 May 2013.