This study will test the effectiveness of an experimental drug called LY300164 on improving
Parkinson's disease symptoms, such as movement impairments and tremor, as well as
involuntary movements produced by long-term treatment with levodopa.
Patients with relatively advanced (Stage II to IV) Parkinson's disease between 30 and 75
years of age may be eligible for this 8-week study. Participants will have a complete
medical history and physical examination, including blood tests and an electrocardiogram,
and possibly brain magnetic resonance imaging (MRI), CT scan, and chest X-ray.
Patients will stop taking all anti-parkinsonism medications except levodopa (Sinemet) and
the experimental drug during the study. For the first 1 to 3 days, patients will be in the
hospital for a levodopa "dose-finding" procedure. For this study, levodopa is infused
through a vein for up to 8 hours, with symptoms monitored frequently to determine the doses
that will produce two results: 1) the dose that is less than what is needed to relieve
symptoms, and 2) the dose that relieves symptoms, but may produce dyskinesias.
When these dose rates are determined, patients will begin treatment in one of two groups.
One will take LY300164 3 times a day, along with levodopa, for 3 weeks. The second group
will take placebo tablets (a look-alike tablet with no active ingredient) and levodopa on
the same schedule as the LY300164 group. A brief medical examination and routine blood and
urine tests will be done weekly. The drug dose will be increased every 3 to 4 days until
significant side effects occur or the maximal dose is reached. Patients will be closely
monitored for 4 hours after every increase. At the end of the 3 weeks, or when the maximal
dose is reached, patients will be readmitted to the hospital for 2 to 3 days for a second
levodopa dose-finding study, while continuing on LY300164 or placebo. After this test,
patients will resume taking levodopa and the experimental drug or placebo as before for
another 2 weeks.
At the end of the 2-weeks, the entire procedure will be repeated in both groups, but the
treatments will be switched-that is, the patients who were taking LY300164 will now take
placebo, and the patients who took placebo will now take the drug. At the end of the second
3 weeks, the levodopa infusion procedure will be repeated once more.
Throughout the study, parkinsonism symptoms and dyskinesias will be evaluated and blood
samples will be drawn periodically to measure drug levels.
The objective of this study is to evaluate the acute effects of
alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor blockade on the
severity of parkinsonian signs and levodopa-associated motor response complications in
patients with Parkinson's disease. In a controlled proof-of-principle clinical trial,
efficacy will be assessed through the use of validated motor function scales. Safety will
be monitored by means of frequent clinical evaluations and laboratory tests.
Males and females between the ages of 30 and 75 are eligible for the study. All will
carry the diagnosis of idiopathic Parkinson's disease based on the presence of a
characteristic clinical history and neurological findings. All will have relatively
advanced disease (Hoehn and Yahr Stages II to IV) with levodopa-associated motor response
complications, including wearing-off fluctuations and peak-dose dyskinesias.
No presence or history of any medical condition that can reasonably be expected to subject
the patient to unwarranted risk.
No clinically significant laboratory abnormalities including liver enzyme elevations more
than three times the upper limit of normal, or neutropenia (WBC less than 4000).
No parkinson's disease patients exhibiting diphasic or end-of-dose dyskinesias or
Since LY300164 is an inhibitor of CP4503A4, patients receiving certain drugs metabolized
by that pathway will not be included.
No patients who are unable to be treated with levodopa/carbidopa alone or a single,
relatively short-acting dopamine agonist.
No patients who require additional treatment with amantadine or other concomitant
No pregnant women or those not practicing effective means of birth control since the
influence of any investigational compound on the unborn child and reproductive organs is