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