Talampanel to Treat Parkinson's Disease
Talampanel to Treat Parkinson's Disease
This study will evaluate the effects of the experimental drug talampanel on dyskinesias
 (involuntary movements) that develop in patients with Parkinson's disease as a result of
 long-term treatment with levodopa (Sinemet). The drug will be tested alone and in combination
 with amantadine-a drug commonly used to alleviate dyskinesias.

 Patients between 21 and 80 years of age with Parkinson's disease and dyskinesias may be
 eligible for this study.

 Screening and baseline evaluation. Participants are evaluated with a medical history,
 physical and neurologic examinations, blood and urine tests, electrocardiogram (EKG) and
 pregnancy test, if applicable. A chest x-ray and MRI or CT scan of the brain are done if
 needed. Patients stop taking all antiparkinsonian medications for one month (2 months if
 taking Selegiline) before the study begins and throughout its duration, except for certain
 medicines allowed, including Sinemet, Mirapex and Requip. Amantadine can be taken up to 1
 week before beginning the study.

 Dose-finding phase. Patients are admitted to the NIH Clinical Center for 2 to 3 days for a
 levodopa "dose-finding" procedure. For this test, patients stop taking Sinemet and instead
 have it infused through a vein. During the infusions, the drug dose is increased slowly until
 parkinsonian symptoms improve or unacceptable side effects occur or the maximum study dose is
 reached. Symptoms are monitored frequently. At given times during the infusion, saline is
 given instead of Sinemet. The infusions usually begin in the early morning and continue until
 evening. Patients resume taking Sinemet between infusions. (Patients who have had dosing
 infusions in the last 3 months do not have to undergo this phase of the study.)

 After the dose-finding phase, patients are randomly assigned to take placebo (a "sugar pill")
 or talampanel. Those taking talampanel also receive amantadine at their usual dosages. At
 some point in the study, amantadine is replaced with placebo. Patients in the talampanel
 group also receive placebo for portions of the study.

 Active study phase. At study weeks 1, 5 and 7, patients are admitted to the Clinical Center
 overnight for a levodopa infusion with talampanel or placebo. The day before the infusion,
 patients have a brief physical examination, blood and urine tests, an EKG, and a review of
 symptoms or changes in their condition. The next day, they receive an infusion of levodopa at
 the dose determined in the dose-finding phase. Then they take a pill containing either
 talampanel or placebo. Their parkinsonian symptoms and dyskinesias are evaluated and
 videotaped every 30 minutes for about 6 hours. Blood is drawn and an EKG is obtained. At the
 end of the infusions and ratings, patients resume their regular Parkinson's medications and
 are given a new supply of study medications to take home.

 At weeks 2, 3, 4 and 6, patients come to the Clinical Center for a review of drug side
 effects. They have blood drawn and receive a new supply of study medications that last until
 the next visit.

 Follow-up. Two weeks after the study ends, patients are contacted by phone for a review of
 side effects or they return to the clinic for an evaluation.
Objective: to evaluate the acute effects of talampanel, a novel antagonist of AMPA type
 glutamate receptors, on the severity of parkinsonian signs and levodopa-associated motor
 response complications.

 Study Population: patients with moderately advanced Parkinson's disease and dopaminergic
 therapy related motor complications, between the age of 21 and 80.

 Study Design: randomized, controlled, proof-of-principle pilot study lasting approximately 7
 weeks.

 Study Outcome Parameters: the pharmacokinetic characteristics of orally administered
 talampanel will be measured by means of plasma drug assays, its therapeutic efficacy will be
 evaluated using validated motor function scales, and safety will be monitored by means of
 frequent clinical evaluations and laboratory tests.
INCLUSION CRITERIA:

 Patients who meet all of the following inclusion criteria on Study Day 1 will be eligible
 to participate in the study:

 1. Between the ages of 21 and 80, inclusive;

 2. Has been diagnosed with idiopathic Parkinson's disease based on the presence of a
 characteristic clinical history and neurologic findings;

 3. Has relatively advanced disease with levodopa-associated motor response complications,
 including ratable peak-dose dyskinesias and wearing-off fluctuations;

 4. Patient is willing to adhere to protocol requirements as evidenced by written,
 informed consent;

 5. Patient is satisfactorily treated with levodopa with or without short acting dopamine
 agonist.

 EXCLUSION CRITERIA:

 Patients meeting any of the following exclusion criteria either at Day 0 or during the
 study will not be enrolled or will be immediately withdrawn from the study, as appropriate:

 1. Has a history of any medical condition that can reasonably be expected to subject them
 to unwarranted risk, including lung disease, liver disease and clinically significant
 cardiac arrhythmias and/or myocardial ischemia;

 2. Has clinically significant laboratory abnormalities including liver enzyme elevation;
 positivity to any of the autoantibodies tested at Screening (ANA, RF, anti-SM,
 anti-LKM)

 3. Is unable to be treated with levodopa/carbidopa alone or with a single, relatively
 short-acting dopamine agonist, such as pramipexole or ropinirole;

 4. Unable or unwilling to discontinue a prohibited concomitant medication as listed
 below; allowable CNS medications will be maintained at a constant dose throughout the
 study;

 5. Has not been using an adequate contraceptive method for the last 30 days or unwilling
 to continue, or is not at least one year post-menopausal (if female);

 6. Is pregnant or breastfeeding;

 7. Is implanted with bilateral deep brain stimulators unless the stimulators are turned
 off during the entire study;

 8. Has prior bilateral pallidotomy or other ablative surgeries for treatment of PD;

 9. Has cognitive impairment (MMSE less than 25);

 10. Has participated in a clinical study with an investigational drug within the last 30
 days;

 11. Has a condition (such as active drug or alcohol abuse) that, in the opinion of the
 investigators, would interfere with compliance or safety;

 12. Is unwilling to sign an informed consent or to comply with protocol requirements.

 13. Unilateral and bilateral pallidotomy

 14. History of alcoholism.

 15. Orthostatic Hypotension